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  1. Myocardial infarction and stem cells

    Directory of Open Access Journals (Sweden)

    K Ananda Krishna

    2011-01-01

    Full Text Available Permanent loss of cardiomyocytes and scar tissue formation after myocardial infarction (MI results in an irreversible damage to the cardiac function. Cardiac repair (replacement, restoration, and regeneration is, therefore, essential to restore function of the heart following MI. Existing therapies lower early mortality rates, prevent additional damage to the heart muscle, and reduce the risk of further heart attacks. However, there is need for treatment to improve the infarcted area by replacing the damaged cells after MI. Thus, the cardiac tissue regeneration with the application of stem cells may be an effective therapeutic option. Recently, interest is more inclined toward myocardial regeneration with the application of stem cells. However, the potential benefits and the ability to improve cardiac function with the stem cell-based therapy need to be further addressed. In this review, we focus on the clinical applications of stem cells in the cardiac repair.

  2. Stem cell therapy for myocardial infarction

    OpenAIRE

    Moelker, Amber

    2007-01-01

    textabstractCoronary heart disease and heart failure continue to be significant burdens to healthcare systems in the Western world and are predicted to become so in emerging economies. Despite mixed results in both experimental and clinical studies, stem cell therapy is a promising option for patients suffering from myocardial infarction or patients with chronic heart failure after myocardial infarction. However, many issues in the field of cellular cardiomyoplasty still need to be resolved. ...

  3. Stem Cell Networks

    OpenAIRE

    Werner, Eric

    2016-01-01

    We present a general computational theory of stem cell networks and their developmental dynamics. Stem cell networks are special cases of developmental control networks. Our theory generates a natural classification of all possible stem cell networks based on their network architecture. Each stem cell network has a unique topology and semantics and developmental dynamics that result in distinct phenotypes. We show that the ideal growth dynamics of multicellular systems generated by stem cell ...

  4. Roles of microRNAs and myocardial cell differentiation.

    Science.gov (United States)

    Takaya, Tomohide; Nishi, Hitoo; Horie, Takahiro; Ono, Koh; Hasegawa, Koji

    2012-01-01

    As drug therapy is of limited efficacy in the treatment of heart diseases related to loss of cardiomyocytes, which have very poor division potential, regenerative medicine is expected to be a new strategy to address regenerative treatment in cardiac diseases. To achieve myocardial regeneration, elucidation of the mechanism of myocardial differentiation from stem cells is essential. Myocardial differentiation from embryonic pluripotent stem cells has been investigated worldwide, and remarkable developments such as establishment of induced pluripotent stem cells and transformation of somatic cells to cardiomyocytes have recently been made, markedly changing the strategy of regenerative medicine. At the same time, the close involvement of microRNA in the maintenance, proliferation, differentiation, and reprogramming of these stem cells has been revealed. In this report, microRNA is outlined, focusing on its role in myocardial differentiation. Copyright © 2012 Elsevier Inc. All rights reserved.

  5. Studying Dynamic Features in Myocardial Infarction Progression by Integrating miRNA-Transcription Factor Co-Regulatory Networks and Time-Series RNA Expression Data from Peripheral Blood Mononuclear Cells.

    Directory of Open Access Journals (Sweden)

    Hongbo Shi

    Full Text Available Myocardial infarction (MI is a serious heart disease and a leading cause of mortality and morbidity worldwide. Although some molecules (genes, miRNAs and transcription factors (TFs associated with MI have been studied in a specific pathological context, their dynamic characteristics in gene expressions, biological functions and regulatory interactions in MI progression have not been fully elucidated to date. In the current study, we analyzed time-series RNA expression data from peripheral blood mononuclear cells. We observed that significantly differentially expressed genes were sharply up- or down-regulated in the acute phase of MI, and then changed slowly until the chronic phase. Biological functions involved at each stage of MI were identified. Additionally, dynamic miRNA-TF co-regulatory networks were constructed based on the significantly differentially expressed genes and miRNA-TF co-regulatory motifs, and the dynamic interplay of miRNAs, TFs and target genes were investigated. Finally, a new panel of candidate diagnostic biomarkers (STAT3 and ICAM1 was identified to have discriminatory capability for patients with or without MI, especially the patients with or without recurrent events. The results of the present study not only shed new light on the understanding underlying regulatory mechanisms involved in MI progression, but also contribute to the discovery of true diagnostic biomarkers for MI.

  6. Depressed natural killer cell activity in acute myocardial infarction

    DEFF Research Database (Denmark)

    Klarlund, K; Pedersen, B K; Theander, T G

    1987-01-01

    Natural killer (NK) cell activity against K562 target cells was measured in patients within 24 h of acute myocardial infarction (AMI) and regularly thereafter for 6 weeks. NK cell activity was suppressed on days 1, 3, and 7 (P less than 0.01), day 14 (P less than 0.05) and at 6 weeks (P = 0...

  7. Myocardial infarction: stem cell transplantation for cardiac regeneration.

    Science.gov (United States)

    Carvalho, Edmund; Verma, Paul; Hourigan, Kerry; Banerjee, Rinti

    2015-11-01

    It is estimated that by 2030, almost 23.6 million people will perish from cardiovascular disease, according to the WHO. The review discusses advances in stem cell therapy for myocardial infarction, including cell sources, methods of differentiation, expansion selection and their route of delivery. Skeletal muscle cells, hematopoietic cells and mesenchymal stem cells (MSCs) and embryonic stem cells (ESCs)-derived cardiomyocytes have advanced to the clinical stage, while induced pluripotent cells (iPSCs) are yet to be considered clinically. Delivery of cells to the sites of injury and their subsequent retention is a major issue. The development of supportive scaffold matrices to facilitate stem cell retention and differentiation are analyzed. The review outlines clinical translation of conjugate stem cell-based cellular therapeutics post-myocardial infarction.

  8. Mesenchymal Stem Cells : Promising for Myocardial Regeneration?

    NARCIS (Netherlands)

    Przybyt, Ewa; Harmsen, Martin C.

    The pandemic of cardiovascular disease is continuously expanding as the result of changing life styles and diets throughout the Old and New World. Immediate intervention therapy saves the lives of many patients after acute myocardial infarction (MI). However, for many this comes at the price of

  9. Stem Cell Therapy for Myocardial Infarction: Are We Missing Time?

    NARCIS (Netherlands)

    ter Horst, Kasper W.

    2010-01-01

    The success of stem cell therapy in myocardial infarction (MI) is modest, and for stem cell therapy to be clinically effective fine-tuning in regard to timing, dosing, and the route of administration is required. Experimental studies suggest the existence of a temporal window of opportunity bound by

  10. Stem cells and injectable hydrogels: Synergistic therapeutics in myocardial repair.

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    Sepantafar, Mohammadmajid; Maheronnaghsh, Reihan; Mohammadi, Hossein; Rajabi-Zeleti, Sareh; Annabi, Nasim; Aghdami, Nasser; Baharvand, Hossein

    2016-01-01

    One of the major problems in the treatment of cardiovascular diseases is the inability of myocardium to self-regenerate. Current therapies are unable to restore the heart's function after myocardial infarction. Myocardial tissue engineering is potentially a key approach to regenerate damaged heart muscle. Myocardial patches are applied surgically, whereas injectable hydrogels provide effective minimally invasive approaches to recover functional myocardium. These hydrogels are easily administered and can be either cell free or loaded with bioactive agents and/or cardiac stem cells, which may apply paracrine effects. The aim of this review is to investigate the advantages and disadvantages of injectable stem cell-laden hydrogels and highlight their potential applications for myocardium repair. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Induced pluripotent stem cells for post myocardial infarction repair

    OpenAIRE

    Rosa Fernández, Eduardo de la

    2016-01-01

    The aim of this review is to study translational aspects of induced pluripotent stem cell technology in cardiac repair after myocardial infarction. This will be achieved by illustrating the current state of the art of this technology and, furthermore, by evaluating the limitations for clinical traslation.

  12. Experimental myocardial stem cell therapy for ST-elevation myocardial infarction

    DEFF Research Database (Denmark)

    Kastrup, Jens; Mygind, Naja D; Qayyum, Abbas A

    2016-01-01

    Ischemic heart disease (IHD) is one of the leading causes of death worldwide and is characterized by the formation of atherosclerotic plaques in the coronary arteries reducing the blood supply to the heart muscle causing ischemia. IHD can result in ST-elevation myocardial infarction (STEMI...... interest in the last 10-15 years especially after STEMI. Many preclinical and clinical studies have shown encouraging results but also very diverse clinical outcomes after stem cell treatment. This diversity in results may be explained by different factors, such as cell isolation technique, infarct...

  13. Use of neural networks to improve quality control of interpretations in myocardial perfusion imaging

    DEFF Research Database (Denmark)

    Tagil, K.; Marving, J.; Lomsky, M.

    2008-01-01

    Tc-sestamibi myocardial perfusion scintigraphy. After a training process, the networks were used to select the 20 cases in each region that were more likely to have a false clinical interpretation. These cases, together with 20 control cases in which the networks detected no likelihood of false clinical interpretation...

  14. Experimental myocardial stem cell therapy for ST-elevation myocardial infarction

    DEFF Research Database (Denmark)

    Kastrup, Jens; Mygind, Naja D; Qayyum, Abbas A

    2016-01-01

    Ischemic heart disease (IHD) is one of the leading causes of death worldwide and is characterized by the formation of atherosclerotic plaques in the coronary arteries reducing the blood supply to the heart muscle causing ischemia. IHD can result in ST-elevation myocardial infarction (STEMI...... interest in the last 10-15 years especially after STEMI. Many preclinical and clinical studies have shown encouraging results but also very diverse clinical outcomes after stem cell treatment. This diversity in results may be explained by different factors, such as cell isolation technique, infarct......), chronic IHD and heart failure. The patients suffer from chest pain (angina), dyspnea and a reduced quality of life. Common for all these conditions is loss of functional cardiomyocytes and endothelial cells. Stem cell therapy to regenerate injured myocardium is a new treatment option which has gained much...

  15. Experimental myocardial stem cell therapy for ST-elevation myocardial infarction

    DEFF Research Database (Denmark)

    Kastrup, Jens; Mygind, Naja D.; Qayyum, Abbas A.

    2016-01-01

    Ischemic heart disease (IHD) is one of the leading causes of death worldwide and is characterized by the formation of atherosclerotic plaques in the coronary arteries reducing the blood supply to the heart muscle causing ischemia. IHD can result in ST-elevation myocardial infarction (STEMI......), chronic IHD and heart failure. The patients suffer from chest pain (angina), dyspnea and a reduced quality of life. Common for all these conditions is loss of functional cardiomyocytes and endothelial cells. Stem cell therapy to regenerate injured myocardium is a new treatment option which has gained much...... interest in the last 10-15 years especially after STEMI. Many preclinical and clinical studies have shown encouraging results but also very diverse clinical outcomes after stem cell treatment. This diversity in results may be explained by different factors, such as cell isolation technique, infarct...

  16. Effect of nicorandil on the myocardial tissue perfusion and myocardial cell injury in patients with diabetes after PCI

    Directory of Open Access Journals (Sweden)

    Xue-Li Ren1

    2017-04-01

    Full Text Available Objective: To study the effect of nicorandil on the myocardial tissue perfusion and myocardial cell damage in patients with diabetes after percutaneous coronary intervention (PCI. Methods: 68 patients with coronary heart disease and type 2 diabetes mellitus who received PCI in our hospital between May 2011 and September 2015 were collected and then divided into observation group and control group (n=34 according to the single-blind randomized control method. Control group of patients received PCI alone, and the observation group of patients received nicorandil therapy after PCI. After treatment, real-time myocardial ultrasound contrast was used to evaluate the myocardial perfusion of two groups of patients; blood biochemical analyzer was used to detect the contents of peripheral blood myocardial enzyme spectrum indexes; the ELISA method was used to detect the contents of serum oxidative stress indicators; RIA method was used to detect the contents of serum apoptosis molecules. Results: After treatment, the myocardial tissue perfusion parameters plateau peak intensity (A, slope rate of curve (β and myocardial blood flow (A×β levels of observation group were significantly higher than those of control group (P<0.05; peripheral blood myocardial enzyme spectrum indexes creatine kinase (CK, lactate dehydrogenase (LDH, troponin I (cTnI and glutamic oxalacetic transaminase (GOT contents of observation group were significantly lower than those of control group (P<0.05; serum vitamin E (VitE and vitamin C (VitC contents of observation group were significantly higher than those of control group while malondialdehyde (MDA, advanced oxidation protein products (AOPPs, soluble apoptosis-associated factor (sFas and soluble apoptosis-associated factor ligand (sFasL contents were lower than those of control group (P<0.05. Conclusion: Adjuvant nicorandil therapy can improve the myocardial perfusion and reduce the myocardial cell injury in patients with coronary

  17. Cells involved in extracellular matrix remodeling after acute myocardial infarction

    Energy Technology Data Exchange (ETDEWEB)

    Garcia, Larissa Ferraz [Faculdade de Medicina do ABC, Santo André, SP (Brazil); Mataveli, Fábio D’Aguiar [Universidade Federal de São Paulo, São Paulo, SP (Brazil); Mader, Ana Maria Amaral Antônio; Theodoro, Thérèse Rachell [Faculdade de Medicina do ABC, Santo André, SP (Brazil); Justo, Giselle Zenker; Pinhal, Maria Aparecida da Silva [Universidade Federal de São Paulo, São Paulo, SP (Brazil)

    2015-07-01

    Evaluate the effects of VEGF{sub 165} gene transfer in the process of remodeling of the extracellular matrix after an acute myocardial infarct. Wistar rats were submitted to myocardial infarction, after the ligation of the left descending artery, and the left ventricle ejection fraction was used to classify the infarcts into large and small. The animals were divided into groups of ten, according to the size of infarcted area (large or small), and received or not VEGF{sub 165} treatment. Evaluation of different markers was performed using immunohistochemistry and digital quantification. The primary antibodies used in the analysis were anti-fibronectin, anti-vimentin, anti-CD44, anti-E-cadherin, anti-CD24, anti-alpha-1-actin, and anti-PCNA. The results were expressed as mean and standard error, and analyzed by ANOVA, considering statistically significant if p≤0.05. There was a significant increase in the expression of undifferentiated cell markers, such as fibronectin (protein present in the extracellular matrix) and CD44 (glycoprotein present in the endothelial cells). However, there was decreased expression of vimentin and PCNA, indicating a possible decrease in the process of cell proliferation after treatment with VEGF{sub 165}. Markers of differentiated cells, E-cadherin (adhesion protein between myocardial cells), CD24 (protein present in the blood vessels), and alpha-1-actin (specific myocyte marker), showed higher expression in the groups submitted to gene therapy, compared to non-treated group. The value obtained by the relation between alpha-1-actin and vimentin was approximately three times higher in the groups treated with VEGF{sub 165}, suggesting greater tissue differentiation. The results demonstrated the important role of myocytes in the process of tissue remodeling, confirming that VEGF{sub 165} seems to provide a protective effect in the treatment of acute myocardial infarct.

  18. Trends in Incidence of Hospitalized Acute Myocardial Infarction in the Cardiovascular Research Network (CVRN).

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    Reynolds, Kristi; Go, Alan S; Leong, Thomas K; Boudreau, Denise M; Cassidy-Bushrow, Andrea E; Fortmann, Stephen P; Goldberg, Robert J; Gurwitz, Jerry H; Magid, David J; Margolis, Karen L; McNeal, Catherine J; Newton, Katherine M; Novotny, Rachel; Quesenberry, Charles P; Rosamond, Wayne D; Smith, David H; VanWormer, Jeffrey J; Vupputuri, Suma; Waring, Stephen C; Williams, Marc S; Sidney, Stephen

    2017-03-01

    Monitoring trends in cardiovascular events can provide key insights into the effectiveness of prevention efforts. Leveraging data from electronic health records provides a unique opportunity to examine contemporary, community-based trends in acute myocardial infarction hospitalizations. We examined trends in hospitalized acute myocardial infarction incidence among adults aged ≥25 years in 13 US health plans in the Cardiovascular Research Network. The first hospitalization per member for acute myocardial infarction overall and for ST-segment elevation myocardial infarction and non-ST-segment elevation myocardial infarction was identified by International Classification of Diseases, Ninth Revision, Clinical Modification primary discharge codes in each calendar year from 2000 through 2008. Age- and sex-adjusted incidence was calculated per 100,000 person-years using direct adjustment with 2000 US census data. Between 2000 and 2008, we identified 125,435 acute myocardial infarction hospitalizations. Age- and sex-adjusted incidence rates (per 100,000 person-years) of acute myocardial infarction decreased an average 3.8%/y from 230.5 in 2000 to 168.6 in 2008. Incidence of ST-segment elevation myocardial infarction decreased 8.7%/y from 104.3 in 2000 to 51.7 in 2008, whereas incidence of non-ST-segment elevation myocardial infarction increased from 126.1 to 129.4 between 2000 and 2004 and then decreased thereafter to 116.8 in 2008. Age- and sex-specific incidence rates generally reflected similar patterns, with relatively larger decreases in ST-segment elevation myocardial infarction rates in women compared with men. As compared with 2000, the age-adjusted incidence of ST-segment elevation myocardial infarction in 2008 was 48% lower among men and 61% lower among women. Among a large, diverse, multicenter community-based insured population, there were significant decreases in incidence of hospitalized acute myocardial infarction and the more serious ST-segment elevation

  19. Stem cell therapy for myocardial infarction

    NARCIS (Netherlands)

    A.D. Moelker (Amber)

    2007-01-01

    textabstractCoronary heart disease and heart failure continue to be significant burdens to healthcare systems in the Western world and are predicted to become so in emerging economies. Despite mixed results in both experimental and clinical studies, stem cell therapy is a promising option for

  20. Biopolymer networks in cells

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    Weitz, David

    2013-03-01

    This talk will discuss the role of biopolymer networks in cells. We probe their properties through measurements of fluctuating motions of particles within the cell. These motions have many similarities to thermal motion and, in fact, are often misinterpreted in the context of passive microrheology. Here, we demonstrate that the motion is, instead, driven by the presence of molecular motors within the cell, and we show how this motion can be interpreted quantitatively to determine the nature of the fluctuating forces in the cell due to the molecular motors. I acknowledge the essential input of Ming Guo and Fred MacKintosh and support from NSF and NIH.

  1. Multi-scale parameterisation of a myocardial perfusion model using whole-organ arterial networks

    NARCIS (Netherlands)

    Hyde, Eoin R.; Cookson, Andrew N.; Lee, Jack; Michler, Christian; Goyal, Ayush; Sochi, Taha; Chabiniok, Radomir; Sinclair, Matthew; Nordsletten, David A.; Spaan, Jos; van den Wijngaard, Jeroen P. H. M.; Siebes, Maria; Smith, Nicolas P.

    2014-01-01

    A method to extract myocardial coronary permeabilities appropriate to parameterise a continuum porous perfusion model using the underlying anatomical vascular network is developed. Canine and porcine whole-heart discrete arterial models were extracted from high-resolution cryomicrotome vessel image

  2. Visualization of network target crosstalk optimizes drug synergism in myocardial ischemia.

    Directory of Open Access Journals (Sweden)

    Xiaojing Wan

    Full Text Available Numerous drugs and compounds have been validated as protecting against myocardial ischemia (MI, a leading cause of heart failure; however, synergistic possibilities among them have not been systematically explored. Thus, there appears to be significant room for optimization in the field of drug combination therapy for MI. Here, we propose an easy approach for the identification and optimization of MI-related synergistic drug combinations via visualization of the crosstalk between networks of drug targets corresponding to different drugs (each drug has a unique network of targets. As an example, in the present study, 28 target crosstalk networks (TCNs of random pairwise combinations of 8 MI-related drugs (curcumin, capsaicin, celecoxib, raloxifene, silibinin, sulforaphane, tacrolimus, and tamoxifen were established to illustrate the proposed method. The TCNs revealed a high likelihood of synergy between curcumin and the other drugs, which was confirmed by in vitro experiments. Further drug combination optimization showed a synergistic protective effect of curcumin, celecoxib, and sililinin in combination against H₂O₂-induced ischemic injury of cardiomyocytes at a relatively low concentration of 500 nM. This result is in agreement with the earlier finding of a denser and modular functional crosstalk between their networks of targets in the regulation of cell apoptosis. Our study offers a simple approach to rapidly search for and optimize potent synergistic drug combinations, which can be used for identifying better MI therapeutic strategies. Some new light was also shed on the characteristic features of drug synergy, suggesting that it is possible to apply this method to other complex human diseases.

  3. Gender gap in medical care in ST segment elevation myocardial infarction networks: Findings from the Catalan network Codi Infart.

    Science.gov (United States)

    Fernández-Rodríguez, D; Regueiro, A; Cevallos, J; Bosch, X; Freixa, X; Trilla, M; Brugaletta, S; Martín-Yuste, V; Sabaté, M; Bosa-Ojeda, F; Masotti, M

    2017-03-01

    To assess the impact of gender upon the prognosis and medical care in a regional acute ST-elevation myocardial infarction management network. An observational study was made of consecutive patients entered in a prospective database. The Catalan acute ST-elevation myocardial infarction management network. Patients treated between January 2010 and December 2011. Primary angioplasty, thrombolysis or conservative management. Time intervals, proportion and type of reperfusion, overall mortality, and in-hospital complication and overall mortality at 30 days and one year were compared in relation to gender. Of the 5,831 patients attended by the myocardial infarction network, 4,380 had a diagnosis of acute ST-elevation myocardial infarction, and 961 (21.9%) were women. Women were older (69.8±13.4 vs. 60.6±12.8 years; PI (24.9 vs. 17.3%; P<.001) and no reperfusion (8.8 vs. 5.2%; P<.001) versus men. In addition, women had greater delays in medical care (first medical contact-to-balloon: 132 vs. 122min; P<.001, and symptoms onset-to-balloon: 236 vs. 210min; P<.001). Women presented higher percentages of overall in-hospital complications (20.6 vs. 17.4%; P=.031), in-hospital mortality (4.8 vs. 2.6%; P=.001), 30-day mortality (9.1 vs. 4.5%; P<.001) and one-year mortality (14.0 vs. 8.3%; P<.001) versus men. Nevertheless, after multivariate adjustment, no gender differences in 30-day and one-year mortality were observed. Despite a higher risk profile and poorer medical management, women present similar 30-day and one-year outcomes as their male counterparts in the context of the myocardial infarction management network. Copyright © 2016 Elsevier España, S.L.U. y SEMICYUC. All rights reserved.

  4. Stem cell mobilization by granulocyte colony-stimulating factor for myocardial recovery after acute myocardial infarction: a meta-analysis

    DEFF Research Database (Denmark)

    Zohlnhofer, D.; Dibra, A.; Koppara, T.

    2008-01-01

    OBJECTIVES: The objective of this meta-analysis was to evaluate the effect of stem cell mobilization by granulocyte colony-stimulating factor (G-CSF) on myocardial regeneration on the basis of a synthesis of the data generated by randomized, controlled clinical trials of G-CSF after acute...

  5. Resveratrol activates endogenous cardiac stem cells and improves myocardial regeneration following acute myocardial infarction.

    Science.gov (United States)

    Ling, Lin; Gu, Shaohua; Cheng, Yan

    2017-03-01

    Stem cell antigen-1-positive (Sca-1+) cardiac stem cells (CSCs) therapy for myocardial regeneration following acute myocardial infarction (AMI) is limited by insufficient cell viability and a high rate of apoptosis, due to the poor regional microenvironment. Resveratrol, which is a compound extracted from red wine, has been reported to protect myocardial tissue post‑AMI by increasing the expression of angiogenic and chemotactic factors. The present study aimed to investigate the effects of resveratrol on Sca‑1+ CSCs, and to optimize Sca‑1+ CSCs therapy for myocardial regeneration post‑AMI. C57/BL6 mice (age, 6 weeks) were divided into two groups, which received intragastric administration of PBS or 2.5 mg/kg.d resveratrol. The endogenous expression of Sca‑1+ CSCs in the heart was assessed on day 7. Furthermore, C57/BL6 mice underwent left anterior descending coronary artery ligation for the construction of an AMI model, and received an injection of 1x106 CSCs into the peri‑ischemic area (n=8/group). Mice received intragastric administration of PBS or resveratrol (2.5 mg/kg.d) for 4 weeks after cell transplantation. Echocardiography was used to evaluate cardiac function 4 weeks after cell transplantation. Capillary density and cardiomyocyte apoptosis in the peri‑ischemic myocardium were assessed by cluster of differentiation 31 immunofluorescent staining and terminal deoxynucleotidyl transferase‑mediated dUTP nick end labeling assay, respectively. Western blot analysis was conducted to detect the protein expression levels of vascular endothelial growth factor (VEGF) and stromal cell‑derived factor (SDF)‑1α in the myocardium. Treatment with resveratrol increased the number of endogenous Sca‑1+ CSCs in heart tissue after 7 days (PBS vs. Res, 1.85±0.41/field vs. 3.14±0.26/field, P<0.05). Furthermore, intragastric administration of resveratrol significantly increased left ventricle (LV) function 4 weeks after AMI, as determined by an

  6. [Effect of selenium on the protection of myocardial cells from injuries induced by overloaded reactive oxygen species, and on the expression of actin in myocardial cells].

    Science.gov (United States)

    Tang, Jing; Tan, Wuhong; Zhu, Yanhe; Wang, Lixin; Zhai, Lianbang

    2012-01-01

    To investigate the effect of selenium on the protection of myocardial cells from injuries induced by H2O2 and on the expression of alpha-actin and beta-actin in myocardial cells. Myocardial cells of suckling mice in the culture were divided into six groups: Controls group (without H2O2 or Se), H2O2 group, Se 0.05 micromol/ L group, Se 0.5 micromol/L group, Se 1.0 micromol/L group and Se 5.0 micromol/L group. The ultrastructure of myocardial cells was observed by transmission electron microscope (TEM), and the LDH and MDA contents in the culture media were determined by colorimetry. The expression of alpha-actin and beta-actin in myocardial cells was detected by Western blot. The injury of myocardial cells observed under TEM was attenuated in the 0.5 micromol/L Se group. The LDH and MDA contents in the culture media of the Se groups was higher than the control group (P contents in the 0.5 micromol/L Se group were the lowest in all Se groups. The expression level of alpha-actin and beta-actin in the 0.5 micromol/L Se group is higher than that in the H2O2 group, even higher than the control group. The protective effect of Se on myocardial cells damaged by H2O2 was better in the 0.5 micromol/ LSe group, which could maintain the expression of alpha-actin and beta-actin, even induce the remolding of cytoskeleton proteins.

  7. Stem Cells for Cardiac Regeneration by Cell Therapy and Myocardial Tissue Engineering

    Science.gov (United States)

    Wu, Jun; Zeng, Faquan; Weisel, Richard D.; Li, Ren-Ke

    Congestive heart failure, which often occurs progressively following a myocardial infarction, is characterized by impaired myocardial perfusion, ventricular dilatation, and cardiac dysfunction. Novel treatments are required to reverse these effects - especially in older patients whose endogenous regenerative responses to currently available therapies are limited by age. This review explores the current state of research for two related approaches to cardiac regeneration: cell therapy and tissue engineering. First, to evaluate cell therapy, we review the effectiveness of various cell types for their ability to limit ventricular dilatation and promote functional recovery following implantation into a damaged heart. Next, to assess tissue engineering, we discuss the characteristics of several biomaterials for their potential to physically support the infarcted myocardium and promote implanted cell survival following cardiac injury. Finally, looking ahead, we present recent findings suggesting that hybrid constructs combining a biomaterial with stem and supporting cells may be the most effective approaches to cardiac regeneration.

  8. Combining angiogenic gene and stem cell therapies for myocardial infarction.

    Science.gov (United States)

    Pons, Jennifer; Huang, Yu; Takagawa, Junya; Arakawa-Hoyt, Janice; Ye, Jianqin; Grossman, William; Kan, Yuet Wai; Su, Hua

    2009-09-01

    Transplantation of stem cells from various sources into infarcted hearts has the potential to promote myocardial regeneration. However, the regenerative capacity is limited partly as a result of the low survival rate of the transplanted cells in the ischemic myocardium. In the present study, we tested the hypothesis that combining cell and angiogenic gene therapies would provide additive therapeutic effects via co-injection of bone marrow-derived mesenchymal stem cells (MSCs) with an adeno-associated viral vector (AAV), MLCVEGF, which expresses vascular endothelial growth factor (VEGF) in a cardiac-specific and hypoxia-inducible manner. MSCs isolated from transgenic mice expressing green fluorescent protein and MLCVEGF packaged in AAV serotype 1 capsid were injected into mouse hearts at the border of ischemic area, immediately after occlusion of the left anterior descending coronary, individually or together. Engrafted cells were detected and quantified by real-time polymerase chain reaction and immunostaining. Angiogenesis and infarct size were analyzed on histological and immunohistochemical stained sections. Cardiac function was analyzed by echocardiography. We found that co-injection of AAV1-MLCVEGF with MSCs reduced cell loss. Although injection of MSCs and AAV1-MLCVEGF individually improved cardiac function and reduced infarct size, co-injection of MSC and AAV1-MLCVEGF resulted in the best improvement in cardiac function as well as the smallest infarct among all groups. Moreover, injection of AAV1-MLCVEGF induced neovasculatures. Nonetheless, injection of MSCs attracted endogenous stem cell homing and increased scar thickness. Co-injection of MLCVEGF and MSCs in ischemic hearts can result in better cardiac function and MSC survival, compared to their individual injections, as a result of the additive effects of each therapy.

  9. Intravenous infusion of bone marrow mesenchymal stem cells improves myocardial function in a rat model of myocardial ischemia.

    Science.gov (United States)

    Wang, Tong; Tang, Wanchun; Sun, Shijie; Ristagno, Giuseppe; Huang, Zitong; Weil, Max Harry

    2007-11-01

    We investigated the effects of three different sites for delivery of bone marrow mesenchymal stem cells (MSCs) in a rat model of myocardial ischemia. Prospective, randomized, controlled study. University affiliated research institute. Male Sprague-Dawley rats. A thoracotomy was performed under general anesthesia. Myocardial ischemia was induced by ligation of the left anterior descending coronary artery. One month later, animals were randomized to receive 5 x 10(6) MSCs labeled with PKH26 in phosphate buffer solution or phosphate buffer solution alone as a placebo by injection into right femoral vein, directly into the left ventricular (LV) cavity, or into the ischemic zone in the anterior ventricular free wall. Echocardiographically measured myocardial function, including ejection fraction and fractional shortening, was quantitated 2 wks and 4 wks after administering MSCs or phosphate buffer solution. Hemodynamics, including cardiac index, LV dP/dt40, LV negative dP/dt, and LV diastolic pressure were measured 4 wks after administering MSCs or phosphate buffer solution. MSCs were counted in 5-microm sections obtained with cryostat from each harvested heart. Significant improvements in ejection fraction, fractional shortening, cardiac index, LV dP/dt40, LV negative dP/dt, and LV diastolic pressure followed injection of MSCs, regardless of the site of injection. However, the number of MSCs counted in the heart sections was significantly greater after direct myocardial injection. Independently of the site of injection and regardless of the different concentration of bone marrow mesenchymal stem cells identified in the myocardium, myocardial function was comparably improved in all groups of animals treated with MSCs.

  10. Allogeneic adipose stem cell therapy in acute myocardial infarction.

    Science.gov (United States)

    Rigol, Montserrat; Solanes, Núria; Roura, Santiago; Roqué, Mercè; Novensà, Laura; Dantas, Ana Paula; Martorell, Jaume; Sitges, Marta; Ramírez, José; Bayés-Genís, Antoni; Heras, Magda

    2014-01-01

    Stem cell therapy offers a promising approach to reduce the long-term mortality rate associated with heart failure after acute myocardial infarction (AMI). To date, in vivo translational studies have not yet fully studied the immune response to allogeneic adipose tissue-derived mesenchymal stem cells (ATMSCs). We analysed the immune response and the histological and functional effects of allogeneic ATMSCs in a porcine model of reperfused AMI and determine the effect of administration timing. Pigs that survived AMI (24/26) received intracoronary administration of culture medium after reperfusion (n = 6), ATMSCs after reperfusion (n = 6), culture medium 7 days after AMI (n = 6) or ATMSCs 7 days after AMI (n = 6). At 3-week follow-up, cardiac function, alloantibodies and histological analysis were evaluated. Administration of ATMSCs after reperfusion and 7 days after AMI resulted in similar rates of cell engraftment; some of those cells expressed endothelial, smooth muscle and cardiomyogenic cell lineage markers. Delivery of ATMSCs after reperfusion compared with that performed at 7 days was more effective in increasing: vascular density (249 ± 64 vs. 161 ± 37 vessels/mm2; P < 0.01), T lymphocytes (1 ± 0.4 vs. 0.4 ± 0.3% of area CD3(+) ; P < 0.05) and expression of vascular endothelial growth factor (VEGF; 32 ± 7% vs. 20 ± 4% of area VEGF(+) ; P < 0.01). Allogeneic ATMSC-based therapy did not change ejection fraction but generated alloantibodies. The present study is the first to demonstrate that allogeneic ATMSCs elicit an immune response and, when administered immediately after reperfusion, are more effective in increasing VEGF expression and neovascularization. © 2013 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.

  11. Stem cell-based therapy : Improving myocardial cell delivery

    NARCIS (Netherlands)

    Feyen, Dries A M|info:eu-repo/dai/nl/413647838; Gaetani, RG; Doevendans, Pieter A.|info:eu-repo/dai/nl/164248366; Sluijter, Joost P G|info:eu-repo/dai/nl/273307908

    2016-01-01

    Stem cell-based therapies form an exciting new class of medicine that attempt to provide the body with the building blocks required for the reconstruction of damaged organs. However, delivering cells to the correct location, while preserving their integrity and functional properties, is a complex

  12. Experimental myocardial stem cell therapy for ST-elevation myocardial infarction

    DEFF Research Database (Denmark)

    Kastrup, Jens; Mygind, Naja D; Qayyum, Abbas A

    2016-01-01

    Ischemic heart disease (IHD) is one of the leading causes of death worldwide and is characterized by the formation of atherosclerotic plaques in the coronary arteries reducing the blood supply to the heart muscle causing ischemia. IHD can result in ST-elevation myocardial infarction (STEMI...

  13. Lack of indication of myocardial cell damage after myocardial ischaemia in patients with severe stable angina

    DEFF Research Database (Denmark)

    Hansen, Knud Nørregaard; Egstrup, K; Nielsen, J R

    1992-01-01

    duration of 804 min, were observed in seven patients during period B. Release of myoglobin, CK, and CK-MB did not increase in relation either to spontaneous or exercise-induced ischaemia. Thus even frequent and prolonged episodes of transient myocardial ischaemia (symptomatic or asymptomatic) in patients...

  14. The cardiac atrial appendage stem cell: a new and promising candidate for myocardial repair.

    OpenAIRE

    Koninckx, Remco; Daniels, Annick; Windmolders, Severina; Mees, Urbain; Macianskiene, Regina; Mubagwa, Kanigula; Steels, Paul; Jamaer, Luc; Dubois, Jasperina; Robic, Boris; Hendrikx, Marc; Rummens, Jean-Luc; Hensen, Karen

    2013-01-01

    AIMS: Considerable shortcomings in the treatment of myocardial infarction (MI) still exist and therefore mortality remains high. Cardiac stem cell (CSC) therapy is a promising approach for myocardial repair. However, identification and isolation of candidate CSCs is mainly based on the presence or absence of certain cell surface markers, which suffers from some drawbacks. In order to find a more specific and reliable identification and isolation method, we investigated whether CSCs can b...

  15. A quantitative structural and morphometric analysis of the Purkinje network and the Purkinje-myocardial junctions in pig hearts.

    Science.gov (United States)

    Garcia-Bustos, V; Sebastian, R; Izquierdo, M; Molina, P; Chorro, F J; Ruiz-Sauri, A

    2017-05-01

    The morpho-functional properties of the distal section of the cardiac Purkinje network (PN) and the Purkinje-myocardial junctions (PMJs) are fundamental to understanding the sequence of electrical activation in the heart. The overall structure of the system has already been described, and several computational models have been developed to gain insight into its involvement in cardiac arrhythmias or its interaction with implantable devices, such as pacemakers. However, anatomical descriptions of the PN in the literature have not enabled enough improvements in the accuracy of anatomical-based electrophysiological simulations of the PN in 3D hearts models. In this work, we study the global distribution and morphological properties of the PN, with special emphasis on the cellular and architectural characterization of its intramural branching structure, mesh-like sub-endocardial network, and the PMJs in adult pig hearts by both histopathological and morphometric evaluation. We have defined three main patterns of PMJ: contact through cell bodies, contact through cell prolongations either thick or piliform, and contact through transitional cells. Moreover, from hundreds of micrographs, we quantified the density of PMJs and provided data for the basal/medial/apical regions, anterior/posterior/septal/lateral regions and myocardial/sub-endocardial distribution. Morphometric variables, such as Purkinje cell density and thickness of the bundles, were also analyzed. After combining the results of these parameters, a different septoanterior distribution in the Purkinje cell density was observed towards the cardiac apex, which is associated with a progressive thinning of the conduction bundles and the posterolateral ascension of intramyocardial terminal scattered fibers. The study of the PMJs revealed a decreasing trend towards the base that may anatomically explain the early apical activation. The anterolateral region contains the greatest number of contacts, followed by the

  16. Intramyocardial Adipose-Derived Stem Cell Transplantation Increases Pericardial Fat with Recovery of Myocardial Function after Acute Myocardial Infarction.

    Directory of Open Access Journals (Sweden)

    Jong-Ho Kim

    Full Text Available Intramyocardial injection of adipose-derived stem cells (ASC with other cell types in acute myocardial infarction (AMI animal models has consistently shown promising clinical regenerative capacities. We investigated the effects of intramyocardial injections of mouse ASC (mASC with mouse endothelial cells (mEC on left ventricular function and generation of pericardial fat in AMI rats. AMI rat models were created by ligating left anterior descending coronary artery and were randomly assigned into four groups: control (n = 10, mASC (n = 10, mEC (n = 10 and mASC+mEC (n = 10 via direct intramyocardial injections, and each rat received 1x106 cells around three peri-infarct areas. Echocardiography and cardiac positron emission tomography (PET were compared at baseline and on 28 days after AMI. Changes in left ventricular ejection fraction measured by PET, increased significantly in mASC and mASC+mEC groups compared to mEC and control groups. Furthermore, significant decreases in fibrosis were confirmed after sacrifice on 28 days in mASC and mASC+mEC groups. Successful cell engraftment was confirmed by positive Y-Chromosome staining in the transplantation region. Pericardial fat increased significantly in mASC and mASC+mEC groups compared to control group, and pericardial fat was shown to originate from the AMI rat. mASC group expressed higher adiponectin and lower leptin levels in plasma than control group. In addition, pericardial fat from AMI rats demonstrated increased phospho-AMPK levels and reduced phospho-ACC levels. Intramyocardial mASC transplantation after AMI in rats increased pericardial fat, which might play a protective role in the recovery of myocardial function after ischemic myocardial damage.

  17. Application of Artificial Neural Network to Computer-Aided Diagnosis of Coronary Artery Disease in Myocardial SPECT Bull's-eye Images

    National Research Council Canada - National Science Library

    Fujita, Hiroshi; Katafuchi, Tetsuro; Uehara, Toshiisa; Nishimura, Tsunehiko

    1992-01-01

    .... The technique employs a neural network to analyze 201 Tl myocardial SPECT bull's-eye images. This multi-layer feed-forward neural network with a backpropagation algorithm has 256 input units (pattern...

  18. Allogeneic mesenchymal precursor cell therapy to limit remodeling after myocardial infarction: the effect of cell dosage.

    Science.gov (United States)

    Hamamoto, Hirotsugu; Gorman, Joseph H; Ryan, Liam P; Hinmon, Robin; Martens, Timothy P; Schuster, Michael D; Plappert, Theodore; Kiupel, Matti; St John-Sutton, Martin G; Itescu, Silviu; Gorman, Robert C

    2009-03-01

    This experiment assessed the dose-dependent effect of a unique allogeneic STRO-3-positive mesenchymal precursor cell (MPC) on postinfarction left ventricular (LV) remodeling. The MPCs were administered in a manner that would simulate an off-the-self, early postinfarction, preventative approach to cardiac cell therapy in a sheep transmural myocardial infarct (MI) model. Allogeneic MPCs were isolated from male crossbred sheep. Forty-six female sheep underwent coronary ligation to produce a transmural LV anteroapical infarction. One hour after infarction, the borderzone myocardium received an injection of 25, 75, 225, or 450 x 10(6) MPCs, or cell medium. Echocardiography was performed at 4 and 8 weeks after MI to quantify LV end-diastolic (LVEDV) and end-systolic volumes (LVESV), ejection fraction (EF), and infarct expansion. CD31 and smooth muscle actin (SMA) immunohistochemical staining was performed on infarct and borderzone specimens to quantify vascular density. Compared with controls, low-dose (25 and 75 x 10(6) cells) MPC treatment significantly attenuated infarct expansion and increases in LVEDV and LVESV. EF was improved at all cell doses. CD31 and SMA immunohistochemical staining demonstrated increased vascular density in the borderzone only at the lower cell doses. There was no evidence of myocardial regeneration within the infarct. Allogeneic STRO-3 positive MPCs attenuate the remodeling response to transmural MI in a clinically relevant large-animal model. This effect is associated with vasculogenesis and arteriogenesis within the borderzone and infarct and is most pronounced at lower cell doses.

  19. COMPARISON OF HUMAN ADIPOSE-DERIVED STEM CELLS AND BONE MARROW-DERIVED STEM CELLS IN A MYOCARDIAL INFARCTION MODEL

    DEFF Research Database (Denmark)

    Rasmussen, Jeppe Grøndahl; Frøbert, Ole; Holst-Hansen, Claus

    2012-01-01

    Background: Treatment of myocardial infarction with bone marrow-derived mesenchymal stem cells and recently also adipose-derived stem cells has shown promising results. In contrast to clinical trials and their use of autologous bone marrow-derived cells from the ischemic patient, the animal...... myocardial infarction models are often using young donors and young, often immune-compromised, recipient animals. Our objective was to compare bone marrow-derived mesenchymal stem cells with adipose-derived stem cells from an elderly ischemic patient in the treatment of myocardial infarction, using a fully...... grown non-immunecompromised rat model. Methods: Mesenchymal stem cells were isolated from adipose tissue and bone marrow and compared with respect to surface markers and proliferative capability. To compare the regenerative potential of the two stem cell populations, male Sprague-Dawley rats were...

  20. [Effects of intracoronary autologous bone marrow mononuclear cells transplantation in patients with anterior myocardial infarction].

    Science.gov (United States)

    Wang, Wei-min; Sun, Ning-ling; Liu, Jian; Zhang, Ping; Liu, Kai-yan; Wang, Qian; Yang, Song-na; Wang, Su-qin; Zang, Yue; Guo, Ji-hong

    2006-02-01

    To investigate the efficacy of intracoronary transfer of autologous bone marrow mononuclear cells (ABMMNCs) to patients with myocardial infarction (MI) on left ventricular function and myocardial perfusion. Thirty-five patients with MI (> 4 weeks) were enrolled in this prospective, open-labeled study (20 patients in cell transplantation group; 15 patients in control group). All patients were treated by standard drug therapy and percutaneous coronary intervention (PCI). Baseline and 3 months follow-up evaluations included complete clinical and laboratory examinations, six minutes walk test, echocardiography, Dual-isotope simultaneous acquisition single photon emission computed tomography (DISA-SPECT) and cardiac magnetic resonance imaging (MRI). Baseline parameters were similar between the two groups. NYHA classification and six minutes walk test at 3 months follow-up were also similar between the two groups. However, left ventricular ejection fraction (LVEF) determined by echocardiography and DISA-SPECT was significantly higher; regional wall motion measured by echocardiography and cardiac MRI, myocardial viability and myocardial perfusion in the infarct zone assessed by DISA-SPECT were all significantly improved than before transplantation and than that in control group at 3 months follow-up. Our results indicate that intracoronary transplantation of ABMMNCs could improve the left ventricular systolic function and beneficially affect myocardial perfusion up to 3 months post transplantation in patients with myocardial infarction.

  1. Titanium dioxide nanoparticle-induced cytotoxicity and the underlying mechanism in mouse myocardial cells

    Science.gov (United States)

    Zhou, Yingjun; Hong, Fashui; Wang, Ling

    2017-11-01

    Exposure to fine particulate matter (PM) is known to cause cardiovascular disease. While extensive research has focused on the risk of atmospheric PM to public health, particularly heart disease, limited studies to date have attempted to clarify the molecular mechanisms underlying myocardial cell damage caused by exposure to titanium dioxide nanoparticles (TiO2 NPs). Data from the current investigation showed that TiO2 NPs are deposited in myocardial mitochondria via the blood circulation accompanied by obvious ultrastructural changes and impairment of mitochondrial structure and function in mouse myocardial cells, including reduction in mitochondrial membrane potential and ATP production, aggravation of oxidative stress along with increased levels of reactive oxygen species, malondialdehyde and protein carbonyl, and decreased glutathione content and enzymatic activities, including superoxide dismutase and glutathione peroxidase. Furthermore, TiO2 NPs induced a significant decrease in the activities of complex I, complex II, complex III, complex IV, succinate dehydrogenase, NADH oxidase, Ca2+-ATPase, Na+/K+-ATPase, and Ca2+/Mg2+-ATPase, and upregulation of cytokine expression (including cytochrome c, caspase-3, and p-JNK) in mitochondria-mediated apoptosis while downregulating Bcl-2 expression in mouse myocardial cells. Our results collectively indicate that chronic exposure to TiO2 NPs induces damage in mitochondrial structure and function as well as mitochondria-mediated apoptosis in mouse myocardial cells, which may be closely associated with heart disease in animals and humans.

  2. Intracoronary administration of autologous bone marrow stem cell transplant in myocardial infarction.

    Science.gov (United States)

    Nuri, Muhammad Masud-ul-Hasan; Hafeez, Shahid

    2011-01-01

    To elaborate in detail the technique of intracoronary administration of autologous bone marrow stem cell transplantation in patients with acute myocardial infarction. This procedure was carried out during a pilot study which was conducted in the department of interventional cardiology of Armed Forces Institute of Cardiology/National Institute of Heart Diseases Rawalpindi from June 2004 to November 2006. The inclusion criteria's were recent anterior myocardial infarction with anteroapical hypokinesia and single vessel disease in left anterior descending artery. The informed consent was obtained. After giving local anaesthesia and light sedation, both posterior superior iliac crests were accessed by multiple punctures to get stem cell harvest. The harvest was analyzed to document total and mean mononuclear cell count. An over the wire balloon catheter was parked in mid left anterior descending artery. The stem cells were injected intermittently into the infarcted myocardium during transient balloon inflation over 45-60 minutes. The clinical, left ventricle cineangiographic and nuclear scintigraphic parameters were analyzed and compared at week 0 and 12 to objectively document the effects of stem cell. The procedure was successfully carried out and well tolerated by all the patients. The minor complications were managed accordingly. Post autologous stem cell therapy, there was amelioration in clinical symptoms, left ventricle ejection fraction and myocardial perfusion. Intracoronary artery infusion of stem cells in acute myocardial infarction is simple, reasonably safe and effective mode of cell delivery in our set up.

  3. Direct evaluation of myocardial viability and stem cell engraftment demonstrates salvage of the injured myocardium.

    Science.gov (United States)

    Kim, Paul J; Mahmoudi, Morteza; Ge, Xiaohu; Matsuura, Yuka; Toma, Ildiko; Metzler, Scott; Kooreman, Nigel G; Ramunas, John; Holbrook, Colin; McConnell, Michael V; Blau, Helen; Harnish, Phillip; Rulifson, Eric; Yang, Phillip C

    2015-03-27

    The mechanism of functional restoration by stem cell therapy remains poorly understood. Novel manganese-enhanced MRI and bioluminescence reporter gene imaging were applied to follow myocardial viability and cell engraftment, respectively. Human-placenta-derived amniotic mesenchymal stem cells (AMCs) demonstrate unique immunoregulatory and precardiac properties. In this study, the restorative effects of 3 AMC-derived subpopulations were examined in a murine myocardial injury model: (1) unselected AMCs, (2) ckit(+)AMCs, and (3) AMC-derived induced pluripotent stem cells (MiPSCs). To determine the differential restorative effects of the AMC-derived subpopulations in the murine myocardial injury model using multimodality imaging. SCID (severe combined immunodeficiency) mice underwent left anterior descending artery ligation and were divided into 4 treatment arms: (1) normal saline control (n=14), (2) unselected AMCs (n=10), (3) ckit(+)AMCs (n=13), and (4) MiPSCs (n=11). Cardiac MRI assessed myocardial viability and left ventricular function, whereas bioluminescence imaging assessed stem cell engraftment during a 4-week period. Immunohistological labeling and reverse transcriptase polymerase chain reaction of the explanted myocardium were performed. The unselected AMC and ckit(+)AMC-treated mice demonstrated transient left ventricular functional improvement. However, the MiPSCs exhibited a significantly greater increase in left ventricular function compared with all the other groups during the entire 4-week period. Left ventricular functional improvement correlated with increased myocardial viability and sustained stem cell engraftment. The MiPSC-treated animals lacked any evidence of de novo cardiac differentiation. The functional restoration seen in MiPSCs was characterized by increased myocardial viability and sustained engraftment without de novo cardiac differentiation, indicating salvage of the injured myocardium. © 2015 American Heart Association, Inc.

  4. Optogenetic determination of the myocardial requirements for extrasystoles by cell type-specific targeting of ChannelRhodopsin-2.

    Science.gov (United States)

    Zaglia, Tania; Pianca, Nicola; Borile, Giulia; Da Broi, Francesca; Richter, Claudia; Campione, Marina; Lehnart, Stephan E; Luther, Stefan; Corrado, Domenico; Miquerol, Lucile; Mongillo, Marco

    2015-08-11

    Extrasystoles lead to several consequences, ranging from uneventful palpitations to lethal ventricular arrhythmias, in the presence of pathologies, such as myocardial ischemia. The role of working versus conducting cardiomyocytes, as well as the tissue requirements (minimal cell number) for the generation of extrasystoles, and the properties leading ectopies to become arrhythmia triggers (topology), in the normal and diseased heart, have not been determined directly in vivo. Here, we used optogenetics in transgenic mice expressing ChannelRhodopsin-2 selectively in either cardiomyocytes or the conduction system to achieve cell type-specific, noninvasive control of heart activity with high spatial and temporal resolution. By combining measurement of optogenetic tissue activation in vivo and epicardial voltage mapping in Langendorff-perfused hearts, we demonstrated that focal ectopies require, in the normal mouse heart, the simultaneous depolarization of at least 1,300-1,800 working cardiomyocytes or 90-160 Purkinje fibers. The optogenetic assay identified specific areas in the heart that were highly susceptible to forming extrasystolic foci, and such properties were correlated to the local organization of the Purkinje fiber network, which was imaged in three dimensions using optical projection tomography. Interestingly, during the acute phase of myocardial ischemia, focal ectopies arising from this location, and including both Purkinje fibers and the surrounding working cardiomyocytes, have the highest propensity to trigger sustained arrhythmias. In conclusion, we used cell-specific optogenetics to determine with high spatial resolution and cell type specificity the requirements for the generation of extrasystoles and the factors causing ectopies to be arrhythmia triggers during myocardial ischemia.

  5. Bioengineering of injectable encapsulated aggregates of pluripotent stem cells for therapy of myocardial infarction

    Science.gov (United States)

    Zhao, Shuting; Xu, Zhaobin; Wang, Hai; Reese, Benjamin E.; Gushchina, Liubov V.; Jiang, Meng; Agarwal, Pranay; Xu, Jiangsheng; Zhang, Mingjun; Shen, Rulong; Liu, Zhenguo; Weisleder, Noah; He, Xiaoming

    2016-10-01

    It is difficult to achieve minimally invasive injectable cell delivery while maintaining high cell retention and animal survival for in vivo stem cell therapy of myocardial infarction. Here we show that pluripotent stem cell aggregates pre-differentiated into the early cardiac lineage and encapsulated in a biocompatible and biodegradable micromatrix, are suitable for injectable delivery. This method significantly improves the survival of the injected cells by more than six-fold compared with the conventional practice of injecting single cells, and effectively prevents teratoma formation. Moreover, this method significantly enhances cardiac function and survival of animals after myocardial infarction, as a result of a localized immunosuppression effect of the micromatrix and the in situ cardiac regeneration by the injected cells.

  6. Experimental myocardial stem cell therapy for ST-elevation myocardial infarction

    DEFF Research Database (Denmark)

    Kastrup, Jens; Mygind, Naja D; Qayyum, Abbas A

    2016-01-01

    ), chronic IHD and heart failure. The patients suffer from chest pain (angina), dyspnea and a reduced quality of life. Common for all these conditions is loss of functional cardiomyocytes and endothelial cells. Stem cell therapy to regenerate injured myocardium is a new treatment option which has gained much...... interest in the last 10-15 years especially after STEMI. Many preclinical and clinical studies have shown encouraging results but also very diverse clinical outcomes after stem cell treatment. This diversity in results may be explained by different factors, such as cell isolation technique, infarct...... location, timing and route of delivery, cell dosage, cell type etc. The present review will try to elaborate and clarify the present status for stem cell therapy in STEMI....

  7. A Cell-Enriched Engineered Myocardial Graft Limits Infarct Size and Improves Cardiac Function

    Directory of Open Access Journals (Sweden)

    Isaac Perea-Gil, MS

    2016-08-01

    Full Text Available Myocardial infarction (MI remains a dreadful disease around the world, causing irreversible sequelae that shorten life expectancy and reduce quality of life despite current treatment. Here, the authors engineered a cell-enriched myocardial graft, composed of a decellularized myocardial matrix refilled with adipose tissue-derived progenitor cells (EMG-ATDPC. Once applied over the infarcted area in the swine MI model, the EMG-ATDPC improved cardiac function, reduced infarct size, attenuated fibrosis progression, and promoted neovascularization of the ischemic myocardium. The beneficial effects exerted by the EMG-ATDPC and the absence of identified adverse side effects should facilitate its clinical translation as a novel MI therapy in humans.

  8. Exogenous Nkx2.5- or GATA-4-transfected rabbit bone marrow mesenchymal stem cells and myocardial cell co-culture on the treatment of myocardial infarction in rabbits.

    Science.gov (United States)

    Li, Pu; Zhang, Lei

    2015-08-01

    The present study aimed to investigate the effects of Nkx2.5 or GATA-4 transfection with myocardial extracellular environment co-culture on the transformation of bone marrow mesenchymal stem cells (BMSCs) into differentiated cardiomyocytes. Nkx2.5 or GATA-4 were transfected into myocardial extracellular environment co-cultured BMSCs, and then injected into the periphery of infarcted myocardium of a myocardial infarction rabbit model. The effects of these gene transfections and culture on the infarcted myocardium were observed and the results may provide an experimental basis for the efficient myocardial cell differentiation of BMSCs. The present study also suggested that these cells may provide a source and clinical basis for myocardial injury repair via stem cell transplantation. The present study examined whether Nkx2.5 or GATA-4 exogenous gene transfection with myocardial cell extracellular environment co-culture were able to induce the differentiation of BMSCs into cardiac cells. In addition, the effect of these transfected BMSCs on the repair of the myocardium following myocardial infarction was determined using New Zealand rabbit models. The results demonstrated that myocardial cell differentiation was significantly less effective following exogenous gene transfection of Nkx2.5 or GATA-4 alone compared with that of transfection in combination with extracellular environment co-culture. In addition, the results of the present study showed that exogenous gene transfection of Nkx2.5 or GATA-4 into myocardial cell extracellular environment co-cultured BMSCs was able to significantly enhance the ability to repair, mitigating the death of myocardial cells and activation of the myocardium in rabbits with myocardial infarction compared with those of the rabbits transplanted with untreated BMSCs. In conclusion, the exogenous Nkx2.5 and GATA-4 gene transfection into myocardial extracellular environment co-cultured BMSCs induced increased differentiation into myocardial

  9. Fibroblast progenitor cells are recruited into the myocardium prior to the development of myocardial fibrosis.

    Science.gov (United States)

    Sopel, Mryanda; Falkenham, Alec; Oxner, Adam; Ma, Irene; Lee, Timothy D G; Légaré, Jean-Francois

    2012-04-01

    Using an established model of myocardial hypertrophy and fibrosis after angiotensin II (AngII) infusion, our aim was to characterize the early cellular element involved in the development of myocardial fibrosis in detail. Male Lewis rats were infused with saline or AngII (0.7 mg/kg per day) for up to seven days. Collagen deposition and cellular infiltration were identified by histology stains. Infiltrating cells were grown in vitro and examined by flow cytometry and immunostaining. Chemokine expression was measured using qRT-PCR. AngII infusion resulted in multifocal myocardial cellular infiltration (peak at three days) that preceded collagen deposition. Monocyte chemotactic protein (MCP)-1 transcripts peaked after one day of AngII exposure. Using a triple-labelling technique, the infiltrating cells were found to express markers of leucocyte (ED1(+)), mesenchymal [α-smooth muscle actin (SMA)(+)] and haematopeotic progenitor cells (CD133(+)) suggesting a fibroblast progenitor phenotype. In vitro, ED1(+)/SMA(+)/CD133(+) cells were isolated and grown from AngII-exposed animals. Comparatively few cells were cultured from untreated control hearts, and they were found to be ED1(-)/SMA(+)/CD133(-). We provide evidence that myocardial ECM deposition is preceded by infiltration into the myocardium by cells that express a combination of haematopoietic (ED1, CD133) and mesenchymal (SMA) cell markers, which is a characteristic of the phenotype of fibroblast precursor cells, termed fibrocytes. This suggests that fibrocytes rather than (as is often presumed) leucocytes may have effector functions in the initiation of myocardial fibrosis. © 2012 The Authors. International Journal of Experimental Pathology © 2012 International Journal of Experimental Pathology.

  10. Hemorrhagic shock impairs myocardial cell volume regulation and membrane integrity in dogs

    Energy Technology Data Exchange (ETDEWEB)

    Horton, J.W.

    1987-06-01

    An in vitro myocardial slice technique was used to quantitate alterations in cell volume regulation and membrane integrity after 2 h or hemorrhagic shock. After in vitro incubation in Krebs-Ringer-phosphate medium containing trace (/sup 14/C)inulin, values (ml H/sub 2/O/g dry wt) for control nonshocked myocardial slices were 4.03 /plus minus/ 0.11 (SE) for total water, 2.16 /plus minus/ 0.07 for inulin impermeable space, and 1.76 /plus minus/ 0.15 for inulin diffusible space. Shocked myocardial slices showed impaired response to cold incubation. After 2 h of in vivo shock, total tissue water, inulin diffusible space, and inulin impermeable space increased significantly for subendocardium, whereas changes in subepicardium parameters were minimal. Shock-induced cellular swelling was accompanied by an increased total tissue sodium, but no change in tissue potassium. Calcium entry blockade in vivo significantly reduced subendocardial total tissue water as compared with shock-untreated dogs. In addition, calcium entry blockade reduced shock-induced increases in inulin diffusible space. In vitro myocardial slice studies confirm alterations in subendocardial membrane integrity after 2 h of in vivo hemorrhagic shock. Shock-induced abnormalities in myocardial cell volume regulation are reduced by calcium entry blockade in vivo.

  11. The organization, function, and outcomes of ST-elevation myocardial infarction networks worldwide: current state, unmet needs and future directions.

    Science.gov (United States)

    Huber, Kurt; Gersh, Bernard J; Goldstein, Patrick; Granger, Christopher B; Armstrong, Paul W

    2014-06-14

    The organization of networks in order to better coordinate and to faster offer reperfusion strategies for acute ST-elevation myocardial infarction (STEMI) is an important recommendation of recent versions of international guidelines. This article focusses on similarities and dissimilarities of world-wide networks, highlights essential network components, offers insights into still unmet needs and discusses potential measures to further improve quality of STEMI treatment. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.

  12. [Benefit of the implementation of a ST-segment elevation myocardial infarction network on women].

    Science.gov (United States)

    Fernández-Rodríguez, Diego; Freixa, Xavier; Kasa, Gizem; Regueiro, Ander; Cevallos, Joaquim; Hernández, Marco; Brugaletta, Salvatore; Martín-Yuste, Victoria; Sabaté, Manel; Masotti, Mónica

    2015-01-01

    The ST-segment elevation myocardial infarction network "Codi Infart" was implemented in Catalonia (Spain) in June 2009. The objective of this study was to evaluate the impact of the implementation of the Codi Infart on women. Women referred for primary percutaneous coronary intervention, were divided into two groups according to Codi Infart: Non-Codi Infart group (January 2003 to May 2009) and Codi Infart group (June 2009 to December 2012). Place of first medical contact, time intervals in diagnosis and treatment, treatments received and rate of major cardiovascular adverse events defined as all-cause death, reinfarction or stroke in-hospital, at 30 and 180 days were compared. From a total population of 2,426 patients, 501 (20.7%) were women. One-hundred eighty-six women (2.09 cases/month) belonged to Non-Codi Infart group and 315 women (10.16 cases/month) to Codi Infart group. The percentage of women attended increased since the introduction of CI (22.2% vs. 18.5%, P=.028). In addition, the Codi Infart group had a higher percentage of women initially attended outside our institution (84.1% vs. 16.7%, P<.001), and lower total ischemia time (220 [155-380] vs. 272 [196-456], P=.003). However, no differences in 180-day major cardiovascular adverse events were detected (14.2% vs. 15.6%, P=.692). The implementation of the major cardiovascular adverse events allowed to increase the rate and the percentage of women with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention and reducing total ischemic time. Copyright © 2014 Instituto Nacional de Cardiología Ignacio Chávez. Published by Masson Doyma México S.A. All rights reserved.

  13. Differential Mechanisms of Myocardial Conduction Slowing by Adipose Tissue-Derived Stromal Cells Derived From Different Species

    NARCIS (Netherlands)

    ten Sande, Judith N.; Smit, Nicoline W.; Parvizi, Mojtaba; van Amersfoorth, Shirley C. M.; Plantinga, Josee A.; van Dessel, Pascal F. H. M.; de Bakker, Jacques M. T.; Harmsen, Marco C.; Coronel, Ruben

    : Stem cell therapy is a promising therapeutic option to treat patients after myocardial infarction. However, the intramyocardial administration of large amounts of stem cells might generate a proarrhythmic substrate. Proarrhythmic effects can be explained by electrotonic and/or paracrine

  14. Cell therapy in myocardial infarction: emphasis on the role of MRI

    Energy Technology Data Exchange (ETDEWEB)

    Ye, Yuxiang; Bogaert, Jan [University Hospital K.U.L., Department of Radiology, Leuven (Belgium)

    2008-03-15

    Despite tremendous progress in myocardial infarct (MI) treatment, mortality rates remain substantial. Permanent loss of cardiomyocytes after ischemic injury, results in irreversible loss of myocardial contractility, reduction in ventricular performance, and may initiate the development of dilated heart failure. The discovery that pluripotent progenitor cells bear the capacity to differentiate to mature cardiac cells raised the hope of cell-based regenerative medicine. Engraftment of stem cells in the damaged myocardium, repair and functional improvement appeared suddenly a nearby reality. Promising results in animal models, and preliminary studies reporting the feasibility and safety of adult stem cell therapy in MI patients led to the first double-blinded randomized, placebo-controlled trials. The initial great enthusiasm for this paradigm shift in MI treatment has been tempered by the mainly negative or modestly positive study findings. Before new, larger clinical trials can be initiated, a number of critical questions and issues need to be considered starting with a scrutinized analysis of currently available data to extending our knowledge of the mechanism of scarless myocardial regeneration. Cardiac cell therapy necessitates a multidisciplinary approach, whereby imaging, in particular MRI, and the input of the imaging specialist is crucial to the success of cardiac cell regenerative medicine. MRI is an appealing technique for cell trafficking depicting engraftment, differentiation and survival. Endomyocardial cell administration can be achieved safely with MR fluoroscopy and MRI is without any doubt the most accurate and reproducible technique to measure study end-points. (orig.)

  15. The alpha-smooth muscle actin-positive cells in healing human myocardial scars

    NARCIS (Netherlands)

    Willems, I. E.; Havenith, M. G.; de Mey, J. G.; Daemen, M. J.

    1994-01-01

    Interstitial cells in the scars of human myocardial infarctions of different postinfarction times (6 hours to 17 years old) were characterized by antibodies to alpha-smooth muscle actin (ASMA), vimentin, and desmin. Basal lamina deposition was studied with antibodies to the basal lamina protein type

  16. Concise Review : Engineering Myocardial Tissue: The Convergence of Stem Cells Biology and Tissue Engineering Technology

    NARCIS (Netherlands)

    Buikema, Jan Willem; Van der Meer, Peter; Sluijter, Joost P. G.; Domian, Ibrahim J.

    2013-01-01

    Advanced heart failure represents a leading public health problem in the developed world. The clinical syndrome results from the loss of viable and/or fully functional myocardial tissue. Designing new approaches to augment the number of functioning human cardiac muscle cells in the failing heart

  17. Myocardial regeneration by transplantation of modified endothelial progenitor cells expressing SDF-1 in a rat model

    DEFF Research Database (Denmark)

    Schuh, A.; Kroh, A.; Konschalla, S.

    2012-01-01

    Cell based therapy has been shown to attenuate myocardial dysfunction after myocardial infarction (MI) in different acute and chronic animal models. It has been further shown that stromal-cell derived factor-1a (SDF-1a) facilitates proliferation and migration of endogenous progenitor cells...... into injured tissue. The aim of the present study was to investigate the role of exogenously applied and endogenously mobilized cells in a regenerative strategy for MI therapy. Lentivirally SDF-1a-infected endothelial progenitor cells (EPCs) were injected after 90 min. of ligation and reperfusion of the left...... anterior descending artery (LAD) intramyocardial and intracoronary using a new rodent catheter system. Eight weeks after transplantation, echocardiography and isolated heart studies revealed a significant improvement of LV function after intramyocardial application of lentiviral with SDF-1 infected EPCs...

  18. Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Relieve Acute Myocardial Ischemic Injury

    Directory of Open Access Journals (Sweden)

    Yuanyuan Zhao

    2015-01-01

    Full Text Available This study is aimed at investigating whether human umbilical cord mesenchymal stem cell- (hucMSC- derived exosomes (hucMSC-exosomes have a protective effect on acute myocardial infarction (AMI. Exosomes were characterized under transmission electron microscopy and the particles of exosomes were further examined through nanoparticle tracking analysis. Exosomes (400 μg protein were intravenously administrated immediately following ligation of the left anterior descending (LAD coronary artery in rats. Cardiac function was evaluated by echocardiography and apoptotic cells were counted using TUNEL staining. The cardiac fibrosis was assessed using Masson’s trichrome staining. The Ki67 positive cells in ischemic myocardium were determined using immunohistochemistry. The effect of hucMSC-exosomes on blood vessel formation was evaluated through tube formation and migration of human umbilical vein endothelial cells (EA.hy926 cells. The results indicated that ligation of the LAD coronary artery reduced cardiac function and induced cardiomyocyte apoptosis. Administration of hucMSC-exosomes significantly improved cardiac systolic function and reduced cardiac fibrosis. Moreover, hucMSC-exosomes protected myocardial cells from apoptosis and promoted the tube formation and migration of EA.hy926 cells. It is concluded that hucMSC-exosomes improved cardiac systolic function by protecting myocardial cells from apoptosis and promoting angiogenesis. These effects of hucMSC-exosomes might be associated with regulating the expression of Bcl-2 family.

  19. Calcium dependent CAMTA1 in adult stem cell commitment to a myocardial lineage.

    Directory of Open Access Journals (Sweden)

    Barbara Muller-Borer

    Full Text Available The phenotype of somatic cells has recently been found to be reversible. Direct reprogramming of one cell type into another has been achieved with transduction and over expression of exogenous defined transcription factors emphasizing their role in specifying cell fate. To discover early and novel endogenous transcription factors that may have a role in adult-derived stem cell acquisition of a cardiomyocyte phenotype, mesenchymal stem cells from human and mouse bone marrow and rat liver were co-cultured with neonatal cardiomyocytes as an in vitro cardiogenic microenvironment. Cell-cell communications develop between the two cell types as early as 24 hrs in co-culture and are required for elaboration of a myocardial phenotype in the stem cells 8-16 days later. These intercellular communications are associated with novel Ca(2+ oscillations in the stem cells that are synchronous with the Ca(2+ transients in adjacent cardiomyocytes and are detected in the stem cells as early as 24-48 hrs in co-culture. Early and significant up-regulation of Ca(2+-dependent effectors, CAMTA1 and RCAN1 ensues before a myocardial program is activated. CAMTA1 loss-of-function minimizes the activation of the cardiac gene program in the stem cells. While the expression of RCAN1 suggests involvement of the well-characterized calcineurin-NFAT pathway as a response to a Ca(2+ signal, the CAMTA1 up-regulated expression as a response to such a signal in the stem cells was unknown. Cell-cell communications between the stem cells and adjacent cardiomyocytes induce Ca(2+ signals that activate a myocardial gene program in the stem cells via a novel and early Ca(2+-dependent intermediate, up-regulation of CAMTA1.

  20. The apoptotic effect and the plausible mechanism of microwave radiation on rat myocardial cells.

    Science.gov (United States)

    Zhu, Wenhe; Cui, Yan; Feng, Xianmin; Li, Yan; Zhang, Wei; Xu, Junjie; Wang, Huiyan; Lv, Shijie

    2016-08-01

    Microwaves may exert adverse biological effects on the cardiovascular system at the integrated system and cellular levels. However, the mechanism underlying such effects remains poorly understood. Here, we report a previously uncharacterized mechanism through which microwaves damage myocardial cells. Rats were treated with 2450 MHz microwave radiation at 50, 100, 150, or 200 mW/cm(2) for 6 min. Microwave treatment significantly enhanced the levels of various enzymes in serum. In addition, it increased the malondialdehyde content while decreasing the levels of antioxidative stress enzymes, activities of enzyme complexes I-IV, and ATP in myocardial tissues. Notably, irradiated myocardial cells exhibited structural damage and underwent apoptosis. Furthermore, Western blot analysis revealed significant changes in expression levels of proteins involved in oxidative stress regulation and apoptotic signaling pathways, indicating that microwave irradiation could induce myocardial cell apoptosis by interfering with oxidative stress and cardiac energy metabolism. Our findings provide useful insights into the mechanism of microwave-induced damage to the cardiovascular system.

  1. Genistein promotes endothelial colony-forming cell (ECFC bioactivities and cardiac regeneration in myocardial infarction.

    Directory of Open Access Journals (Sweden)

    Sang Hun Lee

    Full Text Available Although stem cell-mediated treatment of ischemic diseases offers significant therapeutic promise, the limitation in the therapeutic efficacy of transplanted stem cells in vivo because of poor engraftment remains a challenge. Several strategies aimed at improving survival and engraftment of stem cells in the ischemic myocardium have been developed, such as cell transplantation in combination with growth factor delivery, genetic modification of stem cells, and/or cell therapy using scaffolds. To improve therapeutic efficacy, we investigated the effects of genistein on the engraftment of transplanted ECFCs in an acute myocardial ischemia model.We found that genistein treatment enhanced ECFCs' migration and proliferation, which was accompanied by increases in the expression of ILK, α-parvin, F-actin, and phospholylation of ERK 1/2 signaling. Transplantation of genistein-stimulates ECFCs (GS-ECFCs into myocardial ischemic sites in vivo induced cellular proliferation and secretion of angiogenic cytokines at the ischemic sites and thereby enhanced neovascularization and decreased myocardial fibrosis as well as improved cardiac function, as shown by echocardiography. Taken together, these data suggest that pretreatment of ECFCs with genistein prior to transplantation can improve the regenerative potential in ischemic tissues, providing a novel strategy in adult stem cell therapy for ischemic diseases.

  2. Myocardial injection of apelin-overexpressing bone marrow cells improves cardiac repair via upregulation of Sirt3 after myocardial infarction.

    Directory of Open Access Journals (Sweden)

    Lanfang Li

    Full Text Available Our previous study shows that treatment with apelin increases bone marrow cells (BMCs recruitment and promotes cardiac repair after myocardial infarction (MI. The objective of this study was to investigate whether overexpression of apelin in BMCs improved cell therapy and accelerated cardiac repair and functional recovery in post-MI mice. Mouse myocardial infarction was achieved by coronary artery ligation and BMCs overexpressing apelin (apelin-BMCs or GFP (GFP-BMCs were injected into ischemic area immediately after surgery. In vitro, exposure of cultured BMCs to apelin led to a gradual increase in SDF-1á and CXCR4 expression. Intramyocardial delivery of apelin-BMCs in post-MI mice resulted in a significant increase number of APJ⁺/c-kit⁺/Sca1⁺ cells in the injected area compared to GFP-BMCs treated post-MI mice. Treatment with apelin-BMCs increased expression of VEGF, Ang-1 and Tie-2 in post-MI mice. Apelin-BMCs treatment also significantly increased angiogenesis and attenuated cardiac fibrosis formation in post-MI mice. Most importantly, treatment with apelin-BMCs significantly improved left ventricular (LV systolic function in post-MI mice. Mechanistically, Apelin-BMCs treatment led to a significant increase in Sirtuin3 (Sirt3 expression and reduction of reactive oxygen species (ROS formation. Treatment of cultured BMCs with apelin also increased Notch3 expression and Akt phosphorylation. Apelin treatment further attenuated stress-induced apoptosis whereas knockout of Sirt3 abolished anti-apoptotic effect of apelin in cultured BMCs. Moreover, knockout of Sirt3 significantly attenuated apelin-BMCs-induced VEGF expression and angiogenesis in post-MI mice. Knockout of Sirt3 further blunted apelin-BMCs-mediated improvement of cardiac repair and systolic functional recovery in post-MI mice. These data suggest that apelin improves BMCs therapy on cardiac repair and systolic function in post-MI mice. Upregulation of Sirt3 may contribute to the

  3. Imaging long-term fate of intramyocardially implanted mesenchymal stem cells in a porcine myocardial infarction model.

    Directory of Open Access Journals (Sweden)

    Emerson C Perin

    Full Text Available The long-term fate of stem cells after intramyocardial delivery is unknown. We used noninvasive, repetitive PET/CT imaging with [(18F]FEAU to monitor the long-term (up to 5 months spatial-temporal dynamics of MSCs retrovirally transduced with the sr39HSV1-tk gene (sr39HSV1-tk-MSC and implanted intramyocardially in pigs with induced acute myocardial infarction. Repetitive [(18F]FEAU PET/CT revealed a biphasic pattern of sr39HSV1-tk-MSC dynamics; cell proliferation peaked at 33-35 days after injection, in periinfarct regions and the major cardiac lymphatic vessels and lymph nodes. The sr39HSV1-tk-MSC-associated [(18F]FEAU signals gradually decreased thereafter. Cardiac lymphography studies using PG-Gd-NIRF813 contrast for MRI and near-infrared fluorescence imaging showed rapid clearance of the contrast from the site of intramyocardial injection through the subepicardial lymphatic network into the lymphatic vessels and periaortic lymph nodes. Immunohistochemical analysis of cardiac tissue obtained at 35 and 150 days demonstrated several types of sr39HSV1-tk expressing cells, including fibro-myoblasts, lymphovascular cells, and microvascular and arterial endothelium. In summary, this study demonstrated the feasibility and sensitivity of [(18F]FEAU PET/CT imaging for long-term, in-vivo monitoring (up to 5 months of the fate of intramyocardially injected sr39HSV1-tk-MSC cells. Intramyocardially transplanted MSCs appear to integrate into the lymphatic endothelium and may help improve myocardial lymphatic system function after MI.

  4. Imaging long-term fate of intramyocardially implanted mesenchymal stem cells in a porcine myocardial infarction model.

    Science.gov (United States)

    Perin, Emerson C; Tian, Mei; Marini, Frank C; Silva, Guilherme V; Zheng, Yi; Baimbridge, Fred; Quan, Xin; Fernandes, Marlos R; Gahremanpour, Amir; Young, Daniel; Paolillo, Vincenzo; Mukhopadhyay, Uday; Borne, Agatha T; Uthamanthil, Rajesh; Brammer, David; Jackson, James; Decker, William K; Najjar, Amer M; Thomas, Michael W; Volgin, Andrei; Rabinovich, Brian; Soghomonyan, Suren; Jeong, Hwan-Jeong; Rios, Jesse M; Steiner, David; Robinson, Simon; Mawlawi, Osama; Pan, Tinsu; Stafford, Jason; Kundra, Vikas; Li, Chun; Alauddin, Mian M; Willerson, James T; Shpall, Elizabeth; Gelovani, Juri G

    2011-01-01

    The long-term fate of stem cells after intramyocardial delivery is unknown. We used noninvasive, repetitive PET/CT imaging with [(18)F]FEAU to monitor the long-term (up to 5 months) spatial-temporal dynamics of MSCs retrovirally transduced with the sr39HSV1-tk gene (sr39HSV1-tk-MSC) and implanted intramyocardially in pigs with induced acute myocardial infarction. Repetitive [(18)F]FEAU PET/CT revealed a biphasic pattern of sr39HSV1-tk-MSC dynamics; cell proliferation peaked at 33-35 days after injection, in periinfarct regions and the major cardiac lymphatic vessels and lymph nodes. The sr39HSV1-tk-MSC-associated [(18)F]FEAU signals gradually decreased thereafter. Cardiac lymphography studies using PG-Gd-NIRF813 contrast for MRI and near-infrared fluorescence imaging showed rapid clearance of the contrast from the site of intramyocardial injection through the subepicardial lymphatic network into the lymphatic vessels and periaortic lymph nodes. Immunohistochemical analysis of cardiac tissue obtained at 35 and 150 days demonstrated several types of sr39HSV1-tk expressing cells, including fibro-myoblasts, lymphovascular cells, and microvascular and arterial endothelium. In summary, this study demonstrated the feasibility and sensitivity of [(18)F]FEAU PET/CT imaging for long-term, in-vivo monitoring (up to 5 months) of the fate of intramyocardially injected sr39HSV1-tk-MSC cells. Intramyocardially transplanted MSCs appear to integrate into the lymphatic endothelium and may help improve myocardial lymphatic system function after MI.

  5. 111In-labeled CD34+ hematopoietic progenitor cells in a rat myocardial infarction model.

    Science.gov (United States)

    Brenner, Winfried; Aicher, Alexandra; Eckey, Thomas; Massoudi, Schirin; Zuhayra, Maaz; Koehl, Ulrike; Heeschen, Christopher; Kampen, Willm U; Zeiher, Andreas M; Dimmeler, Stefanie; Henze, Eberhard

    2004-03-01

    Transplantation of progenitor cells (PCs) has been shown to improve neovascularization and left ventricular function after myocardial ischemia. The fate of transplanted PCs has been monitored by fluorescence labeling or by genetic modifications introducing reporter genes. However, these techniques are limited by the need to kill the experimental animal. The aim of this study was to radiolabel CD34(+) hematopoietic PCs (HPCs) with (111)In-oxine and to evaluate the feasibility of this in vivo method for monitoring myocardial homing of transplanted cells in a rat myocardial infarction model. Human HPCs were isolated from mobilized peripheral blood and labeled with (111)In-oxine. Labeled HPCs were injected into the cavity of the left ventricle in nude rats 24 h after induction of myocardial infarction (n = 4) or sham operation (n = 4). Scintigraphic images were acquired up to 96 h after HPC injection. After animals were killed, tissue samples of various organs were harvested to calculate tissue-specific activity and for immunostaining. Labeling efficiency of HPCs was 32% +/- 11%. According to trypan-blue staining, viability of radiolabeled HPCs was impaired by 30% after 48 and 96 h in comparison with unlabeled cells, whereas proliferation and differentiation of HPCs was nullified after 7 d, as assessed by colony-forming assays. After injection of HPCs, the specific activity ratio of heart to peripheral muscle tissue increased from 1.10 +/- 0.32 in sham-operated rats to 2.47 +/- 0.92 (P = 0.020) in infarcted rats. However, the overall radioactivity detected in the heart was only about 1%. A transient high lung uptake of 17% +/- 6% was observed within the first hour after infusion of HPCs. At 24 h after injection, the initial lung activity had shifted toward liver, kidneys, and spleen, resulting in an increase of radioactivity in these organs from 37% +/- 6% to 57% +/- 5%. Radiolabeling with (111)In-oxine is a feasible in vivo method for monitoring transplanted HPCs in a

  6. Molecular Imaging of Stem Cell Transplantation in Myocardial Disease

    OpenAIRE

    Chung, Jaehoon; Yang, Phillip C.

    2010-01-01

    Stem cell therapy has been heralded as a novel therapeutic option for cardiovascular disease. In vivo molecular imaging has emerged as an indispensible tool in investigating stem cell biology post-transplantation into the myocardium and in evaluating the therapeutic efficacy. This review highlights the features of each molecular imaging modality and discusses how these modalities have been applied to evaluate stem cell therapy.

  7. Mesenchymal stromal cells overexpressing vascular endothelial growth factor in ovine myocardial infarction.

    Science.gov (United States)

    Locatelli, P; Olea, F D; Hnatiuk, A; De Lorenzi, A; Cerdá, M; Giménez, C S; Sepúlveda, D; Laguens, R; Crottogini, A

    2015-06-01

    Mesenchymal stromal cells (MSCs) are cardioprotective in acute myocardial infarction (AMI). Besides, we have shown that intramyocardial injection of plasmid-VEGF(165) (pVEGF) in ovine AMI reduces infarct size and improves left ventricular (LV) function. We thus hypothesized that MSCs overexpressing VEGF(165) (MSCs-pVEGF) would afford greater cardioprotection than non-modified MSCs or pVEGF alone. Sheep underwent an anteroapical AMI and, 1 week later, received intramyocardial MSCs-pVEGF in the infarct border. One month post treatment, infarct size (magnetic resonance) decreased by 31% vs pre-treatment. Of note, myocardial salvage occurred predominantly at the subendocardium, the myocardial region displaying the largest contribution to systolic performance. Consistently, LV ejection fraction recovered to almost its baseline value because of marked decrease in end-systolic volume. None of these effects were observed in sheep receiving non-transfected MSCs or pVEGF. Although myocardial retention of MSCs decreased steeply over time, the treatment induced significant capillary and arteriolar proliferation, which reduced subendocardial fibrosis. We conclude that in ovine AMI, allogeneic VEGF-overexpressing MSCs induce subendocardial myocardium salvage through microvascular proliferation, reducing infarct size and improving LV function more than non-transfected MSCs or the naked plasmid. Importantly, the use of a plasmid rather than a virus allows for repeated treatments, likely needed in ischemic heart disease.

  8. Cardiac repair in a porcine model of acute myocardial infarction with human induced pluripotent stem cell-derived cardiovascular cells.

    Science.gov (United States)

    Ye, Lei; Chang, Ying-Hua; Xiong, Qiang; Zhang, Pengyuan; Zhang, Liying; Somasundaram, Porur; Lepley, Mike; Swingen, Cory; Su, Liping; Wendel, Jacqueline S; Guo, Jing; Jang, Albert; Rosenbush, Daniel; Greder, Lucas; Dutton, James R; Zhang, Jianhua; Kamp, Timothy J; Kaufman, Dan S; Ge, Ying; Zhang, Jianyi

    2014-12-04

    Human induced pluripotent stem cells (hiPSCs) hold promise for myocardial repair following injury, but preclinical studies in large animal models are required to determine optimal cell preparation and delivery strategies to maximize functional benefits and to evaluate safety. Here, we utilized a porcine model of acute myocardial infarction (MI) to investigate the functional impact of intramyocardial transplantation of hiPSC-derived cardiomyocytes, endothelial cells, and smooth muscle cells, in combination with a 3D fibrin patch loaded with insulin growth factor (IGF)-encapsulated microspheres. hiPSC-derived cardiomyocytes integrated into host myocardium and generated organized sarcomeric structures, and endothelial and smooth muscle cells contributed to host vasculature. Trilineage cell transplantation significantly improved left ventricular function, myocardial metabolism, and arteriole density, while reducing infarct size, ventricular wall stress, and apoptosis without inducing ventricular arrhythmias. These findings in a large animal MI model highlight the potential of utilizing hiPSC-derived cells for cardiac repair. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Microfluidic Single Cell Analysis Show Porcine Induced Pluripotent Stem Cell-Derived Endothelial Cells Improve Myocardial Function by Paracrine Activation

    Science.gov (United States)

    Gu, Mingxia; Nguyen, Patricia K.; Lee, Andrew S.; Xu, Dan; Hu, Shijun; Plews, Jordan R; Han, Leng; Huber, Bruno C.; Lee, Won Hee; Gong, Yongquan; de Almeida, Patricia E.; Lyons, Jennifer; Ikeno, Fumi; Pacharinsak, Cholawat; Connolly, Andrew J.; Gambhir, Sanjiv S.; Robbins, Robert C.; Longaker, Michael T.; Wu, Joseph C.

    2012-01-01

    Rationale Induced pluripotent stem cells (iPSCs) hold great promise for the development of patient-specific therapies for cardiovascular disease. However, clinical translation will require preclinical optimization and validation of large animal iPSC models. Objective To successfully derive endothelial cells from porcine iPSCs and demonstrate their potential utility for the treatment of myocardial ischemia. Methods and Results Porcine adipose stromal cells were reprogrammed to generate porcine iPSCs (piPSCs). Immunohistochemistry, quantitative PCR, microarray hybridization, and angiogenic assays confirmed that piPSC-derived endothelial cells (piPSC-ECs) shared similar morphological and functional properties as endothelial cells isolated from the autologous pig aorta. To demonstrate their therapeutic potential, piPSC-ECs were transplanted into mice with myocardial infarction (MI). Compared to control, animals transplanted with piPSC-ECs showed significant functional improvement measured by echocardiography (fractional shortening at week 4: 27.2±1.3% vs. 22.3±1.1%; P<0.001) and magnetic resonance imaging (ejection fraction at week 4: 45.8±1.3% vs. 42.3±0.9%; P<0.05). Quantitative protein assays and microfluidic single cell PCR profiling showed that piPSC-ECs released pro-angiogenic and anti-apoptotic factors in the ischemic microenvironment, which promoted neovascularization and cardiomyocyte survival, respectively. Release of paracrine factors varied significantly among subpopulations of transplanted cells, suggesting that transplantation of specific cell populations may result in greater functional recovery. Conclusion In summary, this is the first study to successfully differentiate piPSCs-ECs from piPSCs and demonstrate that transplantation of piPSC-ECs improved cardiac function following MI via paracrine activation. Further development of these large animal iPSC models will yield significant insights into their therapeutic potential and accelerate the

  10. Stem Cell Transplantation in Patients with Acute Myocardial Infarction: a Single Center Registry

    Directory of Open Access Journals (Sweden)

    Seyed Ebrahim Kassaian

    2007-09-01

    Full Text Available Background: Early clinical investigations indicate that an infusion of autologous bone-marrow cells into the infarct-related coronary artery is feasible after acute myocardial infarction. There is increasing evidence that cell transplantation may improve the perfusion and contractile function of the ischemic myocardium. The present study reports primarily the safety of intracoronary bone marrow mononuclear cell (BMMNC injections and secondarily the hypothesis that intracoronary injections of autologous BMMNC in patients with acute myocardial infarction may have a favorable impact on tissue perfusion and contractile performance. Methods: Twelve patients with acute ST-elevation myocardial infarction of the anterior wall treated with percutaneous coronary intervention were enrolled in this prospective, nonrandomized, open-label study. Left ventricular function and number of nonviable segments were assessed with the use of echocardiography and Technetium-sestamibi single photon emission tomography respectively at baseline and after a 4-month follow-up.Results: At 4 months’ follow-up, global left ventricular ejection fraction in echocardiography increased from a mean of 31.78±7.56% at baseline to 38.89±6.97% (p=0.018. Mean wall motion score in rest echocardiography was 29.5±6.67 in basal and 26.75±5.44 at 4 months’ follow-up (p=0.05. Nuclear perfusion imaging studies in the patients for the mean number of nonviable segments were 6.5 at baseline and 6 in 4 months’ follow-up (p=0.17. Three patients were lost to follow-up and did not undergo the 4-month evaluations. Conclusion: This study is small and very preliminary. Data from large, randomized, controlled trials are needed to clarify the effect of stem-cell injection in myocardial function

  11. Gender-related differences in patients with ST-elevation myocardial infarction: results from the registry study of the ST elevation myocardial infarction network Essen.

    Science.gov (United States)

    Hailer, Birgit; Naber, Christoph; Koslowski, Bernd; van Leeuwen, Peter; Schäfer, Harald; Budde, Thomas; Jacksch, Rainer; Sabin, Georg; Erbel, Raimund

    2011-05-01

    The Myocardial Infarction Network Essen was initiated in order to establish a standardized procedure with immediate reopening of the infarcted vessel for patients with ST-elevation myocardial infarction (STEMI) in the city of Essen, Germany. The present study aims to evaluate gender-related differences in presentation of disease and clinical outcome. Gender is associated with differences in presentation and outcome of STEMI. All patients with STEMI were included without exception. Parameters such as risk profile, mortality, and relevant time intervals were documented. The follow-up period was 1 year. For this study, 1365 patients (72.1% male) were recruited. Women were significantly older, with higher prevalence of diabetes (28.1% vs 20.3%, P = 0.004) and hypertension (76.5% vs 64.8%, P<0.0005). Analysis of time intervals between symptoms to actions showed no significant differences. However, women tended to wait longer before calling for medical assistance (358 vs 331 min, P = 0.091). In-hospital mortality was comparable with respect to gender, whereas women had higher 1-year mortality (18.6% vs 13.2%). Age and diabetes were associated with a higher mortality. Adjusted for age, gender is no longer an independent risk factor. In the follow-up period, significantly more women were readmitted to the hospital without a difference in the frequency of reangiography, surgery, or target-vessel revascularization. The present data display a successful implementation of a standardized procedure in patients with STEMI. Although differences between genders are not as obvious as expected, efforts should be taken to perform a gender-specific risk analysis as well as to promote education about proper behavior in case of new onset of angina. 2011 Wiley Periodicals, Inc.

  12. Biomaterial strategies to improve the efficacy of bone marrow cell therapy for myocardial infarction.

    Science.gov (United States)

    Nadlacki, Bora; Suuronen, Erik J

    2016-12-01

    The feasibility and safety of bone marrow cell (BMC) therapy for cardiac repair following myocardial infarction has been demonstrated in clinical studies, albeit with relatively modest structural and functional benefits. In response to the shortcomings of BMC therapy, the use of biomaterials to enhance cell transplantation is being investigated. Areas covered: The authors first review what has been learned from BMC therapies for the treatment of myocardial infarction in animal models and in clinical trials. Some issues that may be limiting the efficacy of BMC therapy are then described. Lastly, they summarize several biomaterial approaches that have been reported to improve transplanted cell retention and functional outcome, and then focus on how a material can enhance cell function such as proliferation, viability, endothelial differentiation and angiogenic potential. Expert opinion: Improvements are needed if BMC therapy is to become a viable treatment in the clinic. There is optimism that a biomaterial strategy will lead to superior results compared to the cell therapy alone. Through the identification of underlying cell-biomaterial mechanisms, the establishment of comparative standards, and an awareness of the lessons learned from cell therapy trials, biomaterial-enhanced BMC therapy may become an option for the treatment of heart disease patients.

  13. Pim1 Kinase Overexpression Enhances ckit+ Cardiac Stem Cell Cardiac Repair Following Myocardial Infarction in Swine.

    Science.gov (United States)

    Kulandavelu, Shathiyah; Karantalis, Vasileios; Fritsch, Julia; Hatzistergos, Konstantinos E; Loescher, Viky Y; McCall, Frederic; Wang, Bo; Bagno, Luiza; Golpanian, Samuel; Wolf, Ariel; Grenet, Justin; Williams, Adam; Kupin, Aaron; Rosenfeld, Aaron; Mohsin, Sadia; Sussman, Mark A; Morales, Azorides; Balkan, Wayne; Hare, Joshua M

    2016-12-06

    Pim1 kinase plays an important role in cell division, survival, and commitment of precursor cells towards a myocardial lineage, and overexpression of Pim1 in ckit+ cardiac stem cells (CSCs) enhances their cardioreparative properties. The authors sought to validate the effect of Pim1-modified CSCs in a translationally relevant large animal preclinical model of myocardial infarction (MI). Human cardiac stem cells (hCSCs, n = 10), hckit+ CSCs overexpressing Pim1 (Pim1+; n = 9), or placebo (n = 10) were delivered by intramyocardial injection to immunosuppressed Yorkshire swine (n = 29) 2 weeks after MI. Cardiac magnetic resonance and pressure volume loops were obtained before and after cell administration. Whereas both hCSCs reduced MI size compared to placebo, Pim1+ cells produced a ∼3-fold greater decrease in scar mass at 8 weeks post-injection compared to hCSCs (-29.2 ± 2.7% vs. -8.4 ± 0.7%; p infarct and border zones (both p infarcted porcine hearts. These findings provide a rationale for genetic modification of stem cells and consequent translation to clinical trials. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  14. Noninvasive prediction of sudden death and sustained ventricular tachycardia after acute myocardial infarction using a neural network algorithm.

    Science.gov (United States)

    Zoni-Berisso, M; Molini, D; Viani, S; Mela, G S; Delfino, L

    2001-08-01

    The early and accurate noninvasive identification of postinfarction patients at risk of sudden death and sustained ventricular tachycardia (arrhythmic events) still remains an unsolved problem. The aim of the present study was to identify the combination of clinical and laboratory noninvasive variables, easy to obtain in most patients, that best predicts the occurrence of arrhythmic events after an acute myocardial infarction. Four hundred and four consecutive patients with acute myocardial infarction were enrolled and followed for a median period of 21.4 months. In each patient, 61 clinical and laboratory noninvasive variables were collected before hospital discharge and used for the prediction of arrhythmic events using an artificial neural network. During follow-up, 13 (3.2%) patients died suddenly and 11(2.5%) had sustained ventricular tachycardia. The neural network showed that the combination best predicting arrhythmic events included: left ventricular failure during coronary care stay, ventricular dyskinesis, late potentials, number of ventricular premature depolarizations/hour, nonsustained ventricular tachycardia, left ventricular ejection fraction, bundle branch block and digoxin therapy at discharge. The neural network algorithm allowed identification of a small high-risk patient subgroup (12% of the study population) with an arrhythmic event rate of 46%. The sensitivity and specificity of the test were 96 and 93% respectively. These results suggest that, in postinfarction patients, it is possible to predict early and accurately arrhythmic events by noninvasive variables easily obtainable in most patients. Patients identified as being at risk are candidates for prophylactic antiarrhythmic therapy.

  15. Validation of the cardiosphere method to culture cardiac progenitor cells from myocardial tissue.

    Science.gov (United States)

    Davis, Darryl R; Zhang, Yiqiang; Smith, Rachel R; Cheng, Ke; Terrovitis, John; Malliaras, Konstantinos; Li, Tao-Sheng; White, Anthony; Makkar, Raj; Marbán, Eduardo

    2009-09-25

    At least four laboratories have shown that endogenous cardiac progenitor cells (CPCs) can be grown directly from adult heart tissue in primary culture, as cardiospheres or their progeny (cardiosphere-derived cells, CDCs). Indeed, CDCs are already being tested in a clinical trial for cardiac regeneration. Nevertheless, the validity of the cardiosphere strategy to generate CPCs has been called into question by reports based on variant methods. In those reports, cardiospheres are argued to be cardiomyogenic only because of retained cardiomyocytes, and stem cell activity has been proposed to reflect hematological contamination. We use a variety of approaches (including genetic lineage tracing) to show that neither artifact is applicable to cardiospheres and CDCs grown using established methods, and we further document the stem cell characteristics (namely, clonogenicity and multilineage potential) of CDCs. CPCs were expanded from human endomyocardial biopsies (n = 160), adult bi-transgenic MerCreMer-Z/EG mice (n = 6), adult C57BL/6 mice (n = 18), adult GFP(+) C57BL/6 transgenic mice (n = 3), Yucatan mini pigs (n = 67), adult SCID beige mice (n = 8), and adult Wistar-Kyoto rats (n = 80). Cellular yield was enhanced by collagenase digestion and process standardization; yield was reduced in altered media and in specific animal strains. Heparinization/retrograde organ perfusion did not alter the ability to generate outgrowth from myocardial sample. The initial outgrowth from myocardial samples was enriched for sub-populations of CPCs (c-Kit(+)), endothelial cells (CD31(+), CD34(+)), and mesenchymal cells (CD90(+)). Lineage tracing using MerCreMer-Z/EG transgenic mice revealed that the presence of cardiomyocytes in the cellular outgrowth is not required for the generation of CPCs. Rat CDCs are shown to be clonogenic, and cloned CDCs exhibit spontaneous multineage potential. This study demonstrates that direct culture and expansion of CPCs from myocardial tissue is simple

  16. Improved outcomes of cardiopulmonary resuscitation in rats with myocardial infarction treated with allogenic bone marrow mesenchymal stem cells.

    Science.gov (United States)

    Wang, Tong; Tang, Wanchun; Sun, Shijie; Ristagno, Giuseppe; Xu, Tingyan; Weil, Max Harry

    2009-03-01

    We hypothesized that rats in which myocardial infarction had been treated with mesenchymal stem cells (MSCs) would have better outcomes following the global myocardial ischemia of cardiac arrest and cardiopulmonary resuscitation (CPR) compared with rats in which myocardial infarction had been treated with phosphate buffer solution (PBS). Prospective, randomized controlled study. University-affiliated research institute. Male Sprague-Dawley rats. Myocardial infarction was induced in 18 male Sprague-Dawley rats. Four weeks later, animals were randomized to receive 5 x 10 MSCs labeled with red fluorescent dye gel (PKH26) in PBS or a PBS-alone injection into right femoral vein. Echocardiographically measured myocardial function, including ejection fraction, left ventricular end-diastolic volume, and left ventricular end-systolic volume, was quantitated 2 and 4 weeks after administering MSCs or PBS. Four weeks after MSCs or PBS injection, 6 minutes of ventricular fibrillation (VF) and 6 minutes of CPR were performed before defibrillation. Myocardial function, including cardiac index, left ventricular, dP/dt max (dP/dt max), left ventricular negative dP/dt min (-dP/dt min), and left ventricular diastolic pressure, was measured before inducing VF and hourly following return of spontaneous circulation. Labeled MSCs were observed in 5-mum cryostat sections from each harvested heart. Significant improvements in ejection fraction, left ventricular end-diastolic volume, left ventricular end-systolic volume, cardiac index, dP/dt max, -dP/dt min, and left ventricular diastolic pressure followed injection of MSCs before inducing VF. Following return of spontaneous circulation, myocardial function was significantly better in animals pretreated with MSCs; this was associated with significantly increased duration of postresuscitation survival. Myocardial function before and after CPR and duration of survival after CPR were significantly improved in animals in which myocardial

  17. G-CSF therapy with mobilization of bone marrow stem cells for myocardial recovery after acute myocardial infarction - a relevant treatment?

    DEFF Research Database (Denmark)

    Ripa, R.S.; Kastrup, J.

    2008-01-01

    This review of adjunctive therapy with subcutaneous granulocyte-colony stimulating factor (G-CSF) to patients with acute myocardial infarction (AMI) focus on the cardioprotective effects and potential mechanisms of G-CSF and discuss the therapeutic potential of G-CSF. All clinical trials published...... in peer-reviewed journals identified through PubMed are discussed. G-CSF treatment seems to be safe, and initial unblinded trials in patients with AMI were encouraging. However, larger double-blind placebo-controlled trials have not been able to demonstrate improved myocardial recovery after G......-CSF treatment. Current controversies in interpretation of the results include 1) importance of direct cardiac effect of G-CSF vs indirect through bone marrow stem and progenitor cell mobilization, 2) importance of timing of G-CSF therapy, 3) importance of G-CSF dose, and 4) importance of cell types mobilized...

  18. Magnetic Nanoparticles for Targeting and Imaging of Stem Cells in Myocardial Infarction

    Directory of Open Access Journals (Sweden)

    Michelle R. Santoso

    2016-01-01

    Full Text Available Stem cell therapy has broad applications in regenerative medicine and increasingly within cardiovascular disease. Stem cells have emerged as a leading therapeutic option for many diseases and have broad applications in regenerative medicine. Injuries to the heart are often permanent due to the limited proliferation and self-healing capability of cardiomyocytes; as such, stem cell therapy has become increasingly important in the treatment of cardiovascular diseases. Despite extensive efforts to optimize cardiac stem cell therapy, challenges remain in the delivery and monitoring of cells injected into the myocardium. Other fields have successively used nanoscience and nanotechnology for a multitude of biomedical applications, including drug delivery, targeted imaging, hyperthermia, and tissue repair. In particular, superparamagnetic iron oxide nanoparticles (SPIONs have been widely employed for molecular and cellular imaging. In this mini-review, we focus on the application of superparamagnetic iron oxide nanoparticles in targeting and monitoring of stem cells for the treatment of myocardial infarctions.

  19. The Citrus Flavanone Naringenin Protects Myocardial Cells against Age-Associated Damage

    Directory of Open Access Journals (Sweden)

    Eleonora Da Pozzo

    2017-01-01

    Full Text Available In recent years, the health-promoting effects of the citrus flavanone naringenin have been examined. The results have provided evidence for the modulation of some key mechanisms involved in cellular damage by this compound. In particular, naringenin has been revealed to have protective properties such as an antioxidant effect in cardiometabolic disorders. Very recently, beneficial effects of naringenin have been demonstrated in old rats. Because aging has been demonstrated to be directly related to the occurrence of cardiac disorders, in the present study, the ability of naringenin to prevent cardiac cell senescence was investigated. For this purpose, a cellular model of senescent myocardial cells was set up and evaluated using colorimetric, fluorimetric, and immunometric techniques. Relevant cellular senescence markers, such as X-gal staining, cell cycle regulator levels, and the percentage of cell cycle-arrested cells, were found to be reduced in the presence of naringenin. In addition, cardiac markers of aging-induced damage, including radical oxidative species levels, mitochondrial metabolic activity, mitochondrial calcium buffer capacity, and estrogenic signaling functions, were also modulated by the compound. These results suggested that naringenin has antiaging effects on myocardial cells.

  20. Dynamical Adaptation in Terrorist Cells/Networks

    DEFF Research Database (Denmark)

    Hussain, Dil Muhammad Akbar; Ahmed, Zaki

    2010-01-01

    Typical terrorist cells/networks have dynamical structure as they evolve or adapt to changes which may occur due to capturing or killing of a member of the cell/network. Analytical measures in graph theory like degree centrality, betweenness and closeness centralities are very common and have long...... history of their successful use in revealing the importance of various members of the network. However, modeling of covert, terrorist or criminal networks through social graph dose not really provide the hierarchical structure which exist in these networks as these networks are composed of leaders...... and followers etc. In this research we analyze and predict the most likely role a particular node can adapt once a member of the network is either killed or caught. The adaptation is based on computing Bayes posteriori probability of each node and the level of the said node in the network structure....

  1. Cell-based therapy for myocardial repair in patients with acute myocardial infarction: rationale and study design of the SWiss multicenter Intracoronary Stem cells Study in Acute Myocardial Infarction (SWISS-AMI).

    Science.gov (United States)

    Sürder, Daniel; Schwitter, Jürg; Moccetti, Tiziano; Astori, Giuseppe; Rufibach, Kaspar; Plein, Sven; Lo Cicero, Viviana; Soncin, Sabrina; Windecker, Stephan; Moschovitis, Aris; Wahl, Andreas; Erne, Paul; Jamshidi, Peiman; Auf der Maur, Christoph; Manka, Robert; Soldati, Gianni; Bühler, Ines; Wyss, Christophe; Landmesser, Ulf; Lüscher, Thomas F; Corti, Roberto

    2010-07-01

    Recent studies report that intracoronary administration of autologous bone marrow mononucleated cells (BM-MNCs) may improve remodeling of the left ventricle after acute myocardial infarction (AMI). Subgroup analysis suggest that early treatment between days 4 and 7 after AMI is probably most effective; however, the optimal time point of intracoronary cell administration has never been addressed in clinical trials. Furthermore, reliable clinical predictors are lacking for identifying patients who are thought to have most benefit from cellular therapy. In a multicenter trial, 192 patients with AMI successfully treated by percutaneous coronary intervention (PCI) of the infarct-related artery will be randomized in a 1:1:1 pattern to 1 control and 2 BM-MNC treatment groups. The control group will be treated with state-of-the-art medical management. The treatment groups will receive intracoronary administration of autologous BM-MNC at 5 to 7 days or 3 to 4 weeks after the initial event, respectively. Left ventricular function as well as scar size, transmural extension, and regional wall motion score will be assessed by cardiac magnetic resonance (CMR) studies at baseline and after 4 and 12 months. Fifty milliliters of bone marrow will be harvested by aspiration from the iliac crest and then carried by courier to a centralized cell processing facility. The mononucleated cell fraction will be isolated by density gradient centrifugation, washed, and resuspended in 10 mL of injection medium. The cells will be characterized by fluorescence-activated cell sorting analysis and tested for sterility and potency both "in vitro" and "in vivo." Bone marrow MNC will then be reinfused directly in the infarct-related coronary artery. The primary end point is the change in global left ventricular (LV) ejection fraction by CMR at 4 months as compared to baseline. Comparisons will then be made between each of the prespecified therapy subgroups (early and late after AMI) and the control

  2. Combining white blood cell count and thrombosis for predicting in-hospital outcomes after acute myocardial infraction

    OpenAIRE

    Rohani, Atooshe; Akbari, Vahid; Moradian, Karim; Malekzade, Janmohammad

    2011-01-01

    Introduction: Admission white blood cell (WBC) count and thrombosis in myocardial infarction (TIMI) risk score have been associated with adverse outcomes after acute myocardial infarction (AMI). This study investigated the joint effect of WBC count and TIMI risk score on predicting in-hospital outcomes in patients with AMI. Materials and Methods: WBC count and TIMI risk score were measured at the time of hospital admission in 70 patients with AMI. Echocardiogram was done on prior to discharge...

  3. Intracoronary Administration of Allogeneic Adipose Tissue-Derived Mesenchymal Stem Cells Improves Myocardial Perfusion But Not Left Ventricle Function, in a Translational Model of Acute Myocardial Infarction.

    Science.gov (United States)

    Bobi, Joaquim; Solanes, Núria; Fernández-Jiménez, Rodrigo; Galán-Arriola, Carlos; Dantas, Ana Paula; Fernández-Friera, Leticia; Gálvez-Montón, Carolina; Rigol-Monzó, Elisabet; Agüero, Jaume; Ramírez, José; Roqué, Mercè; Bayés-Genís, Antoni; Sánchez-González, Javier; García-Álvarez, Ana; Sabaté, Manel; Roura, Santiago; Ibáñez, Borja; Rigol, Montserrat

    2017-05-03

    Autologous adipose tissue-derived mesenchymal stem cells (ATMSCs) therapy is a promising strategy to improve post-myocardial infarction outcomes. In a porcine model of acute myocardial infarction, we studied the long-term effects and the mechanisms involved in allogeneic ATMSCs administration on myocardial performance. Thirty-eight pigs underwent 50 minutes of coronary occlusion; the study was completed in 33 pigs. After reperfusion, allogeneic ATMSCs or culture medium (vehicle) were intracoronarily administered. Follow-ups were performed at short (2 days after acute myocardial infarction vehicle-treated, n=10; ATMSCs-treated, n=9) or long term (60 days after acute myocardial infarction vehicle-treated, n=7; ATMSCs-treated, n=7). At short term, infarcted myocardium analysis showed reduced apoptosis in the ATMSCs-treated animals (48.6±6% versus 55.9±5.7% in vehicle; P =0.017); enhancement of the reparative process with up-regulated vascular endothelial growth factor, granulocyte macrophage colony-stimulating factor, and stromal-derived factor-1α gene expression; and increased M2 macrophages (67.2±10% versus 54.7±10.2% in vehicle; P =0.016). In long-term groups, increase in myocardial perfusion at the anterior infarct border was observed both on day-7 and day-60 cardiac magnetic resonance studies in ATMSCs-treated animals, compared to vehicle (87.9±28.7 versus 57.4±17.7 mL/min per gram at 7 days; P =0.034 and 99±22.6 versus 43.3±14.7 22.6 mL/min per gram at 60 days; P =0.0001, respectively). At day 60, higher vascular density was detected at the border zone in the ATMSCs-treated animals (118±18 versus 92.4±24.3 vessels/mm 2 in vehicle; P =0.045). Cardiac magnetic resonance-measured left ventricular ejection fraction of left ventricular volumes was not different between groups at any time point. In this porcine acute myocardial infarction model, allogeneic ATMSCs-based therapy was associated with increased cardioprotective and reparative

  4. An open-source framework of neural networks for diagnosis of coronary artery disease from myocardial perfusion SPECT.

    Science.gov (United States)

    Guner, Levent A; Karabacak, Nese Ilgin; Akdemir, Ozgur U; Karagoz, Pinar Senkul; Kocaman, Sinan A; Cengel, Atiye; Unlu, Mustafa

    2010-06-01

    The purpose of this study is to develop and analyze an open-source artificial intelligence program built on artificial neural networks that can participate in and support the decision making of nuclear medicine physicians in detecting coronary artery disease from myocardial perfusion SPECT (MPS). Two hundred and forty-three patients, who had MPS and coronary angiography within three months, were selected to train neural networks. Six nuclear medicine residents, one experienced nuclear medicine physician, and neural networks evaluated images of 65 patients for presence of coronary artery stenosis. Area under the curve (AUC) of receiver operating characteristics analysis for networks and expert was .74 and .84, respectively. The AUC of the other physicians ranged from .67 to .80. There were no significant differences between expert, neural networks, and standard quantitative values, summed stress score and total stress defect extent. The open-source neural networks developed in this study may provide a framework for further testing, development, and integration of artificial intelligence into nuclear cardiology environment.

  5. Strategies Affording Prevascularized Cell-Based Constructs for Myocardial Tissue Engineering

    Directory of Open Access Journals (Sweden)

    Claudio Muscari

    2014-01-01

    Full Text Available The production of a functional cardiac tissue to be transplanted in the injured area of the infarcted myocardium represents a challenge for regenerative medicine. Most cell-based grafts are unviable because of inadequate perfusion; therefore, prevascularization might be a suitable approach for myocardial tissue engineering. To this aim, cells with a differentiation potential towards vascular and cardiac muscle phenotypes have been cocultured in 2D or 3D appropriate scaffolds. In addition to these basic approaches, more sophisticated strategies have been followed employing mixed-cell sheets, microvascular modules, and inosculation from vascular explants. Technologies exerting spatial control of vascular cells, such as topographical surface roughening and ordered patterning, represent other ways to drive scaffold vascularization. Finally, microfluidic devices and bioreactors exerting mechanical stress have also been employed for high-throughput scaling-up production in order to accelerate muscle differentiation and speeding the endothelialization process. Future research should address issues such as how to optimize cells, biomaterials, and biochemical components to improve the vascular integration of the construct within the cardiac wall, satisfying the metabolic and functional needs of the myocardial tissue.

  6. Transplantation of mesenchymal stem cells overexpressing IL10 attenuates cardiac impairments in rats with myocardial infarction.

    Science.gov (United States)

    Meng, Xin; Li, Jianping; Yu, Ming; Yang, Jian; Zheng, Minjuan; Zhang, Jinzhou; Sun, Chao; Liang, Hongliang; Liu, Liwen

    2018-01-01

    Mesenchymal stem cell (MSC) has been well known to exert therapeutic potential for patients with myocardial infarction (MI). In addition, interleukin-10 (IL10) could attenuate MI through suppressing inflammation. Thus, the combination of MSC implantation with IL10 delivery may extend health benefits to ameliorate cardiac injury after MI. Here we established overexpression of IL10 in bone marrow-derived MSC through adenoviral transduction. Cell viability, apoptosis, and IL10 secretion under ischemic challenge in vitro were examined. In addition, MSC was transplanted into the injured hearts in a rat model of MI. Four weeks after the MI induction, MI, cardiac functions, apoptotic cells, and inflammation cytokines were assessed. In response to in vitro oxygen-glucose deprivation (OGD), IL10 overexpression in MSC (Ad.IL10-MSC) enhanced cell viability, decreased apoptosis, and increased IL10 secretion. Consistently, the implantation of Ad.IL10-MSCs into MI animals resulted in more reductions in myocardial infarct size, cardiac impairment, and cell apoptosis, compared to the individual treatments of either MSC or IL10 administration. Moreover, the attenuation of both systemic and local inflammations was most prominent for Ad.IL10-MSC treatment. IL10 overexpression and MSC may exert a synergistic anti-inflammatory effect to alleviate cardiac injury after MI. © 2017 Wiley Periodicals, Inc.

  7. Enhancement of myocardial regeneration through genetic engineering of cardiac progenitor cells expressing Pim-1 kinase.

    Science.gov (United States)

    Fischer, Kimberlee M; Cottage, Christopher T; Wu, Weitao; Din, Shabana; Gude, Natalie A; Avitabile, Daniele; Quijada, Pearl; Collins, Brett L; Fransioli, Jenna; Sussman, Mark A

    2009-11-24

    Despite numerous studies demonstrating the efficacy of cellular adoptive transfer for therapeutic myocardial regeneration, problems remain for donated cells with regard to survival, persistence, engraftment, and long-term benefits. This study redresses these concerns by enhancing the regenerative potential of adoptively transferred cardiac progenitor cells (CPCs) via genetic engineering to overexpress Pim-1, a cardioprotective kinase that enhances cell survival and proliferation. Intramyocardial injections of CPCs overexpressing Pim-1 were given to infarcted female mice. Animals were monitored over 4, 12, and 32 weeks to assess cardiac function and engraftment of Pim-1 CPCs with echocardiography, in vivo hemodynamics, and confocal imagery. CPCs overexpressing Pim-1 showed increased proliferation and expression of markers consistent with cardiogenic lineage commitment after dexamethasone exposure in vitro. Animals that received CPCs overexpressing Pim-1 also produced greater levels of cellular engraftment, persistence, and functional improvement relative to control CPCs up to 32 weeks after delivery. Salutary effects include reduction of infarct size, greater number of c-kit(+) cells, and increased vasculature in the damaged region. Myocardial repair is significantly enhanced by genetic engineering of CPCs with Pim-1 kinase. Ex vivo gene delivery to enhance cellular survival, proliferation, and regeneration may overcome current limitations of stem cell-based therapeutic approaches.

  8. Small cell networks deployment, management, and optimization

    CERN Document Server

    Claussen, Holger; Ho, Lester; Razavi, Rouzbeh; Kucera, Stepan

    2018-01-01

    Small Cell Networks: Deployment, Management, and Optimization addresses key problems of the cellular network evolution towards HetNets. It focuses on the latest developments in heterogeneous and small cell networks, as well as their deployment, operation, and maintenance. It also covers the full spectrum of the topic, from academic, research, and business to the practice of HetNets in a coherent manner. Additionally, it provides complete and practical guidelines to vendors and operators interested in deploying small cells. The first comprehensive book written by well-known researchers and engineers from Nokia Bell Labs, Small Cell Networks begins with an introduction to the subject--offering chapters on capacity scaling and key requirements of future networks. It then moves on to sections on coverage and capacity optimization, and interference management. From there, the book covers mobility management, energy efficiency, and small cell deployment, ending with a section devoted to future trends and applicat...

  9. Stem Cell Therapy in Acute Myocardial Infarction: A Pot of Gold or Pandora's Box

    Directory of Open Access Journals (Sweden)

    V. K. Shah

    2011-01-01

    Full Text Available Stem cell therapy for conditions characterized by myocyte loss in myocardial infarction and heart failure is intuitively appealing. Stem cells from various sources, including heart itself in preclinical and animal studies, have shown the potential to improve the function of ventricular muscle after ischaemic injury. The clinical experience from worldwide studies have indicated the safety profile but with modest benefits. The predominant mechanisms of transplanted cells for improving cardiac function have pointed towards paracrine effects rather than transdifferentiation into cardiomyocytes. Thus, further investigations should be encouraged towards bench side and bedside to resolve various issues for ensuring the correct type and dosing of cells, time, and method of delivery and identify correct mechanism of functional improvement. An interdisciplinary effort at the scientific, clinical, and the government front will bring successful realization of this therapy for healing the heart and may convert what seems now a Pandora's Box into a Pot of Gold.

  10. Engineered myocardial tissues constructed in vivo using cardiomyocyte-like cells derived from bone marrow mesenchymal stem cells in rats

    Directory of Open Access Journals (Sweden)

    Xing Yujie

    2012-01-01

    Full Text Available Abstract Background To explore the feasibility of constructing engineered myocardial tissues (EMTs in vivo, using polylactic acid -co-glycolic acid (PLGA for scaffold and cardiomyocyte-like cells derived from bone marrow mesenchymal stem cells (BMMSCs for seeded cells. Methods BMMSCs were isolated from femur and tibia of Sprague-Dawley (SD rats by density-gradient centrifugation. The third passage cells were treated with 10 μmol/L 5-azacytidine (5-aza and 0.1 μmol/L angiotensin II (Ang II for 24 h, followed by culturing in complete medium for 3 weeks to differentiated into cardiomyocyte-like cells. The cardiomyocyte-like cells were seeded into PLGA scaffolds to form the grafts. The grafts were cultured in the incubator for three days and then implanted into the peritoneal cavity of SD rats. Four weeks later, routine hematoxylin-eosin (HE staining, immunohistochemical staining for myocardium-specific cardiac troponin I (cTnI, scanning electron microscopy and transmission electron microscopy were used to analyze the morphology and microconstruction of the EMTs in host rats. Results HE staining showed that the cardiomyocyte-like cells distributed equally in the PLGA scaffold, and the nuclei arranged in the spindle shape. Immunohistochemical staining revealed that majority of engrafted cells in the PLGA -Cardiomyocyte-like cells group were positive for cTnI. Scanning electron microscopy showed that the inoculated cells well attached to PLGA and grew in 3 dimensions in construct. Transmission electron microscopy showed that the EMTs contained well arranged myofilaments paralleled to the longitudinal cell axis, the cells were rich in endoplasmic reticulum and mitochondria, while desmosomes, gap junction and Z line-like substances were also can be observed as well within the engrafted cells. Conclusion We have developed an in vivo method to construct engineered myocardial tissue. The in vivo microenvironment helped engrafted cells/tissue survive and

  11. The core regulatory network in human cells.

    Science.gov (United States)

    Kim, Man-Sun; Kim, Dongsan; Kang, Nam Sook; Kim, Jeong-Rae

    2017-03-04

    In order to discover the common characteristics of various cell types in the human body, many researches have been conducted to find the set of genes commonly expressed in various cell types and tissues. However, the functional characteristics of a cell is determined by the complex regulatory relationships among the genes rather than by expressed genes themselves. Therefore, it is more important to identify and analyze a core regulatory network where all regulatory relationship between genes are active across all cell types to uncover the common features of various cell types. Here, based on hundreds of tissue-specific gene regulatory networks constructed by recent genome-wide experimental data, we constructed the core regulatory network. Interestingly, we found that the core regulatory network is organized by simple cascade and has few complex regulations such as feedback or feed-forward loops. Moreover, we discovered that the regulatory links from genes in the core regulatory network to genes in the peripheral regulatory network are much more abundant than the reverse direction links. These results suggest that the core regulatory network locates at the top of regulatory network and plays a role as a 'hub' in terms of information flow, and the information that is common to all cells can be modified to achieve the tissue-specific characteristics through various types of feedback and feed-forward loops in the peripheral regulatory networks. We also found that the genes in the core regulatory network are evolutionary conserved, essential and non-disease, non-druggable genes compared to the peripheral genes. Overall, our study provides an insight into how all human cells share a common function and generate tissue-specific functional traits by transmitting and processing information through regulatory network. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Myocardial Bridge

    Science.gov (United States)

    ... Sudden Cardiac Arrest Valve Disease Vulnerable Plaque Myocardial Bridge Related terms: myocardium, coronary arteries, myocardial ischemia Your ... surface of the heart. What is a myocardial bridge? A myocardial bridge is a band of heart ...

  13. Autologous Mesenchymal Stem Cells Show More Benefit on Systolic Function Compared to Bone Marrow Mononuclear Cells in a Porcine Model of Chronic Myocardial Infarction

    NARCIS (Netherlands)

    van der Spoel, T. I G; Gathier, W. A.; Koudstaal, S.; van Slochteren, F.; Of Lorkeers, S. Jansen; Sluijter, J. P G; Hoefer, I. E.|info:eu-repo/dai/nl/267105649; Steendijk, P.; Cramer, M. J M|info:eu-repo/dai/nl/155240706; Doevendans, P. A.|info:eu-repo/dai/nl/164248366; van Belle, E.; Chamuleau, S. A J|info:eu-repo/dai/nl/236454161

    2015-01-01

    Cardiac cell therapy is a strategy to treat patients with chronic myocardial infarction (MI). No consensus exists regarding the optimal cell type. First, a comparison between autologous bone marrow-derived mononuclear cells (BMMNC) and mesenchymal stem cells (MSC) on therapeutic efficacy after MI

  14. Effects of adipose tissue-derived stem cell therapy after myocardial infarction: impact of the route of administration.

    Science.gov (United States)

    Rigol, Montserrat; Solanes, Núria; Farré, Jordi; Roura, Santiago; Roqué, Mercè; Berruezo, Antonio; Bellera, Neus; Novensà, Laura; Tamborero, David; Prat-Vidal, Cristina; Huzman, M A Angeles; Batlle, Montserrat; Hoefsloot, Margo; Sitges, Marta; Ramírez, José; Dantas, Ana Paula; Merino, Anna; Sanz, Ginés; Brugada, Josep; Bayés-Genís, Antoni; Heras, Magda

    2010-04-01

    Cell-based therapies offer a promising approach to reducing the short-term mortality rate associated with heart failure after a myocardial infarction. The aim of the study was to analyze histological and functional effects of adipose tissue-derived stem cells (ADSCs) after myocardial infarction and compare 2 types of administration pathways. ADSCs from 28 pigs were labeled by transfection. Animals that survived myocardial infarction (n = 19) received: intracoronary culture media (n = 4); intracoronary ADSCs (n = 5); transendocardial culture media (n = 4); or transendocardial ADSCs (n = 6). At 3 weeks' follow-up, intracoronary and transendocardial administration of ADSCs resulted in similar rates of engrafted cells (0.85 [0.19-1.97] versus 2 [1-2] labeled cells/cm(2), respectively; P = NS) and some of those cells expressed smooth muscle cell markers. The intracoronary administration of ADSCs was more effective in increasing the number of small vessels than transendocardial administration (223 +/- 40 versus 168 +/- 35 vessels/mm(2); P < .05). Ejection fraction was not modified by stem cell therapy. This is the first study to compare intracoronary and transendocardial administration of autologous ADSCs in a porcine model of myocardial infarction. Both pathways of ADSCs delivery are feasible, producing a similar number of engrafted and differentiated cells, although intracoronary administration was more effective in increasing neovascularization. (c) 2010 Elsevier Inc. All rights reserved.

  15. Effect of exogenous apelin-13 on cardiac stem cell mobilization in rats with myocardial infarction

    Directory of Open Access Journals (Sweden)

    Nan ZHENG

    2013-11-01

    0.39±0.08 vs 0.70±0.08, P<0.05; mRNA level: C-kit 2.89±1.89 vs 18.77±14.19, Flk1 2.14±0.95 vs 4.59±0.92, Sca1 4.32±2.44 vs 29.39±11.90, P<0.05, and there was no obvious expression of C-kit, Flk1 or Sca1 protein in sham-operated group. Conclusion Exogenous apelin-13 protein has protective effect on rats against myocardial infarction, which is closely related to stimulating the proliferation of endogenous cardiac stem cells. DOI: 10.11855/j.issn.0577-7402.2013.10.004

  16. Development of Bioactive Patch for Maintenance of Implanted Cells at the Myocardial Infarcted Site

    Directory of Open Access Journals (Sweden)

    C. Castells-Sala

    2015-01-01

    Full Text Available Ischemia produced as a result of myocardial infarction might cause moderate or severe tissue death. Studies under development propose grafting stem cells into the affected area and we hypothesize that this mechanism could be enhanced by the application of a “bioactive implant.” The implant herein proposed consists of a thin porous elastomeric membrane, filled with self-assembling nanofibers and human subcutaneous adipose tissue derived progenitor cells. We describe the development and characterization of two elastomeric membranes: poly(ethyl acrylate (PEA and poly(caprolactone 2-(methacryloyloxyethyl ester (PCLMA. Both are a good material support to deliver cells within a soft self-assembling peptide and are elastic enough to withstand the stresses arising from the heartbeat. Both developed composites (PEA and PCLMA, combined with self-assembling peptide equally facilitate the propagation of electrical pulses and maintain their genetic profile of the seeded cells. Preliminary studies with small animal models suggest that, at short times, the bioimplant shows good adhesion with the myocardium. After three days cells loaded in the patch remain alive at the implanted site. We propose that the bioactive patch (elastomeric membranes with self-assembling peptide and cells could increase the efficacy of future cardiac cell therapy by improving cell immobilization and survival at the affected site.

  17. Epicardial delivery of VEGF and cardiac stem cells guided by 3-dimensional PLLA mat enhancing cardiac regeneration and angiogenesis in acute myocardial infarction.

    Science.gov (United States)

    Chung, Hye-Jin; Kim, Jong-Tae; Kim, Hee-Jung; Kyung, Hei-Won; Katila, Pramila; Lee, Jeong-Han; Yang, Tae-Hyun; Yang, Young-Il; Lee, Seung-Jin

    2015-05-10

    Congestive heart failure is mostly resulted in a consequence of the limited myocardial regeneration capacity after acute myocardial infarction. Targeted delivery of proangiogenic factors and/or stem cells to the ischemic myocardium is a promising strategy for enhancing their local and sustained therapeutic effects. Herein, we designed an epicardial delivery system of vascular endothelial growth factor (VEGF) and cardiac stem cells (CSCs) using poly(l-lactic acid) (PLLA) mat applied to the acutely infarcted myocardium. The fibrous VEGF-loaded PLLA mat was fabricated by an electrospinning method using PLLA solution emulsified VEGF. This mat not only allowed for sustained release of VEGF for 4weeks but boosted migration and proliferation of both endothelial cells and CSCs in vitro. Furthermore, sustained release of VEGF showed a positive effect on in vitro capillary-like network formation of endothelial cells compared with bolus treatment of VEGF. PLLA mat provided a permissive 3-dimensional (3D) substratum that led to spontaneous cardiomyogenic differentiation of CSCs in vitro. Notably, sustained stimulation by VEGF-loaded PLLA mat resulted in a substantial increase in the expression of proangiogenic mRNAs of CSCs in vitro. The epicardially implanted VEGF-loaded PLLA mat showed modest effects on angiogenesis and cardiomyogenesis in the acutely infarcted hearts. However, co-implantation of VEGF and CSCs using the PLLA mat showed meaningful therapeutic effects on angiogenesis and cardiomyogenesis compared with controls, leading to reduced cardiac remodeling and enhanced global cardiac function. Collectively, the PLLA mat allowed a smart cargo that enabled the sustained release of VEGF and the delivery of CSCs, thereby synergistically inducing angiogenesis and cardiomyogenesis in acute myocardial infarction. Copyright © 2015 Elsevier B.V. All rights reserved.

  18. [The RUTA project (Registro UTIC Triveneto ANMCO). An e-network for the coronary care units for acute myocardial infarction].

    Science.gov (United States)

    Di Chiara, Antonio; Zonzin, Pietro; Pavoni, Daisy; Fioretti, Paolo Maria

    2003-06-01

    In the era of evidence-based medicine, the monitoring of the adherence to the guidelines is fundamental, in order to verify the diagnostic and therapeutic processes. Informatic paperless databases allow a higher data quality, lower costs and timely analysis with overall advantages over the traditional surveys. The RUTA project (acronym of Triveneto Registry of ANMCO CCUs) was designed in 1999, aiming at creating an informatic network among the coronary care units of a large Italian region, for a permanent survey of patients admitted for acute myocardial infarction. Information ranges from the pre-hospital phase to discharge, including all relevant clinical and management variables. The database uses DBMS Personal Oracle and Power-Builder as user interface, on Windows platform. Anonymous data are sent to a central server.

  19. Intracoronary and retrograde coronary venous myocardial delivery of adipose-derived stem cells in swine infarction lead to transient myocardial trapping with predominant pulmonary redistribution.

    Science.gov (United States)

    Hong, Soon Jun; Hou, Dongming; Brinton, Todd J; Johnstone, Brian; Feng, Dongni; Rogers, Pamela; Fearon, William F; Yock, Paul; March, Keith L

    2014-01-01

    To examine the comparative fate of adipose-derived stem cells (ASCs) as well as their impact on coronary microcirculation following either retrograde coronary venous (RCV) or arterial delivery. Local delivery of ASCs to the heart has been proposed as a practical approach to limiting the extent of myocardial infarction. Mouse models of mesenchymal stem cell effects on the heart have also demonstrated significant benefits from systemic (intravenous) delivery, prompting a question about the advantage of local delivery. There has been no study addressing the extent of myocardial vs. systemic disposition of ASCs in large animal models following local delivery to the myocardium. In an initial experiment, dose-dependent effects of ASC delivery on coronary circulation in normal swine were evaluated to establish a tolerable ASC dosing range for intracoronary (IC) delivery. In a set of subsequent experiments, an anterior acute myocardial infarction (AMI) was created by balloon occlusion of the proximal left anterior descending (LAD) artery, followed by either IC or RCV infusion of 10(7) (111)Indium-labeled autologous ASCs 6 days following AMI. Indices of microcirculatory resistance (IMR) and coronary flow reserve (CFR) were measured before sacrifices to collect tissues for analysis at 1 or 24 hr after cell delivery. IC delivery of porcine ASCs to normal myocardium was well tolerated up to a cumulative dose of 14 × 10(6) cells (approximately 0.5 × 10(6) cells/kg). There was evidence suggesting microcirculatory trapping of ASC: at unit doses of 50 × 10(6) ASCs, IMR and CFR were found to be persistently altered in the target LAD distribution at 7 days following delivery, whereas at 10 × 10(6) ASCs, only CFR was altered. In the context of recent MI, a significantly higher percentage of ASCs was retained at 1 hr with IC delivery compared with RCV delivery (57.2 ± 12.7% vs. 17.9 ± 1.6%, P = 0.037) but this initial difference was not apparent at 24 hr (22.6 ± 5.5% vs. 18.7

  20. Myocardial regeneration by activation of multipotent cardiac stem cells in ischemic heart failure

    Science.gov (United States)

    Urbanek, Konrad; Torella, Daniele; Sheikh, Farooq; de Angelis, Antonella; Nurzynska, Daria; Silvestri, Furio; Beltrami, C. Alberto; Bussani, Rossana; Beltrami, Antonio P.; Quaini, Federico; Bolli, Roberto; Leri, Annarosa; Kajstura, Jan; Anversa, Piero

    2005-06-01

    In this study, we tested whether the human heart possesses a cardiac stem cell (CSC) pool that promotes regeneration after infarction. For this purpose, CSC growth and senescence were measured in 20 hearts with acute infarcts, 20 hearts with end-stage postinfarction cardiomyopathy, and 12 control hearts. CSC number increased markedly in acute and, to a lesser extent, in chronic infarcts. CSC growth correlated with the increase in telomerase-competent dividing CSCs from 1.5% in controls to 28% in acute infarcts and 14% in chronic infarcts. The CSC mitotic index increased 29-fold in acute and 14-fold in chronic infarcts. CSCs committed to the myocyte, smooth muscle, and endothelial cell lineages increased 85-fold in acute infarcts and 25-fold in chronic infarcts. However, p16INK4a-p53-positive senescent CSCs also increased and were 10%, 18%, and 40% in controls, acute infarcts, and chronic infarcts, respectively. Old CSCs had short telomeres and apoptosis involved 0.3%, 3.8%, and 9.6% of CSCs in controls, acute infarcts, and chronic infarcts, respectively. These variables reduced the number of functionally competent CSCs from 26,000/cm3 of viable myocardium in acute to 7,000/cm3 in chronic infarcts, respectively. In seven acute infarcts, foci of spontaneous myocardial regeneration that did not involve cell fusion were identified. In conclusion, the human heart possesses a CSC compartment, and CSC activation occurs in response to ischemic injury. The loss of functionally competent CSCs in chronic ischemic cardiomyopathy may underlie the progressive functional deterioration and the onset of terminal failure. cardiac progenitor cells | human heart | myocardial infarction

  1. eNOS overexpressing bone marrow cells are safe and effective in a porcine model of myocardial regeneration following acute myocardial infarction.

    Science.gov (United States)

    Ward, Michael R; Connelly, Kim A; Vijayaraghavan, Ram; Vaags, Andrea K; Graham, John J; Foltz, Warren; Hough, Margaret R; Stewart, Duncan J; Dick, Alexander

    2013-12-01

    Cell therapy has been shown to be effective in improving LV function postmyocardial infarction (MI). We hypothesized that eNOS-transfected bone marrow cells (BMCs) are safe in a swine model of myocardial infarction (MI). We also hypothesized that endothelial nitric oxide synthase (eNOS) transfection would enhance cell function, as assessed by myocardial functional recovery post-MI. Fifteen female Yorkshire pigs underwent bone marrow aspiration and creation of MI. Bone marrow cells were cultured for 7 days, and each pig received either autologous BMCs transiently transfected with eNOS plasmid (eNOS-BMC, n = 5), nontransfected BMCs (nt-BMC, n = 4), or phosphate-buffered saline (PBS) control (n = 6). Cardiac MRI was performed at baseline (1 week post-MI) and 6 weeks post-MI. There was no difference in safety outcomes between groups. Absolute left ventricular ejection fraction (LVEF) at 6 weeks showed a trend toward improvement in both cell therapy groups compared with baseline but worsened in the PBS control group. The absolute improvement in LVEF was significantly greater in both cell therapy groups compared with PBS control. Infarct mass was significantly lower in the eNOS-BMC group between baseline and 6 weeks, but the absolute change in infarct mass was not different between groups. Finally, there was a trend toward reduced LV mass in the eNOS-BMC group. Bone marrow cell delivery, with and without eNOS overexpression, is safe and leads to improvement in LVEF when administered in the coronary circulation 7 days following acute MI in swine. Transfection of healthy BMCs with eNOS resulted in some improvement in left ventricular remodeling. Further study is warranted in a preclinical model that approximates the impact of cardiovascular risk factors on BMC function. © 2013 John Wiley & Sons Ltd.

  2. Atorvastatin treatment improves effects of implanted mesenchymal stem cells: meta-analysis of animal models with acute myocardial infarction.

    Science.gov (United States)

    Dai, Guo; Xu, Qing; Luo, Rong; Gao, Jianfang; Chen, Hui; Deng, Yun; Li, Yongqing; Wang, Yuequn; Yuan, Wuzhou; Wu, Xiushan

    2015-12-14

    Previous studies reported that Atorvastatin (ATOR) can improve the efficacy of Mesenchymal stem cells (MSCs) transplantation after acute myocardial infarction (AMI). However, the results of those studies were inconsistent. To clarify the beneficial effects of atorvastatin added to the cell therapy with MSCs in animal model of acute myocardial infarction (AMI), we performed a systematic review and meta-analysis of case-control studies. Searches were performed using the PubMed database, the Excerpta Medica Database (Embase), the Science Citation Index, the China National Knowledge Information database, the Wanfang database, and the Chinese Scientific and Technological Journal Database (VIP database). The search term included "Atorvastatin (or Ator)", "Mesenchymal Stem Cells (or Mesenchymal Stem Cell or MSC or MSCs)" and "Acute Myocardial Infarction (or Myocardial Infarction or AMI or MI)". The endpoints were the left ventricular ejection fraction (LVEF) in animal model with AMI. In total, 5 studies were included in the meta-analysis. Pooled analysis indicated a significant LVEF difference at 4 weeks follow-up between MSCs + ATOR combine group and MSCs alone group (95 % CI, 9.09-13.62 %; P 0.05) and inconsistency (I(2): 22 %). Atorvastatin can enhance the existing effects of MSCs transplantation, and this combinational therapy is a superior cell/pharmacological therapeutic approach that merits future preclinical and clinical studies.

  3. MicroRNA and transcription factor mediated regulatory network analysis reveals critical regulators and regulatory modules in myocardial infarction.

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    Guangde Zhang

    Full Text Available Myocardial infarction (MI is a severe coronary artery disease and a leading cause of mortality and morbidity worldwide. However, the molecular mechanisms of MI have yet to be fully elucidated. In this study, we compiled MI-related genes, MI-related microRNAs (miRNAs and known human transcription factors (TFs, and we then identified 1,232 feed-forward loops (FFLs among these miRNAs, TFs and their co-regulated target genes through integrating target prediction. By merging these FFLs, the first miRNA and TF mediated regulatory network for MI was constructed, from which four regulators (SP1, ESR1, miR-21-5p and miR-155-5p and three regulatory modules that might play crucial roles in MI were then identified. Furthermore, based on the miRNA and TF mediated regulatory network and literature survey, we proposed a pathway model for miR-21-5p, the miR-29 family and SP1 to demonstrate their potential co-regulatory mechanisms in cardiac fibrosis, apoptosis and angiogenesis. The majority of the regulatory relations in the model were confirmed by previous studies, which demonstrated the reliability and validity of this miRNA and TF mediated regulatory network. Our study will aid in deciphering the complex regulatory mechanisms involved in MI and provide putative therapeutic targets for MI.

  4. [Effects of moxibustion with seed-sized moxa cone on apoptosis of myocardial cells after sport fatigue in mice].

    Science.gov (United States)

    Xu, Huiqian; Hu, Yin; Gu, Yihuang; Zhang, Hongru

    2015-03-01

    To observe the effects of moxibustion on factors related with apoptosis of myocardial cells after sports fatigue in mice as well as the relationship among histone acetyltransferases p300 (p300), CREB binding protein (CBP) and cell apoptosis to discuss the role of p300 and CBP in moxibustion against apoptosis of myocardial cells. Sixty clean-grade male Kunming mice were randomly divided into a control group, a sport group and a moxibustion group, 20 cases in each one. Mice in all group received identical feeding environment. Mice in the control group did not received sport nor moxibustion; mice in the sport group and moxibustion group received non-weight swimming training which lasted from 30 min per day to 90 min per day gradually for 21 days; 1 h after swimming training, mice in the moxibustion group received moxibustion with seed-sized moxa cone at "Zusanli" (ST 36) and "Guanyuan" (CV 4), 5 cones at each acupoint, once a day for 21 days. 24 h after the final swimming training, cardiac muscle tissue was collected to test factor associated suicide (Fas), B cell lymphoma/lewkmia-2 (Bcl-2) by immunohistochemical method and expression of p300 and CBP. Compared with the control group, the apoptosis rate of myocardial cells in the sport group was significantly increased (Psport group, the apoptosis rate of myocardial cells in the moxibustion group was significantly reduced (Psports fatigue in mice to inhibit the starting of apoptotic process, therefore reducing the apoptosis of myocardial cells after heavy exercise and protecting heart function.

  5. Human cardiac extracellular matrix supports myocardial lineage commitment of pluripotent stem cells.

    Science.gov (United States)

    Oberwallner, Barbara; Brodarac, Andreja; Anić, Petra; Šarić, Tomo; Wassilew, Katharina; Neef, Klaus; Choi, Yeong-Hoon; Stamm, Christof

    2015-03-01

    Cross-talk between organ-specific extracellular matrix (ECM) and stem cells is often assumed but has not been directly demonstrated. We developed a protocol for the preparation of human cardiac ECM (cECM) and studied whether cECM has effects on pluripotent stem cell differentiation that may be useful for future cardiac regeneration strategies in patients with end-stage heart failure. Of note, 0.3 mm-thick cECM slices were prepared from samples of myocardium from patients with end-stage non-ischaemic dilated cardiomyopathy, using a three-step protocol involving hypotonic lysis buffer, sodium dodecyl sulphate (SDS) and foetal bovine serum (FBS). Murine embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and mesenchymal stromal cells (MSCs) were seeded and grown in standard culture, on cECM or on non-specific ECM preparations (Matrigel® or Geltrex®). Cell attachment, apoptosis induction (Caspase 3/7 activity) and metabolic activity (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium conversion) were followed. Transcriptional activation of genes involved in pluripotency; early and late myocardial development; and endothelial, ectodermal or endodermal commitment were monitored by quantitative real-time polymerase chain reaction (rtPCR). Protein expression of selected markers was confirmed by immunohistology. cECM supported the proliferation of ESCs and iPSCs, and Caspase 3/7 activity was significantly lower compared with standard culture. Cardiac lineage commitment was favoured when ESCs or iPSCs were grown on cECM, as evidenced by the significantly increased mRNA expression of cardiac alpha myosin heavy polypeptide 6 (Myh6), cardiac troponin T2 (Tnnt2) and NK2 homeobox 5 (Nkx2.5) as well as positive immunohistology for cardiac troponin T and heavy-chain cardiac myosin protein. In contrast, Matrigel or Geltrex did not induce cardiac-specific markers. MSCs showed no evidence of cardiomyocyte differentiation. Human

  6. Strategy to prime the host and cells to augment therapeutic efficacy of progenitor cells for patients with myocardial infarction

    Directory of Open Access Journals (Sweden)

    Jeehoon Kang

    2016-11-01

    Full Text Available Cell therapy in myocardial infarction (MI is an innovative strategy that is regarded as a rescue therapy to repair the damaged myocardium and to promote neovascularization for the ischemic border zone. Among several stem cell sources for this purpose, autologous progenitors from bone marrow or peripheral blood would be the most feasible and safest cell-source. Despite the theoretical benefit of cell therapy, this method is not widely adopted in the actual clinical practice due to its low therapeutic efficacy. Various methods have been used to augment the efficacy of cell therapy in MI, such as using different source of progenitors, genetic manipulation of cells, or priming of the cells or hosts (patients with agents. Among these methods, the strategy to augment the therapeutic efficacy of the autologous peripheral blood mononuclear cells by priming agents may be the most feasible and the safest method that can be applied directly to the clinic. In this review, we will discuss the current status and future directions of priming peripheral blood mononuclear cells or patients, as for cell therapy of MI.

  7. Bone Marrow Mononuclear Cell Transplantation Restores Inflammatory Balance of Cytokines after ST Segment Elevation Myocardial Infarction.

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    Kirsi Alestalo

    Full Text Available Acute myocardial infarction (AMI launches an inflammatory response and a repair process to compensate cardiac function. During this process, the balance between proinflammatory and anti-inflammatory cytokines is important for optimal cardiac repair. Stem cell transplantation after AMI improves tissue repair and increases the ventricular ejection fraction. Here, we studied in detail the acute effect of bone marrow mononuclear cell (BMMNC transplantation on proinflammatory and anti-inflammatory cytokines in patients with ST segment elevation myocardial infarction (STEMI.Patients with STEMI treated with thrombolysis followed by percutaneous coronary intervention (PCI were randomly assigned to receive either BMMNC or saline as an intracoronary injection. Cardiac function was evaluated by left ventricle angiogram during the PCI and again after 6 months. The concentrations of 27 cytokines were measured from plasma samples up to 4 days after the PCI and the intracoronary injection.Twenty-six patients (control group, n = 12; BMMNC group, n = 14 from the previously reported FINCELL study (n = 80 were included to this study. At day 2, the change in the proinflammatory cytokines correlated with the change in the anti-inflammatory cytokines in both groups (Kendall's tau, control 0.6; BMMNC 0.7. At day 4, the correlation had completely disappeared in the control group but was preserved in the BMMNC group (Kendall's tau, control 0.3; BMMNC 0.7.BMMNC transplantation is associated with preserved balance between pro- and anti-inflammatory cytokines after STEMI in PCI-treated patients. This may partly explain the favorable effect of stem cell transplantation after AMI.

  8. Empagliflozin Limits Myocardial Infarction in Vivo and Cell Death in Vitro: Role of STAT3, Mitochondria, and Redox Aspects

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    Ioanna Andreadou

    2017-12-01

    Full Text Available Empagliflozin (EMPA, a drug approved for type 2 diabetes management, reduced cardiovascular death but is unknown if it reduces myocardial infarction. We sought to investigate: (i the effect of EMPA on myocardial function and infarct size after ischemia/reperfusion in mice fed with western diet (WD, (ii the underlying signaling pathways, (iii its effects on cell survival in rat embryonic-heart-derived cardiomyoblasts (H9C2 and endothelial cells (ECs. To facilitate the aforementioned aims, mice were initially randomized in Control and EMPA groups and were subjected to 30 min ischemia and 2 h reperfusion. EMPA reduced body weight, blood glucose levels, and mean arterial pressure. Cholesterol, triglyceride, and AGEs remained unchanged. Left ventricular fractional shortening was improved (43.97 ± 0.92 vs. 40.75 ± 0.61% and infarct size reduced (33.2 ± 0.01 vs. 17.6 ± 0.02%. In a second series of experiments, mice were subjected to the above interventions up to the 10th min of reperfusion and myocardial biopsies were obtained for assessment of the signaling cascade. STAT3 was increased in parallel with reduced levels of malondialdehyde (MDA and reduced expression of myocardial iNOS and interleukin-6. Cell viability and ATP content were increased in H9C2 and in ECs. While, STAT3 phosphorylation is known to bestow infarct sparing properties through interaction with mitochondria, we observed that EMPA did not directly alter the mitochondrial calcium retention capacity (CRC; therefore, its effect in reducing myocardial infarction is STAT3 dependent. In conclusion, EMPA improves myocardial function and reduces infarct size as well as improves redox regulation by decreasing iNOS expression and subsequently lipid peroxidation as shown by its surrogate marker MDA. The mechanisms of action implicate the activation of STAT3 anti-oxidant and anti-inflammatory properties.

  9. Cardiac Stem Cell Treatment in Myocardial Infarction : A Systematic Review and Meta-Analysis of Preclinical Studies

    NARCIS (Netherlands)

    Zwetsloot, Peter Paul; Végh, Anna M D; Jansen of Lorkeers, Sanne Johanna; van Hout, Gerardus P; Currie, Gillian L; Sena, Emily S; Gremmels, Hendrik; Buikema, Jan Willem; Goumans, Marie-Jose; Macleod, Malcolm R; Doevendans, Pieter A; Chamuleau, Steven A J; Sluijter, Joost P.G.

    2016-01-01

    RATIONALE: Cardiac stem cells (CSC) therapy has been clinically introduced for cardiac repair after myocardial infarction (MI). To date there has been no systematic overview and meta-analysis of studies using CSC therapy for MI. OBJECTIVE: Here, we used meta-analysis to establish the overall effect

  10. Effect of a stable Angiotensin-(1-7) analogue on progenitor cell recruitment and cardiovascular function post myocardial infarction

    NARCIS (Netherlands)

    Sevá Pessôa, Bruno; Becher, Peter M oritz; Van Veghel, Richard; De Vries, René; Tempel, Dennie; Sneep, Stefan; Van Beusekom, Heleen; Van Der Velden, Vincent H J; Westermann, Dirk; Danser, A. H Jan; Roks, Anton J M

    2015-01-01

    BACKGROUND: Angiotensin-(1-7) improves cardiac function and remodeling after myocardial infarction (MI). This may involve recruitment of hematopoietic progenitor cells that support angiogenesis. However, angiotensin-(1-7) is rapidly metabolized in plasma and tissue. The authors investigated in mice

  11. Intramural Purkinje cell network of sheep ventricles as the terminal pathway of conduction system.

    Science.gov (United States)

    Ryu, Shonosuke; Yamamoto, Shoji; Andersen, Clark R; Nakazawa, Kiyoshi; Miyake, Fumihiko; James, Thomas N

    2009-01-01

    To identify the anatomical basis for cardiac electrical signal conduction, particularly seeking the intramural terminals of conduction pathway within the ventricles, sheep hearts were examined compared with human hearts utilizing the characteristic morphology of Purkinje cells as a histological marker. In 15 sheep and five human autopsies of noncardiac death, prevalence of Purkinje or Purkinje-type cells were histologically examined in the atrioventricular node, its distal conduction pathway, the interventricular septum, and the right- and left-ventricular free walls. Myocardial tissue cleavages were examined in the transmural sections (along cardiac base-to-apex axis) obtained from the septum and ventricular free walls. Serial histological sections through virtually the entirety of the septum in selected sheep were used as the basis of a three-dimensional reconstruction of the conduction pathway, particularly of the intramural Purkinje cell network. Purkinje cells were found within the mural myocardium of sheep ventricles whereas no intramural Purkinje-type cell was detected within the human ventricles. In the sheep septum, every intramural Purkinje cell composed a three-dimensional network throughout the mural myocardium, which proximally connected to the subendocardial extension of the bundle branches and distally formed an occasional junction with ordinary working myocytes. The Purkinje-cell network may participate in the ventricular excitation as the terminal conduction pathway. Individual connections among the Purkinje cells contain the links of through-wall orientation which would benefit the signal conduction crossing the architectural barriers by cleavages in sheep hearts. The myocardial architectural changes found in diseased hearts could disrupt the network links including those with transmural orientation. Anat Rec, 2009. (c) 2008 Wiley-Liss, Inc.

  12. Cell Therapies for Heart Function Recovery: Focus on Myocardial Tissue Engineering and Nanotechnologies

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    Marie-Noëlle Giraud

    2012-01-01

    Full Text Available Cell therapies have gained increasing interest and developed in several approaches related to the treatment of damaged myocardium. The results of multiple clinical trials have already been reported, almost exclusively involving the direct injection of stem cells. It has, however, been postulated that the efficiency of injected cells could possibly be hindered by the mechanical trauma due to the injection and their low survival in the hostile environment. It has indeed been demonstrated that cell mortality due to the injection approaches 90%. Major issues still need to be resolved and bed-to-bench followup is paramount to foster clinical implementations. The tissue engineering approach thus constitutes an attractive alternative since it provides the opportunity to deliver a large number of cells that are already organized in an extracellular matrix. Recent laboratory reports confirmed the interest of this approach and already encouraged a few groups to investigate it in clinical studies. We discuss current knowledge regarding engineered tissue for myocardial repair or replacement and in particular the recent implementation of nanotechnological approaches.

  13. Injectable biodegradable hydrogels for embryonic stem cell transplantation: improved cardiac remodelling and function of myocardial infarction.

    Science.gov (United States)

    Wang, Haibin; Liu, Zhiqiang; Li, Dexue; Guo, Xuan; Kasper, F Kurtis; Duan, Cuimi; Zhou, Jin; Mikos, Antonios G; Wang, Changyong

    2012-06-01

    In this study, an injectable, biodegradable hydrogel composite of oligo[poly(ethylene glycol) fumarate] (OPF) was investigated as a carrier of mouse embryonic stem cells (mESCs) for the treatment of myocardial infarction (MI). The OPF hydrogels were used to encapsulate mESCs. The cell differentiation in vitro over 14 days was determined via immunohistochemical examination. Then, mESCs encapsulated in OPF hydrogels were injected into the LV wall of a rat MI model. Detailed histological analysis and echocardiography were used to determine the structural and functional consequences after 4 weeks of transplantation. With ascorbic acid induction, mESCs could differentiate into cardiomyocytes and other cell types in all three lineages in the OPF hydrogel. After transplantation, both the 24-hr cell retention and 4-week graft size were significantly greater in the OPF + ESC group than that of the PBS + ESC group (P OPF hydrogel alone significantly reduced the infarct size and collagen deposition and improved the cardiac function. The heart function and revascularization improved significantly, while the infarct size and fibrotic area decreased significantly in the OPF + ESC group compared with that of the PBS + ESC, OPF and PBS groups (P OPF + ESC group decreased most by Western blotting. Transplanted mESCs expressed cardiovascular markers. This study suggests the potential of a method for heart regeneration involving OPF hydrogels for stem cell encapsulation and transplantation. © 2011 The Authors Journal compilation © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

  14. Stem cell transplantation dose in patients with acute myocardial infarction: A meta-analysis

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    Jia-Ying Xu

    2016-06-01

    Full Text Available Objective: To evaluate whether stem cell transplantation improves global left ventricular ejection fraction (LVEF in patients with acute myocardial infarction (AMI, and to determine the appropriate stem cell therapy dose as well as the effective period after stem cell transplantation for therapy. Methods: A systematic literature search included Pubmed, MEDLINE, China National Knowledge Infrastructure (CNKI, Chinese Biomedical Literature Database (CBM, and Cochrane Evidence-Based Medicine databases. The retrieval time limit ranged from January 1990 to June 2016. We also obtained full texts through manual retrieval, interlibrary loan and document delivery service, or by contacting the authors directly. According to our inclusion and exclusion criteria, data were extracted independently by two evaluators. In case of disagreement, a joint discussion occurred and a third researcher was utilized. Data were analyzed quantitatively using Revman 5.2. Summary results are presented as the weighted mean difference (WMD with 95% confidence intervals (CIs. We collected individual trial data and conducted a meta-analysis to compare changes in global left ventricular ejection fraction (ΔLVEF after stem cell therapy. In this study, four subgroups were based on stem cell dose (≤1 × 107 cells, ≤1 × 108 cells, ≤1 × 109 cells, and ≤1 × 1010 cells and three subgroups were based on follow-up time (<6 months, 6–12 months, and ≥12 months. Results: Thirty-four studies, which included 40 randomized controlled trials, were included in this meta-analysis, and 1927 patients were evaluated. Changes in global LVEF were significantly higher in the stem cell transplantation group than in the control group (95% CI: 2.35–4.26%, P < 0.01. We found no significant differences in ΔLVEF between the bone marrow stem cells (BMCs group and control group when the dose of BMCs was ≤1

  15. Microencapsulation to reduce mechanical loss of microspheres: implications in myocardial cell therapy.

    Science.gov (United States)

    Al Kindi, Adil H; Asenjo, Juan Francisco; Ge, Yin; Chen, Guang Yong; Bhathena, Jasmine; Chiu, Ray C-J; Prakash, Satya; Shum-Tim, Dominique

    2011-02-01

    Previous regenerative studies have demonstrated massive cell losses after intramyocardial cellular delivery. Therefore, efforts at reducing mechanical losses may prove more successful in optimising cellular therapy. In this study, we hypothesized that escalating mesenchymal stem cells (MSCs) dose will not produce corresponding improvement in cardiac function due to washout of the small cells in microcirculation. Using microspheres similar in size to MSCs, that are encapsulated in alginate-poly-l-lysine-alginate (APA), we tested the hypothesis that size is an important factor in early losses. In experiment I, five groups of rats (n=9 each) underwent coronary ligation; group I had no treatment; the other groups received escalating 0.5 × 10(6), 1.5 × 10(6), 3 × 10(6) and 5 × 10(6) of MSCs each. Echocardiogram was performed at baseline, 2 days and 7 weeks after surgery. In experiment II, cell-sized microspheres (10 μm) were encapsulated in APA microcapsules. In group I (n=16), rats received bare microspheres, group II (n=16) microspheres within 200 μm microcapsules and in group III (n=16), microspheres within 400 μm microcapsules. After 20 min, hearts were quantified for the amount retained. Myocardial function did not improve further with escalating cell doses beyond an initial response at 1.5 × 10(6) cells. Encapsulated microspheres in 200 μm and 400 μm microcapsules demonstrated a fourfold increase in retention rate compared with 10 μm microspheres. We concluded that suboptimal functional improvement in this animal model starts at 1.5 × 10(6) cells and does not respond to escalating cell doses. Improving mechanical retention is possible by increasing the size of the injectate. Microencapsulation could be used to encapsulate donor cells and facilitate functional improvement in cellular heart failure therapy. Copyright © 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

  16. Autologous bone marrow concentrate enriched in progenitor cells — An adjuvant in the treatment of acute myocardial infarction

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    Vinay Sanghi

    2016-06-01

    Full Text Available Despite advances in revascularization techniques, acute myocardial infarction (AMI still carries significant morbidity and mortality. Over the past decade, the use of regenerative medicine methodologies, and specifically bone marrow derived progenitor cell therapy has been tested in more than 35 Phase I and Phase II clinical studies demonstrating overall safety and measurable clinical benefit, 12–61 months post-treatment as evaluated by improvement in the Left Ventricular Ejection Fraction (LVEF and changes in infarct size post AMI. Recent meta-analysis on the subject highlighted several important parameters that include timing of the cell therapy post AMI, the cell dose, and the baseline LVEF on enrollment. We further postulate that the mythologies and timing for cell handling and delivery including the specific devices are essential for clinical efficacy. Addressing this we have developed a rapid 60 to 90 minute process and integrated system which is carried out in the heart catheter lab, using a combination product (U.S. Food and Drug broadly defined as the combination of co-labeled optimized “cell friendly” devices, effective cell/biological formulation and dose for harvesting, processing, verifying, and delivering an autologous dose of bone marrow progenitor/stem cells via the intracoronary artery proximal to the infarct myocardial region. The methodology has been demonstrated to be safe and feasible for autologous in vivo use and presented by our groups' earlier studies1–3 and most recently used in a Phase Ib critical limb ischemia trial of 17 subjects (NCT01472289 (manuscript under preparation. This is the first case study prior to beginning the AMIRST trial [Acute Myocardial Infarction Rapid Stem cell Therapy], specific to our proprietary combination product kit for acute myocardial infarction, and was completed under the Independent Ethics Committee and Institutional Committee for Stem Cell Research and Therapy approval (TIEC

  17. Xenotransplantation of human unrestricted somatic stem cells in a pig model of acute myocardial infarction.

    Science.gov (United States)

    Gahremanpour, Amir; Vela, Deborah; Zheng, Yi; Silva, Guilherme V; Fodor, William; Cardoso, Cristiano O; Baimbridge, Fred; Fernandes, Marlos R; Buja, L Maximilian; Perin, Emerson C

    2013-01-01

    Stem cell therapy may help restore cardiac function after acute myocardial infarction (AMI), but the optimal therapeutic cell type has not been identified. We examined the effects of CD34-/CD45- human unrestricted somatic stem cells (USSCs) in pigs (n = 30) with an AMI created by a 90-min occlusion of the left anterior descending coronary artery. Pigs were randomly assigned to receive either USSCs (302 ± 23 × 10(6) cells) or phosphate-buffered saline via 15 NOGA-guided transendocardial injections 10 days after AMI. Cyclosporine A (10 mg/kg orally, twice a day) was started in all pigs 3 days before control or cell treatment. Cardiac function was assessed by echocardiography before injection and at 4 and 8 weeks after treatment. Serum titers for pig IgG antibodies against USSCs were also measured at these time points and before AMI. Compared with control pigs, USSC-treated pigs showed no significant differences in any of the functional parameters examined. USSC-treated pigs showed variable increases in anti-USSC IgG antibody titers in the blood and chronic inflammatory infiltrates at the cell injection sites. Immunohistochemical studies of the injection sites using human anti-mitochondrial antibodies failed to detect implanted USSCs. We conclude that human USSCs did not improve cardiac function in a pig model of AMI. Cell transplantation in a xenogeneic setting may obscure the benefits of stem cell therapy. © 2013 John Wiley & Sons A/S.

  18. Mast cells regulate myofilament calcium sensitization and heart function after myocardial infarction.

    Science.gov (United States)

    Ngkelo, Anta; Richart, Adèle; Kirk, Jonathan A; Bonnin, Philippe; Vilar, Jose; Lemitre, Mathilde; Marck, Pauline; Branchereau, Maxime; Le Gall, Sylvain; Renault, Nisa; Guerin, Coralie; Ranek, Mark J; Kervadec, Anaïs; Danelli, Luca; Gautier, Gregory; Blank, Ulrich; Launay, Pierre; Camerer, Eric; Bruneval, Patrick; Menasche, Philippe; Heymes, Christophe; Luche, Elodie; Casteilla, Louis; Cousin, Béatrice; Rodewald, Hans-Reimer; Kass, David A; Silvestre, Jean-Sébastien

    2016-06-27

    Acute myocardial infarction (MI) is a severe ischemic disease responsible for heart failure and sudden death. Inflammatory cells orchestrate postischemic cardiac remodeling after MI. Studies using mice with defective mast/stem cell growth factor receptor c-Kit have suggested key roles for mast cells (MCs) in postischemic cardiac remodeling. Because c-Kit mutations affect multiple cell types of both immune and nonimmune origin, we addressed the impact of MCs on cardiac function after MI, using the c-Kit-independent MC-deficient (Cpa3(Cre/+)) mice. In response to MI, MC progenitors originated primarily from white adipose tissue, infiltrated the heart, and differentiated into mature MCs. MC deficiency led to reduced postischemic cardiac function and depressed cardiomyocyte contractility caused by myofilament Ca(2+) desensitization. This effect correlated with increased protein kinase A (PKA) activity and hyperphosphorylation of its targets, troponin I and myosin-binding protein C. MC-specific tryptase was identified to regulate PKA activity in cardiomyocytes via protease-activated receptor 2 proteolysis. This work reveals a novel function for cardiac MCs modulating cardiomyocyte contractility via alteration of PKA-regulated force-Ca(2+) interactions in response to MI. Identification of this MC-cardiomyocyte cross-talk provides new insights on the cellular and molecular mechanisms regulating the cardiac contractile machinery and a novel platform for therapeutically addressable regulators. ©2016 Ngkelo et al.

  19. Regional myocardial function after intracoronary bone marrow cell injection in reperfused anterior wall infarction - a cardiovascular magnetic resonance tagging study

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    Arnesen Harald

    2011-03-01

    Full Text Available Abstract Background Trials have brought diverse results of bone marrow stem cell treatment in necrotic myocardium. This substudy from the Autologous Stem Cell Transplantation in Acute Myocardial Infarction trial (ASTAMI explored global and regional myocardial function after intracoronary injection of autologous mononuclear bone marrow cells (mBMC in acute anterior wall myocardial infarction treated with percutaneous coronary intervention. Methods Cardiovascular magnetic resonance (CMR tagging was performed 2-3 weeks and 6 months after revascularization in 15 patients treated with intracoronary stem cell injection (mBMC group and in 13 controls without sham injection. Global and regional left ventricular (LV strain and LV twist were correlated to cine CMR and late gadolinium enhancement (LGE. Results In the control group myocardial function as measured by strain improved for the global LV (6 months: -13.1 ± 2.4 versus 2-3 weeks: -11.9 ± 3.4%, p = 0.014 and for the infarct zone (-11.8 ± 3.0 versus -9.3 ± 4.1%, p = 0.001, and significantly more than in the mBMC group (inter-group p = 0.027 for global strain, respectively p = 0.009 for infarct zone strain. LV infarct mass decreased (35.7 ± 20.4 versus 45.7 ± 29.5 g, p = 0.024, also significantly more pronounced than the mBMC group (inter-group p = 0.034. LV twist was initially low and remained unchanged irrespective of therapy. Conclusions LGE and strain findings quite similarly demonstrate subtle differences between the mBMC and control groups. Intracoronary injection of autologous mBMC did not strengthen regional or global myocardial function in this substudy. Trial registration ClinicalTrials.gov: NCT00199823

  20. N-glycans: phenotypic homology and structural differences between myocardial cells and induced pluripotent stem cell-derived cardiomyocytes.

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    Takuji Kawamura

    Full Text Available Cell surface glycans vary widely, depending on cell properties. We hypothesized that glycan expression on induced pluripotent stem cells (iPSCs might change during cardiomyogenic differentiation toward the myocardial phenotype. N-glycans were isolated from iPSCs, iPSC-derived cardiomyocytes (iPSC-CM, and original C57BL/6 mouse myocardium (Heart. Their structures were analyzed by a mapping technique based on HPLC elution times and MALDI-TOF/MS spectra. Sixty-eight different N-glycans were isolated; the structures of 60 of these N-glycans were identified. The quantity of high-mannose type (immature N-glycans on the iPSCs decreased with cardiomyogenic differentiation, but did not reach the low levels observed in the heart. We observed a similar reduction in neutral N-glycans and an increase in fucosylated or sialyl N-glycans. Some structural differences were detected between iPSC-CM and Heart. No N-glycolyl neuraminic acid (NeuGc structures were detected in iPSC-CM, whereas the heart contained numerous NeuGc structures, corresponding to the expression of cytidine monophosphate-N-acetylneuraminic acid hydroxylase. Furthermore, several glycans containing Galα1-6 Gal, rarely identified in the other cells, were detected in the iPSC-CM. The expression of N-glycan on murine iPSCs changed toward the myocardial phenotype during cardiomyogenic differentiation, leaving the structural differences of NeuGc content or Galα1-6 Gal structures. Further studies will be warranted to reveal the meaning of the difference of N-glycans between the iPSC-CM and the myocardium.

  1. Clinical trials using autologous bone marrow and peripheral blood-derived progenitor cells in patients with acute myocardial infarction.

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    Michał Tendera

    2005-12-01

    Full Text Available This paper discusses the current data concerning the results of major clinical trials using bone marrow-derived and peripheral blood-derived stem/progenitor cells in treatment of patients with acute myocardial infarction (AMI and depressed left ventricular ejection fraction. In all major trials (TOPCARE-AMI, BOOST, the primary outcome measure was increase in left ventricular systolic function (LVEF and left ventricle remodeling. The most consistent finding is the significant increase in LVEF. Some trials suggest also reduction of left ventricular remodeling. Although the absolute LVEF increase is small (6-9%, it may substantially contribute to the improvement of global LV contractility. None of the studies in AMI patients treated with intracoronary infusion of progenitor cells revealed excess risk of arrythmia, restenosis or other adverse effects attributable to the therapy. The exact mechanism of improved myocardial contractile function remains unknown, however, there are several possible explanations: therapeutic angiogenesis improving the blood supply to the infarct border zone, paracrine modulation of myocardial fibrosis and remodeling (e.g. inhibition of myocyte apoptosis and transdifferentiation of stem/progenitor cells into functional cardiomyocytes. No study showed the superiority of the particular subpopulation of autologous progenitor cells in terms of left ventricular function improvement in AMI. In fact, most of the clinical trials used the whole population of mononuclear bone marrow-derived progenitor cells, peripheral blood derived progenitor cells (endothelial progenitors.

  2. Intracoronary Transplantation of Mesenchymal Stem Cells with Overexpressed Integrin-Linked Kinase Improves Cardiac Function in Porcine Myocardial Infarction.

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    Mu, Dan; Zhang, Xin-Lin; Xie, Jun; Yuan, Hui-Hua; Wang, Kun; Huang, Wei; Li, Guan-Nan; Lu, Jian-Rong; Mao, Li-Juan; Wang, Lian; Cheng, Le; Mai, Xiao-Li; Yang, Jun; Tian, Chuan-Shuai; Kang, Li-Na; Gu, Rong; Zhu, Bin; Xu, Biao

    2016-01-11

    The effect of mesenchymal stem cell (MSCs)-based therapy on treating acute myocardial infarction (MI) is limited due to poor engraftment and limited regenerative potential. Here we engineered MSCs with integrin-linked kinase (ILK), a pleiotropic protein critically regulating cell survival, proliferation, differentiation, and angiogenesis. We firstly combined ferumoxytol with poly-L-lysine (PLL), and found this combination promisingly enabled MRI visualization of MSCs in vitro and in vivo with good safety. We provided visually direct evidence that intracoronary ILK-MSCs had substantially enhanced homing capacity to infarct myocardium in porcine following cardiac catheterization induced MI. Intracoronary transplantation of allogeneic ILK-MSCs, but not vector-MSCs, significantly enhanced global left ventricular ejection fraction (LVEF) by 7.8% compared with baseline, by 10.3% compared with vehicles, and inhibited myocardial remodeling compared with vehicles at 15-day follow-up. Compared with vector-MSCs, ILK-MSCs significantly improved regional LV contractile function, reduced scar size, fibrosis, cell apoptosis, and increased regional myocardial perfusion and cell proliferation. This preclinical study indicates that ILK-engineered MSCs might promote the clinical translation of MSC-based therapy in post-MI patients, and provides evidence that ferumoxytol labeling of cells combined with PLL is feasible in in vivo cell tracking.

  3. Assessment of functional effects using gated myocardial perfusion SPECT after mesenchymal stem cells transplantation in a porcine model of myocardial infarction

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    Heo, Young Jun; Ahn, Young Eun; Lim, Sang Yup; Song, Ho Chun; Bom, Hee Seung; Min, Joeng Jun; Jeong, Myung Ho; Cho, Jeong Gwan; Park, Jong Chun; K, Jung Chaee [School of Medicine, Chonnam National University, Gwangju (Korea, Republic of)

    2004-07-01

    Bone-marrow-derived Mesenchymal stem cells(MSCs) have shown therapeutic potential of successfully delivered to the intended site of myocardial infarction. The purpose of study is to test the feasibility and usefulness of gated myocardial perfusion SPECT(GSPECT) in the evaluation of the function and perfusion of the left ventricle(LV) after transplantation of MSCs transduced with Akt in a porcine model of myocardial infarction(MI). MSCs were separated from hematopoietic cells based on their preferential attachment to polystyrene surfaces and genetically engineered using ex-vivo myr-Akt-adenoviral gene transfer. MSCs were delivered by intracoronary injection to adult farm pigs (n=15) after MI [group I(control:n=5), media only:group II(n=5), MSCs only:group III(n=5), MSCs modified with Akt]. GSPECT with Tc-99m tetrofosmin was done before and 4 weeks after MSC transplantation. LV volume, left ventricular ejection fraction(LVEF) and area of MI were calculated from the GSPECT data by QGS. Pigs were sacrificed for immunocytochemical characterization. Mean LVEF was 44.8{+-}16.6%, 29.8{+-}7.6%, and 41.2{+-}8.3% at first (each n=5) and changed to 29.8{+-}8.5%, 39.0{+-}9.5%, and 60.1{+-}17.4% at 4 weeks after the MSC implantation in group I, II, and III, respectively. Mean MI area was 17.6{+-}9.2%, 35.0{+-}11.8%, and 24.3{+-}11.2% at first, and changed to 19.6{+-}10.1%, 27.2{+-}13.9%, and 7.4{+-}5.3% in group I, II, and III, respectively. Transplantation of {approx}107cells into the ischemic porcine myocardium in group II increased the LVEF (-14.9{+-}15.3% versus 9.0{+-}8.6%, n=5 in each, p=0.016) and decreased the area of MI (2.1{+-}1.3% versus -7.9{+-}9.0%, n=5 in each, p=0.04) compared with control group and much more different in group III in LVEF (19.2{+-}16.4%, p=0.006) and in area of MI (-16.3{+-}6.4%, p=0.037). GSPECT is useful to estimate the functional effects on repair of the injured area, remodeling, and systolic performance in infarcted hearts after the

  4. Mesenchymal Stem Cells with eNOS Over-Expression Enhance Cardiac Repair in Rats with Myocardial Infarction.

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    Chen, Leilei; Zhang, Yuan; Tao, Liangliang; Yang, Zhijian; Wang, Liansheng

    2017-02-01

    Transplantation of mesenchymal stem cells (MSCs) is a promising therapeutic option for patients with acute myocardial infarction. We show here that the ectopic overexpression of endothelial nitric oxide synthases (eNOS), an endothelial form of NOS, could enhance the ability of MSCs in treating ischemic heart damage after the occlusion of the coronary artery. Adenoviral delivery of human eNOS gene into mouse bone marrow-derived MSCs (BM-MSCs) conferred resistance to oxygen glucose deprivation (OGD)-induced cell death in vitro, and elevated the bioavailability of nitric oxide when injected into the myocardium in vivo. In a rat model of acute myocardial infarction, the transplantation of eNOS-overexpressing BM-MSCs significantly reduced myocardial infarct size, corrected hemodynamic parameters and increased capillary density. We also found that the synergistic effects were consistently better than either treatment alone. These findings reveal a positive role of elevated eNOS expression in cardiac repair, and suggest the combination of eNOS and MSC transplant therapy as a potential approach for treating myocardial infarction.

  5. Over-Expression of Catalase in Myeloid Cells Confers Acute Protection Following Myocardial Infarction

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    E. Bernadette Cabigas

    2014-05-01

    Full Text Available Cardiovascular disease is the leading cause of death in the United States and new treatment options are greatly needed. Oxidative stress is increased following myocardial infarction and levels of antioxidants decrease, causing imbalance that leads to dysfunction. Therapy involving catalase, the endogenous scavenger of hydrogen peroxide (H2O2, has been met with mixed results. When over-expressed in cardiomyocytes from birth, catalase improves function following injury. When expressed in the same cells in an inducible manner, catalase showed a time-dependent response with no acute benefit, but a chronic benefit due to altered remodeling. In myeloid cells, catalase over-expression reduced angiogenesis during hindlimb ischemia and prevented monocyte migration. In the present study, due to the large inflammatory response following infarction, we examined myeloid-specific catalase over-expression on post-infarct healing. We found a significant increase in catalase levels following infarction that led to a decrease in H2O2 levels, leading to improved acute function. This increase in function could be attributed to reduced infarct size and improved angiogenesis. Despite these initial improvements, there was no improvement in chronic function, likely due to increased fibrosis. These data combined with what has been previously shown underscore the need for temporal, cell-specific catalase delivery as a potential therapeutic option.

  6. Preliminary evaluation of treatment efficacy of umbilical cord blood-derived mesenchymal stem cell-differentiated cardiac pro-genitor cells in a myocardial injury mouse model

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    Truc Le-Buu Pham

    2015-12-01

    Full Text Available Recently, stem cell therapy has been investigated as a strategy to prevent or reverse damage to heart tissue. Although the results of cell transplantation in animal models and patients with myocardial ischemia are promising, the selection of the appropriate cell type remains an issue that requires consideration. In this study, we aimed to evaluate the effect of cardiac progenitor cell transplantation in a mouse model of myocardial ischemia. The cardiac progenitor cells used for transplantation were differentiated from umbilical cord blood mesenchymal stem cells. Animal models injected with phosphate-buffered saline (PBS and healthy mice were used as controls. Cell grafting was assessed by changes in blood pressure and histological evaluation. After 14 days of transplantation, the results demonstrated that the blood pressure of transplanted mice was stable, similar to healthy mice, whereas it fluctuated in PBS-injected mice. Histological analysis showed that heart tissue had regenerated in transplanted mice, but remained damaged in PBS-injected mice. Furthermore, trichrome staining revealed that the transplanted mice did not generate significant amount of scar tissue compared with PBS-injected control mice. In addition, the cardiac progenitor cells managed to survive and integrate with local cells in cell-injected heart tissue 14 days after transplantation. Most importantly, the transplanted cells did not exhibit tumorigenesis. In conclusion, cardiac progenitor cell transplantation produced a positive effect in a mouse model of myocardial ischemia. [Biomed Res Ther 2015; 2(12.000: 435-445

  7. Hybrid approach of ventricular assist device and autologous bone marrow stem cells implantation in end-stage ischemic heart failure enhances myocardial reperfusion

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    Khayat Andre

    2011-01-01

    Full Text Available Abstract We challenge the hypothesis of enhanced myocardial reperfusion after implanting a left ventricular assist device together with bone marrow mononuclear stem cells in patients with end-stage ischemic cardiomyopathy. Irreversible myocardial loss observed in ischemic cardiomyopathy leads to progressive cardiac remodelling and dysfunction through a complex neurohormonal cascade. New generation assist devices promote myocardial recovery only in patients with dilated or peripartum cardiomyopathy. In the setting of diffuse myocardial ischemia not amenable to revascularization, native myocardial recovery has not been observed after implantation of an assist device as destination therapy. The hybrid approach of implanting autologous bone marrow stem cells during assist device implantation may eventually improve native cardiac function, which may be associated with a better prognosis eventually ameliorating the need for subsequent heart transplantation. The aforementioned hypothesis has to be tested with well-designed prospective multicentre studies.

  8. T-cell immunity in myocardial inflammation: pathogenic role and therapeutic manipulation.

    Science.gov (United States)

    Stephenson, E; Savvatis, K; Mohiddin, S A; Marelli-Berg, F M

    2017-11-01

    T-cell-mediated immunity has been linked not only to a variety of heart diseases, including classic inflammatory diseases such as myocarditis and post-myocardial infarction (Dressler's) syndrome, but also to conditions without an obvious inflammatory component such as idiopathic dilated cardiomyopathy and hypertensive cardiomyopathy. It has been recently proposed that in all these conditions, the heart becomes the focus of T-cell-mediated autoimmune inflammation following ischaemic or infectious injury. For example, in acute myocarditis, an inflammatory disease of heart muscle, T-cell responses are thought to arise as a consequence of a viral infection. In a number of patients, persistent T-cell-mediated responses in acute viral myocarditis can lead to autoimmunity and chronic cardiac inflammation resulting in dilated cardiomyopathy. In spite of the major progress made in understanding the mechanisms of pathogenic T-cell responses, effective and safe therapeutic targeting of the immune system in chronic inflammatory diseases of the heart has not yet been developed due to the lack of specific diagnostic and prognostic biomarkers at an early stage. This has also prevented the identification of targets for patient-tailored immunomodulatory therapies that are both disease- and organ-selective. In this review, we discuss current knowledge of the development and functional characteristics of pathogenic T-cell-mediated immune responses in the heart, and, in particular, in myocarditis, as well as recent advances in experimental models which have the potential to translate into heart-selective immunomodulation. This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc. © 2016 The British Pharmacological Society.

  9. Inflammation in lung after acute myocardial infarction is induced by dendritic cell-mediated immune response.

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    Hu, L J; Ren, W Y; Shen, Q J; Ji, H Y; Zhu, L

    2017-01-01

    The present study was performed to describe the changes of lung tissues in mice with acute myocardial infarction (AMI) and also explain the cell mechanism involved in inflammation in lung. AMI was established by left coronary ligation in mice. Then mice were divided into three groups: control group, MW1 group (sampling after surgery for one week) and MW2 group (sampling after surgery for two weeks). Afterwards, measurement of lung weight and lung histology, cell sorting in bronchoalveolar lavage (BAL) fluid and detection of several adhesive molecules, inflammatory molecules as well as enzyme associated with inflammation were performed. Moreover, dendritic cells (DCs) were isolated from bone marrow of C57B/L6 mice. After incubating with necrotic myocardium, the expression of antigen presenting molecules, co-stimulatory molecules and inflammatory molecules were detected by flow cytometry or immunohistochemistry in DCs. We also detected T-cell proliferation after incubating with necrotic myocardium-treated DCs. AMI induced pathological changes of lung tissue and increased inflammatory cell amount in BAL fluid. AMI also increased the expression of several inflammatory factors, adhesive molecules and enzymes associated with inflammation. CD11c and TLR9, which are DC surface markers, showed a significantly increased expression in mice with AMI. Additionally, necrotic myocardium significantly increased the expression of co-stimulatory factors including CD83 and CD80, inflammatory cytokines including TNF-α, IFN-γ and NF-κB in DCs. Furthermore, DCs treated with necrotic myocardium also significantly promoted T-cell proliferation. AMI induced inflammation in lung and these pathological changes were mediated by DC-associated immune response.

  10. Local myocardial insulin-like growth factor 1 (IGF-1) delivery with biotinylated peptide nanofibers improves cell therapy for myocardial infarction

    Science.gov (United States)

    Davis, Michael E.; Hsieh, Patrick C. H.; Takahashi, Tomosaburo; Song, Qing; Zhang, Shuguang; Kamm, Roger D.; Grodzinsky, Alan J.; Anversa, Piero; Lee, Richard T.

    2006-05-01

    Strategies for cardiac repair include injection of cells, but these approaches have been hampered by poor cell engraftment, survival, and differentiation. To address these shortcomings for the purpose of improving cardiac function after injury, we designed self-assembling peptide nanofibers for prolonged delivery of insulin-like growth factor 1 (IGF-1), a cardiomyocyte growth and differentiation factor, to the myocardium, using a "biotin sandwich" approach. Biotinylated IGF-1 was complexed with tetravalent streptavidin and then bound to biotinylated self-assembling peptides. This biotin sandwich strategy allowed binding of IGF-1 but did not prevent self-assembly of the peptides into nanofibers within the myocardium. IGF-1 that was bound to peptide nanofibers activated Akt, decreased activation of caspase-3, and increased expression of cardiac troponin I in cardiomyocytes. After injection into rat myocardium, biotinylated nanofibers provided sustained IGF-1 delivery for 28 days, and targeted delivery of IGF-1 in vivo increased activation of Akt in the myocardium. When combined with transplanted cardiomyocytes, IGF-1 delivery by biotinylated nanofibers decreased caspase-3 cleavage by 28% and increased the myocyte cross-sectional area by 25% compared with cells embedded within nanofibers alone or with untethered IGF-1. Finally, cell therapy with IGF-1 delivery by biotinylated nanofibers improved systolic function after experimental myocardial infarction, demonstrating how engineering the local cellular microenvironment can improve cell therapy. engineering | maturation | scaffold

  11. Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Encapsulating Bioactive Hydrogels Improve Rat Heart Function Post Myocardial Infarction.

    Science.gov (United States)

    Chow, Andre; Stuckey, Daniel J; Kidher, Emaddin; Rocco, Mark; Jabbour, Richard J; Mansfield, Catherine A; Darzi, Ara; Harding, Sian E; Stevens, Molly M; Athanasiou, Thanos

    2017-10-04

    Tissue engineering offers an exciting possibility for cardiac repair post myocardial infarction. We assessed the effects of combined polyethylene glycol hydrogel (PEG), human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM), and erythropoietin (EPO) therapy in a rat model of myocardial infarction. PEG with/out iPSC-CMs and EPO; iPSC-CMs in saline; or saline alone was injected into infarcted hearts shortly after infarction. Injection of almost any combination of the therapeutics limited acute elevations in chamber volumes. After 10 weeks, attenuation of ventricular remodeling was identified in all groups that received PEG injections, while ejection fractions were significantly increased in the gel-EPO, cell, and gel-cell-EPO groups. In all treatment groups, infarct thickness was increased and regions of muscle were identified within the scar. However, no grafted cells were detected. Hence, iPSC-CM-encapsulating bioactive hydrogel therapy can improve cardiac function post myocardial infarction and increase infarct thickness and muscle content despite a lack of sustained donor-cell engraftment. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  12. WeAidU-a decision support system for myocardial perfusion images using artificial neural networks.

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    Ohlsson, Mattias

    2004-01-01

    This paper presents a computer-based decision support system for automated interpretation of diagnostic heart images (called WeAidU), which is made available via the Internet. The system is based on image processing techniques, artificial neural networks (ANNs) and large well-validated medical databases. We present results using artificial neural networks, and compare with two other classification methods, on a retrospective data set containing 1320 images from the clinical routine. The performance of the artificial neural networks detecting infarction and ischemia in different parts of the heart, measured as areas under the receiver operating characteristic curves, is in the range 0.83-0.96. These results indicate a high potential for the tool as a clinical decision support system.

  13. Adipose stromal vascular fraction cell construct sustains coronary microvascular function after acute myocardial infarction

    Science.gov (United States)

    LeBlanc, Amanda J.; Touroo, Jeremy S.; Hoying, James B.

    2012-01-01

    A three-dimensional tissue construct was created using adipose-derived stromal vascular fraction (SVF) cells and evaluated as a microvascular protection treatment in a myocardial infarction (MI) model. This study evaluated coronary blood flow (BF) and global left ventricular function after MI with and without the SVF construct. Fischer-344 rats were separated into four groups: sham operation (sham), MI, MI Vicryl patch (no cells), and MI SVF construct (MI SVF). SVF cells were labeled with green fluorescent protein (GFP). Immediately postinfarct, constructs were implanted onto the epicardium at the site of ischemia. Four weeks postsurgery, the coronary BF reserve was significantly decreased by 67% in the MI group and 75% in the MI Vicryl group compared with the sham group. The coronary BF reserve of the sham and MI SVF groups in the area at risk was not significantly different (sham group: 83 ± 22% and MI SVF group: 57 ± 22%). Griffonia simplicifolia I and GFP-positive SVF immunostaining revealed engrafted SVF cells around microvessels in the infarct region 4 wk postimplant. Overall heart function, specifically ejection fraction, was significantly greater in MI SVF hearts compared with MI and MI Vicryl hearts (MI SVF: 66 ± 4%, MI: 37 ± 8%, and MI Vicryl: 29 ± 6%). In conclusion, adipose-derived SVF cells can be used to construct a novel therapeutic modality for treating microvascular instability and ischemia through implantation on the epicardial surface of the heart. The SVF construct implanted immediately after MI not only maintains heart function but also sustains microvascular perfusion and function in the infarct area by sustaining the coronary BF reserve. PMID:22140045

  14. Alcohol consumption negates estrogen-mediated myocardial repair in ovariectomized mice by inhibiting endothelial progenitor cell mobilization and function.

    Science.gov (United States)

    Mackie, Alexander R; Krishnamurthy, Prasanna; Verma, Suresh K; Thorne, Tina; Ramirez, Veronica; Qin, Gangjian; Abramova, Tatiana; Hamada, Hiromichi; Losordo, Douglas W; Kishore, Raj

    2013-06-21

    We have shown previously that estrogen (estradiol, E2) supplementation enhances voluntary alcohol consumption in ovariectomized female rodents and that increased alcohol consumption impairs ischemic hind limb vascular repair. However, the effect of E2-induced alcohol consumption on post-infarct myocardial repair and on the phenotypic/functional properties of endothelial progenitor cells (EPCs) is not known. Additionally, the molecular signaling of alcohol-estrogen interactions remains to be elucidated. This study examined the effect of E2-induced increases in ethanol consumption on post-infarct myocardial function/repair. Ovariectomized female mice, implanted with 17β-E2 or placebo pellets were given access to alcohol for 6 weeks and subjected to acute myocardial infarction. Left ventricular functions were consistently depressed in mice consuming ethanol compared with those receiving only E2. Alcohol-consuming mice also displayed significantly increased infarct size and reduced capillary density. Ethanol consumption also reduced E2-induced mobilization and homing of EPCs to injured myocardium compared with the E2-alone group. In vitro, exposure of EPCs to ethanol suppressed E2-induced proliferation, survival, and migration and markedly altered E2-induced estrogen receptor-dependent cell survival signaling and gene expression. Furthermore, ethanol-mediated suppression of EPC biology was endothelial nitric oxide synthase-dependent because endothelial nitric oxide synthase-null mice displayed an exaggerated response to post-acute myocardial infarction left ventricular functions. These data suggest that E2 modulation of alcohol consumption, and the ensuing EPC dysfunction, may negatively compete with the beneficial effects of estrogen on post-infarct myocardial repair.

  15. miR-133a Enhances the Protective Capacity of Cardiac Progenitors Cells after Myocardial Infarction

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    Alberto Izarra

    2014-12-01

    Full Text Available miR-133a and miR-1 are known as muscle-specific microRNAs that are involved in cardiac development and pathophysiology. We have shown that both miR-1 and miR-133a are early and progressively upregulated during in vitro cardiac differentiation of adult cardiac progenitor cells (CPCs, but only miR-133a expression was enhanced under in vitro oxidative stress. miR-1 was demonstrated to favor differentiation of CPCs, whereas miR-133a overexpression protected CPCs against cell death, targeting, among others, the proapoptotic genes Bim and Bmf. miR-133a-CPCs clearly improved cardiac function in a rat myocardial infarction model by reducing fibrosis and hypertrophy and increasing vascularization and cardiomyocyte proliferation. The beneficial effects of miR-133a-CPCs seem to correlate with the upregulated expression of several relevant paracrine factors and the plausible cooperative secretion of miR-133a via exosomal transport. Finally, an in vitro heart muscle model confirmed the antiapoptotic effects of miR-133a-CPCs, favoring the structuration and contractile functionality of the artificial tissue.

  16. CellNet: network biology applied to stem cell engineering.

    Science.gov (United States)

    Cahan, Patrick; Li, Hu; Morris, Samantha A; Lummertz da Rocha, Edroaldo; Daley, George Q; Collins, James J

    2014-08-14

    Somatic cell reprogramming, directed differentiation of pluripotent stem cells, and direct conversions between differentiated cell lineages represent powerful approaches to engineer cells for research and regenerative medicine. We have developed CellNet, a network biology platform that more accurately assesses the fidelity of cellular engineering than existing methodologies and generates hypotheses for improving cell derivations. Analyzing expression data from 56 published reports, we found that cells derived via directed differentiation more closely resemble their in vivo counterparts than products of direct conversion, as reflected by the establishment of target cell-type gene regulatory networks (GRNs). Furthermore, we discovered that directly converted cells fail to adequately silence expression programs of the starting population and that the establishment of unintended GRNs is common to virtually every cellular engineering paradigm. CellNet provides a platform for quantifying how closely engineered cell populations resemble their target cell type and a rational strategy to guide enhanced cellular engineering. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. Cortical Bone Stem Cell Therapy Preserves Cardiac Structure and Function After Myocardial Infarction.

    Science.gov (United States)

    Sharp, Thomas E; Schena, Giana J; Hobby, Alexander R; Starosta, Timothy; Berretta, Remus M; Wallner, Markus; Borghetti, Giulia; Gross, Polina; Yu, Daohai; Johnson, Jaslyn; Feldsott, Eric; Trappanese, Danielle M; Toib, Amir; Rabinowitz, Joseph E; George, Jon C; Kubo, Hajime; Mohsin, Sadia; Houser, Steven R

    2017-11-10

    Cortical bone stem cells (CBSCs) have been shown to reduce ventricular remodeling and improve cardiac function in a murine myocardial infarction (MI) model. These effects were superior to other stem cell types that have been used in recent early-stage clinical trials. However, CBSC efficacy has not been tested in a preclinical large animal model using approaches that could be applied to patients. To determine whether post-MI transendocardial injection of allogeneic CBSCs reduces pathological structural and functional remodeling and prevents the development of heart failure in a swine MI model. Female Göttingen swine underwent left anterior descending coronary artery occlusion, followed by reperfusion (ischemia-reperfusion MI). Animals received, in a randomized, blinded manner, 1:1 ratio, CBSCs (n=9; 2×10 7 cells total) or placebo (vehicle; n=9) through NOGA-guided transendocardial injections. 5-ethynyl-2'deoxyuridine (EdU)-a thymidine analog-containing minipumps were inserted at the time of MI induction. At 72 hours (n=8), initial injury and cell retention were assessed. At 3 months post-MI, cardiac structure and function were evaluated by serial echocardiography and terminal invasive hemodynamics. CBSCs were present in the MI border zone and proliferating at 72 hours post-MI but had no effect on initial cardiac injury or structure. At 3 months, CBSC-treated hearts had significantly reduced scar size, smaller myocytes, and increased myocyte nuclear density. Noninvasive echocardiographic measurements showed that left ventricular volumes and ejection fraction were significantly more preserved in CBSC-treated hearts, and invasive hemodynamic measurements documented improved cardiac structure and functional reserve. The number of EdU + cardiac myocytes was increased in CBSC- versus vehicle- treated animals. CBSC administration into the MI border zone reduces pathological cardiac structural and functional remodeling and improves left ventricular functional reserve

  18. Murine and human pluripotent stem cell-derived cardiac bodies form contractile myocardial tissue in vitro.

    Science.gov (United States)

    Kensah, George; Roa Lara, Angelica; Dahlmann, Julia; Zweigerdt, Robert; Schwanke, Kristin; Hegermann, Jan; Skvorc, David; Gawol, Anke; Azizian, Azadeh; Wagner, Stefan; Maier, Lars S; Krause, Andreas; Dräger, Gerald; Ochs, Matthias; Haverich, Axel; Gruh, Ina; Martin, Ulrich

    2013-04-01

    We explored the use of highly purified murine and human pluripotent stem cell (PSC)-derived cardiomyocytes (CMs) to generate functional bioartificial cardiac tissue (BCT) and investigated the role of fibroblasts, ascorbic acid (AA), and mechanical stimuli on tissue formation, maturation, and functionality. Murine and human embryonic/induced PSC-derived CMs were genetically enriched to generate three-dimensional CM aggregates, termed cardiac bodies (CBs). Addressing the critical limitation of major CM loss after single-cell dissociation, non-dissociated CBs were used for BCT generation, which resulted in a structurally and functionally homogenous syncytium. Continuous in situ characterization of BCTs, for 21 days, revealed that three critical factors cooperatively improve BCT formation and function: both (i) addition of fibroblasts and (ii) ascorbic acid supplementation support extracellular matrix remodelling and CB fusion, and (iii) increasing static stretch supports sarcomere alignment and CM coupling. All factors together considerably enhanced the contractility of murine and human BCTs, leading to a so far unparalleled active tension of 4.4 mN/mm(2) in human BCTs using optimized conditions. Finally, advanced protocols were implemented for the generation of human PSC-derived cardiac tissue using a defined animal-free matrix composition. BCT with contractile forces comparable with native myocardium can be generated from enriched, PSC-derived CMs, based on a novel concept of tissue formation from non-dissociated cardiac cell aggregates. In combination with the successful generation of tissue using a defined animal-free matrix, this represents a major step towards clinical applicability of stem cell-based heart tissue for myocardial repair.

  19. RORγt-expressing cells attenuate cardiac remodeling after myocardial infarction.

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    Daichi Enomoto

    Full Text Available Retinoic acid receptor-related orphan nuclear receptor γt (RORγt is a transcriptional factor responsible for IL-17-producing T-cell differentiation. Although it was demonstrated that RORγt plays essential roles in the onset of autoimmune myocarditis, pathophysiological significance of RORγt in cardiac remodeling after myocardial infarction (MI remains to be fully elucidated.MI was generated by ligating coronary artery. The expression of RORγt and IL-17A transcripts increased in murine hearts after MI. Additionally, immunohistochemical staining revealed that RORγt-expressing cells infiltrated in the border zone after MI. Flow cytometric analysis showed that RORγt-expressing cells were released from the spleen at day 1 after MI. Though RORγt-expressing cells in spleen expressed γδTCR or CD4, γδTCR+ cells were major population of RORγt-expressing cells that infiltrated into post-infarct myocardium. To address the biological functions of RORγt-expressing cells in infarcted hearts, we used mice with enhanced GFP gene heterozygously knocked-in at RORγt locus (RORγt+/- mice, which physiologically showed reduced expression of RORγt mRNA in thymus. Kaplan-Meier analysis showed that MI-induced mortality was higher in RORγt+/- mice than wild-type (WT mice. Masson's trichrome staining demonstrated that cardiac injury was exacerbated in RORγt+/- mice 7 days after MI (Injured area: RORγt+/-; 42.1±6.5%, WT; 34.0±3.7%, circumference of injured myocardium: RORγt+/-; 61.8±4.8%, WT; 49.6±5.1%, accompanied by exacerbation of cardiac function (fractional shortening: RORγt+/-; 32.9±2.9%, WT; 38.3±3.6%. Moreover, immunohistochemical analyses revealed that capillary density in border zone was significantly reduced in RORγt+/- mice after MI, compared with WT mice, associated with the reduced expression of angiopoietin 2. Finally, the mRNA expression of RORγt, IL-17A, IL-17F and IL-23 receptor (IL-23R mRNA and protein expression of IL-10

  20. Allogeneic amniotic membrane-derived mesenchymal stromal cell transplantation in a porcine model of chronic myocardial ischemia

    Science.gov (United States)

    Kimura, M; Toyoda, M; Gojo, S; Itakura, Y; Kami, D; Miyoshi, S; Kyo, S; Ono, M; Umezawa, A

    2012-01-01

    Introduction. Amniotic membrane contains a multipotential stem cell population and is expected to possess the machinery to regulate immunological reactions. We investigated the safety and efficacy of allogeneic amniotic membrane-derived mesenchymal stromal cell (AMSC) transplantation in a porcine model of chronic myocardial ischemia as a preclinical trial. Methods. Porcine AMSCs were isolated from amniotic membranes obtained by cesarean section just before delivery and were cultured to increase their numbers before transplantation. Chronic myocardial ischemia was induced by implantation of an ameroid constrictor around the left circumflex coronary artery. Four weeks after ischemia induction, nine swine were assigned to undergo either allogeneic AMSC transplantation or normal saline injection. Functional analysis was performed by echocardiography, and histological examinations were carried out by immunohistochemistry 4 weeks after AMSC transplantation. Results. Echocardiography demonstrated that left ventricular ejection fraction was significantly improved and left ventricular dilatation was well attenuated 4 weeks after AMSC transplantation. Histological assessment showed a significant reduction in percentage of fibrosis in the AMSC transplantation group. Injected allogeneic green fluorescent protein (GFP)-expressing AMSCs were identified in the immunocompetent host heart without the use of any immunosuppressants 4 weeks after transplantation. Immunohistochemistry revealed that GFP colocalized with cardiac troponin T and cardiac troponin I. Conclusions. We have demonstrated that allogeneic AMSC transplantation produced histological and functional improvement in the impaired myocardium in a porcine model of chronic myocardial ischemia. The transplanted allogeneic AMSCs survived without the use of any immunosuppressants and gained cardiac phenotype through either their transdifferentiation or cell fusion. PMID:24693195

  1. Allogeneic amniotic membrane-derived mesenchymal stromal cell transplantation in a porcine model of chronic myocardial ischemia

    Directory of Open Access Journals (Sweden)

    Kimura M

    2012-01-01

    Full Text Available Introduction. Amniotic membrane contains a multipotential stem cell population and is expected to possess the machinery to regulate immunological reactions. We investigated the safety and efficacy of allogeneic amniotic membrane-derived mesenchymal stromal cell (AMSC transplantation in a porcine model of chronic myocardial ischemia as a preclinical trial. Methods. Porcine AMSCs were isolated from amniotic membranes obtained by cesarean section just before delivery and were cultured to increase their numbers before transplantation. Chronic myocardial ischemia was induced by implantation of an ameroid constrictor around the left circumflex coronary artery. Four weeks after ischemia induction, nine swine were assigned to undergo either allogeneic AMSC transplantation or normal saline injection. Functional analysis was performed by echocardiography, and histological examinations were carried out by immunohistochemistry 4 weeks after AMSC transplantation. Results. Echocardiography demonstrated that left ventricular ejection fraction was significantly improved and left ventricular dilatation was well attenuated 4 weeks after AMSC transplantation. Histological assessment showed a significant reduction in percentage of fibrosis in the AMSC transplantation group. Injected allogeneic green fluorescent protein (GFP-expressing AMSCs were identified in the immunocompetent host heart without the use of any immunosuppressants 4 weeks after transplantation. Immunohistochemistry revealed that GFP colocalized with cardiac troponin T and cardiac troponin I. Conclusions. We have demonstrated that allogeneic AMSC transplantation produced histological and functional improvement in the impaired myocardium in a porcine model of chronic myocardial ischemia. The transplanted allogeneic AMSCs survived without the use of any immunosuppressants and gained cardiac phenotype through either their transdifferentiation or cell fusion.

  2. Serial in vivo positive contrast MRI of iron oxide-labeled embryonic stem cell-derived cardiac precursor cells in a mouse model of myocardial infarction.

    Science.gov (United States)

    Mani, Venkatesh; Adler, Eric; Briley-Saebo, Karen C; Bystrup, Anne; Fuster, Valentin; Keller, Gordon; Fayad, Zahi A

    2008-07-01

    Myocardial regeneration with stem-cell transplantation is a possible treatment option to reverse deleterious effects that occur after myocardial infarction. Since little is known about stem cell survival after transplantation, developing techniques for "tracking" cells would be desirable. Iron-oxide-labeled stem cells have been used for in vivo tracking using MRI but produce negative contrast images that are difficult to interpret. The aim of the current study was to test a positive contrast MR technique using reduced z-gradient rephasing (GRASP) to aid in dynamically tracking stem cells in an in vivo model of mouse myocardial infraction. Ferumoxides and protamine sulfate were complexed and used to magnetically label embryonic stem cell-derived cardiac-precursor-cells (ES-CPCs). A total of 500,000 ES-CPCs were injected in the border zone of infarcted mice and MR imaging was performed on a 9.4T scanner using T(2)*-GRE sequences (negative contrast) and positive contrast GRASP technique before, 24 hours, and 1 week after ES-CPC implantation. Following imaging, mice were sacrificed for histology and Perl's staining was used to confirm iron within myocardium. Good correlation was observed between signal loss seen on conventional T(2)* images, bright areas on GRASP, and the presence of iron on histology. This demonstrated the feasibility of in vivo stem cell imaging with positive contrast MRI. (c) 2008 Wiley-Liss, Inc.

  3. Suicide gene reveals the myocardial neovascularization role of mesenchymal stem cells overexpressing CXCR4 (MSC(CXCR4)).

    Science.gov (United States)

    Liang, Jialiang; Huang, Wei; Yu, Xiyong; Ashraf, Atif; Wary, Kishore K; Xu, Meifeng; Millard, Ronald W; Ashraf, Muhammad; Wang, Yigang

    2012-01-01

    Our previous studies indicated that MSC(CXCR4) improved cardiac function after myocardial infarction (MI). This study was aimed to investigate the specific role of MSC(CXCR4) in neovascularization of infarcted myocardium using a suicide gene approach. MSCs were transduced with either lentivirus-null vector/GFP (MSC(Null) as control) or vector encoding for overexpressing CXCR4/GFP. The MSC derived-endothelial cell (EC) differentiation was assessed by a tube formation assay, Dil-ac-LDL uptake, EC marker expression, and VE-cadherin promoter activity assay. Gene expression was analyzed by quantitative RT-PCR or Western blot. The suicide gene approach was under the control of VE-cadherin promoter. In vivo studies: Cell patches containing MSC(Null) or MSC(CXCR4) were transduced with suicide gene and implanted into the myocardium of MI rat. Rats received either ganciclovir (GCV) or vehicle after cell implantation. After one month, the cardiac functional changes and neovascularization were assessed by echocardiography, histological analysis, and micro-CT imaging. The expression of VEGF-A and HIF-1α was significantly higher in MSC(CXCR4) as compared to MSC(Null) under hypoxia. Additionally, MSC(CXCR4) enhanced new vessel formation and EC differentiation, as well as STAT3 phosphorylation under hypoxia. STAT3 participated in the transcription of VE-cadherin in MSC(CXCR4) under hypoxia, which was inhibited by WP1066 (a STAT3 inhibitor). In addition, GCV specifically induced death of ECs with suicide gene activation. In vivo studies: MSC(CXCR4) implantation promoted cardiac functional restoration, reduced infarct size, improved cardiac remodeling, and enhanced neovascularization in ischemic heart tissue. New vessels derived from MSC(CXCR4) were observed at the injured heart margins and communicated with native coronary arteries. However, the derived vessel networks were reduced by GCV, reversing improvement of cardiac function. The transplanted MSC(CXCR4) enhanced

  4. Suicide gene reveals the myocardial neovascularization role of mesenchymal stem cells overexpressing CXCR4 (MSC(CXCR4.

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    Jialiang Liang

    Full Text Available BACKGROUND: Our previous studies indicated that MSC(CXCR4 improved cardiac function after myocardial infarction (MI. This study was aimed to investigate the specific role of MSC(CXCR4 in neovascularization of infarcted myocardium using a suicide gene approach. METHODS: MSCs were transduced with either lentivirus-null vector/GFP (MSC(Null as control or vector encoding for overexpressing CXCR4/GFP. The MSC derived-endothelial cell (EC differentiation was assessed by a tube formation assay, Dil-ac-LDL uptake, EC marker expression, and VE-cadherin promoter activity assay. Gene expression was analyzed by quantitative RT-PCR or Western blot. The suicide gene approach was under the control of VE-cadherin promoter. In vivo studies: Cell patches containing MSC(Null or MSC(CXCR4 were transduced with suicide gene and implanted into the myocardium of MI rat. Rats received either ganciclovir (GCV or vehicle after cell implantation. After one month, the cardiac functional changes and neovascularization were assessed by echocardiography, histological analysis, and micro-CT imaging. RESULTS: The expression of VEGF-A and HIF-1α was significantly higher in MSC(CXCR4 as compared to MSC(Null under hypoxia. Additionally, MSC(CXCR4 enhanced new vessel formation and EC differentiation, as well as STAT3 phosphorylation under hypoxia. STAT3 participated in the transcription of VE-cadherin in MSC(CXCR4 under hypoxia, which was inhibited by WP1066 (a STAT3 inhibitor. In addition, GCV specifically induced death of ECs with suicide gene activation. In vivo studies: MSC(CXCR4 implantation promoted cardiac functional restoration, reduced infarct size, improved cardiac remodeling, and enhanced neovascularization in ischemic heart tissue. New vessels derived from MSC(CXCR4 were observed at the injured heart margins and communicated with native coronary arteries. However, the derived vessel networks were reduced by GCV, reversing improvement of cardiac function. CONCLUSION: The

  5. Cardiac repair in a porcine model of acute myocardial infarction with human induced pluripotent stem cell-derived cardiovascular cell populations

    Science.gov (United States)

    Ye, Lei; Chang, Ying-Hua; Xiong, Qiang; Zhang, Pengyuan; Zhang, Liying; Somasundaram, Porur; Lepley, Mike; Swingen, Cory; Su, Liping; Wendel, Jacqueline S.; Guo, Jing; Jang, Albert; Rosenbush, Daniel; Greder, Lucas; Dutton, James R.; Zhang, Jianhua; Kamp, Timothy J.; Kaufman, Dan S.; Ge, Ying; Zhang, Jianyi

    2014-01-01

    Summary Human induced pluripotent stem cells (hiPSCs) hold promise for myocardial repair following injury, but preclinical studies in large animal models are required to determine optimal cell preparation and delivery strategies to maximize functional benefits and to evaluate safety. Here, we utilized a porcine model of acute myocardial infarction (MI) to investigate the functional impact of intramyocardial transplantation of hiPSC-derived cardiomyocytes, endothelial cells, and smooth muscle cells, in combination with a 3D fibrin patch loaded with insulin growth factor (IGF)-encapsulated microspheres. hiPSC-derived cardiomyocytes integrated into host myocardium and generated organized sarcomeric structures, and endothelial and smooth muscle cells contributed to host vasculature. Tri-lineage cell transplantation significantly improved left ventricular function, myocardial metabolism, and arteriole density, while reducing infarct size, ventricular wall stress and apoptosis without inducing ventricular arrhythmias. These findings in a large animal MI model highlight the potential of utilizing hiPSC-derived cells for cardiac repair. PMID:25479750

  6. Myocardial tissue engineering.

    Science.gov (United States)

    Jawad, Hedeer; Lyon, Alex R; Harding, Sian E; Ali, Nadire N; Boccaccini, Aldo R

    2008-01-01

    Regeneration of the infarcted myocardium after a heart attack is one of the most challenging aspects in tissue engineering. Suitable cell sources and optimized biocompatible materials must be identified. In this review, we briefly discuss the current therapeutic options available to patients with heart failure post-myocardial infarction. We describe the various strategies currently proposed to encourage myocardial regeneration, with focus on the achievements in myocardial tissue engineering (MTE). We report on the current cell types, materials and methods being investigated for developing a tissue-engineered myocardial construct. Generally, there is agreement that a 'vehicle' is required to transport cells to the infarcted heart to help myocardial repair and regeneration. Suitable cell source, biomaterials, cell environment and implantation time post-infarction remain obstacles in the field of MTE. Research is being focused on optimizing natural and synthetic biomaterials for tissue engineering. The type of cell and its origin (autologous or derived from embryonic stem cells), cell density and method of cell delivery are also being explored. The possibility is being explored that materials may not only act as a support for the delivered cell implants, but may also add value by changing cell survival, maturation or integration, or by prevention of mechanical and electrical remodelling of the failing heart.

  7. Differentiation of allogeneic mesenchymal stem cells induces immunogenicity and limits their long-term benefits for myocardial repair.

    Science.gov (United States)

    Huang, Xi-Ping; Sun, Zhuo; Miyagi, Yasuo; McDonald Kinkaid, Heather; Zhang, Li; Weisel, Richard D; Li, Ren-Ke

    2010-12-07

    Cardiac cell therapy for older patients who experience a myocardial infarction may require highly regenerative cells from young, healthy (allogeneic) donors. Bone marrow mesenchymal stem cells (MSCs) are currently under clinical investigation because they can induce cardiac repair and may also be immunoprivileged (suitable for allogeneic applications). However, it is unclear whether allogeneic MSCs retain their immunoprivilege or functional efficacy late after myocardial implantation. We evaluated the effects of MSC differentiation on the immune characteristics of cells in vitro and in vivo and monitored cardiac function for 6 months after post-myocardial infarction MSC therapy. In the in vitro experiments, inducing MSCs to acquire myogenic, endothelial, or smooth muscle characteristics (via 5-azacytidine or cytokine treatment) increased major histocompatibility complex-Ia and -II (immunogenic) expression and reduced major histocompatibility complex-Ib (immunosuppressive) expression, in association with increased cytotoxicity in coculture with allogeneic leukocytes. In the in vivo experiments, we implanted allogeneic or syngeneic MSCs into infarcted rat myocardia. We measured cell differentiation and survival (immunohistochemistry, real-time polymerase chain reaction) and cardiac function (echocardiography, pressure-volume catheter) for 6 months. MSCs (versus media) significantly improved ventricular function for at least 3 months after implantation. Allogeneic (but not syngeneic) cells were eliminated from the heart by 5 weeks after implantation, and their functional benefits were lost within 5 months. The long-term ability of allogeneic MSCs to preserve function in the infarcted heart is limited by a biphasic immune response whereby they transition from an immunoprivileged to an immunogenic state after differentiation, which is associated with an alteration in major histocompatibility complex-immune antigen profile.

  8. Adipose-derived mesenchymal stromal cells for chronic myocardial ischemia (MyStromalCell Trial)

    DEFF Research Database (Denmark)

    Qayyum, Abbas Ali; Haack-Sørensen, Mandana; Mathiasen, Anders Bruun

    2012-01-01

    . In addition, we give an introduction to the first-in-man clinical trial, MyStromalCell Trial, which is a prospective, randomized, double-blind, placebo-controlled study using culture-expanded ADSCs obtained from adipose-derived cells from abdominal adipose tissue and stimulated with VEGF-A(165) the week...

  9. Stimulated mast cells promote maturation of myocardial microvascular endothelial cell neovessels by modulating the angiopoietin-Tie-2 signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Z.H. [Division of Cardiology, Shanghai Sixth People' s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China, Division of Cardiology, Shanghai Sixth People’s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai (China); Yancheng People' s First Hospital, Division of Cardiology, Yancheng, Jiangsu, China, Division of Cardiology, Yancheng People’s First Hospital, Yancheng, Jiangsu (China); Zhu, W.; Tao, J.P.; Zhang, Q.Y.; Wei, M. [Division of Cardiology, Shanghai Sixth People' s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China, Division of Cardiology, Shanghai Sixth People’s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai (China)

    2013-10-22

    Angiopoietin (Ang)-1 and Ang-2 interact in angiogenesis to activate the Tie-2 receptor, which may be involved in new vessel maturation and regression. Mast cells (MCs) are also involved in formation of new blood vessels and angiogenesis. The present study was designed to test whether MCs can mediate angiogenesis in myocardial microvascular endothelial cells (MMVECs). Using a rat MMVEC and MC co-culture system, we observed that Ang-1 protein levels were very low even though its mRNA levels were increased by MCs. Interestingly, MCs were able to enhance migration, proliferation, and capillary-like tube formation, which were associated with suppressed Ang-2 protein expression, but not Tie-2 expression levels. These MCs induced effects that could be reversed by either tryptase inhibitor [N-tosyl-L-lysine chloromethyl ketone (TLCK)] or chymase inhibitor (N-tosyl-L-phenylalanyl chloromethyl ketone), with TLCK showing greater effects. In conclusion, our data indicated that MCs can interrupt neovessel maturation via suppression of the Ang-2/Tie-2 signaling pathway.

  10. Potential advantages of cell administration on the inflammatory response compared to standard ACE inhibitor treatment in experimental myocardial infarction

    Directory of Open Access Journals (Sweden)

    De Camilli Elisa

    2008-06-01

    Full Text Available Abstract Background Bone Marrow (BM progenitor cells can target the site of myocardial injury, contributing to tissue repair by neovascolarization and/or by a possible direct paracrine effect on the inflammatory cascade. Angiotensin Converting Enzyme inhibitors (ACE-I are effective in reducing mortality and preventing left ventricular (LV function deterioration after myocardial infarction. Methods We investigated the short term effects of BM mononuclear cells (BMMNCs therapy on the pro-inflammatory cytokines (pro-CKs and on LV remodelling and compared these effects over a standard ACE-I therapy in a rat model of myocardial cryodamage. Forty two adult inbread Fisher-F344 rats were randomized into three groups: untreated (UT; n = 12, pharmacological therapy (ACE-I; n = 14, receiving quinapril, and cellular therapy (BMMNCs; n = 16, receiving BMMNCs infusion. Rats underwent to a standard echocardiogram in the acute setting and 14 days after the damage, before the sacrifice. Pro-CKs analysis (interleukin (IL1β, IL-6, tumor necrosis factor (TNFα was performed (multiplex proteome arrays on blood samples obtained by direct aorta puncture before the sacrifice; a control group of 6 rats was considered as reference. Results Concerning the extension of the infarcted area as well as the LV dimensions, no differences were observed among the animal groups; treated rats had lower left atrial diameters and higher indexes of LV function. Pro-Cks were increased in infarcted-UT rats if compared with controls, and significantly reduced by BMMNCs and ACE-I ; TNFα inversely correlated with LV fractional shortening. Conclusion After myocardial infarction, both BMMNCs and ACE-I reduce the pattern of pro-Ck response, probably contributing to prevent the deterioration of LV function observed in UT rats.

  11. Permanently Hypoxic Cell Culture Yields Rat Bone Marrow Mesenchymal Cells with Higher Therapeutic Potential in the Treatment of Chronic Myocardial Infarction.

    Science.gov (United States)

    Liu, Yihua; Yang, Xiaoxi; Maureira, Pablo; Falanga, Aude; Marie, Vanessa; Gauchotte, Guillaume; Poussier, Sylvain; Groubatch, Frederique; Marie, Pierre-Yves; Tran, Nguyen

    2017-01-01

    The mismatch between traditional in vitro cell culture conditions and targeted chronic hypoxic myocardial tissue could potentially hamper the therapeutic effects of implanted bone marrow mesenchymal stem cells (BMSCs). This study sought to address (i) the extent of change to BMSC biological characteristics in different in vitro culture conditions and (ii) the effectiveness of permanent hypoxic culture for cell therapy in treating chronic myocardial infarction (MI) in rats. rat BMSCs were harvested and cultured in normoxic (21% O2, n=27) or hypoxic conditions (5% O2, n=27) until Passage 4 (P4). Cell growth tests, flow cytometry, and Bio-Plex assays were conducted to explore variations in the cell proliferation, phenotype, and cytokine expression, respectively. In the in vivo set-up, P3-BMSCs cultured in normoxia (n=6) or hypoxia (n=6) were intramyocardially injected into rat hearts that had previously experienced 1-month-old MI. The impact of cell therapy on cardiac segmental viability and hemodynamic performance was assessed 1 month later by 2-Deoxy-2[18F]fluoro-D-glucose (18F-FDG) positron emission tomography (PET) imaging and pressure-volume catheter, respectively. Additional histomorphological examinations were conducted to evaluate inflammation, fibrosis, and neovascularization. Hypoxic preconditioning significantly enhanced rat BMSC clonogenic potential and proliferation without altering the multipotency. Different profiles of inflammatory, fibrotic, and angiogenic cytokine secretion were also documented, with a marked correlation observed between in vitro and in vivo proangiogenic cytokine expression and tissue neovessels. Hypoxic-preconditioned cells presented a beneficial effect on the myocardial viability of infarct segments and intrinsic contractility. Hypoxic-preconditioned BMSCs were able to benefit myocardial perfusion and contractility, probably by modulating the inflammation and promoting angiogenesis. © 2017 The Author(s). Published by S. Karger AG

  12. Permanently Hypoxic Cell Culture Yields Rat Bone Marrow Mesenchymal Cells with Higher Therapeutic Potential in the Treatment of Chronic Myocardial Infarction

    Directory of Open Access Journals (Sweden)

    Yihua Liu

    2017-11-01

    Full Text Available Background: The mismatch between traditional in vitro cell culture conditions and targeted chronic hypoxic myocardial tissue could potentially hamper the therapeutic effects of implanted bone marrow mesenchymal stem cells (BMSCs. This study sought to address (i the extent of change to BMSC biological characteristics in different in vitro culture conditions and (ii the effectiveness of permanent hypoxic culture for cell therapy in treating chronic myocardial infarction (MI in rats. Methods: rat BMSCs were harvested and cultured in normoxic (21% O2, n=27 or hypoxic conditions (5% O2, n=27 until Passage 4 (P4. Cell growth tests, flow cytometry, and Bio-Plex assays were conducted to explore variations in the cell proliferation, phenotype, and cytokine expression, respectively. In the in vivo set-up, P3-BMSCs cultured in normoxia (n=6 or hypoxia (n=6 were intramyocardially injected into rat hearts that had previously experienced 1-month-old MI. The impact of cell therapy on cardiac segmental viability and hemodynamic performance was assessed 1 month later by 2-Deoxy-2[18F]fluoro-D-glucose (18F-FDG positron emission tomography (PET imaging and pressure-volume catheter, respectively. Additional histomorphological examinations were conducted to evaluate inflammation, fibrosis, and neovascularization. Results: Hypoxic preconditioning significantly enhanced rat BMSC clonogenic potential and proliferation without altering the multipotency. Different profiles of inflammatory, fibrotic, and angiogenic cytokine secretion were also documented, with a marked correlation observed between in vitro and in vivo proangiogenic cytokine expression and tissue neovessels. Hypoxic-preconditioned cells presented a beneficial effect on the myocardial viability of infarct segments and intrinsic contractility. Conclusion: Hypoxic-preconditioned BMSCs were able to benefit myocardial perfusion and contractility, probably by modulating the inflammation and promoting

  13. Myocardial Ischemia

    Science.gov (United States)

    ... pectoris: Chest pain caused by myocardial ischemia. www.uptodate.com/home. Accessed June 1, 2015. Deedwania PC. Silent myocardial ischemia: Epidemiology and pathogenesis. www.uptodate.com/home. Accessed June 1, 2015. Mann DL, ...

  14. Left ventricular myocardial performance assessed by 2-dimensional speckle tracking echocardiography in patients with sickle cell crisis.

    Science.gov (United States)

    Sengupta, Shantanu P; Jaju, Rahul; Nugurwar, Abhijeet; Caracciolo, Giuseppe; Sengupta, Partho P

    2012-01-01

    The status of left ventricle in sickle cell anemia presenting in sickle crisis and follow up has been minimally studied in past. To determine the left ventricular (LV) myocardial performance in these patients, we performed the study to assess two dimensional strains imaging which allowed a rapid and an accurate analysis of global and regional LV myocardial performance in longitudinal, radial, and circumferential directions. In this prospective study, 2-dimensional echocardiography (2DE) images of the LV were obtained in 52 subjects which included 32 patients (23 ± 8yrs, 16 male) with homozygous sickle cell anemia (SCA) in sickle cell crisis and 20 healthy controls (23 ± 5 yrs, 11 male) using apical 4-chamber and parasternal short-axis at the basal, mid, and apical levels. Of these 32 patients, 2DE was performed again in 18 patients in follow up (8 months ± 5 days). Longitudinal, circumferential and radial strains (LS, CS and RS respectively) were quantified and compared in an 18-segment model using a novel speckle tracking system (2D Cardiac Performance Analysis, TomTec Imaging System, Munich, Germany). There was no significant difference in LV ejection fraction between both the groups (59.32 ± 12.6 vs. 52.3 ± 7.9; p-value > 0.05). In comparison with normal controls and follow up of sickle cell patients, peak LS was significantly attenuated in the subendocardial and subepicardial regions during sickle cell crisis (p crisis showed significantly higher radial strain parameters than controls (p crisis have reduced longitudinal shortening. LV myocardial performance remains unaltered due to relatively preserved circumferential shortening and increased radial thickening. Copyright © 2012 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.

  15. Preclinical evaluation of the engineered stem cell chemokine stromal cell-derived factor 1α analog in a translational ovine myocardial infarction model.

    Science.gov (United States)

    Macarthur, John W; Cohen, Jeffrey E; McGarvey, Jeremy R; Shudo, Yasuhiro; Patel, Jay B; Trubelja, Alen; Fairman, Alexander S; Edwards, Bryan B; Hung, George; Hiesinger, William; Goldstone, Andrew B; Atluri, Pavan; Wilensky, Robert L; Pilla, James J; Gorman, Joseph H; Gorman, Robert C; Woo, Y Joseph

    2014-02-14

    After myocardial infarction, there is an inadequate blood supply to the myocardium, and the surrounding borderzone becomes hypocontractile. To develop a clinically translatable therapy, we hypothesized that in a preclinical ovine model of myocardial infarction, the modified endothelial progenitor stem cell chemokine, engineered stromal cell-derived factor 1α analog (ESA), would induce endothelial progenitor stem cell chemotaxis, limit adverse ventricular remodeling, and preserve borderzone contractility. Thirty-six adult male Dorset sheep underwent permanent ligation of the left anterior descending coronary artery, inducing an anteroapical infarction, and were randomized to borderzone injection of saline (n=18) or ESA (n=18). Ventricular function, geometry, and regional strain were assessed using cardiac MRI and pressure-volume catheter transduction. Bone marrow was harvested for in vitro analysis, and myocardial biopsies were taken for mRNA, protein, and immunohistochemical analysis. ESA induced greater chemotaxis of endothelial progenitor stem cells compared with saline (P<0.01) and was equivalent to recombinant stromal cell-derived factor 1α (P=0.27). Analysis of mRNA expression and protein levels in ESA-treated animals revealed reduced matrix metalloproteinase 2 in the borderzone (P<0.05), with elevated levels of tissue inhibitor of matrix metalloproteinase 1 and elastin in the infarct (P<0.05), whereas immunohistochemical analysis of borderzone myocardium showed increased capillary and arteriolar density in the ESA group (P<0.01). Animals in the ESA treatment group also had significant reductions in infarct size (P<0.01), increased maximal principle strain in the borderzone (P<0.01), and a steeper slope of the end-systolic pressure-volume relationship (P=0.01). The novel, biomolecularly designed peptide ESA induces chemotaxis of endothelial progenitor stem cells, stimulates neovasculogenesis, limits infarct expansion, and preserves contractility in an ovine

  16. Right and left ventricular function and myocardial scarring in adult patients with sickle cell disease: a comprehensive magnetic resonance assessment of hepatic and myocardial iron overload.

    Science.gov (United States)

    Junqueira, Flávia P; Fernandes, Juliano L; Cunha, Guilherme M; T A Kubo, Tadeu; M A O Lima, Claudio; B P Lima, Daniel; Uellendhal, Marly; Sales, Sidney R; A S Cunha, Carolina; L R de Pessoa, Viviani; L C Lobo, Clarisse; Marchiori, Edson

    2013-09-19

    Patients with Sickle cell disease (SCD) who receive regular transfusions are at risk for developing cardiac toxicity from iron overload. The aim of this study was to assess right and left cardiac volumes and function, late gadolinium enhancement (LGE) and iron deposits in patients with SCD using CMR, correlating these values with transfusion burden, ferritin and hemoglobin levels. Thirty patients with SCD older than 20 years of age were studied in a 1.5 T scanner and compared to age- and sex-matched normal controls. Patients underwent analysis of biventricular volumes and function, LGE and T2* assessment of the liver and heart. When compared to controls, patients with SCD presented higher left ventricular (LV) volumes with decreased ejection fraction (EF) with an increase in stroke volume (SV) and LV hypertrophy. The right ventricle (RV) also presented with a decreased EF and hypertrophy, with an increased end-systolic volume. Although twenty-six patients had increased liver iron concentrations (median liver iron concentration value was 11.83 ± 9.66 mg/g), only one patient demonstrated an abnormal heart T2* < 20 msec. Only four patients (13%) LGE, with only one patient with an ischemic pattern. Abnormal heart iron levels and myocardial scars are not a common finding in SCD despite increased liver iron overload. The significantly different ventricular function seen in SCD compared to normal suggests the changes in RV and LV function may not be due to the anemia alone. Future studies are necessary to confirm this association.

  17. Impairment of myocardial perfusion in children with sickle cell disease; Alteration de la perfusion myocardique chez l'enfant drepanocytaire

    Energy Technology Data Exchange (ETDEWEB)

    Maunoury, C. [Hopital Necker-Enfants-Malades, Service de Medecine Nucleaire, 75 - Paris (France); Acar, P. [Centre Hospitalier Universitaire, Hopital des Enfants, Service de Cardiologie Pediatrique, 31 - Toulouse (France); Montalembert, M. de [Hopital Necker-Enfants-Malades, Service de Pediatrie Generale, 75 - Paris (France)

    2003-10-01

    While brain, bone and spleen strokes are well documented in children with sickle cell disease (SCD), impairment of myocardial perfusion is an unknown complication. Non invasive techniques such as exercise testing and echocardiography have a low sensitivity to detect myocardial ischemia in patients with SCD. We have prospectively assessed myocardial perfusion with Tl-201 SPECT in 23 patients with SCD (10 female, 13 male, mean age 12 {+-} 5 years). Myocardial SPECT was performed after stress and 3 hours later after reinjection on a single head gamma camera equipped with a LEAP collimator (64 x 64 matrix size format, 30 projections over 180 deg C, 30 seconds per step). Left ventricular ejection fraction (LVEF) was assessed by equilibrium radionuclide angiography at rest on the same day. Myocardial perfusion was impaired in 14/23 patients: 9 reversible defects and 5 fixed defects. The left ventricular cavity was dilated in 14/23 patients. The mean LVEF was 63 {+-} 9%. There was no relationship between myocardial perfusion and left ventricular dilation or function. The frequent impairment of myocardial perfusion in children with SCD could lead to suggest a treatment with hydroxyurea, an improvement of perfusion can be noted with hydroxyurea. (author)

  18. Bone marrow mononuclear cell implantation in myocardial laser channels in the ischemic heart disease surgery. Long-term results

    Science.gov (United States)

    Chernyavskiy, Alexander; Fomichev, Alexey; Minin, Stanislav; Nikitin, Nikita

    2017-10-01

    Background: The problem of incomplete myocardial revascularization for diffuse and distal lesions of the myocardium is still relevant. We assessed the clinical and instrumental long-term results of autologous bone marrow cell (BMC) implantation in laser channels in ischemic heart disease with diffuse and distal coronary disease. 35 coronary heart disease (CHD) patients with diffuse and distal coronary disease during coronary artery bypass grafting (CABG) underwent BMC implantation in laser channels. The control group consisted of 29 patients. All patients in this group underwent only CABG. Clinical and instrumental assessment of the method's effect was carried out at two weeks, six months, and six years after surgery. Indirect revascularization showed more significant decreasing of the functional class (FC) New York Heart Association (NYHA), myocardial perfusion and contractility improvement. Autologous BMC implantation in laser channels is an effective method of CHD surgical treatment if it is impossible to perform direct myocardial revascularization. The indirect revascularization effect is formed in the first six months after surgery and remains at the same level for six years.

  19. Hyaluronan Mixed Esters of Butyric and Retinoic Acid Affording Myocardial Survival and Repair without Stem Cell Transplantation*

    Science.gov (United States)

    Lionetti, Vincenzo; Cantoni, Silvia; Cavallini, Claudia; Bianchi, Francesca; Valente, Sabrina; Frascari, Irene; Olivi, Elena; Aquaro, Giovanni D.; Bonavita, Francesca; Scarlata, Ignazio; Maioli, Margherita; Vaccari, Valentina; Tassinari, Riccardo; Bartoli, Antonietta; Recchia, Fabio A.; Pasquinelli, Gianandrea; Ventura, Carlo

    2010-01-01

    Possible cardiac repair by adult stem cell transplantation is currently hampered by poor cell viability and delivery efficiency, uncertain differentiating fate in vivo, the needs of ex vivo cell expansion, and consequent delay in transplantation after the onset of heart attack. By the aid of magnetic resonance imaging, positron emission tomography, and immunohistochemistry, we show that injection of a hyaluronan mixed ester of butyric and retinoic acid (HBR) into infarcted rat hearts afforded substantial cardiovascular repair and recovery of myocardial performance. HBR restored cardiac [18F]fluorodeoxyglucose uptake and increased capillary density and led to the recruitment of endogenous Stro-1-positive stem cells. A terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assay demonstrated that HBR-treated hearts exhibited a decrease in the number of apoptotic cardiomyocytes. In isolated rat cardiomyocytes and Stro-1 stem cells, HBR enhanced the transcription of vascular endothelial growth factor, hepatocyte growth factor, kdr, akt, and pim-1. HBR also increased the secretion of vascular endothelial growth factor and hepatocyte growth factor, suggesting that the mixed ester may have recruited both myocardial and Stro-1 cells also. An increase in capillarogenesis was induced in vitro with medium obtained from HBR-exposed cells. In the infarcted myocardium, HBR injection increased histone H4 acetylation significantly. Acetyl-H4 immunoreactivity increased in rat cardiomyocytes and Stro-1 cells exposed to HBR, compared with untreated cells. In conclusion, efficient cardiac regenerative therapy can be afforded by HBR without the need of stem cell transplantation or vector-mediated gene delivery. PMID:20097747

  20. Hyaluronan mixed esters of butyric and retinoic acid affording myocardial survival and repair without stem cell transplantation.

    Science.gov (United States)

    Lionetti, Vincenzo; Cantoni, Silvia; Cavallini, Claudia; Bianchi, Francesca; Valente, Sabrina; Frascari, Irene; Olivi, Elena; Aquaro, Giovanni D; Bonavita, Francesca; Scarlata, Ignazio; Maioli, Margherita; Vaccari, Valentina; Tassinari, Riccardo; Bartoli, Antonietta; Recchia, Fabio A; Pasquinelli, Gianandrea; Ventura, Carlo

    2010-03-26

    Possible cardiac repair by adult stem cell transplantation is currently hampered by poor cell viability and delivery efficiency, uncertain differentiating fate in vivo, the needs of ex vivo cell expansion, and consequent delay in transplantation after the onset of heart attack. By the aid of magnetic resonance imaging, positron emission tomography, and immunohistochemistry, we show that injection of a hyaluronan mixed ester of butyric and retinoic acid (HBR) into infarcted rat hearts afforded substantial cardiovascular repair and recovery of myocardial performance. HBR restored cardiac [(18)F]fluorodeoxyglucose uptake and increased capillary density and led to the recruitment of endogenous Stro-1-positive stem cells. A terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assay demonstrated that HBR-treated hearts exhibited a decrease in the number of apoptotic cardiomyocytes. In isolated rat cardiomyocytes and Stro-1 stem cells, HBR enhanced the transcription of vascular endothelial growth factor, hepatocyte growth factor, kdr, akt, and pim-1. HBR also increased the secretion of vascular endothelial growth factor and hepatocyte growth factor, suggesting that the mixed ester may have recruited both myocardial and Stro-1 cells also. An increase in capillarogenesis was induced in vitro with medium obtained from HBR-exposed cells. In the infarcted myocardium, HBR injection increased histone H4 acetylation significantly. Acetyl-H4 immunoreactivity increased in rat cardiomyocytes and Stro-1 cells exposed to HBR, compared with untreated cells. In conclusion, efficient cardiac regenerative therapy can be afforded by HBR without the need of stem cell transplantation or vector-mediated gene delivery.

  1. Enhanced cell survival and paracrine effects of mesenchymal stem cells overexpressing hepatocyte growth factor promote cardioprotection in myocardial infarction

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Liyan; Liu, Xiaolin [Section of Pacing and Electrophysiology, Division of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing (China); Zhang, Yuelin [Cardiology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong (China); Liang, Xiaoting; Ding, Yue [Pudong District Clinical Translational Medical Research Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai (China); Xu, Yan; Fang, Zhen [Section of Pacing and Electrophysiology, Division of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing (China); Zhang, Fengxiang, E-mail: njzfx6@njmu.edu.cn [Section of Pacing and Electrophysiology, Division of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing (China)

    2016-05-15

    Poor cell survival post transplantation compromises the therapeutic benefits of mesenchymal stem cells (MSCs) in myocardial infarction (MI). Hepatocyte growth factor (HGF) is an important cytokine for angiogenesis, anti-inflammation and anti-apoptosis. This study aimed to evaluate the cardioprotective effects of MSCs overexpressing HGF in a mouse model of MI. The apoptosis of umbilical cord-derived MSCs (UC-MSCs) and HGF-UC-MSCs under normoxic and hypoxic conditions was detected. The conditioned medium (CdM) of UC-MSCs and HGF-UC-MSCs under a hypoxic condition was harvested and its protective effect on neonatal cardiomyocytes (NCMs) exposed to a hypoxic challenge was examined. UC-MSCs and HGF-UC-MSCs were transplanted into the peri-infarct region in mice following MI and heart function assessed 4 weeks post transplantation. The apoptosis of HGF-UC-MSCs under hypoxic conditions was markedly decreased compared with that of UC-MSCs. NCMs treated with HGF-UC-MSC hypoxic CdM (HGF-UC-MSCs-hy-CdM) exhibited less cell apoptosis in response to hypoxic challenge than those treated with UC-MSC hypoxic CdM (UC-MSCs-hy-CdM). HGF-UC-MSCs-hy-CdM released the inhibited p-Akt and lowered the enhanced ratio of Bax/Bcl-2 induced by hypoxia in the NCMs. HGF-UC-MSCs-hy-CdM expressed higher levels of HGF, EGF, bFGF and VEGF than UC-MSCs-hy-CdM. Transplantation of HGF-UC-MSCs or UC-MSCs greatly improved heart function in the mouse model of MI. Compared with UC-MSCs, transplantation of HGF-UC-MSCs was associated with less cardiomyocyte apoptosis, enhanced angiogenesis and increased proliferation of cardiomyocytes. This study may provide a novel therapeutic strategy for MSC-based therapy in cardiovascular disease.

  2. Preclinical Safety Evaluation of Allogeneic Induced Pluripotent Stem Cell-Based Therapy in a Swine Model of Myocardial Infarction.

    Science.gov (United States)

    Gálvez-Montón, Carolina; Soler-Botija, Carolina; Iborra-Egea, Oriol; Díaz-Güemes, Idoia; Martí, Mercè; Iglesias-García, Olalla; Prat-Vidal, Cristina; Crisóstomo, Verónica; Llucià-Valldeperas, Aida; Perea-Gil, Isaac; Roura, Santiago; Sánchez-Margallo, Francisco M; Raya, Ángel; Bayes-Genis, Antoni

    2017-11-01

    The combination of biomatrices and induced pluripotent stem cell (iPSC) derivatives to aid repair and myocardial scar formation may soon become a reality for cardiac regenerative medicine. However, the tumor risk associated with residual undifferentiated cells remains an important safety concern of iPSC-based therapies. This concern is not satisfactorily addressed in xenotransplantation, which requires immune suppression of the transplanted animal. In this study, we assessed the safety of transplanting undifferentiated iPSCs in an allogeneic setting. Given that swine are commonly used as large animal models in cardiac medicine, we used porcine iPSCs (p-iPSCs) in conjunction with bioengineered constructs that support recovery after acute myocardial infarction. Histopathology analyses found no evidence of p-iPSCs or p-iPSC-derived cells within the host myocardium or biomatrices after 30 and 90 days of follow-up. Consistent with the disappearance of the implanted cells, we could not observe functional benefit of these treatments in terms of left ventricular ejection fraction, cardiac output, ventricular volumes, or necrosis. We therefore conclude that residual undifferentiated iPSCs should pose no safety concern when used on immune-competent recipients in an allogeneic setting, at least in the context of cardiac regenerative medicine.

  3. Protein kinase G1 α overexpression increases stem cell survival and cardiac function after myocardial infarction.

    Directory of Open Access Journals (Sweden)

    Linlin Wang

    Full Text Available We hypothesized that overexpression of cGMP-dependent protein kinase type 1α (PKG1α could mimic the effect of tadalafil on the survival of bone marrow derived mesenchymal stem cells (MSCs contributing to regeneration of the ischemic heart.MSCs from male rats were transduced with adenoviral vector encoding for PKG1α ((PKG1αMSCs.Controls included native MSCs ((NatMSCs and MSCs transduced with an empty vector ((NullMSCs. PKG1α activity was increased approximately 20, 5 and 16 fold respectively in (PKG1αMSCs. (PKG1αMSCs showed improved survival under oxygen and glucose deprivation (OGD which was evidenced by lower LDH release, caspase-3/7 activity and number of positive TUNEL cells. Anti-apoptotic proteins pAkt, pGSK3β, and Bcl-2 were significantly increased in (PKG1αMSCs compared to (NatMSCs and (NullMSCs. Higher release of multiple prosurvival and angiogenic factors such as HGF, bFGF, SDF-1 and Ang-1 was observed in (PKG1αMSCs before and after OGD. In a female rat model of acute myocardial infarction, (PKG1αMSCs group showed higher survival compared with (NullMSCs group at 3 and 7 days after transplantation as determined by TUNEL staining and sry-gene quantitation by real-time PCR. Increased anti-apoptotic proteins and paracrine factors in vitro were also identified. Immunostaining for cardiac troponin I combined with GFP showed increased myogenic differentiation of (PKG1αMSCs. At 4 weeks after transplantation, compared to DMEM group and (NullMSCs group, (PKG1αMSCs group showed increased blood vessel density in infarct and peri-infarct areas (62.5±7.7; 68.8±7.3 per microscopic view, p<0.05 and attenuated infarct size (27.2±2.5%, p<0.01. Heart function indices including ejection fraction (52.1±2.2%, p<0.01 and fractional shortening (24.8%±1.3%, p<0.01 were improved significantly in (PKG1αMSCs group.Overexpression of PKG1α transgene could be a powerful approach to improve MSCs survival and their angiomyogenic potential in the

  4. Simulation of developing human neuronal cell networks.

    Science.gov (United States)

    Lenk, Kerstin; Priwitzer, Barbara; Ylä-Outinen, Laura; Tietz, Lukas H B; Narkilahti, Susanna; Hyttinen, Jari A K

    2016-08-30

    Microelectrode array (MEA) is a widely used technique to study for example the functional properties of neuronal networks derived from human embryonic stem cells (hESC-NN). With hESC-NN, we can investigate the earliest developmental stages of neuronal network formation in the human brain. In this paper, we propose an in silico model of maturating hESC-NNs based on a phenomenological model called INEX. We focus on simulations of the development of bursts in hESC-NNs, which are the main feature of neuronal activation patterns. The model was developed with data from developing hESC-NN recordings on MEAs which showed increase in the neuronal activity during the investigated six measurement time points in the experimental and simulated data. Our simulations suggest that the maturation process of hESC-NN, resulting in the formation of bursts, can be explained by the development of synapses. Moreover, spike and burst rate both decreased at the last measurement time point suggesting a pruning of synapses as the weak ones are removed. To conclude, our model reflects the assumption that the interaction between excitatory and inhibitory neurons during the maturation of a neuronal network and the spontaneous emergence of bursts are due to increased connectivity caused by the forming of new synapses.

  5. Concise Review: Optimized Strategies for Stem Cell-Based Therapy in Myocardial Repair: Clinical Translatability and Potential Limitation.

    Science.gov (United States)

    Wu, Rongrong; Hu, Xinyang; Wang, Jian'an

    2018-01-13

    Ischemic heart diseases (IHDs) remain major public health problems with high rates of morbidity and mortality worldwide. Despite significant advances, current therapeutic approaches are unable to rescue the extensive and irreversible loss of cardiomyocytes caused by severe ischemia. Over the past 16 years, stem cell-based therapy has been recognized as an innovative strategy for cardiac repair/regeneration and functional recovery after IHDs. Although substantial preclinical animal studies using a variety of stem/progenitor cells have shown promising results, there is a tremendous degree of skepticism in the clinical community as many stem cell trials do not confer any beneficial effects. How to accelerate stem cell-based therapy toward successful clinical application attracts considerate attention. However, many important issues need to be fully addressed. In this Review, we have described and compared the effects of different types of stem cells with their dose, delivery routes, and timing that have been routinely tested in recent preclinical and clinical findings. We have also discussed the potential mechanisms of action of stem cells, and explored the role and underlying regulatory components of stem cell-derived secretomes/exosomes in myocardial repair. Furthermore, we have critically reviewed the different strategies for optimizing both donor stem cells and the target cardiac microenvironments to enhance the engraftment and efficacy of stem cells, highlighting their clinical translatability and potential limitation. Stem Cells 2018. © AlphaMed Press 2018.

  6. Percutaneous intramyocardial delivery of mesenchymal stem cells induces superior improvement in regional left ventricular function compared with bone marrow mononuclear cells in porcine myocardial infarcted heart.

    Science.gov (United States)

    Tao, Bo; Cui, Mingliang; Wang, Chen; Ma, Sai; Wu, Feng; Yi, Fu; Qin, Xing; Liu, Junting; Wang, Haichang; Wang, Zhe; Ma, Xiaowei; Tian, Jie; Chen, Yundai; Wang, Jing; Cao, Feng

    2015-01-01

    To investigate the efficacy and feasibility of percutaneous intramyocardial injection of bone marrow mesenchymal stem cells (MSC) and autologous bone marrow-derived mononuclear cells (BMMNC) on cardiac functional improvement in porcine myocardial infarcted hearts. Acute myocardial infarction (AMI) was induced in 22 minipigs by temporary balloon occlusion of the left anterior descending coronary artery for 60 min.Two weeks post AMI, BMMNC (n = 7, 245 ± 98 × 10(6)), MSC (n = 8, 56 ± 17 × 10(6)), or phosphate buffered saline (PBS; n = 7) were injected intramyocardially. Cardiac function and myocardial perfusion were analyzed by echocardiography and gated single-photon emission computed tomography/computed tomography (SPECT/CT) at 1 week before AMI and 2 and 10 weeks after AMI. Cell engraftment, proliferation, vascular density, and cardiac fibrosis were evaluated by histology analysis. In all groups, the echocardiography revealed no significant change in the left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), or left ventricular end-diastolic volume (LVEDV) at 10 weeks after AMI compared with those at 2 weeks after AMI. However, the wall motion score index (WMSI) and left ventricular systolic wall thickening (WT%) were significantly improved at 10 weeks compared with those at 2 weeks after AMI in the MSC group (WMSI 1.55 ± 0.06 vs. 1.87 ± 0.10, WT 33.4 ± 2.3% vs.24.8 ± 2.7%,p < 0.05) but not in the BMMNC group. In addition, myocardial perfusion quantified by SPECT/CT was improved in both the MSC and BMMNC groups, whereas the MSC group showed a superior improvement in vascular density and collagen volume fraction (p < 0.05). This preclinically relevant study suggests that when delivered by percutaneous (transcatheter) intramyocardial injection, MSC might be more effective than BMMNC to improve ischemia and reperfusion after AMI.

  7. Random matrix analysis for gene interaction networks in cancer cells

    CERN Document Server

    Kikkawa, Ayumi

    2016-01-01

    Motivation: The investigation of topological modifications of the gene interaction networks in cancer cells is essential for understanding the desease. We study gene interaction networks in various human cancer cells with the random matrix theory. This study is based on the Cancer Network Galaxy (TCNG) database which is the repository of huge gene interactions inferred by Bayesian network algorithms from 256 microarray experimental data downloaded from NCBI GEO. The original GEO data are provided by the high-throughput microarray expression experiments on various human cancer cells. We apply the random matrix theory to the computationally inferred gene interaction networks in TCNG in order to detect the universality in the topology of the gene interaction networks in cancer cells. Results: We found the universal behavior in almost one half of the 256 gene interaction networks in TCNG. The distribution of nearest neighbor level spacing of the gene interaction matrix becomes the Wigner distribution when the net...

  8. Effects of Intracoronary Administration of Autologous Adipose Tissue-Derived Stem Cells on Acute Myocardial Infarction in a Porcine Model.

    Science.gov (United States)

    Lee, Hye Won; Lee, Han Cheol; Park, Jong Ha; Kim, Bo Won; Ahn, Jinhee; Kim, Jin Hee; Park, Jin Sup; Oh, Jun-Hyok; Choi, Jung Hyun; Cha, Kwang Soo; Hong, Taek Jong; Park, Tae Sik; Kim, Sang-Pil; Song, Seunghwan; Kim, Ji Yeon; Park, Mi Hwa; Jung, Jin Sup

    2015-11-01

    Adipose-derived stem cells (ADSCs) are known to be potentially effective in regeneration of damaged tissue. We aimed to assess the effectiveness of intracoronary administration of ADSCs in reducing the infarction area and improving function after acute transmural myocardial infarction (MI) in a porcine model. ADSCs were obtained from each pig's abdominal subcutaneous fat tissue by simple liposuction. After 3 passages of 14-days culture, 2 million ADSCs were injected into the coronary artery 30 min after acute transmural MI. At baseline and 4 weeks after the ADSC injection, 99mTc methoxyisobutylisonitrile-single photon emission computed tomography (MIBISPECT) was performed to evaluate the left ventricular volume, left ventricular ejection fraction (LVEF; %), and perfusion defects as well as the myocardial salvage (%) and salvage index. At 4 weeks, each pig was sacrificed, and the heart was extracted and dissected. Gross and microscopic analyses with specific immunohistochemistry staining were then performed. Analysis showed improvement in the perfusion defect, but not in the LVEF in the ADSC group (n=14), compared with the control group (n=14) (perfusion defect, -13.0±10.0 vs. -2.6±12.0, p=0.019; LVEF, -8.0±15.4 vs. -15.9±14.8, p=0.181). There was a tendency of reducing left ventricular volume in ADSC group. The ADSCs identified by stromal cell-derived factor-1 (SDF-1) staining were well co-localized by von Willebrand factor and Troponin T staining. Intracoronary injection of cultured ADSCs improved myocardial perfusion in this porcine acute transmural MI model.

  9. Intravenously Delivered Mesenchymal Stem Cells: Systemic Anti-Inflammatory Effects Improve Left Ventricular Dysfunction in Acute Myocardial Infarction and Ischemic Cardiomyopathy.

    Science.gov (United States)

    Luger, Dror; Lipinski, Michael J; Westman, Peter C; Glover, David K; Dimastromatteo, Julien; Frias, Juan C; Albelda, M Teresa; Sikora, Sergey; Kharazi, Alex; Vertelov, Grigory; Waksman, Ron; Epstein, Stephen E

    2017-05-12

    Virtually all mesenchymal stem cell (MSC) studies assume that therapeutic effects accrue from local myocardial effects of engrafted MSCs. Because few intravenously administered MSCs engraft in the myocardium, studies have mainly utilized direct myocardial delivery. We adopted a different paradigm. To test whether intravenously administered MSCs reduce left ventricular (LV) dysfunction both post-acute myocardial infarction and in ischemic cardiomyopathy and that these effects are caused, at least partly, by systemic anti-inflammatory activities. Mice underwent 45 minutes of left anterior descending artery occlusion. Human MSCs, grown chronically at 5% O 2 , were administered intravenously. LV function was assessed by serial echocardiography, 2,3,5-triphenyltetrazolium chloride staining determined infarct size, and fluorescence-activated cell sorting assessed cell composition. Fluorescent and radiolabeled MSCs (1×10 6 ) were injected 24 hours post-myocardial infarction and homed to regions of myocardial injury; however, the myocardium contained only a small proportion of total MSCs. Mice received 2×10 6 MSCs or saline intravenously 24 hours post-myocardial infarction (n=16 per group). At day 21, we harvested blood and spleens for fluorescence-activated cell sorting and hearts for 2,3,5-triphenyltetrazolium chloride staining. Adverse LV remodeling and deteriorating LV ejection fraction occurred in control mice with large infarcts (≥25% LV). Intravenous MSCs eliminated the progressive deterioration in LV end-diastolic volume and LV end-systolic volume. MSCs significantly decreased natural killer cells in the heart and spleen and neutrophils in the heart. Specific natural killer cell depletion 24 hours pre-acute myocardial infarction significantly improved infarct size, LV ejection fraction, and adverse LV remodeling, changes associated with decreased neutrophils in the heart. In an ischemic cardiomyopathy model, mice 4 weeks post-myocardial infarction were

  10. [Evaluation of myocardial viability with 201Tl/18F-FDG DISA-SPECT technique in patients with acute myocardial infarction after emergent intracoronary autologous bone marrow mononuclear cells transplantation].

    Science.gov (United States)

    Huang, Rong-chong; Yao, Kang; Qian, Ju-ying; Niu, Yu-hong; Ge, Lei; Chen, Shu-guang; Shi, Hong-cheng; Zhang, Yi-Qi; Sun, Ai-jun; Wang, Ke-qiang; Zou, Yun-zeng; Ge, Jun-bo

    2007-06-01

    To evaluate the myocardial viability with (201)Tl/(18)F-FDG DISA-SPECT technique in patients with acute myocardial infarction underwent emergent intracoronary autologous bone marrow mononuclear cells (BM-MNC) transplantation. Patients with first acute myocardial infarction underwent emergent percutaneous coronary intervention (PCI) were randomized in a 1:1 ratio to either intracoronary transplantation of autologous BM-MNC (n = 20) or to sodium chloride concluding heparin (control, n = 20) via a micro infusion catheter group immediately after PCI. Change in global left ventricular function (LVEF measured by echocardiography) and the myocardial viability detected by (201)Tl/(18)F-FDG DISA-SPECT from baseline and 6-months post transplantation were analyzed. Left ventricular ejection fraction (LVEF) was improved in both groups and the absolute increase (DeltaLVEF) in BM-MNC group was significantly higher than that in control group (7.6% +/- 2.8% vs. 3.0% +/- 2.8%, P DISA-SPECT technique.

  11. CD8+ T-Cells Count in Acute Myocardial Infarction in HIV Disease in a Predominantly Male Cohort

    Directory of Open Access Journals (Sweden)

    Oluwatosin A. Badejo

    2015-01-01

    Full Text Available Human Immunodeficiency Virus- (HIV- infected persons have a higher risk for acute myocardial infarction (AMI than HIV-uninfected persons. Earlier studies suggest that HIV viral load, CD4+ T-cell count, and antiretroviral therapy are associated with cardiovascular disease (CVD risk. Whether CD8+ T-cell count is associated with CVD risk is not clear. We investigated the association between CD8+ T-cell count and incident AMI in a cohort of 73,398 people (of which 97.3% were men enrolled in the U.S. Veterans Aging Cohort Study-Virtual Cohort (VACS-VC. Compared to uninfected people, HIV-infected people with high baseline CD8+ T-cell counts (>1065 cells/mm3 had increased AMI risk (adjusted HR=1.82, P<0.001, 95% CI: 1.46 to 2.28. There was evidence that the effect of CD8+ T-cell tertiles on AMI risk differed by CD4+ T-cell level: compared to uninfected people, HIV-infected people with CD4+ T-cell counts ≥200 cells/mm3 had increased AMI risk with high CD8+ T-cell count, while those with CD4+ T-cell counts <200 cells/mm3 had increased AMI risk with low CD8+ T-cell count. CD8+ T-cell counts may add additional AMI risk stratification information beyond that provided by CD4+ T-cell counts alone.

  12. Myocardial Bridging

    Directory of Open Access Journals (Sweden)

    Shi-Min Yuan

    2016-02-01

    Full Text Available Abstract Myocardial bridging is rare. Myocardial bridges are most commonly localized in the middle segment of the left anterior descending coronary artery. The anatomic features of the bridges vary significantly. Alterations of the endothelial morphology and the vasoactive agents impact on the progression of atherosclerosis of myocardial bridging. Patients may present with chest pain, myocardial infarction, arrhythmia and even sudden death. Patients who respond poorly to the medical treatment with β-blockers warrant a surgical intervention. Myotomy is a preferred surgical procedure for the symptomatic patients. Coronary stent deployment has been in limited use due to the unsatisfactory long-term results.

  13. Effects of Intracoronary Infusion of Escalating Doses of Cardiac Stem Cells in Rats With Acute Myocardial Infarction.

    Science.gov (United States)

    Tang, Xian-Liang; Rokosh, Gregg; Sanganalmath, Santosh K; Tokita, Yukichi; Keith, Matthew C L; Shirk, Gregg; Stowers, Heather; Hunt, Gregory N; Wu, Wenjian; Dawn, Buddhadeb; Bolli, Roberto

    2015-07-01

    Although c-kit(pos) cardiac stem cells (CSCs) preserve left ventricular (LV) function and structure after myocardial infarction, CSC doses have been chosen arbitrarily, and the dose-effect relationship is unknown. Rats underwent a 90-minute coronary occlusion followed by 35 days of reperfusion. Vehicle or CSCs at 5 escalating doses (0.3×10(6), 0.75×10(6), 1.5×10(6), 3.0×10(6), and 6.0×10(6) cells/heart) were given intracoronarily 4 h after reperfusion. The lowest dose (0.3×10(6)) had no effect on LV function and morphology, whereas 0.75, 1.5, and 3.0×10(6) significantly improved regional and global LV function (echocardiography and hemodynamic studies). These 3 doses had similar effects on echocardiographic parameters (infarct wall thickening fraction, LV end-systolic and end-diastolic volumes, LV ejection fraction) and hemodynamic variables (LV end-diastolic pressure, LV dP/dtmax, preload adjusted maximal power, end-systolic elastance, preload recruitable stroke work) and produced similar reductions in apoptosis, scar size, infarct wall thinning, and LV expansion index and similar increases in viable myocardium in the risk region (morphometry). Infusion of 6.0×10(6) CSCs markedly increased postprocedural mortality. Green fluorescent protein and 5-bromo-2'-deoxyuridine staining indicated that persistence of donor cells and formation of new myocytes were negligible with all doses. Surprisingly, in this rat model of acute myocardial infarction, the dose-response relationship for intracoronary CSCs is flat. A minimal dose between 0.3 and 0.75×10(6) is necessary for efficacy; above this threshold, a 4-fold increase in cell number does not produce greater improvement in LV function or structure. Further increases in cell dose are harmful. © 2015 American Heart Association, Inc.

  14. Human adipose stem cell and ASC-derived cardiac progenitor cellular therapy improves outcomes in a murine model of myocardial infarction

    Science.gov (United States)

    Davy, Philip MC; Lye, Kevin D; Mathews, Juanita; Owens, Jesse B; Chow, Alice Y; Wong, Livingston; Moisyadi, Stefan; Allsopp, Richard C

    2015-01-01

    Background Adipose tissue is an abundant and potent source of adult stem cells for transplant therapy. In this study, we present our findings on the potential application of adipose-derived stem cells (ASCs) as well as induced cardiac-like progenitors (iCPs) derived from ASCs for the treatment of myocardial infarction. Methods and results Human bone marrow (BM)-derived stem cells, ASCs, and iCPs generated from ASCs using three defined cardiac lineage transcription factors were assessed in an immune-compromised mouse myocardial infarction model. Analysis of iCP prior to transplant confirmed changes in gene and protein expression consistent with a cardiac phenotype. Endpoint analysis was performed 1 month posttransplant. Significantly increased endpoint fractional shortening, as well as reduction in the infarct area at risk, was observed in recipients of iCPs as compared to the other recipient cohorts. Both recipients of iCPs and ASCs presented higher myocardial capillary densities than either recipients of BM-derived stem cells or the control cohort. Furthermore, mice receiving iCPs had a significantly higher cardiac retention of transplanted cells than all other groups. Conclusion Overall, iCPs generated from ASCs outperform BM-derived stem cells and ASCs in facilitating recovery from induced myocardial infarction in mice. PMID:26604802

  15. Acute myocardial infarction is associated with endothelial glycocalyx and cell damage and a parallel increase in circulating catecholamines.

    Science.gov (United States)

    Ostrowski, Sisse R; Pedersen, Sune H; Jensen, Jan S; Mogelvang, Rasmus; Johansson, Pär I

    2013-02-22

    Excessive sympathoadrenal activation in critical illness contributes directly to organ damage, and high concentrations of catecholamines damage the vascular endothelium. This study investigated associations between potential drivers of sympathoadrenal activation, circulating catecholamines and biomarkers of endothelial damage and outcome in ST segment elevation myocardial infarction (STEMI)-patients, hypothesizing that the catecholamine surge would reflect shock degree and correlate with biomarkers of endothelial damage. This was a prospective study of 678 consecutive STEMI-patients admitted to a single high-volume invasive heart centre for primary percutaneous coronary intervention (pPCI) from September 2006 to July 2008. Blood samples were drawn immediately before pPCI. Plasma adrenaline, noradrenaline, syndecan-1 and thrombomodulin were measured retrospectively with complete data in 571 patients (84%). Median follow-up time was 28 (IQR 23 to 34) months. Follow-up was 99.7% complete. Outcomes were all-cause and cardiovascular mortality, re-myocardial infarction and admission due to heart failure. Circulating noradrenaline and adrenaline correlated weakly but independently with syndecan-1 (rho = 0.15 and rho = 0.13, both P catecholamines correlated strongly with thrombomodulin and syndecan-1 (rho = 0.31 to 0.42, all P catecholamines correlated weakly with biomarkers of endothelial damage, with the strongest correlations and highest adrenaline and syndecan-1 levels in patients with shock. Furthermore, adrenaline and syndecan-1 were weakly but independently associated with mortality and heart failure. Acute myocardial infarction appears to cause significant endothelial cell and glycocalyx injury and a parallel increase in circulating catecholamines.

  16. Clinical efficacy and safety of autologous stem cell transplantation for patients with ST-segment elevation myocardial infarction

    Directory of Open Access Journals (Sweden)

    Li R

    2016-08-01

    Full Text Available Rong Li,1,* Xiao-Ming Li,2,* Jun-Rong Chen,3 1Department of Intensive Care Unit, The People’s Hospital of Baoji City, 2Department of Cardiovascular Medicine, 3Department of Function, Baoji Central Hospital, Baoji, Shaanxi, People’s Republic of China *These authors contributed equally to this work Purpose: The purpose of this study is to evaluate the therapeutic efficacy and safety of stem cells for the treatment of patients with ST-segment elevation myocardial infarction (STEMI.Materials and methods: We performed a systematic review and meta-analysis of relevant published clinical studies. A computerized search was conducted for randomized controlled trials of stem cell therapy for STEMI.Results: Twenty-eight randomized controlled trials with a total of 1,938 STEMI patients were included in the present meta-analysis. Stem cell therapy resulted in an improvement in long-term (12 months left ventricular ejection fraction of 3.15% (95% confidence interval 1.01–5.29, P<0.01. The 3-month to 4-month, 6-month, and 12-month left ventricular end-systolic volume showed favorable results in the stem cell therapy group compared with the control group (P≤0.05. Significant decrease was also observed in left ventricular end-diastolic volume after 3-month to 4-month and 12-month follow-up compared with controls (P<0.05. Wall mean score index was reduced significantly in stem cell therapy group when compared with the control group at 6-month and 12-month follow-up (P=0.01. Moreover, our analysis showed a significant change of 12-month infarct size decrease in STEMI patients treated with stem cells compared with controls (P<0.01. In addition, no significant difference was found between treatment group and control in adverse reactions (P>0.05.Conclusion: Overall, stem cell therapy is efficacious in the treatment of patients with STEMI, with low rates of adverse events compared with control group patients. Keywords: ST-segment elevation myocardial

  17. The C60-Fullerene Porphyrin Adducts for Prevention of the Doxorubicin-Induced Acute Cardiotoxicity in Rat Myocardial Cells

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    Seyed Vahid Shetab Boushehri

    2010-09-01

    Full Text Available "nThis is a fullerene-based low toxic nanocationite designed for targeted delivery of the paramagnetic stable isotope of magnesium to the doxorubicin (DXR-induced damaged heart muscle providing a prominent effect close to about 80% recovery of the tissue hypoxia symptoms in less than 24 hrs after a single injection (0.03 - 0.1 LD50. Magnesium magnetic isotope effect selectively stimulates the ATP formation in the oxygen-depleted cells due to a creatine kinase (CK and mitochondrial respiratory chain-focusing "attack" of 25Mg2+ released by nanoparticles. These "smart nanoparticles" with membranotropic properties release the overactivating cations only in response to the intracellular acidosis. The resulting positive changes in the energy metabolism of heart cell may help to prevent local myocardial hypoxic (ischemic disorders and, hence, to protect the heart muscle from a serious damage in a vast variety of the hypoxia-induced clinical situations including DXR side effects.

  18. The C60-Fullerene Porphyrin Adducts for Prevention of the Doxorubicin-Induced Acute Cardiotoxicity in Rat Myocardial Cells

    Directory of Open Access Journals (Sweden)

    Seyed Vahid Shetab Boushehri

    2010-10-01

    Full Text Available This is a fullerene-based low toxic nanocationite designed for targeted delivery of the paramagnetic stable isotope of magnesium to the doxorubicin (DXR-induced damaged heart muscle providing a prominent effect close to about 80% recovery of the tissue hypoxia symptoms in less than 24 hrs after a single injection (0.03 - 0.1 LD50. Magnesium magnetic isotope effect selectively stimulates the ATP formation in the oxygen-depleted cells due to a creatine kinase (CK and mitochondrial respiratory chain-focusing "attack" of 25Mg2+ released by nanoparticles. These "smart nanoparticles" with membranotropic properties release the overactivating cations only in response to the intracellular acidosis. The resulting positive changes in the energy metabolism of heart cell may help to prevent local myocardial hypoxic (ischemic disorders and, hence, to protect the heart muscle from a serious damage in a vast variety of the hypoxia-induced clinical situations including DXR side effects.

  19. Maternal treatment with agonistic autoantibodies against type-1 angiotensin II receptor in late pregnancy increases apoptosis of myocardial cells and myocardial susceptibility to ischemia-reperfusion injury in offspring rats.

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    Zhu Jin

    Full Text Available Epidemiological studies have demonstrated that offspring born to mothers preeclampsia (PE are at increased risk for developing cardiovascular diseases after birth, but the underlying mechanism is unknown. Angiotensin II receptor type 1 autoantibody (AT1-AA, an agonist acting via activation of the AT1 receptor, is believed to be involved in the pathogenesis of both PE and fetal growth restriction. The aim of the present study was to confirm the hypothesis that prenatal AT1-AA exposure increases the heart susceptibility to ischemia/reperfusion injury (IRI in the offspring in an AT1-AA-induced animal model of PE, and determine whether or not the increase of maternal AT1-AA level is a factor contributing to sustained abnormalities of the heart structure during infancy. The hearts of 45-day-old offspring rats were studied using Langendorff preparation to determine the susceptibility of the heart to IRI. The results showed that the body weight of the maternal rats was not significantly different between the study and control groups, but the body weight of their offspring in AT1-AA group was decreased slightly at day 21 of gestational age, and at day 3 after birth. Although the heart weight index was not significantly affected at all ages examined, AT1-AA significantly increased the size of myocardial cells of the left ventricle (LV at the age of 45 days. AT1-AA gained access to fetal circulation via the placenta and induced apoptosis of fetal myocardial cells. AT1-AA also significantly delayed recovery from IRI and affected the LV function of 45-day-old offspring. This was associated with a significant increase in IRI-induced LV myocardial infarct size. These results suggest that AT1-AA induced abnormal apoptosis of fetal myocardial cells during the fetal period and increased the cardiac susceptibility to IRI in adult offspring.

  20. Maternal treatment with agonistic autoantibodies against type-1 angiotensin II receptor in late pregnancy increases apoptosis of myocardial cells and myocardial susceptibility to ischemia-reperfusion injury in offspring rats.

    Science.gov (United States)

    Jin, Zhu; Zhang, Wenhui; Yang, Hailiang; Wang, Xiaofang; Zheng, Yanqian; Zhang, Qiaoyan; Zhi, Jianming

    2013-01-01

    Epidemiological studies have demonstrated that offspring born to mothers preeclampsia (PE) are at increased risk for developing cardiovascular diseases after birth, but the underlying mechanism is unknown. Angiotensin II receptor type 1 autoantibody (AT1-AA), an agonist acting via activation of the AT1 receptor, is believed to be involved in the pathogenesis of both PE and fetal growth restriction. The aim of the present study was to confirm the hypothesis that prenatal AT1-AA exposure increases the heart susceptibility to ischemia/reperfusion injury (IRI) in the offspring in an AT1-AA-induced animal model of PE, and determine whether or not the increase of maternal AT1-AA level is a factor contributing to sustained abnormalities of the heart structure during infancy. The hearts of 45-day-old offspring rats were studied using Langendorff preparation to determine the susceptibility of the heart to IRI. The results showed that the body weight of the maternal rats was not significantly different between the study and control groups, but the body weight of their offspring in AT1-AA group was decreased slightly at day 21 of gestational age, and at day 3 after birth. Although the heart weight index was not significantly affected at all ages examined, AT1-AA significantly increased the size of myocardial cells of the left ventricle (LV) at the age of 45 days. AT1-AA gained access to fetal circulation via the placenta and induced apoptosis of fetal myocardial cells. AT1-AA also significantly delayed recovery from IRI and affected the LV function of 45-day-old offspring. This was associated with a significant increase in IRI-induced LV myocardial infarct size. These results suggest that AT1-AA induced abnormal apoptosis of fetal myocardial cells during the fetal period and increased the cardiac susceptibility to IRI in adult offspring.

  1. Early onset of endothelial cell proliferation in coronary thrombi of patients with an acute myocardial infarction: implications for plaque healing.

    Science.gov (United States)

    Li, X; Kramer, M C; VAN DER Loos, C M; Ploegmakers, H J P; DE Boer, O J; Koch, K T; Tijssen, J G P; DE Winter, R J; VAN DER Wal, A C

    2012-03-01

    Coronary thrombotic occlusion in ST-segment elevation myocardial infarction (STEMI) patients is often preceded by episodes of progressive growth of the thrombus mass. Similar to wound healing, the organization of thrombus could depend on ingrowth of microvessels in order to stabilize its structure. We investigated the patterns of neovascularization in different stages of coronary thrombus evolution. Thrombectomy materials obtained from STEMI patients were histologically classified according to thrombus age in three groups: fresh ( 5 days) thrombi. Forty thrombi of each group were randomly collected. Neovascularization in the thrombi was evaluated histomorphologically and with immunodouble stains to visualize various differentiation antigens of endothelial cells (ECs) and primitive cells. Morphologically, ECs in the coronary thrombi manifested as: single cells, cell clusters or microvessels. CD31+/CD34+ ECs were present in 98% of all the thrombi. In addition, endothelial clusters were found in 63% of the fresh thrombi (thrombi (> 5 days) compared with fresh and lytic ones (< 5 days), and mainly as cell clusters (P ≤ 0.05 for all). CD133+ primitive cells were found only sporadically in 11% of all the samples. EC proliferation is initiated very early, and gradually progresses during the organization process of thrombus after coronary plaque disruption, with only a limited contribution of primitive cells in this process. © 2012 International Society on Thrombosis and Haemostasis.

  2. Infarcted Myocardium-Primed Dendritic Cells Improve Remodeling and Cardiac Function After Myocardial Infarction by Modulating the Regulatory T Cell and Macrophage Polarization.

    Science.gov (United States)

    Choo, Eun Ho; Lee, Jun-Ho; Park, Eun-Hye; Park, Hyo Eun; Jung, Nam-Chul; Kim, Tae-Hoon; Koh, Yoon-Seok; Kim, Eunmin; Seung, Ki-Bae; Park, Cheongsoo; Hong, Kwan-Soo; Kang, Kwonyoon; Song, Jie-Young; Seo, Han Geuk; Lim, Dae-Seog; Chang, Kiyuk

    2017-04-11

    Inflammatory responses play a critical role in left ventricular remodeling after myocardial infarction (MI). Tolerogenic dendritic cells (tDCs) can modulate immune responses, inducing regulatory T cells in a number of inflammatory diseases. We generated tDCs by treating bone marrow-derived dendritic cells with tumor necrosis factor-α and cardiac lysate from MI mice. We injected MI mice, induced by a ligation of the left anterior descending coronary artery in C57BL/6 mice, twice with tDCs within 24 hours and at 7 days after the ligation. In vivo cardiac magnetic resonance imaging and ex vivo histology confirmed the beneficial effect on postinfarct left ventricular remodeling in MI mice treated with tDCs. Subcutaneously administered infarct lysate-primed tDCs near the inguinal lymph node migrated to the regional lymph node and induced infarct tissue-specific regulatory T-cell populations in the inguinal and mediastinal lymph nodes, spleen, and infarcted myocardium, indicating that a local injection of tDCs induces a systemic activation of MI-specific regulatory T cells. These events elicited an inflammatory-to-reparative macrophage shift. The altered immune environment in the infarcted heart resulted in a better wound remodeling, preserved left ventricular systolic function after myocardial tissue damage, and improved survival. This study showed that tDC therapy in a preclinical model of MI was potentially translatable into an antiremodeling therapy for ischemic tissue repair. © 2017 American Heart Association, Inc.

  3. Myocardial Ischemia

    Science.gov (United States)

    ... occurs when blood flow to the heart muscle (myocardium) is obstructed by a partial or complete blockage of a coronary artery by a buildup of plaques (atherosclerosis). If the plaques rupture, you can have a heart attack (myocardial infarction). Myocardial ischemia occurs when blood flow ...

  4. Autologous Mesenchymal Stem Cells Show More Benefit on Systolic Function Compared to Bone Marrow Mononuclear Cells in a Porcine Model of Chronic Myocardial Infarction.

    Science.gov (United States)

    van der Spoel, T I G; Gathier, W A; Koudstaal, S; van Slochteren, F; Of Lorkeers, S Jansen; Sluijter, J P G; Hoefer, I E; Steendijk, P; Cramer, M J M; Doevendans, P A; van Belle, E; Chamuleau, S A J

    2015-10-01

    Cardiac cell therapy is a strategy to treat patients with chronic myocardial infarction (MI). No consensus exists regarding the optimal cell type. First, a comparison between autologous bone marrow-derived mononuclear cells (BMMNC) and mesenchymal stem cells (MSC) on therapeutic efficacy after MI was performed. Next, the effect of repetitive, NOGA-guided transendocardial injection was determined via a crossover design. Nineteen pigs were allocated in three groups: (1) placebo (at 4 and 8 weeks), (2) MSC (followed by placebo at 8 weeks), or (3) BMMNC (followed by MSC at 8 weeks) delivery including a priming strategy to enhance MSC effect. At 4 weeks, ejection fraction (EF) was significantly improved after MSC injection and not by BMMNC injection. After 8 weeks, no difference was observed in EF between cell-treated groups demonstrating the positive systolic effect of MSC. This study showed that MSC rather than BMMNC injection improves systolic function in chronic MI.

  5. The Aplnr GPCR regulates myocardial progenitor development via a novel cell-non-autonomous, Gαi/o protein-independent pathway

    Directory of Open Access Journals (Sweden)

    Sivani Paskaradevan

    2012-01-01

    Myocardial progenitor development involves the migration of cells to the anterior lateral plate mesoderm (ALPM where they are exposed to the necessary signals for heart development to proceed. Whether the arrival of cells to this location is sufficient, or whether earlier signaling events are required, for progenitor development is poorly understood. Here we demonstrate that in the absence of Aplnr signaling, cells fail to migrate to the heart-forming region of the ALPM. Our work uncovers a previously uncharacterized cell-non-autonomous function for Aplnr signaling in cardiac development. Furthermore, we show that both the single known Aplnr ligand, Apelin, and the canonical Gαi/o proteins that signal downstream of Aplnr are dispensable for Aplnr function in the context of myocardial progenitor development. This novel Aplnr signal can be substituted for by activation of Gata5/Smarcd3 in myocardial progenitors, suggesting a novel mechanism for Aplnr signaling in the establishment of a niche required for the proper migration/development of myocardial progenitor cells.

  6. Myocardial Lineage Development

    Science.gov (United States)

    Evans, Sylvia M.; Yelon, Deborah; Conlon, Frank L.; Kirby, Margaret L.

    2010-01-01

    The myocardium of the heart is composed of multiple highly specialized myocardial lineages, including those of the ventricular and atrial myocardium, and the specialized conduction system. Specification and maturation of each of these lineages during heart development is a highly ordered, ongoing process involving multiple signaling pathways and their intersection with transcriptional regulatory networks. Here, we attempt to summarize and compare much of what we know about specification and maturation of myocardial lineages from studies in several different vertebrate model systems. To date, most research has focused on early specification, and while there is still more to learn, less is known about factors that promote subsequent maturation of myocardial lineages required to build the functioning adult heart. PMID:21148449

  7. Myocardial dysfunction in patients with type 2 diabetes mellitus: role of endothelial progenitor cells and oxidative stress

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    Zhao Chun

    2012-12-01

    Full Text Available Abstract Background Endothelial progenitor cells (EPCs are responsible for angiogenesis and maintenance of microvascular integrity, the number of EPCs is correlated with oxidative stress. Their relation to myocardial dysfunction in patients with type 2 diabetes mellitus (T2DM is nonetheless unknown. Methods Eighty-seven patients with T2DM and no history of coronary artery disease were recruited. Transthoracic echocardiography and detailed evaluation of left ventricular (LV systolic function by 2-dimensional (2D speckle tracking derived strain analysis in 3 orthogonal directions was performed. Four subpopulations of EPCs, including CD34+, CD133+, CD34+/kinase insert domain-containing receptor (KDR + and CD133+/KDR + EPCs, were measured by flow cytometry. Oxidative stress was assessed by superoxide dismutase (SOD. Results The mean age of the patients was 62 ± 9 years and 39.6% were male. Those with an impaired longitudinal strain had a lower number of CD34+ EPCs (2.82 ± 1.87% vs. 3.74 ± 2.12%, P  Conclusions LV global circumferential strain was independently associated with number of CD34+ EPCs and SOD. These findings suggest that myocardial dysfunction in patients with T2DM is related to depletion of EPCs and increased oxidative stress.

  8. Human adipose stem cell and ASC-derived cardiac progenitor cellular therapy improves outcomes in a murine model of myocardial infarction

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    Davy PMC

    2015-10-01

    Full Text Available Philip MC Davy,1 Kevin D Lye,2,3 Juanita Mathews,1 Jesse B Owens,1 Alice Y Chow,1 Livingston Wong,2 Stefan Moisyadi,1 Richard C Allsopp1 1Institute for Biogenesis Research, 2John A. Burns School of Medicine, University of Hawaii at Mānoa, 3Tissue Genesis, Inc., Honolulu, HI, USA Background: Adipose tissue is an abundant and potent source of adult stem cells for transplant therapy. In this study, we present our findings on the potential application of adipose-derived stem cells (ASCs as well as induced cardiac-like progenitors (iCPs derived from ASCs for the treatment of myocardial infarction. Methods and results: Human bone marrow (BM-derived stem cells, ASCs, and iCPs generated from ASCs using three defined cardiac lineage transcription factors were assessed in an immune-compromised mouse myocardial infarction model. Analysis of iCP prior to transplant confirmed changes in gene and protein expression consistent with a cardiac phenotype. Endpoint analysis was performed 1 month posttransplant. Significantly increased endpoint fractional shortening, as well as reduction in the infarct area at risk, was observed in recipients of iCPs as compared to the other recipient cohorts. Both recipients of iCPs and ASCs presented higher myocardial capillary densities than either recipients of BM-derived stem cells or the control cohort. Furthermore, mice receiving iCPs had a significantly higher cardiac retention of transplanted cells than all other groups. Conclusion: Overall, iCPs generated from ASCs outperform BM-derived stem cells and ASCs in facilitating recovery from induced myocardial infarction in mice. Keywords: adipose stem cells, myocardial infarction, cellular reprogramming, cellular therapy, piggyBac, induced cardiac-like progenitors

  9. Extracellular talaporfin sodium-induced photosensitization reaction with various albumin animal species on myocardial cells in vitro

    Science.gov (United States)

    Ogawa, Emiyu; Arai, Tsunenori

    2017-02-01

    It is reported that the albumin has different structure among animal species. We have proposed a new methodology of cardiac ablation using talaporfin sodium-induced photosensitization reaction with short drug-light interval to realize immediate and permanent therapeutic effect by singlet oxygen production mainly in the interstitial space. The photosensitization reaction efficacy with different animal species should be investing to consider the optimal animal therapeutic model to evaluate the therapeutic effect of new cardiac ablation methodology. We studied the cell-killing efficacy of extracellular talaporfin sodium-induced photosensitization reaction using talaporfin sodium on myocardial cells in vitro with different albumin animal species: human, canine, bovine, and porcine serum albumin. We obtained that the albumin concentration tendency on the binding ratio and cell lethality was different among the animal species but there was no correlation between binding ratio and cell lethality. We found that the cell lethality dependence on albumin concentration showed 2 different groups, human-canine and bovine-porcine. We think that the canine might be useful as a therapeutic animal model since the cytotoxicity tendency on albumin concentration was similar with that of human albumin. These cell lethality tendency difference would be suggested to explain by the existence of the diazepam site that talaporfin sodium binds mainly.

  10. Interleukin-2/Anti-Interleukin-2 Immune Complex Attenuates Cardiac Remodeling after Myocardial Infarction through Expansion of Regulatory T Cells

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    Zhipeng Zeng

    2016-01-01

    Full Text Available CD4+CD25+Foxp3+ regulatory T cells (Treg cells have protective effects in wound healing and adverse ventricular remodeling after myocardial infarction (MI. We hypothesize that the interleukin- (IL- 2 complex comprising the recombinant mouse IL-2/anti-IL-2 mAb (JES6-1 attenuates cardiac remodeling after MI through the expansion of Treg. Mice were subjected to surgical left anterior descending coronary artery ligation and treated with either PBS or IL-2 complex. The IL-2 complex significantly attenuates ventricular remodeling, as demonstrated by reduced infarct size, improved left ventricular (LV function, and attenuated cardiomyocyte apoptosis. The IL-2 complex increased the percentage of CD4+CD25+Foxp3+ Treg cells, which may be recruited to the infarcted heart, and decreased the frequencies of IFN-γ- and IL-17-producing CD4+ T helper (Th cells among the CD4+Foxp3− T cells in the spleen. Furthermore, the IL-2 complex inhibited the gene expression of proinflammatory cytokines as well as macrophage infiltrates in the infarcted myocardium and induced the differentiation of macrophages from M1 to M2 phenotype in border zone of infarcted myocardium. Our studies indicate that the IL-2 complex may serve as a promising therapeutic approach to attenuate adverse remodeling after MI through expanding Treg cells specifically.

  11. Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction

    Science.gov (United States)

    Zangi, Lior; Lui, Kathy O.; von Gise, Alexander; Ma, Qing; Ebina, Wataru; Ptaszek, Leon M.; Später, Daniela; Xu, Huansheng; Tabebordbar, Mohammadsharif; Gorbatov, Rostic; Sena, Brena; Nahrendorf, Matthias; Briscoe, David M.; Li, Ronald A.; Wagers, Amy J.; Rossi, Derrick J.; Pu, William T.; Chien, Kenneth R.

    2014-01-01

    In a cell-free approach to regenerative therapeutics, transient application of paracrine factors in vivo could be used to alter the behavior and fate of progenitor cells to achieve sustained clinical benefits. Here we show that intramyocardial injection of synthetic modified RNA (modRNA) encoding human vascular endothelial growth factor-A (VEGF-A) resulted in the expansion and directed differentiation of endogenous heart progenitors in a murine myocardial infarction model. VEGF-A modRNA markedly improved heart function and enhanced long-term survival of recipients. This improvement was in part due to mobilization of epicardial progenitor cells and redirection of their differentiation toward cardiovascular cell types. Direct in vivo comparison with DNA vectors, and temporal control with VEGF inhibitors, documented the markedly increased efficacy of pulse-like delivery of VEGF-A. Our results suggest that modRNA is a versatile approach for expressing paracrine factors as cell fate switches to control progenitor cell fate and thereby enhance long term organ repair. PMID:24013197

  12. Glutamine reduces myocardial cell apoptosis in a rat model of sepsis by promoting expression of heat shock protein 90.

    Science.gov (United States)

    Li, Wanxia; Tao, Shaoyu; Wu, Qinghua; Wu, Tao; Tao, Ran; Fan, Jun

    2017-12-01

    Myocardial cell injury and cardiac myocyte apoptosis are associated with sepsis. Glutamine (Gln) has been reported to repair myocardial cell injury. The aim of this study was to explore the role of Gln on cardiac myocytes in a cecal ligation and puncture (CLP) model of sepsis in Wistar rats. Following induction of sepsis in a CLP rat model, viral encoding heat shock protein 90 (Hsp90) gene and Hsp90dsDNA were designed to express and knockdown Hsp90, respectively. Rat cardiac tissues were examined histologically, and apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling staining. The expression of B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein, Hsp90, p53 upregulated modulator of apoptosis, and p53 was measured by western blotting and real-time polymerase chain reaction. Caspase-3, caspase-8, and caspase-9 were detected by enzyme-linked immunosorbent assay. Rat cardiac myocyte damage induced by CLP was reduced by Gln treatment and Hsp90 overexpression, and these changes were reversed by Hsp90 knockdown. Bcl-2 expression, Bcl-2-associated X protein, p53, p53 upregulated modulator of apoptosis, caspase-8, caspase-9, and caspase-3 activities were significantly upregulated in the CLP model, which were reduced by Gln treatment and Hsp90 overexpression. Gln reduced apoptosis of cardiac myocytes in a rat model of sepsis, by promoting Hsp90 expression. Further studies are needed to determine the possible therapeutic action of Gln in sepsis in human tissue. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. A randomized double-blind control study of early intra-coronary autologous bone marrow cell infusion in acute myocardial infarction

    DEFF Research Database (Denmark)

    Choudry, Fizzah; Hamshere, Stephen; Saunders, Natalie

    2016-01-01

    Aims: Clinical trials suggest that intracoronary delivery of autologous bone marrow-derived cells (BMCs) 1-7 days post-Acute myocardial infarction (AMI) may improve left ventricular (LV) function. Earlier time points have not been evaluated. We sought to determine the effect of intracoronary auto...

  14. IgM Antibodies Against Apoptotic Cells and Phosphorylcholine in Patients with Acute Myocardial Infarction in Relation to Infarct Size and Inflammatory Response

    NARCIS (Netherlands)

    Diepenhorst, Gwen M. P.; Ciurana, Caroline L. F.; Diaz Padilla, Niubel; Boekholdt, S. Matthijs; Krijnen, Paul A. J.; Lagrand, Wim K.; Niessen, Hans W. M.; Hack, C. Erik

    2012-01-01

    Background. Natural IgM antibodies, and anti-phosphorylcholine IgM (anti-PC IgM) in particular, may modulate the pathogenesis of acute myocardial infarction (AMI). Objectives. An exploratory study was conducted to evaluate the hypothesis that circulating anti-PC IgM and IgM binding to damaged cells

  15. Induction of a monocyte/macrophage phenotype switch by mesenchymal stem cells might contribute to improved infarct healing postacute myocardial infarction

    NARCIS (Netherlands)

    ter Horst, E. N.; Naaijkens, B. A.; Krijnen, P. A.; van der Laan, A. M.; Piek, J. J.; Niessen, H. W.

    2013-01-01

    Inadequate healing following acute myocardial infarction (AMI) can lead to the development of heart failure. The ischemic myocardium triggers an inflammatory response that clears cell debris and initiates the onset of scar tissue formation. The duration and intensity of this inflammatory response

  16. Impact of intracoronary bone marrow cell therapy on left ventricular function in the setting of ST-segment elevation myocardial infarction: a collaborative meta-analysis

    NARCIS (Netherlands)

    Delewi, Ronak; Hirsch, Alexander; Tijssen, Jan G.; Schächinger, Volker; Wojakowski, Wojciech; Roncalli, Jérôme; Aakhus, Svend; Erbs, Sandra; Assmus, Birgit; Tendera, Michal; Goekmen Turan, R.; Corti, Roberto; Henry, Tim; Lemarchand, Patricia; Lunde, Ketil; Cao, Feng; Huikuri, Heikki V.; Sürder, Daniel; Simari, Robert D.; Janssens, Stefan; Wollert, Kai C.; Plewka, Michal; Grajek, Stefan; Traverse, Jay H.; Zijlstra, Felix; Piek, Jan J.

    2014-01-01

    The objective of the present analysis was to systematically examine the effect of intracoronary bone marrow cell (BMC) therapy on left ventricular (LV) function after ST-segment elevation myocardial infarction in various subgroups of patients by performing a collaborative meta-analysis of randomized

  17. CADUCEUS, SCIPIO, ALCADIA: Cell therapy trials using cardiac-°©‐derived cells for patients with post myocardial infarction LV dysfunction, still evolving

    Directory of Open Access Journals (Sweden)

    Magdi H Yacoub

    2012-03-01

    Full Text Available The early results of the CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction study were recently published in the Lancet [1]. This study is a phase 1 prospective randomised study, performed at two centres. The study was designed to test the hypothesis that intracoronary infusion of autologous cardiac-derived cells following myocardial infarction can reduce the size of the infarct and increase the amount of viable myocardium. The eligible patients were randomised in a 2:1 ratio to receive CDCs or standard care. In all, 17 patients were randomised to cell therapy and 8 to standard care. The cell therapy consisted of an infusion of 25 million cells into the infarct related artery, 1.5–3 months after successful primary angioplasty in patients who developed LV dysfunction (EF less than 37 per cent. The cells were derived from RV endomyocardial biopsies performed within the previous 37 days. The number of cells was determined from previous experimental studies of the maximum number of cells which can be injected without inducing infarction. The study was not blinded because of ethical considerations regarding performing right ventricular biopsy on the controls. The exclusion criteria included patients who had evidence of right ventricular infarction, or could not have an MRI examination because of claustrophobia or prior insertion of devices. There was no death, myocardial infarction or serious arrhythmia reported in either group during the period of follow up, which was between 6-12 months. Serious adverse events were observed in 24 percent of the intervention group versus 12 per cent in the controls (p not significant.

  18. Inflammatory cell content of coronary thrombi is dependent on thrombus age in patients with ST-elevation myocardial infarction.

    Science.gov (United States)

    Fuijkschot, Wessel W; Groothuizen, Wouter E; Appelman, Yolande; Radonic, Teodora; van Royen, Niels; van Leeuwen, Maarten A H; Krijnen, Paul A J; van der Wal, Allard C; Smulders, Yvo M; Niessen, Hans W M

    2017-01-01

    ST-elevation myocardial infarction (STEMI) is typically caused by an occlusive coronary thrombus. The process of intracoronary thrombus formation is poorly understood. It is known that inflammatory cells play a role in the formation and resolution of venous thrombi, however their role in coronary thrombosis is not clear. We therefore analyzed inflammatory cells in thrombi derived from patients with STEMI in relation to histologically classified thrombus age. Thrombus aspirates of 113 patients treated with primary percutaneous coronary intervention were prospectively collected and classified (fresh, lytic, or organized) based on hematoxylin and eosin staining. The density of inflammatory cells neutrophils (MPO), monocytes/macrophages (CD68), lymphocytes (CD45), and the platelet area (CD31), were visualized using immunohistochemistry. Patients' history, medication, and laboratory data were registered. Fresh thrombi (76.1%) were the most abundant as compared to lytic (16.8%) and organized (7.1%) thrombi. Neutrophils were significantly less present in organized (169cells/mm2) compared to fresh (327 cells/mm2) and lytic thrombi (311 cells/mm2). Monocytes/macrophages were significantly more present in lytic (471 cells/mm2) than in fresh (312 cells/mm2) thrombi. We additionally found that thrombi from patients aged 50 years old contained significantly more neutrophils and monocytes/macrophages irrespective of thrombus age. Furthermore platelet area was smaller in patients on aspirin again irrespective of thrombus age. No gender differences were found. The composition of inflammatory cells differs with thrombus age in thrombosuction material of STEMI patients that in part depends on patient age and medication. Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

  19. Screening β1AR inhibitors by cell membrane chromatography and offline UPLC/MS method for protecting myocardial ischemia.

    Science.gov (United States)

    Yue, Yuan; Dou, Lili; Wang, Xin; Xue, Hui; Song, Yanhong; Li, Xiaoni

    2015-11-10

    A high expression β1AR/cell membrane chromatography (β1AR-CMC) and offline UPLC/MS method has been developed for screening active ingredients from Coptis chinensis. In this study, the fractions retained by CMC column were separated and identified by UPLC/MS system. Using metoprolol as a positive control drug, coptisine from C. chinensis was identified as the active component which could inhibit β1AR. Compared with the control group: coptisine could attenuate the infarct size and release malondialdehyde (MDA) while increasing superoxide dismutase (SOD) activity, suggesting a role in reducing myocardial injury. In vitro, coptisine could decrease apoptosis, showing their protective effects upon cardiomyocytes. This β1AR-CMC-offline-UPLC/MS method can be applied for screening active components acting on β1AR from traditional Chinese medicines. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. An on-chip cardiomyocyte cell network assay for stable drug screening regarding community effect of cell network size.

    Science.gov (United States)

    Kaneko, Tomoyuki; Kojima, Kensuke; Yasuda, Kenji

    2007-09-01

    We investigate the effect of haloperidol on a four-cell and nine-cell cardiomyocyte network on an agarose microchamber array chip to evaluate a cell-based model for drug screening. Using a network of cardiomyocytes whose beating intervals were stable and relatively uniform (they only fluctuated 10% from the mean beating interval), we easily observed the effect of haloperidol on the cell network beating interval 5 min after administering it. We also observed the beating interval returned to its original state 10 min after the haloperidol was washed out of the chip. Although the four-cell network showed the unstable recovery of its beating rhythm after washout of haloperidol, the nine-cell network recovered completely to the stable original beating rhythm even after a second administration of haloperidol. The results indicate the importance of the community size in cell networks used in the stable cell-based screening model. Moreover, they indicate the advantage of using direct cell-based measurements in which the amount of drug administered and the time course over which it is administered are strictly controlled for evaluating the quantitative chemical effects of drugs on cells.

  1. Localization and expression of Hsp27 and αB-crystallin in rat primary myocardial cells during heat stress in vitro.

    Directory of Open Access Journals (Sweden)

    Shu Tang

    Full Text Available Neonatal rat primary myocardial cells were subjected to heat stress in vitro, as a model for investigating the distribution and expression of Hsp27 and αB-crystallin. After exposure to heat stress at 42°C for different durations, the activities of enzymes expressed during cell damage increased in the supernatant of the heat-stressed myocardial cells from 10 min, and the pathological lesions were characterized by karyopyknosis and acute degeneration. Thus, cell damage was induced at the onset of heat stress. Immunofluorescence analysis showed stronger positive signals for both Hsp27 and αB-crystallin from 10 min to 240 min of exposure compared to the control cells. According to the Western blotting results, during the 480 min of heat stress, no significant variation was found in Hsp27 and αB-crystallin expression; however, significant differences were found in the induction of their corresponding mRNAs. The expression of these small heat shock proteins (sHsps was probably delayed or overtaxed due to the rapid consumption of sHsps in myocardial cells at the onset of heat stress. Our findings indicate that Hsp27 and αB-crystallin do play a role in the response of cardiac cells to heat stress, but the details of their function remain to be investigated.

  2. Omentum-derived stromal cells improve myocardial regeneration in pig post-infarcted heart through a potent paracrine mechanism

    Energy Technology Data Exchange (ETDEWEB)

    De Siena, Rocco; Balducci, Luigi; Blasi, Antonella; Montanaro, Manuela Gessica; Saldarelli, Marilisa [Medestea Research and Production Laboratories, Consorzio Carso, 70010 Valenzano, Bari (Italy); Saponaro, Vittorio [Department of Veterinary Medicine, University of Bari, 70010 Valenzano, Bari (Italy); Martino, Carmela [Medestea Research and Production Laboratories, Consorzio Carso, 70010 Valenzano, Bari (Italy); Logrieco, Gaetano [Department of Surgery, Hospital ' F. Miulli' 70021 AcquaViva delle Fonti, Bari (Italy); Soleti, Antonio; Fiobellot, Simona [Medestea Research and Production Laboratories, Consorzio Carso, 70010 Valenzano, Bari (Italy); Madeddu, Paolo [Experimental Cardiovascular Medicine, Bristol Heart Institute, Bristol BS2 8WH (United Kingdom); Rossi, Giacomo [Department of Pathology, University of Camerino, 63100 Ascoli Piceno (Italy); Ribatti, Domenico [Department of Human Anatomy, University of Bari, 70125 Bari (Italy); Crovace, Antonio [Department of Veterinary Medicine, University of Bari, 70010 Valenzano, Bari (Italy); Cristini, Silvia; Invernici, Gloria; Parati, Eugenio Agostino [Cellular Neurobiology Laboratory, Department of Cerebrovascular Diseases, Fondazione IRCCS Neurological Institute ' Carlo Besta' , 20133 Milan (Italy); Alessandri, Giulio, E-mail: cisiamo2@yahoo.com [Cellular Neurobiology Laboratory, Department of Cerebrovascular Diseases, Fondazione IRCCS Neurological Institute ' Carlo Besta' , 20133 Milan (Italy)

    2010-07-01

    Cell-based therapy could be a valid option to treat myocardial infarct (MI). Adipose-derived stromal cells (ADStCs) have demonstrated tissue regenerative potential including cardiomyogenesis. Omentum is an extremely rich source of visceral fat and its accumulation seems to correlate with cardiovascular diseases. We investigated the capacity of human fat Omentum-derived StCs (FOStCs) to affect heart function upon acute infarct in pigs induced by permanent ligation of the anterior interventricular artery (IVA). We demonstrated for the first time that the local injection of 50 x 10{sup 6} of FOStCs ameliorates the functional parameters of post-infarct heart. Most importantly, histology of FOStCs treated hearts demonstrated a substantial improvement of cardiomyogenesis. In culture, FOStCs produced an impressive number and amount of angiogenic factors and cytokines. Moreover, the conditioned medium of FOStCs (FOStCs-CM) stimulates in vitro cardiac endothelial cells (ECs) proliferation and vascular morphogenesis and inhibits monocytes, EC activation and cardiomyocyte apoptosis. Since FOStCs in vivo did not trans-differentiate into cardiomyocyte-like cells, we conclude that FOStCs efficacy was presumably mediated by a potent paracrine mechanism involving molecules that concomitantly improved angiogenesis, reduced inflammation and prevented cardiomyocytes death. Our results highlight for the first time the important role that human FOStCs may have in cardiac regeneration.

  3. Good manufacturing practice-compliant validation and preparation of BM cells for the therapy of acute myocardial infarction.

    Science.gov (United States)

    Griesel, C; Heuft, H-G; Herrmann, D; Franke, A; Ladas, D; Stiehler, N; Stucki, A; Braun, M; Wollert, K C; Meyer, G P; Drexler, H; Hertenstein, B; Ganser, A; Rüdinger, W; Arseniev, L

    2007-01-01

    Intracoronary application of BM-derived cells for the treatment of acute myocardial infarction (AMI) is currently being studied intensively. Simultaneously, strict legal requirements surround the production of cells for clinical studies. Thus good manufacturing practice (GMP)-compliant collection and preparation of BM for patients with AMI was established by the Cytonet group. As well as fulfillment of standard GMP requirements, including a manufacturing license, validation of the preparation process and the final product was performed. Whole blood (n=6) and BM (n=3) validation samples were processed under GMP conditions by gelafundin or hydroxyethylstarch sedimentation in order to reduce erythrocytes/platelets and volume and to achieve specifications defined in advance. Special attention was paid to the free potassium (preparations for clinical use were carried out following the validated methodology and standards. Additionally three selections of CD34+ BM cells for infusion were performed. All specification limits were met. Discussion In conclusion, preparation of BM cells for intracoronary application is feasible under GMP conditions. As the results of sterility testing may not be available at the time of intracoronary application, the highest possible standards to avoid bacterial and other contaminations have to be applied. The increased expense of the GMP-compliant process can be justified by higher safety for patients and better control of the final product.

  4. Epac-Rap1-activated mesenchymal stem cells improve cardiac function in rat model of myocardial infarction.

    Science.gov (United States)

    Khan, Irfan; Ali, Anwar; Akhter, Muhammad Aleem; Naeem, Nadia; Chotani, Maqsood Ahmed; Iqbal, Hana'a; Kabir, Nurul; Atiq, Mehnaz; Salim, Asmat

    2017-04-01

    Rap1, a member of Ras superfamily of small GTP-binding proteins, is involved in cardiovascular biology in numerous ways. It is an evolutionary conserved regulator of adhesion, polarity, differentiation and growth. Our aim was to analyze Rap1-activated rat bone marrow mesenchymal stem cells (MSCs) for their potential role in adhesion and cardiac differentiation. Myocardial infarction (MI) was produced in Sprague Dawley (SD) rats through occlusion of the left anterior descending coronary artery. MSCs were treated with 8-pCPT-2'-O-Me-cAMP (CPT) to activate Rap1. Normal (untreated) and CPT-treated MSCs were transplanted through intramyocardial injection in respective groups. Cardiac function was assessed by echocardiography at 2 and 4 weeks after cell transplantation. Histological analysis was performed to observe changes at tissue level. Homing of CPT-treated MSCs was significantly (***Pinfarcted hearts. This may be due to increase in the gene expression of some of the cell adhesion molecules as evident by qRT-PCR analysis. Significant (***Ptherapy groups showed significant increase as compared to MI model. Our findings showed that pharmacological activation of Epac-Rap1 improves cardiac function through better survival, adhesion and differentiation of transplanted cells. Transplantation of these MSCs in the infarct area restored functional myocardium. © 2016 John Wiley & Sons Ltd.

  5. Omentum-derived stromal cells improve myocardial regeneration in pig post-infarcted heart through a potent paracrine mechanism.

    Science.gov (United States)

    De Siena, Rocco; Balducci, Luigi; Blasi, Antonella; Montanaro, Manuela Gessica; Saldarelli, Marilisa; Saponaro, Vittorio; Martino, Carmela; Logrieco, Gaetano; Soleti, Antonio; Fiobellot, Simona; Madeddu, Paolo; Rossi, Giacomo; Ribatti, Domenico; Crovace, Antonio; Cristini, Silvia; Invernici, Gloria; Parati, Eugenio Agostino; Alessandri, Giulio

    2010-07-01

    Cell-based therapy could be a valid option to treat myocardial infarct (MI). Adipose-derived stromal cells (ADStCs) have demonstrated tissue regenerative potential including cardiomyogenesis. Omentum is an extremely rich source of visceral fat and its accumulation seems to correlate with cardiovascular diseases. We investigated the capacity of human fat Omentum-derived StCs (FOStCs) to affect heart function upon acute infarct in pigs induced by permanent ligation of the anterior interventricular artery (IVA). We demonstrated for the first time that the local injection of 50x10(6) of FOStCs ameliorates the functional parameters of post-infarct heart. Most importantly, histology of FOStCs treated hearts demonstrated a substantial improvement of cardiomyogenesis. In culture, FOStCs produced an impressive number and amount of angiogenic factors and cytokines. Moreover, the conditioned medium of FOStCs (FOStCs-CM) stimulates in vitro cardiac endothelial cells (ECs) proliferation and vascular morphogenesis and inhibits monocytes, EC activation and cardiomyocyte apoptosis. Since FOStCs in vivo did not trans-differentiate into cardiomyocyte-like cells, we conclude that FOStCs efficacy was presumably mediated by a potent paracrine mechanism involving molecules that concomitantly improved angiogenesis, reduced inflammation and prevented cardiomyocytes death. Our results highlight for the first time the important role that human FOStCs may have in cardiac regeneration.

  6. Intramyocardial transplantation and tracking of human mesenchymal stem cells in a novel intra-uterine pre-immune fetal sheep myocardial infarction model: a proof of concept study.

    Directory of Open Access Journals (Sweden)

    Maximilian Y Emmert

    Full Text Available Although stem-cell therapies have been suggested for cardiac-regeneration after myocardial-infarction (MI, key-questions regarding the in-vivo cell-fate remain unknown. While most available animal-models require immunosuppressive-therapy when applying human cells, the fetal-sheep being pre-immune until day 75 of gestation has been proposed for the in-vivo tracking of human cells after intra-peritoneal transplantation. We introduce a novel intra-uterine myocardial-infarction model to track human mesenchymal stem cells after direct intra-myocardial transplantation into the pre-immune fetal-sheep. Thirteen fetal-sheep (gestation age: 70-75 days were included. Ten animals either received an intra-uterine induction of MI only (n = 4 or MI+intra-myocardial injection (IMI;n = 6 using micron-sized, iron-oxide (MPIO labeled human mesenchymal stem cells either derived from the adipose-tissue (ATMSCs;n = 3 or the bone-marrow (BMMSCs;n = 3. Three animals received an intra-peritoneal injection (IPI;n = 3; ATMSCs;n = 2/BMMSCs;n = 1. All procedures were performed successfully and follow-up was 7-9 days. To assess human cell-fate, multimodal cell-tracking was performed via MRI and/or Micro-CT, Flow-Cytometry, PCR and immunohistochemistry. After IMI, MRI displayed an estimated amount of 1×10(5-5×10(5 human cells within ventricular-wall corresponding to the injection-sites which was further confirmed on Micro-CT. PCR and IHC verified intra-myocardial presence via detection of human-specific β-2-microglobulin, MHC-1, ALU-Sequence and anti-FITC targeting the fluorochrome-labeled part of the MPIOs. The cells appeared viable, integrated and were found in clusters or in the interstitial-spaces. Flow-Cytometry confirmed intra-myocardial presence, and showed further distribution within the spleen, lungs, kidneys and brain. Following IPI, MRI indicated the cells within the intra-peritoneal-cavity involving the liver and kidneys. Flow

  7. Intramyocardial transplantation and tracking of human mesenchymal stem cells in a novel intra-uterine pre-immune fetal sheep myocardial infarction model: a proof of concept study.

    Science.gov (United States)

    Emmert, Maximilian Y; Weber, Benedikt; Wolint, Petra; Frauenfelder, Thomas; Zeisberger, Steffen M; Behr, Luc; Sammut, Sebastien; Scherman, Jacques; Brokopp, Chad E; Schwartländer, Ruth; Vogel, Viola; Vogt, Peter; Grünenfelder, Jürg; Alkadhi, Hatem; Falk, Volkmar; Boss, Andreas; Hoerstrup, Simon P

    2013-01-01

    Although stem-cell therapies have been suggested for cardiac-regeneration after myocardial-infarction (MI), key-questions regarding the in-vivo cell-fate remain unknown. While most available animal-models require immunosuppressive-therapy when applying human cells, the fetal-sheep being pre-immune until day 75 of gestation has been proposed for the in-vivo tracking of human cells after intra-peritoneal transplantation. We introduce a novel intra-uterine myocardial-infarction model to track human mesenchymal stem cells after direct intra-myocardial transplantation into the pre-immune fetal-sheep. Thirteen fetal-sheep (gestation age: 70-75 days) were included. Ten animals either received an intra-uterine induction of MI only (n = 4) or MI+intra-myocardial injection (IMI;n = 6) using micron-sized, iron-oxide (MPIO) labeled human mesenchymal stem cells either derived from the adipose-tissue (ATMSCs;n = 3) or the bone-marrow (BMMSCs;n = 3). Three animals received an intra-peritoneal injection (IPI;n = 3; ATMSCs;n = 2/BMMSCs;n = 1). All procedures were performed successfully and follow-up was 7-9 days. To assess human cell-fate, multimodal cell-tracking was performed via MRI and/or Micro-CT, Flow-Cytometry, PCR and immunohistochemistry. After IMI, MRI displayed an estimated amount of 1×10(5)-5×10(5) human cells within ventricular-wall corresponding to the injection-sites which was further confirmed on Micro-CT. PCR and IHC verified intra-myocardial presence via detection of human-specific β-2-microglobulin, MHC-1, ALU-Sequence and anti-FITC targeting the fluorochrome-labeled part of the MPIOs. The cells appeared viable, integrated and were found in clusters or in the interstitial-spaces. Flow-Cytometry confirmed intra-myocardial presence, and showed further distribution within the spleen, lungs, kidneys and brain. Following IPI, MRI indicated the cells within the intra-peritoneal-cavity involving the liver and kidneys. Flow

  8. Dual isotope simultaneous imaging to evaluate the effects of intracoronary bone marrow-derived mesenchymal stem cells on perfusion and metabolism in canines with acute myocardial infarction

    OpenAIRE

    HAO, LINJUN; Hao, Jin; Fang, Wei; Han, Chunlei; ZHANG, KAIXIU; Wang, Xuemei

    2015-01-01

    Stem cell therapy on acute myocardial infarction (AMI) has been performed for over a decade. In the present study, cardiac perfusion, metabolism and function in dogs with AMI treated by intracoronary injection of bone marrow-derived mesenchymal stem cells (MSCs) were evaluated by dual isotope simultaneous acquisition (DISA) of single positron emission computed tomography (SPECT). Dogs (n=12, 20–30 kg) were randomly assigned to two groups: A graft study (n=6) and control group (n=6). Bone marr...

  9. Treatment of Chronic Myocardial Infarction in a Pig (Sus scrofa) Model with Extracellular Matrix and Stem Cells

    Science.gov (United States)

    2015-08-13

    Use additional pages If necessary.) PROTOCOL #: FDG20140039A DATE: 13 August 2015 PROTOCOL TITLE: Treatment of Chronic Myocardial Infarction in a...model developed in protocols FDG20120019A and FDG20130043A, we were able to successfully create myocardial infarctions in pigs with a high survival rate...applications.) ObJectives: The goal of this protocol was to create myocardial infarctions in miniplgs using polystyrene microspheres to Infarct a

  10. Does transendocardial injection of mesenchymal stem cells improve myocardial function locally or globally?: An analysis from the Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis (POSEIDON) randomized trial.

    Science.gov (United States)

    Suncion, Viky Y; Ghersin, Eduard; Fishman, Joel E; Zambrano, Juan Pablo; Karantalis, Vasileios; Mandel, Nicole; Nelson, Katarina H; Gerstenblith, Gary; DiFede Velazquez, Darcy L; Breton, Elayne; Sitammagari, Kranthi; Schulman, Ivonne H; Taldone, Sabrina N; Williams, Adam R; Sanina, Cristina; Johnston, Peter V; Brinker, Jeffrey; Altman, Peter; Mushtaq, Muzammil; Trachtenberg, Barry; Mendizabal, Adam M; Tracy, Melissa; Da Silva, Jose; McNiece, Ian K; Lardo, Alberto C; George, Richard T; Hare, Joshua M; Heldman, Alan W

    2014-04-11

    Transendocardial stem cell injection (TESI) with mesenchymal stem cells improves remodeling in chronic ischemic cardiomyopathy, but the effect of the injection site remains unknown. To address whether TESI exerts its effects at the site of injection only or also in remote areas, we hypothesized that segmental myocardial scar and segmental ejection fraction improve to a greater extent in injected than in noninjected segments. Biplane ventriculographic and endocardial tracings were recorded. TESI was guided to 10 sites in infarct-border zones. Sites were mapped according to the 17-myocardial segment model. As a result, 510 segments were analyzed in 30 patients before and 13 months after TESI. Segmental early enhancement defect (a measure of scar size) was reduced by TESI in both injected (-43.7 ± 4.4%; n=95; PTESI. Although scar size reduction was evident in all scar segments, scar size reduction and ventricular functional responses preferentially occurred at the sites of TESI versus non-TESI sites. Furthermore, improvement was greatest when segmental left ventricular dysfunction was severe.

  11. Mitotically inactivated embryonic stem cells can be used as an in vivo feeder layer to nurse damaged myocardium after acute myocardial infarction: a preclinical study.

    Science.gov (United States)

    Burt, Richard K; Chen, You-hong; Verda, Larissa; Lucena, Carolina; Navale, Shankararao; Johnson, Jesse; Han, Xiaoqiang; Lomasney, Jon; Baker, Jessa M; Ngai, Ka-Leung; Kino, Aya; Carr, James; Kajstura, Jan; Anversa, Piero

    2012-10-26

    Various types of viable stem cells have been reported to result in modest improvement in cardiac function after acute myocardial infarction. The mechanisms for improvement from different stem cell populations remain unknown. To determine whether irradiated (nonviable) embryonic stem cells (iESCs) improve postischemic cardiac function without adverse consequences. After coronary artery ligation-induced cardiac infarction, either conditioned media or male murine or male human iESCs were injected into the penumbra of ischemic myocardial tissue of female mice or female rhesus macaque monkeys, respectively. Murine and human iESCs, despite irradiation doses that prevented proliferation and induced cell death, significantly improved cardiac function and decreased infarct size compared with untreated or media-treated controls. Fluorescent in situ hybridization of the Y chromosome revealed disappearance of iESCs within the myocardium, whereas 5-bromo-2'-deoxyuridine assays revealed de novo in vivo cardiomyocyte DNA synthesis. Microarray gene expression profiling demonstrated an early increase in metabolism, DNA proliferation, and chromatin remodeling pathways, and a decrease in fibrosis and inflammatory gene expression compared with media-treated controls. As a result of irradiation before injection, ex vivo and in vivo iESC existence is transient, yet iESCs provide a significant improvement in cardiac function after acute myocardial infarction. The mechanism(s) of action of iESCs seems to be related to cell-cell exchange, paracrine factors, and a scaffolding effect between iESCs and neighboring host cardiomyocytes.

  12. hHO-1 combined with GATA-4 transduction promotes myocardial transdifferentiation and anti- apoptosis of rat mesenchymal stem cells

    Directory of Open Access Journals (Sweden)

    Ning-bo DENG

    2017-06-01

    Full Text Available Objectives To explore if the rat bone marrow mesenchymal stem cells (BMSCs modified by human heme oxygenase 1 (hHO-1 gene combined with GATA-4 gene may promote the ability of anti-apoptosis and myocardial transdifferentiation in vitro in hypoxia ischemic environment. Methods The rat BMSCs were isolated and cultured by whole bone marrow adherence and identified in vitro, and then were transfected with recombinant adenovirus; Western blotting was used to determinate the optimal time of gene expression; the genetically modified BMSCs were taken to hypoxia serum-free conditions simulating ischemia hypoxia microenvironment in vivo; CCK-8 kit and trypan blue staining were performed to detect the 12, 24, 48 and 72h survival rates in hypoxia ischemia respectively; flow cytometry was used to detect the apoptosis of BMSCs in hypoxia ischemia for 24h. The cardiomyocyte-specific cardiac troponin I (cTnI was detected by Western blotting and cellular immunofluorescence. Results The 12, 24, 48 and 72h survival rates were higher in hHO-1+GATA-4 group cultured in ischemia and hypoxia condition than in hHO-1 group (P<0.05 and GATA-4 group (P<0.05. After 24h cultivation in ischemia hypoxia condition, the apoptotic rates were lower in hHO-1+GATA-4 group than in hHO-1 group (P<0.05 and GATA-4 group (P<0.05. No significant difference existed in cTnI expressions between GATA-4 group and hHO-1+GATA-4 group. Conclusion Compared with transfection of hHO-1 or GATA-4 single gene, hHO-1 combined with GATA-4 transduction can significantly increase the survival rate of BMSCs in hypoxia ischemic condition, but myocardial transdifferentiation does not increase significantly. DOI: 10.11855/j.issn.0577-7402.2017.04.08

  13. Delayed administration of allogeneic cardiac stem cell therapy for acute myocardial infarction could ameliorate adverse remodeling: experimental study in swine.

    Science.gov (United States)

    Crisostomo, Veronica; Baez-Diaz, Claudia; Maestre, Juan; Garcia-Lindo, Monica; Sun, Fei; Casado, Javier G; Blazquez, Rebeca; Abad, Jose L; Palacios, Itziar; Rodriguez-Borlado, Luis; Sanchez-Margallo, Francisco M

    2015-05-12

    The optimal timing of cardiac stem cells administration is still unclear. We assessed the safety of same-day and delayed (one week) delivery and the possible influence of the timing on the therapeutic outcomes of allogeneic porcine cardiac stem cells administration after acute myocardial infarction in a closed-chest ischemia-reperfusion model. Female swine surviving 90 min occlusion of the mid left anterior descending coronary artery received an intracoronary injection of 25x10(6) porcine cardiac stem cells either two hours (n = 5, D0) or 7 days (n = 6, D7) after reperfusion. Controls received intracoronary injection of vehicle on day 7 (n = 6, CON). Safety was defined in terms of absence of major cardiac events, changes to the ECG during injection, post-administration coronary flow assessed using the TIMI scale and cardiac troponin I determination after the intervention. Cardiac Magnetic Resonance was performed for morphological and functional assessment prior to infarction, before injection (D7 and CON groups only), at one and 10 weeks. Samples were taken from the infarct and transition areas for pathological examination. No major adverse cardiac events were seen during injection in any group. Animals receiving the therapy on the same day of infarction (D0 group) showed mild transient ST changes during injection (n = 4) and, in one case, slightly compromised coronary flow (TIMI 2). Cardiac function parameters and infarct sizes were not significantly different between groups, with a trend towards higher ejection fraction in the treated groups. Ventricular volumes indexed to body surface area increased over time in control animals, and decreased by the end of the study in animals receiving the therapy, significantly so when comparing End Diastolic Volume between CON and D7 groups (CON: 121.70 ml/m(2) ± 26.09 ml/m(2), D7: 98.71 ml/m(2) ± 8.30 ml/m(2), p = 0.037). The treated groups showed less organization of the collagenous scar, and a significantly (p = 0

  14. Comparing the effects of MSCs and CD34+ cell therapy in a rat model of myocardial infarction.

    Science.gov (United States)

    Shalaby, Sally M; El-Shal, Amal S; Zidan, Haidy E; Mazen, Nehad F; Abd El-Haleem, Manal R; Abd El Motteleb, Dalia M

    2016-05-01

    Stem cell therapy is considered as a promising approach in the treatment of myocardial infarction (MI). This study was designed as a comparison of human umbilical cord blood (HUCB)-derived CD34+ and HUCB-derived MSCs for the repair of cardiac tissue by induction of the angiogenesis. Forty-eight male rats were randomized into four groups: sham-operated group, MI group, MSCs-treated group, and CD34+ cells-treated group. After 4 weeks, the rats were sacrificed. All sections from left ventricles of all groups were subjected to hematoxylin & eosin, Masson's trichrome, and immunohistochemical stains (CD133, CD44, and α-smooth muscle actin). RNA was extracted for gene expression of the angiogenic markers. A significant reduction of the infarct size and the amplitude of T-wave in the CD34+ cells-treated group when compared with the MSCs-treated group were determined. Histologically, the MI group showed scar tissue, congested blood capillaries around the infarcted area, some necrotic cells, and inflammatory cells. Administration of either MSCs or CD34+ cells had a therapeutic potential to induce regenerative changes in the myocardium with better results in CD34+cells-treated group. Quantitative RT-PCR analysis revealed a significant increase in the expression of vascular endothelial growth factor (VEGF), VEGFR-2, Ang-1, and Tie-2 and a significant decreased expression of Ang-2 in stem cells transplanted groups when compared with the noncell transplanted hearts. A significant increase of VEGF, VEGFR-2, Ang-1, and Tie-2 expression in the group receiving CD34+ cells than those receiving MSCs was found. Finally, there was an upregulation of both human VEGF and human hypoxia-inducible factor 1α in the infarcted hearts treated by CD34+ cells than that treated by MSCs. We first revealed a superior efficacy of CD34+ cells when compared with MSCs in induction of regenerative changes in the MI model. Both cell therapies may repair the damaged heart tissue primarily by secretion of

  15. Nano-topography Enhances Communication in Neural Cells Networks

    KAUST Repository

    Onesto, V.

    2017-08-23

    Neural cells are the smallest building blocks of the central and peripheral nervous systems. Information in neural networks and cell-substrate interactions have been heretofore studied separately. Understanding whether surface nano-topography can direct nerve cells assembly into computational efficient networks may provide new tools and criteria for tissue engineering and regenerative medicine. In this work, we used information theory approaches and functional multi calcium imaging (fMCI) techniques to examine how information flows in neural networks cultured on surfaces with controlled topography. We found that substrate roughness Sa affects networks topology. In the low nano-meter range, S-a = 0-30 nm, information increases with Sa. Moreover, we found that energy density of a network of cells correlates to the topology of that network. This reinforces the view that information, energy and surface nano-topography are tightly inter-connected and should not be neglected when studying cell-cell interaction in neural tissue repair and regeneration.

  16. Influence of the fibroblastic reticular network on cell-cell interactions in lymphoid organs.

    Directory of Open Access Journals (Sweden)

    Frederik Graw

    Full Text Available Secondary lymphoid organs (SLO, such as lymph nodes and the spleen, display a complex micro-architecture. In the T cell zone the micro-architecture is provided by a network of fibroblastic reticular cells (FRC and their filaments. The FRC network is thought to enhance the interaction between immune cells and their cognate antigen. However, the effect of the FRC network on cell interaction cannot be quantified to date because of limitations in immunological methodology. We use computational models to study the influence of different densities of FRC networks on the probability that two cells meet. We developed a 3D cellular automaton model to simulate cell movements and interactions along the FRC network inside lymphatic tissue. We show that the FRC network density has only a small effect on the probability of a cell to come into contact with a static or motile target. However, damage caused by a disruption of the FRC network is greatest at FRC densities corresponding to densities observed in the spleen of naïve mice. Our analysis suggests that the FRC network as a guiding structure for moving T cells has only a minor effect on the probability to find a corresponding dendritic cell. We propose alternative hypotheses by which the FRC network might influence the functionality of immune responses in a more significant way.

  17. Influence of the Fibroblastic Reticular Network on Cell-Cell Interactions in Lymphoid Organs

    Science.gov (United States)

    Graw, Frederik; Regoes, Roland R.

    2012-01-01

    Secondary lymphoid organs (SLO), such as lymph nodes and the spleen, display a complex micro-architecture. In the T cell zone the micro-architecture is provided by a network of fibroblastic reticular cells (FRC) and their filaments. The FRC network is thought to enhance the interaction between immune cells and their cognate antigen. However, the effect of the FRC network on cell interaction cannot be quantified to date because of limitations in immunological methodology. We use computational models to study the influence of different densities of FRC networks on the probability that two cells meet. We developed a 3D cellular automaton model to simulate cell movements and interactions along the FRC network inside lymphatic tissue. We show that the FRC network density has only a small effect on the probability of a cell to come into contact with a static or motile target. However, damage caused by a disruption of the FRC network is greatest at FRC densities corresponding to densities observed in the spleen of naïve mice. Our analysis suggests that the FRC network as a guiding structure for moving T cells has only a minor effect on the probability to find a corresponding dendritic cell. We propose alternative hypotheses by which the FRC network might influence the functionality of immune responses in a more significant way. PMID:22457613

  18. Interference Management with Successive Cancellation for Dense Small Cell Networks

    DEFF Research Database (Denmark)

    Lopez, Victor Fernandez; Pedersen, Klaus I.; Steiner, Jens

    2016-01-01

    , known as Symbol-Level Interference Cancellation (SLIC), with respect to a baseline Minimum Mean Square Error-Interference Rejection Combining (MMSE-IRC) receiver. The study is carried out on a dense, clusterized small cell network, illustrating to which extent NAICS can overcome the additional......Network-Assisted Interference Cancellation and Suppression (NAICS) receivers have appeared as a promising way to curb inter-cell interference in future dense network deployments. This investigation compares the performance of a NAICS receiver with successive interference cancellation capabilities...

  19. Microtubule networks for plant cell division

    NARCIS (Netherlands)

    Keijzer, de Jeroen; Mulder, B.M.; Janson, M.E.

    2014-01-01

    During cytokinesis the cytoplasm of a cell is divided to form two daughter cells. In animal cells, the existing plasma membrane is first constricted and then abscised to generate two individual plasma membranes. Plant cells on the other hand divide by forming an interior dividing wall, the so-called

  20. Allogeneic transplantation of fetal membrane-derived mesenchymal stem cell sheets increases neovascularization and improves cardiac function after myocardial infarction in rats.

    Science.gov (United States)

    Ishikane, Shin; Hosoda, Hiroshi; Yamahara, Kenichi; Akitake, Yoshiharu; Kyoungsook, Jung; Mishima, Kenichi; Iwasaki, Katsunori; Fujiwara, Michihiro; Miyazato, Mikiya; Kangawa, Kenji; Ikeda, Tomoaki

    2013-10-27

    Mesenchymal stem cell (MSC) transplantation has been pursued as a new method to repair damaged myocardium. We focused on the fetal membrane (FM) as an alternative source to bone marrow (BM)-derived MSCs. In this study, we investigated whether transplantation of allogeneic FM-MSC sheets could attenuate myocardial dysfunction in a rat chronic myocardial infarction (MI) model. Sheets of allogeneic FM-MSC or autologous BM-MSC were transplanted into the scarred myocardium 4 weeks after coronary ligation. Four weeks after transplantation, both allogeneic FM-MSC and autologous BM-MSC sheets had significantly improved cardiac function and reduced myocardial fibrosis compared with the untreated MI group. In both MSC sheet-transplanted groups, the peri-infarct regional capillary density was increased. Some engrafted MSCs formed vascular structures and were positive for lectin I and α-smooth muscle actin. The numbers of engrafted cells and differentiated cells were very low after both types of MSC sheet transplantation. CD3 T cells did not increase in the transplantation site, but CD163 M2 macrophages increased in the groups transplanted with allogeneic FM-MSC and autologous BM-MSC. Transplantation of allogeneic FM-MSC or autologous BM-MSC sheets attenuated myocardial dysfunction in a rat MI model to a similar degree. The engraftment rate of transplanted cells and immune cell infiltration into the transplanted area did not differ between the two types of MSC transplants. M2 macrophage induction has possible involvement in the therapeutic effects of MSC transplantation. Allogeneic FM-MSC sheet transplantation might be a new therapeutic strategy after MI.

  1. PEM Fuel Cell Modelling Using Artificial Neural Networks

    OpenAIRE

    Doumbia, Mamadou Lamine

    2016-01-01

    Fuel cells are electrochemical devices that convert the chemical energy of a reaction directly into dc electrical energy. Proton Exchange Membrane (PEM) fuel cell is a suitable alternative for both electrical transportation and stationary applications. In this article, an Artificial Neural Network (ANN) modelling approach of a PEM fuel cell is developed. This model describes the behaviour of PEM fuel cell voltage under both steady-state and transient conditions. Moreover, the prediction of th...

  2. Comparison of the Cytotoxic Potential of Cigarette Smoke and Electronic Cigarette Vapour Extract on Cultured Myocardial Cells

    Directory of Open Access Journals (Sweden)

    Dimitris Tsiapras

    2013-10-01

    Full Text Available Background: Electronic cigarettes (ECs have been marketed as an alternative-to-smoking habit. Besides chemical studies of the content of EC liquids or vapour, little research has been conducted on their in vitro effects. Smoking is an important risk factor for cardiovascular disease and cigarette smoke (CS has well-established cytotoxic effects on myocardial cells. The purpose of this study was to evaluate the cytotoxic potential of the vapour of 20 EC liquid samples and a “base” liquid sample (50% glycerol and 50% propylene glycol, with no nicotine or flavourings on cultured myocardial cells. Included were 4 samples produced by using cured tobacco leaves in order to extract the tobacco flavour. Methods: Cytotoxicity was tested according to the ISO 10993-5 standard. By activating an EC device at 3.7 volts (6.2 watts—all samples, including the “base” liquid and at 4.5 volts (9.2 watts—four randomly selected samples, 200 mg of liquid evaporated and was extracted in 20 mL of culture medium. Cigarette smoke (CS extract from three tobacco cigarettes was produced according to ISO 3308 method (2 s puffs of 35 mL volume, one puff every 60 s. The extracts, undiluted (100% and in four dilutions (50%, 25%, 12.5%, and 6.25%, were applied to myocardial cells (H9c2; percent-viability was measured after 24 h incubation. According to ISO 10993-5, viability of 6.25% (viability: 76.9 ± 2.0% at 6.25%, 38.2 ± 0.5% at 12.5%, 3.1 ± 0.2% at 25%, 5.2 ± 0.8% at 50%, and 3.9 ± 0.2% at 100% extract concentration. Three EC extracts (produced by tobacco leaves were cytotoxic at 100% and 50% extract concentrations (viability range: 2.2%–39.1% and 7.4%–66.9% respectively and one (“Cinnamon-Cookies” flavour was cytotoxic at 100% concentration only (viability: 64.8 ± 2.5%. Inhibitory concentration 50 was >3 times lower in CS extract compared to the worst-performing EC vapour extract. For EC extracts produced by high-voltage and energy, viability was

  3. Comparison of the cytotoxic potential of cigarette smoke and electronic cigarette vapour extract on cultured myocardial cells.

    Science.gov (United States)

    Farsalinos, Konstantinos E; Romagna, Giorgio; Allifranchini, Elena; Ripamonti, Emiliano; Bocchietto, Elena; Todeschi, Stefano; Tsiapras, Dimitris; Kyrzopoulos, Stamatis; Voudris, Vassilis

    2013-10-16

    Electronic cigarettes (ECs) have been marketed as an alternative-to-smoking habit. Besides chemical studies of the content of EC liquids or vapour, little research has been conducted on their in vitro effects. Smoking is an important risk factor for cardiovascular disease and cigarette smoke (CS) has well-established cytotoxic effects on myocardial cells. The purpose of this study was to evaluate the cytotoxic potential of the vapour of 20 EC liquid samples and a "base" liquid sample (50% glycerol and 50% propylene glycol, with no nicotine or flavourings) on cultured myocardial cells. Included were 4 samples produced by using cured tobacco leaves in order to extract the tobacco flavour. Cytotoxicity was tested according to the ISO 10993-5 standard. By activating an EC device at 3.7 volts (6.2 watts-all samples, including the "base" liquid) and at 4.5 volts (9.2 watts-four randomly selected samples), 200 mg of liquid evaporated and was extracted in 20 mL of culture medium. Cigarette smoke (CS) extract from three tobacco cigarettes was produced according to ISO 3308 method (2 s puffs of 35 mL volume, one puff every 60 s). The extracts, undiluted (100%) and in four dilutions (50%, 25%, 12.5%, and 6.25%), were applied to myocardial cells (H9c2); percent-viability was measured after 24 h incubation. According to ISO 10993-5, viability of 6.25% (viability: 76.9 ± 2.0% at 6.25%, 38.2 ± 0.5% at 12.5%, 3.1 ± 0.2% at 25%, 5.2 ± 0.8% at 50%, and 3.9 ± 0.2% at 100% extract concentration). Three EC extracts (produced by tobacco leaves) were cytotoxic at 100% and 50% extract concentrations (viability range: 2.2%-39.1% and 7.4%-66.9% respectively) and one ("Cinnamon-Cookies" flavour) was cytotoxic at 100% concentration only (viability: 64.8 ± 2.5%). Inhibitory concentration 50 was >3 times lower in CS extract compared to the worst-performing EC vapour extract. For EC extracts produced by high-voltage and energy, viability was reduced but no sample was cytotoxic according to

  4. Energy Efficiency Challenges of 5G Small Cell Networks.

    Science.gov (United States)

    Ge, Xiaohu; Yang, Jing; Gharavi, Hamid; Sun, Yang

    2017-05-01

    The deployment of a large number of small cells poses new challenges to energy efficiency, which has often been ignored in fifth generation (5G) cellular networks. While massive multiple-input multiple outputs (MIMO) will reduce the transmission power at the expense of higher computational cost, the question remains as to which computation or transmission power is more important in the energy efficiency of 5G small cell networks. Thus, the main objective in this paper is to investigate the computation power based on the Landauer principle. Simulation results reveal that more than 50% of the energy is consumed by the computation power at 5G small cell base stations (BSs). Moreover, the computation power of 5G small cell BS can approach 800 watt when the massive MIMO (e.g., 128 antennas) is deployed to transmit high volume traffic. This clearly indicates that computation power optimization can play a major role in the energy efficiency of small cell networks.

  5. Rationale and Design of a Clinical Trial to Evaluate the Safety and Efficacy of Intracoronary Infusion of Allogeneic Human Cardiac Stem Cells in Patients With Acute Myocardial Infarction and Left Ventricular Dysfunction: The Randomized Multicenter Double-Blind Controlled CAREMI Trial (Cardiac Stem Cells in Patients With Acute Myocardial Infarction).

    Science.gov (United States)

    Sanz-Ruiz, Ricardo; Casado Plasencia, Ana; Borlado, Luis R; Fernández-Santos, María Eugenia; Al-Daccak, Reem; Claus, Piet; Palacios, Itziar; Sádaba, Rafael; Charron, Dominique; Bogaert, Jan; Mulet, Miguel; Yotti, Raquel; Gilaberte, Immaculada; Bernad, Antonio; Bermejo, Javier; Janssens, Stefan; Fernández-Avilés, Franciso

    2017-06-23

    Stem cell therapy has increased the therapeutic armamentarium in the fight against ischemic heart disease and heart failure. The administration of exogenous stem cells has been investigated in patients suffering an acute myocardial infarction, with the final aim of salvaging jeopardized myocardium and preventing left ventricular adverse remodeling and functional deterioration. However, phase I and II clinical trials with autologous and first-generation stem cells have yielded inconsistent benefits and mixed results. In the search for new and more efficient cellular regenerative products, interesting cardioprotective, immunoregulatory, and cardioregenerative properties have been demonstrated for human cardiac stem cells. On the other hand, allogeneic cells show several advantages over autologous sources: they can be produced in large quantities, easily administered off-the-shelf early after an acute myocardial infarction, comply with stringent criteria for product homogeneity, potency, and quality control, and may exhibit a distinctive immunologic behavior. With a promising preclinical background, CAREMI (Cardiac Stem Cells in Patients With Acute Myocardial Infarction) has been designed as a double-blind, 2:1 randomized, controlled, and multicenter clinical trial that will evaluate the safety, feasibility, and efficacy of intracoronary delivery of allogeneic human cardiac stem cell in 55 patients with large acute myocardial infarction, left ventricular dysfunction, and at high risk of developing heart failure. This phase I/II clinical trial represents a novel experience in humans with allogeneic cardiac stem cell in a rigorously imaging-based selected group of acute myocardial infarction patients, with detailed safety immunologic assessments and magnetic resonance imaging-based efficacy end points. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02439398. © 2017 American Heart Association, Inc.

  6. Novel regenerative therapy using cell-sheet covered with omentum flap delivers a huge number of cells in a porcine myocardial infarction model.

    Science.gov (United States)

    Shudo, Yasuhiro; Miyagawa, Shigeru; Fukushima, Satsuki; Saito, Atsuhiro; Shimizu, Tatsuya; Okano, Teruo; Sawa, Yoshiki

    2011-11-01

    A key challenge to applying cell transplantation to treat severely damaged myocardium is in delivering large numbers of cells with minimum cell loss. We developed a new implantation method using skeletal myoblast (SMB) sheets, wrapped with an omentum flap as a blood supply to deliver huge numbers of SMBs to the damaged heart. We examined whether this method could be used to deliver a large amount of cells to deteriorated porcine myocardium. Cell sheets were obtained by culturing mini-pig autologous SMB cells on temperature-responsive culture dishes. Myocardial infarction was induced by placing an ameroid constrictor around the left anterior descending artery. The mini-pigs were divided into 4 treatment groups (n = 6 in each): cell sheets with omentum, cell sheets only, omentum only, and sham operation. Each animal implant consisted of 30 cell sheets (1.5 × 10(7) cells per sheet). Six 5-layer constructs were each placed on a different area, immediately adjacent to but not overlapping one another, to cover the infarct and border regions. The new regenerative cell delivery system using SMB sheets covered and wrapped with omentum resulted in (1) a significantly reduced infarct size causing, at least in part, a thin scar with thick well-vascularized cardiac tissue; (2) increased angiogenesis, as determined by a significantly higher vascular density; and (3) improved cardiac function, as determined by echocardiography, compared with the conventional method (SMB sheet implantation). This cell delivery system shows potential for repairing the severely failed heart. Copyright © 2011. Published by Mosby, Inc.

  7. Adult Bone Marrow Mesenchymal Stem Cells Primed for fhe Repair of Damaged Cardiac Tissue After Myocardial Infarction

    Science.gov (United States)

    Marks, Edward D.

    The burden of cardiovascular disease around the world is growing, despite improvements in hospital care and time to treatment. As more people survive an initial myocardial infarction (MI), the decompensated heart tissue is strained, leading to heart failure (HF) and an increased risk for a second MI. While extensive progress has been made in treating the symptoms after MI, including HF and angina, little success has come from repairing the damaged heart tissue to alleviate the progression to these end- stage symptoms. One promising area of regenerative research has been the use of adult stem cells, particularly from the bone marrow (BMSCs). These cells can differentiate towards the cardiac cell lineage in vitro while producing trophic factors that can repair damaged tissue. When placed in the heart after MI though, BMSCs have mixed results, producing profound changes in some patients but zero or even negative effects in others. In this report, we used BMSCs as a stem cell base for a regenerative medicine system for the repair of damaged cardiac tissue. These cells are seeded on a polycaprolactone nanoscaffolding support system, which provides a growth substrate for in vitro work, as well as a housing system for protected in vivo delivery. When the nanoscaffold is pre-coated with a novel combination of a cardiac protein, thymosin beta4 (Tbeta4), and a small molecule effector of the WNT protein pathway, IWP-2, BMSCs differentiated towards the cardiac lineage in as little as 24hours. When injected into rat hearts that have been given an ischemic MI, the nanoscaffolding system slowly dissolves, leaving the cells in place of the damaged cardiac tissue. After two weeks of monitoring, BMSCs are present within the damaged hearts, as evidenced by immunofluorescence and nanoparticle tracking. Injections of the nanoscaffolding/cell system led to robust healing of the rat hearts that had been given small- and medium- damage heart attacks, outperforming PBS sham and cell

  8. Gene expression profiles following intracoronary injection of mesenchymal stromal cells using a porcine model of chronic myocardial infarction.

    Science.gov (United States)

    Barallobre-Barreiro, Javier; de Ilárduya, Oskar Martínez; Moscoso, Isabel; Calviño-Santos, Ramón; Aldama, Guillermo; Centeno, Alberto; López-Pelaez, Eduardo; Doménech, Nieves

    2011-04-01

    We evaluated the therapeutic potential of injection of in vitro differentiated bone marrow mesenchymal stromal cells (MSC) using a swine model. Myocardial infarction was induced by coronary occlusion. Three groups (n = 5 each) were analyzed: one group received an injection of 17.8 ± 9.3 × 10(6) 5-azacytidine-treated allogeneic MSC 1 month after infarction; a placebo group received an injection of medium; and controls were kept untreated. After 4 weeks, heart samples were taken from three infarcted areas, interventricular septa, ventricles and atria. Gene expression profiles of genes related to contractility (Serca2a), fibrosis (Col1a1), cardiomyogenesis (Mef2c, Gata4 and Nkx2.5) and mobilization of stem cells (Sdf1, Cxcr4 and c-kit) were compared by quantitative real-time PCR (qRT-PCR). Gene expression profiles varied in different heart areas. Thus Serca2a expression was reduced in infarcted groups in all heart regions except for the left ventricles, where Col1a1 was overexpressed. The expression of genes related to cardiomyogenesis decreased in the infarcted zones and left atria compared with healthy hearts. Interestingly, increased expression of Cxcr4 was detected in infarcted regions of MSC-treated pigs compared with the placebo group. Infarction induced changes in expression of genes involved in various biologic processes. Genes involved in cardiomyogenesis were downregulated in the left atrium. The intracoronary injection of MSC resulted in localized changes in the expression of Cxcr4.

  9. Regulation of Na+-K+-ATPase effected high glucose-induced myocardial cell injury through c-Src dependent NADPH oxidase/ROS pathway.

    Science.gov (United States)

    Yan, Xiaofei; Xun, Meng; Dou, Xiaojuan; Wu, Litao; Han, Yan; Zheng, Jin

    2017-08-15

    Depressed Na+/K+-ATPase activity has long been reported to be involved in diabetic-related cardiomyocyte death and cardiac dysfunction. However, the nature of directly regulating Na+-K+-ATPase in diabetic-related myocardial diseases remains unknown. Hyperglycemia is believed as one of major factors responsible for diabetic-related myocardial apoptosis and dysfunction. In this study, whether inhibiting Na+-K+-ATPase by ouabain or activating Na+-K+-ATPase by DRm217 has functions on high glucose (HG) -induced myocardial injury was investigated. Here we found that addition of DRm217 or ouabain to HG-treated cells had opposite effects. DRm217 decreased but ouabain increased HG-induced cell injury and apoptosis. This was mediated by changing Na+-K+-ATPase activity and Na+-K+-ATPase cell surface expression. The inhibition of Na+-K+-ATPase endocytosis alleviated HG-induced ROS accumulation. Na+-K+-ATPase·c-Src dependent NADPH oxidase/ROS pathway was also involved in the effects of ouabain and DRm217 on HG-induced cell injury. These novel results may help us to understand the important role of the Na+-K+-ATPase in diabetic cardiovascular diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. [Effect of implantation of cardiosphere-derived cells combined with rat heart tissue-derived extracellular matrix on acute myocardial infarction in rats].

    Science.gov (United States)

    Jiang, Da-Qing; Gu, Tian-Xiang; Xu, Zhao-Fa; Liu, Shuang; Li, Xue-Yuan

    2016-10-20

    To investigate whether heart tissue-derived extracellular matrix (ECM) promotes the differentiation of cardiosphere-derived cells (CDCs) implanted in rat infracted myocardium to improve the cardiac structure and function. Rat CDCs were cultured by cardiac explant methods, and ECM was prepared by decelluariztion method. In a Wistar rat model of acute myocardial infarction established by ligating the left anterior descending branch, IMDM solution, ECM suspension, 10 6 CDCs in IMDM solution, or 10 6 CDCs in ECM suspension were injected into the infracted rat myocardium (6 rats in each group). The cardiac function of the rats was evaluated by cardiac ultrasonography, and the percentage of positive heart fibrosis area after infarction was determined with Masson staining. The differentiation of implanted CDCs in the infarcted myocardium was detected using immunofluorescence assay for the markers of cardiac muscle cells (α-SA), vascular endothelial cells (vWF) and smooth muscle cells (α-SMA). Three weeks after acute myocardial infarction, the rats with injection of CDCs in ECM showed the highest left ventricular ejection fraction (LVEF) and percentage of fraction shortening with the lowest percentage of positive heart fibrosis area; implantation of CDCs with ECM resulted in significantly higher rates of CDC differentiation into cardiac muscle cells, vascular endothelial cells and smooth muscle cell (P<0.05). Heart-tissue derived ECM significantly promotes the differentiation of CDCs implanted in the infracted myocardium into cardiac muscle cells, vascular endothelial cells and smooth muscle cells to improve the cardiac structure and cardiac functions in rats.

  11. Intramyocardial Injection of Pig Pluripotent Stem Cells Improves Left Ventricular Function and Perfusion: A Study in a Porcine Model of Acute Myocardial Infarction.

    Science.gov (United States)

    Li, Xiaorong; Zhang, Fengxiang; Song, Guixian; Gu, Weijuan; Chen, Minglong; Yang, Bing; Li, Dianfu; Wang, Daowu; Cao, Kejiang

    2013-01-01

    Induced pluripotent stem (iPS) cells have the potential to differentiate to various types of cardiovascular cells to repair an injured heart. The potential therapeutic benefits of iPS cell based treatment have been established in small-animal models of myocardial infarction (MI). We hypothesize that porcine iPS (piPS) cell transplantation may be an effective treatment for MI. After a 90-minute occlusion of the left anterior descending artery in a porcine model, undifferentiated piPS cells or PBS were injected into the ischemic myocardium. Cardiac function, myocardial perfusion and cell differentiation were investigated. One week after piPS cell delivery, global left ventricular ejection fraction (LVEF) significantly decreased in both the iPS group and the PBS group compared to the Sham group (pinfarct area was significantly smaller in the iPS group than the PBS group (12.04% vs. 15.98% p = 0.01). PiPS cells engrafted into the myocardium can differentiate into vessel cells, which result in increased formation of new vessels in the infarcted heart. Direct intramyocardial injection of piPS cells can decrease infarct size and improve left ventricular function and perfusion for an immunosuppressed porcine AMI model.

  12. Alpha- and beta-adrenergic stimulation induces distinct patterns of immediate early gene expression in neonatal rat myocardial cells. fos/jun expression is associated with sarcomere assembly; Egr-1 induction is primarily an alpha 1-mediated response

    National Research Council Canada - National Science Library

    K Iwaki; V P Sukhatme; H E Shubeita; K R Chien

    1990-01-01

    The present study was designed to determine if alpha- and beta-adrenergic stimulation of neonatal rat myocardial cells might induce common and/or distinct members of the immediate early gene program...

  13. Effect of siRNA silencing of inducible co-stimulatory molecule on myocardial cell hypertrophy after cardiac infarction in rats.

    Science.gov (United States)

    Wang, W M; Liu, Z; Chen, G

    2016-05-20

    As the most common cardiac disease, myocardial infarction is followed by hypertrophy of cardiac myocytes and reconstruction of ventricular structure. The up-regulation of a series of factors including metalloproteinases, inflammatory factors, and growth factors after primary infarction lead to the hypertrophy, apoptosis, necrosis, and fibroblast proliferation in cardiac muscle tissues. Recent studies have reported on the potency of small interfering RNA (siRNA) in treating cardiac diseases. We thus investigated the efficacy of inducible co-stimulatory molecule (ICOS)-specific siRNA silencing in myocardial hypertrophy in a cardiac infarction rat model. This cardiac infarction model was prepared by ligating the left anterior descending coronary artery. ICOS-siRNA treatment was administered in parallel with non-sense siRNA. After 18 days, the cross-sectional area of cardiac muscle tissues and the left ventricle weight index were measured, along with ICOS mRNA and protein expression levels, and pathological staining. Compared to those in the control groups, in myocardial infarcted rats, the application of ICOS-siRNA effectively decreased the left ventricle weight index, as well as the surface area of cardiac myocytes. Both mRNA and protein levels of ICOS were also significantly decreased. HE staining was consistent with these results. In conclusion, ICOS-targeted siRNA can effectively silence gene expression of ICOS, and provided satisfactory treatment efficacy for myocardial cell hypertrophy after infarction.

  14. Lack of "obesity paradox" in patients presenting with ST-segment elevation myocardial infarction including cardiogenic shock: a multicenter German network registry analysis.

    Science.gov (United States)

    Akin, Ibrahim; Schneider, Henrik; Nienaber, Christoph A; Jung, Werner; Lübke, Mike; Rillig, Andreas; Ansari, Uzair; Wunderlich, Nina; Birkemeyer, Ralf

    2015-07-11

    Studies have associated obesity with better outcomes in comparison to non-obese patients after elective and emergency coronary revascularization. However, these findings might have been influenced by patient selection. Therefore we thought to look into the obesity paradox in a consecutive network STEMI population. The database of two German myocardial infarction network registries were combined and data from a total of 890 consecutive patients admitted and treated for acute STEMI including cardiogenic shock and cardiopulmonary resuscitation according to standardized protocols were analyzed. Patients were categorized in normal weight (≤24.9 kg/m(2)), overweight (25-30 kg/m(2)) and obese (>30 kg/m(2)) according to BMI. Baseline clinical parameters revealed a higher comorbidity index for overweight and obese patients; 1-year follow-up comparison between varying groups revealed similar rates of all-cause death (9.1 % vs. 8.3 % vs. 6.2 %; p = 0.50), major adverse cardiac and cerebrovascular [MACCE (15.1 % vs. 13.4 % vs. 10.2 %; p = 0.53)] and target vessel revascularization in survivors [TVR (7.0 % vs. 5.0 % vs. 4.0 %; p = 0.47)] with normal weight when compared to overweight or obese patients. These results persisted after risk-adjustment for heterogeneous baseline characteristics of groups. An analysis of patients suffering from cardiogenic shock showed no impact of BMI on clinical endpoints. Our data from two network systems in Germany revealed no evidence of an "obesity paradox"in an all-comer STEMI population including patients with cardiogenic shock.

  15. Impact on Mortality of Different Network Systems in the Treatment of ST-segment Elevation Acute Myocardial Infarction. The Spanish Experience.

    Science.gov (United States)

    Cequier, Ángel; Ariza-Solé, Albert; Elola, Francisco J; Fernández-Pérez, Cristina; Bernal, José L; Segura, José V; Iñiguez, Andrés; Bertomeu, Vicente

    2017-03-01

    To analyze the association between the development of network systems of care for ST-segment elevation myocardial infarction (STEMI) in the autonomous communities (AC) of Spain and the regional rate of percutaneous coronary intervention (PCI) and in-hospital mortality. From 2003 to 2012, data from the minimum basic data set of the Spanish taxpayer-funded health system were analyzed, including admissions from general hospitals. Diagnoses of STEMI and related procedures were codified by the International Diseases Classification. Discharge episodes (n = 302 471) were distributed in 3 groups: PCI (n = 116 621), thrombolysis (n = 46 720), or no reperfusion (n = 139 130). Crude mortality throughout the evaluation period was higher for the no-PCI or thrombolysis group (17.3%) than for PCI (4.8%) and thrombolysis (8.6%) (P < .001). For the aggregate of all communities, the PCI rate increased (21.6% in 2003 vs 54.5% in 2012; P < .001) with a decrease in risk-standardized mortality rates (10.2% in 2003; 6.8% in 2012; P < .001). Significant differences were observed in the PCI rate across the AC. The development of network systems was associated with a 50% increase in the PCI rate (P < .001) and a 14% decrease in risk-standardized mortality rates (P < .001). From 2003 to 2012, the PCI rate in STEMI substantially increased in Spain. The development of network systems was associated with an increase in the PCI rate and a decrease in in-hospital mortality. Copyright © 2016 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

  16. Mitochondrial Networking in T Cell Memory.

    Science.gov (United States)

    Liesa, Marc; Shirihai, Orian S

    2016-06-30

    T-lymphocytes show large changes in ATP demand and nutrient utilization, imposed by their different roles as T memory and T effector cells. Therefore, T cell remodeling represents a bioenergetic challenge to mitochondria. New work from Buck et al. links changes in mitochondrial shape to T cell fate choice. Copyright © 2016. Published by Elsevier Inc.

  17. Cell proliferation along vascular islands during microvascular network growth

    Directory of Open Access Journals (Sweden)

    Kelly-Goss Molly R

    2012-06-01

    Full Text Available Abstract Background Observations in our laboratory provide evidence of vascular islands, defined as disconnected endothelial cell segments, in the adult microcirculation. The objective of this study was to determine if vascular islands are involved in angiogenesis during microvascular network growth. Results Mesenteric tissues, which allow visualization of entire microvascular networks at a single cell level, were harvested from unstimulated adult male Wistar rats and Wistar rats 3 and 10 days post angiogenesis stimulation by mast cell degranulation with compound 48/80. Tissues were immunolabeled for PECAM and BRDU. Identification of vessel lumens via injection of FITC-dextran confirmed that endothelial cell segments were disconnected from nearby patent networks. Stimulated networks displayed increases in vascular area, length density, and capillary sprouting. On day 3, the percentage of islands with at least one BRDU-positive cell increased compared to the unstimulated level and was equal to the percentage of capillary sprouts with at least one BRDU-positive cell. At day 10, the number of vascular islands per vascular area dramatically decreased compared to unstimulated and day 3 levels. Conclusions These results show that vascular islands have the ability to proliferate and suggest that they are able to incorporate into the microcirculation during the initial stages of microvascular network growth.

  18. Cognitive small cell networks: energy efficiency and trade-offs

    NARCIS (Netherlands)

    Wildemeersch, M.; Wildemeersch, Matthias; Quek, T.Q.S.; Slump, Cornelis H.; Rabbachin, A.

    2013-01-01

    Heterogeneous networks using a mix of macrocells and small cells are foreseen as one of the solutions to meet the ever increasing mobile traffic demand. Nevertheless, a massive deployment of small cell access points (SAPs) leads also to a considerable increase in energy consumption. Spurred by

  19. Workshop: Theory an Applications of Coupled Cell Networks

    Science.gov (United States)

    2006-03-22

    Economia and Centro de Matematica , Universidade do Porto) Application of coupled cell systems have been made to a wide range of problems in the physical and...Departamento de Matematica Pura da Faculdade de Ciencias do Porto) As pointed by [1], in the class of coupled cell networks that permits self-coupling

  20. Increase in cholinergic modulation with pyridostigmine induces anti-inflammatory cell recruitment soon after acute myocardial infarction in rats.

    Science.gov (United States)

    Rocha, Juraci Aparecida; Ribeiro, Susan Pereira; França, Cristiane Miranda; Coelho, Otávio; Alves, Gisele; Lacchini, Silvia; Kallás, Esper Georges; Irigoyen, Maria Cláudia; Consolim-Colombo, Fernanda M

    2016-04-15

    We tested the hypothesis that an increase in the anti-inflammatory cholinergic pathway, when induced by pyridostigmine (PY), may modulate subtypes of lymphocytes (CD4+, CD8+, FOXP3+) and macrophages (M1/M2) soon after myocardial infarction (MI) in rats. Wistar rats, randomly allocated to receive PY (40 mg·kg(-1)·day(-1)) in drinking water or to stay without treatment, were followed for 4 days and then were subjected to ligation of the left coronary artery. The groups-denominated as the pyridostigmine-treated infarcted (IP) and infarcted control (I) groups-were submitted to euthanasia 3 days after MI; the heart was removed for immunohistochemistry, and the peripheral blood and spleen were collected for flow cytometry analysis. Noninfarcted and untreated rats were used as controls (C Group). Echocardiographic measurements were registered on the second day after MI, and heart rate variability was measured on the third day after MI. The infarcted groups had similar MI areas, degrees of systolic dysfunction, blood pressures, and heart rates. Compared with the I Group, the IP Group showed a significant higher parasympathetic modulation and a lower sympathetic modulation, which were associated with a small, but significant, increase in diastolic function. The IP Group showed a significant increase in M2 macrophages and FOXP3(+)cells in the infarcted and peri-infarcted areas, a significantly higher frequency of circulating Treg cells (CD4(+)CD25(+)FOXP3(+)), and a less extreme decrease in conventional T cells (CD25(+)FOXP3(-)) compared with the I Group. Therefore, increasing cholinergic modulation with PY induces greater anti-inflammatory cell recruitment soon after MY in rats. Copyright © 2016 the American Physiological Society.

  1. Preclinical Evaluation of the Engineered Stem Cell Chemokine Stromal Cell-Derived Factor 1–alpha Analogue in a Translational Ovine Myocardial Infarction Model

    Science.gov (United States)

    MacArthur, John W.; Cohen, Jeffrey E.; McGarvey, Jeremy R.; Shudo, Yasuhiro; Patel, Jay B.; Trubelja, Alen; Fairman, Alexander S.; Edwards, Bryan B.; Hung, George; Hiesinger, William; Goldstone, Andrew B.; Atluri, Pavan; Wilensky, Robert L.; Pilla, James J.; Gorman, Joseph H.; Gorman, Robert C.; Woo, Y. Joseph

    2014-01-01

    Rationale Following myocardial infarction (MI) there is an inadequate blood supply to the myocardium and the surrounding borderzone becomes hypocontractile. Objective To develop a clinically translatable therapy, we hypothesized that in a preclinical ovine model of MI, the modified endothelial progenitor stem cell (EPC) chemokine, engineered stromal cell-derived factor 1-alpha analogue (ESA), would induce EPC chemotaxis, limit adverse ventricular remodeling, and preserve borderzone contractility. Methods and Results Thirty six adult male Dorset sheep underwent permanent ligation of the left anterior descending coronary artery, inducing an anteroapical infarction and were randomized to borderzone injection of saline (n=18) or ESA (n=18). Ventricular function, geometry, and regional strain were assessed using cardiac magnetic resonance imaging and pressure-volume catheter transduction. Bone marrow was harvested for in-vitro analysis, and myocardial biopsies were taken for mRNA, protein and immunohistochemical analysis. ESA induced greater chemotaxis of EPCs compared to saline (p<0.01), and was equivalent to recombinant stromal cell-derived factor 1-alpha (p=0.27). Analysis of mRNA expression and protein levels in ESA treated animals revealed reduced MMP-2 in the borderzone (p<0.05), with elevated levels of TIMP-1 and elastin in the infarct (p<0.05), while immunohistochemical analysis of borderzone myocardium showed increased capillary and arteriolar density in the ESA group (p<0.01). Animals in the ESA treatment group also had significant reductions in infarct size (p<0.01), increased maximal principle strain in the borderzone (p<0.01), and a steeper slope of the end systolic pressure volume relationship (p=0.01). Conclusions The novel, biomolecularly-designed peptide ESA induces chemotaxis of EPCs, stimulates neovasculogenesis, limits infarct expansion, and preserves contractility in an ovine model of MI. PMID:24366171

  2. Dynamics of regulatory networks in gastrin-treated adenocarcinoma cells.

    Directory of Open Access Journals (Sweden)

    Naresh Doni Jayavelu

    Full Text Available Understanding gene transcription regulatory networks is critical to deciphering the molecular mechanisms of different cellular states. Most studies focus on static transcriptional networks. In the current study, we used the gastrin-regulated system as a model to understand the dynamics of transcriptional networks composed of transcription factors (TFs and target genes (TGs. The hormone gastrin activates and stimulates signaling pathways leading to various cellular states through transcriptional programs. Dysregulation of gastrin can result in cancerous tumors, for example. However, the regulatory networks involving gastrin are highly complex, and the roles of most of the components of these networks are unknown. We used time series microarray data of AR42J adenocarcinoma cells treated with gastrin combined with static TF-TG relationships integrated from different sources, and we reconstructed the dynamic activities of TFs using network component analysis (NCA. Based on the peak expression of TGs and activity of TFs, we created active sub-networks at four time ranges after gastrin treatment, namely immediate-early (IE, mid-early (ME, mid-late (ML and very late (VL. Network analysis revealed that the active sub-networks were topologically different at the early and late time ranges. Gene ontology analysis unveiled that each active sub-network was highly enriched in a particular biological process. Interestingly, network motif patterns were also distinct between the sub-networks. This analysis can be applied to other time series microarray datasets, focusing on smaller sub-networks that are activated in a cascade, allowing better overview of the mechanisms involved at each time range.

  3. Dynamics of regulatory networks in gastrin-treated adenocarcinoma cells.

    Science.gov (United States)

    Doni Jayavelu, Naresh; Bar, Nadav

    2014-01-01

    Understanding gene transcription regulatory networks is critical to deciphering the molecular mechanisms of different cellular states. Most studies focus on static transcriptional networks. In the current study, we used the gastrin-regulated system as a model to understand the dynamics of transcriptional networks composed of transcription factors (TFs) and target genes (TGs). The hormone gastrin activates and stimulates signaling pathways leading to various cellular states through transcriptional programs. Dysregulation of gastrin can result in cancerous tumors, for example. However, the regulatory networks involving gastrin are highly complex, and the roles of most of the components of these networks are unknown. We used time series microarray data of AR42J adenocarcinoma cells treated with gastrin combined with static TF-TG relationships integrated from different sources, and we reconstructed the dynamic activities of TFs using network component analysis (NCA). Based on the peak expression of TGs and activity of TFs, we created active sub-networks at four time ranges after gastrin treatment, namely immediate-early (IE), mid-early (ME), mid-late (ML) and very late (VL). Network analysis revealed that the active sub-networks were topologically different at the early and late time ranges. Gene ontology analysis unveiled that each active sub-network was highly enriched in a particular biological process. Interestingly, network motif patterns were also distinct between the sub-networks. This analysis can be applied to other time series microarray datasets, focusing on smaller sub-networks that are activated in a cascade, allowing better overview of the mechanisms involved at each time range.

  4. Stem cells with FGF4-bFGF fused gene enhances the expression of bFGF and improves myocardial repair in rats

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Xiang-Qi; Chen, Liang-Long, E-mail: xhzlyx@126.com; Fan, Lin; Fang, Jun; Chen, Zhao-Yang; Li, Wei-Wei

    2014-04-25

    Highlights: • BFGF exists only in the cytoplasm of live cells. • BFGF cannot be secreted into the extracellular space to promote cell growth. • We combine the secretion-promoting signal peptide of FGF4. • We successfully modified BMSCs with the fused genes of FGF4-bFGF. • We promoted the therapeutic effects of transplanted BMSCs in myocardial infarction. - Abstract: The aim of this study was to investigate whether the modification of bone marrow-derived mesenchymal stem cells (BMSCs) with the fused FGF4 (fibroblast growth factor 4)-bFGF (basic fibroblast growth factor) gene could improve the expression and secretion of BFGF, and increase the efficacies in repairing infarcted myocardium. We used In-Fusion technique to construct recombinant lentiviral vectors containing the individual gene of bFGF, enhanced green fluorescent protein (EGFP), or genes of FGF4-bFGF and EGFP, and then transfected these lentiviruses into rat BMSCs. We conducted an in vitro experiment to compare the secretion of bFGF in BMSCs infected by these lentiviruses and also examined their therapeutic effects in the treatment of myocardial infraction in a rodent study. Sixty rats were tested in the following five conditions: Group-SHAM received only sham operation as controls; Group-AMI received only injection of placebo PBS buffer; Group-BMSC, Group-bFGF and Group-FGF4-bFGF received implantation of BMSCs with empty lentivirus, bFGF lentivirus, and FGF4-bFGF lentivirus, respectively. Our results found out that the transplanted FGF4-bFGF BMSCs had the highest survival rate, and also the highest myocardial expression of bFGF and microvascular density as evidenced by Western blotting and immunohistochemistry, respectively. As compared to other groups, the Group-FGF4-BFGF rats had the lowest myocardial fibrotic fraction, and the highest left ventricular ejection fraction. These results suggest that the modification of BMSCs with the FGF4-bFGF fused gene can not only increase the expression of

  5. Evolution of networks and sequences in eukaryotic cell cycle control.

    Science.gov (United States)

    Cross, Frederick R; Buchler, Nicolas E; Skotheim, Jan M

    2011-12-27

    The molecular networks regulating the G1-S transition in budding yeast and mammals are strikingly similar in network structure. However, many of the individual proteins performing similar network roles appear to have unrelated amino acid sequences, suggesting either extremely rapid sequence evolution, or true polyphyly of proteins carrying out identical network roles. A yeast/mammal comparison suggests that network topology, and its associated dynamic properties, rather than regulatory proteins themselves may be the most important elements conserved through evolution. However, recent deep phylogenetic studies show that fungal and animal lineages are relatively closely related in the opisthokont branch of eukaryotes. The presence in plants of cell cycle regulators such as Rb, E2F and cyclins A and D, that appear lost in yeast, suggests cell cycle control in the last common ancestor of the eukaryotes was implemented with this set of regulatory proteins. Forward genetics in non-opisthokonts, such as plants or their green algal relatives, will provide direct information on cell cycle control in these organisms, and may elucidate the potentially more complex cell cycle control network of the last common eukaryotic ancestor.

  6. Connectivity in the yeast cell cycle transcription network: inferences from neural networks.

    Directory of Open Access Journals (Sweden)

    Christopher E Hart

    2006-12-01

    Full Text Available A current challenge is to develop computational approaches to infer gene network regulatory relationships based on multiple types of large-scale functional genomic data. We find that single-layer feed-forward artificial neural network (ANN models can effectively discover gene network structure by integrating global in vivo protein:DNA interaction data (ChIP/Array with genome-wide microarray RNA data. We test this on the yeast cell cycle transcription network, which is composed of several hundred genes with phase-specific RNA outputs. These ANNs were robust to noise in data and to a variety of perturbations. They reliably identified and ranked 10 of 12 known major cell cycle factors at the top of a set of 204, based on a sum-of-squared weights metric. Comparative analysis of motif occurrences among multiple yeast species independently confirmed relationships inferred from ANN weights analysis. ANN models can capitalize on properties of biological gene networks that other kinds of models do not. ANNs naturally take advantage of patterns of absence, as well as presence, of factor binding associated with specific expression output; they are easily subjected to in silico "mutation" to uncover biological redundancies; and they can use the full range of factor binding values. A prominent feature of cell cycle ANNs suggested an analogous property might exist in the biological network. This postulated that "network-local discrimination" occurs when regulatory connections (here between MBF and target genes are explicitly disfavored in one network module (G2, relative to others and to the class of genes outside the mitotic network. If correct, this predicts that MBF motifs will be significantly depleted from the discriminated class and that the discrimination will persist through evolution. Analysis of distantly related Schizosaccharomyces pombe confirmed this, suggesting that network-local discrimination is real and complements well-known enrichment of

  7. Permeabilized myocardial fibers as model to detect mitochondrial dysfunction during sepsis and melatonin effects without disruption of mitochondrial network.

    Science.gov (United States)

    Doerrier, Carolina; García, José A; Volt, Huayqui; Díaz-Casado, María E; Luna-Sánchez, Marta; Fernández-Gil, Beatriz; Escames, Germaine; López, Luis C; Acuña-Castroviejo, Darío

    2016-03-01

    Analysis of mitochondrial function is crucial to understand their involvement in a given disease. High-resolution respirometry of permeabilized myocardial fibers in septic mice allows the evaluation of the bioenergetic system, maintaining mitochondrial ultrastructure and intracellular interactions, which are critical for an adequate functionality. OXPHOS and electron transport system (ETS) capacities were assessed using different substrate combinations. Our findings show a severe septic-dependent impairment in OXPHOS and ETS capacities with mitochondrial uncoupling at early and late phases of sepsis. Moreover, sepsis triggers complex III (CIII)-linked alterations in supercomplexes structure, and loss of mitochondrial density. In these conditions, melatonin administration to septic mice prevented sepsis-dependent mitochondrial injury in mitochondrial respiration. Likewise, melatonin improved cytochrome b content and ameliorated the assembly of CIII in supercomplexes. These results support the use of permeabilized fibers to identify properly the respiratory deficits and specific melatonin effects in sepsis. Copyright © 2015 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

  8. Reoxygenation-derived toxic reactive oxygen/nitrogen species modulate the contribution of bone marrow progenitor cells to remodeling after myocardial infarction.

    Science.gov (United States)

    Moldovan, Nicanor I; Anghelina, Mirela; Varadharaj, Saradhadevi; Butt, Omer I; Wang, Tiangshen; Yang, Fuchun; Moldovan, Leni; Zweier, Jay L

    2014-02-21

    The core region of a myocardial infarction is notoriously unsupportive of cardiomyocyte survival. However, there has been less investigation of the potentially beneficial spontaneous recruitment of endogenous bone marrow progenitor cells (BMPCs) within infarcted areas. In the current study we examined the role of tissue oxygenation and derived toxic species in the control of BMPC engraftment during postinfarction heart remodeling. For assessment of cellular origin, local oxygenation, redox status, and fate of cells in the infarcted region, myocardial infarction in mice with or without LacZ(+) bone marrow transplantation was induced by coronary ligation. Sham-operated mice served as controls. After 1 week, LacZ(+) BMPC-derived cells were found inhomogeneously distributed into the infarct zone, with a lower density at its core. Electron paramagnetic resonance (EPR) oximetry showed that pO2 in the infarct recovered starting on day 2 post-myocardial infarction, concomitant with wall thinning and erythrocytes percolating through muscle microruptures. Paralleling this reoxygenation, increased generation of reactive oxygen/nitrogen species was detected at the infarct core. This process delineated a zone of diminished BMPC engraftment, and at 1 week infiltrating cells displayed immunoreactive 3-nitrotyrosine and apoptosis. In vivo treatment with a superoxide dismutase mimetic significantly reduced reactive oxygen species formation and amplified BMPC accumulation. This treatment also salvaged wall thickness by 43% and left ventricular ejection fraction by 27%, with significantly increased animal survival. BMPC engraftment in the infarct inversely mirrored the distribution of reactive oxygen/nitrogen species. Antioxidant treatment resulted in increased numbers of engrafted BMPCs, provided functional protection to the heart, and decreased the incidence of myocardial rupture and death.

  9. Cell therapy in reperfused acute myocardial infarction does not improve the recovery of perfusion in the infarcted myocardium: a cardiac MR imaging study.

    Science.gov (United States)

    Robbers, Lourens F H J; Nijveldt, Robin; Beek, Aernout M; Hirsch, Alexander; van der Laan, Anja M; Delewi, Ronak; van der Vleuten, Pieter A; Tio, René A; Tijssen, Jan G P; Hofman, Mark B M; Piek, Jan J; Zijlstra, Felix; van Rossum, Albert C

    2014-07-01

    To investigate the effects of cell therapy on myocardial perfusion recovery after treatment of acute myocardial infarction (MI) with primary percutaneous coronary intervention (PCI). In this HEBE trial substudy, which was approved by the institutional review board (trial registry number ISRCTN95796863), the authors assessed the effects of intracoronary infusion with bone marrow-derived mononuclear cells (BMMCs) or peripheral blood-derived mononuclear cells (PBMCs) on myocardial perfusion recovery by using cardiac magnetic resonance (MR) imaging after revascularization. In 152 patients with acute MI treated with PCI, cardiac MR imaging was performed after obtaining informed consent-before randomization to BMMC, PBMC, or standard therapy (control group)-and repeated at 4-month follow-up. Cardiac MR imaging consisted of cine, rest first-pass perfusion, and late gadolinium enhancement imaging. Perfusion was evaluated semiquantitatively with signal intensity-time curves by calculating the relative upslope (percentage signal intensity change). The relative upslope was calculated for the MI core, adjacent border zone, and remote myocardium. Perfusion differences among treatment groups or between baseline and follow-up were assessed with the Wilcoxon signed rank or Mann-Whitney U test. At baseline, myocardial perfusion differed between the MI core (median, 6.0%; interquartile range [IQR], 4.1%-8.0%), border zone (median, 8.4%; IQR, 6.4%-10.2%), and remote myocardium (median, 12.2%; IQR, 10.5%-15.9%) (P < .001 for all), with equal distribution among treatment groups. These interregional differences persisted at follow-up (P < .001 for all). No difference in perfusion recovery was found between the three treatment groups for any region. After revascularization of ST-elevation MI, cell therapy does not augment the recovery of resting perfusion in either the MI core or border zone. © RSNA, 2014.

  10. Role of TFEB Mediated Autophagy, Oxidative Stress, Inflammation, and Cell Death in Endotoxin Induced Myocardial Toxicity of Young and Aged Mice

    Directory of Open Access Journals (Sweden)

    Fang Li

    2016-01-01

    Full Text Available Elderly patients are susceptible to sepsis. LPS induced myocardial injury is a widely used animal model to assess sepsis induced cardiac dysfunction. The age dependent mechanisms behind sepsis susceptibility were not studied. We analyzed age associated changes to cardiac function, cell death, inflammation, oxidative stress, and autophagy in LPS induced myocardial injury. Both young and aged C57BL/6 mice were used for LPS administration. The results demonstrated that LPS induced more cardiac injury (creatine kinase, lactate dehydrogenase, troponin I, and cardiac myosin-light chains 1, cardiac dysfunction (left ventricular inner dimension, LVID, and ejection fraction (EF, cell death, inflammation, and oxidative stress in aged mice compared to young mice. However, a significant age dependent decline in autophagy was observed. Translocation of Transcription Factor EB (TFEB to nucleus and formation of LC3-II were significantly reduced in LPS administered aged mice compared to young ones. In addition to that, downstream effector of TFEB, LAMP-1, was induced in response to LPS challenge in young mice. The present study newly demonstrates that TFEB mediated autophagy is crucial for protection against LPS induced myocardial injury particularly in aging senescent heart. Targeting this autophagy-oxidative stress-inflammation-cell death axis may provide a novel therapeutic strategy for cardioprotection in the elderly.

  11. The AII amacrine cell connectome: a dense network hub.

    Science.gov (United States)

    Marc, Robert E; Anderson, James R; Jones, Bryan W; Sigulinsky, Crystal L; Lauritzen, James S

    2014-01-01

    The mammalian AII retinal amacrine cell is a narrow-field, multistratified glycinergic neuron best known for its role in collecting scotopic signals from rod bipolar cells and distributing them to ON and OFF cone pathways in a crossover network via a combination of inhibitory synapses and heterocellular AII::ON cone bipolar cell gap junctions. Long considered a simple cell, a full connectomics analysis shows that AII cells possess the most complex interaction repertoire of any known vertebrate neuron, contacting at least 28 different cell classes, including every class of retinal bipolar cell. Beyond its basic role in distributing rod signals to cone pathways, the AII cell may also mediate narrow-field feedback and feedforward inhibition for the photopic OFF channel, photopic ON-OFF inhibitory crossover signaling, and serves as a nexus for a collection of inhibitory networks arising from cone pathways that likely negotiate fast switching between cone and rod vision. Further analysis of the complete synaptic counts for five AII cells shows that (1) synaptic sampling is normalized for anatomic target encounter rates; (2) qualitative targeting is specific and apparently errorless; and (3) that AII cells strongly differentiate partner cohorts by synaptic and/or coupling weights. The AII network is a dense hub connecting all primary retinal excitatory channels via precisely weighted drive and specific polarities. Homologs of AII amacrine cells have yet to be identified in non-mammalians, but we propose that such homologs should be narrow-field glycinergic amacrine cells driving photopic ON-OFF crossover via heterocellular coupling with ON cone bipolar cells and glycinergic synapses on OFF cone bipolar cells. The specific evolutionary event creating the mammalian AII scotopic-photopic hub would then simply be the emergence of large numbers of pure rod bipolar cells.

  12. CO-GENERATION AND OPERATING NETWORK CELLS

    DEFF Research Database (Denmark)

    Nielsen, John Eli

    2008-01-01

    In Denmark several thousands of generators are connected to the distribution system (10 kV and 0.4 kV). The production from these generators many times exceeds the load. The generators can be divided into two types, Wind turbines and CHP generators. These generators have one thing in common, the ...... concept in along these lines is the “Network Cell”....

  13. Myocardial dysfunction in patients with type 2 diabetes mellitus: role of endothelial progenitor cells and oxidative stress.

    Science.gov (United States)

    Zhao, Chun Ting; Wang, Mei; Siu, Chung Wah; Hou, Ying Long; Wang, Tian; Tse, Hung Fat; Yiu, Kai Hang

    2012-12-05

    Endothelial progenitor cells (EPCs) are responsible for angiogenesis and maintenance of microvascular integrity, the number of EPCs is correlated with oxidative stress. Their relation to myocardial dysfunction in patients with type 2 diabetes mellitus (T2DM) is nonetheless unknown. Eighty-seven patients with T2DM and no history of coronary artery disease were recruited. Transthoracic echocardiography and detailed evaluation of left ventricular (LV) systolic function by 2-dimensional (2D) speckle tracking derived strain analysis in 3 orthogonal directions was performed. Four subpopulations of EPCs, including CD34+, CD133+, CD34+/kinase insert domain-containing receptor (KDR) + and CD133+/KDR + EPCs, were measured by flow cytometry. Oxidative stress was assessed by superoxide dismutase (SOD). The mean age of the patients was 62 ± 9 years and 39.6% were male. Those with an impaired longitudinal strain had a lower number of CD34+ EPCs (2.82 ± 1.87% vs. 3.74 ± 2.12%, P oxidative stress.

  14. Myocardial remodeling in diabetic cardiomyopathy associated with cardiac mast cell activation.

    Directory of Open Access Journals (Sweden)

    Zhi Gang Huang

    Full Text Available Diabetic cardiomyopathy is a specific disease process distinct from coronary artery disease and hypertension. The disease features cardiac remodeling stimulated by hyperglycemia of the left ventricle wall and disrupts contractile functions. Cardiac mast cells may be activated by metabolic byproducts resulted from hyperglycermia and then participate in the remodeling process by releasing a multitude of cytokines and bioactive enzymes. Nedocromil, a pharmacologic stabilizer of mast cells, has been shown to normalize cytokine levels and attenuate cardiac remodeling. In this study, we describe the activation of cardiac mast cells by inducing diabetes in normal mice using streptozotocin (STZ. Next, we treated the diabetic mice with nedocromil for 12 weeks and then examined their hearts for signs of cardiac remodeling and quantified contractile function. We observed significantly impaired heart function in diabetic mice, as well as increased cardiac mast cell density and elevated mast cell secretions that correlated with gene expression and aberrant cytokine levels associated with cardiac remodeling. Nedocromil treatment halted contractile dysfunction in diabetic mice and reduced cardiac mast cell density, which correlated with reduced bioactive enzyme secretions, reduced expression of extracellular matrix remodeling factors and collagen synthesis, and normalized cytokine levels. However, the results showed nedocromil treatments did not return diabetic mice to a normal state. We concluded that manipulation of cardiac mast cell function is sufficient to attenuate cardiomyopathy stimulated by diabetes, but other cellular pathways also contribute to the disease process.

  15. Apelin enhances cardiac neovascularization after myocardial infarction by recruiting aplnr+ circulating cells

    NARCIS (Netherlands)

    Tempel, D.; de Boer, M.; van Deel, E.D.; Haasdijk, R.A.; Duncker, D.J.G.M.; Cheng, C.; Schulte-Merker, S.; Duckers, H.J.

    2012-01-01

    RATIONALE: Neovascularization stimulated by local or recruited stem cells after ischemia is a key process that salvages damaged tissue and shows similarities with embryonic vascularization. Apelin receptor (Aplnr) and its endogenous ligand apelin play an important role in cardiovascular development.

  16. Apelin Enhances Cardiac Neovascularization After Myocardial Infarction By Recruiting Aplnr+ Circulating Cells

    NARCIS (Netherlands)

    Tempel, D.; Boer, de M.; Deel, van E.D.; Haasdijk, A.; Duncker, D.J.; Cheng, C.; Schulte-Merker, S.; Duckers, H.J.

    2012-01-01

    Rationale: Neovascularization stimulated by local or recruited stem cells after ischemia is a key process that salvages damaged tissue and shows similarities with embryonic vascularization. Apelin receptor (Aplnr) and its endogenous ligand apelin play an important role in cardiovascular development.

  17. Co-expression of vascular and lymphatic endothelial cell markers on early endothelial cells present in aspirated coronary thrombi from patients with ST-elevation myocardial infarction.

    Science.gov (United States)

    Rakocevic, Jelena; Kojic, Snezana; Orlic, Dejan; Stankovic, Goran; Ostojic, Miodrag; Petrovic, Olga; Zaletel, Ivan; Puskas, Nela; Todorovic, Vera; Labudovic-Borovic, Milica

    2016-02-01

    Angiogenesis is the growth of both new vascular and lymphatic blood vessels from the existing vasculature. During this process, blood endothelial cells (BECs) and lymphatic endothelial cells (LECs) express specific markers, which help their discrimination and easier identification. Since the coronary thrombi material aspirated from patients with ST-elevation myocardial infarction (STEMI) proved as good angiogenesis model, we investigated the expression of CD34 and CD31 as BECs markers, and D2-40, LYVE-1 and VEGFR3 as LEC markers in this material. Aspirated thrombi were stained immunohistochemically for CD34, CD31, D2-40, LYVE-1 and VEGFR3. Organizational patterns of immunopositive cells were graded as single cells, clusters or microvessels. Double immunofluorescence for CD31, D2-40, LYVE-1 and VEGRF3 was done. Thrombi were also graded as fresh (5days old). Serial sections of aspirated thrombi showed concordant BEC and LEC markers immunopositivity. Double immunoflorescence proved co-expression of CD31 and LEC markers on the same cells. Cells expressing LEC markers organized in clusters and microvessels were mainly present in lytic and organized thrombi. Co-expression of BEC and LEC markers on the same non-tumorous cell during thrombus neovascularization indicates existing in vivo plasticity of endothelial cells under non-tumorous pathological conditions. It also points that CD34 and CD31 on one hand, and D2-40, LYVE-1 and VEGFR3 immunostaining on the other hand, cannot solely be a reliable indicators whether vessel is lymphatic or not. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Boolean network model predicts cell cycle sequence of fission yeast.

    Directory of Open Access Journals (Sweden)

    Maria I Davidich

    Full Text Available A Boolean network model of the cell-cycle regulatory network of fission yeast (Schizosaccharomyces Pombe is constructed solely on the basis of the known biochemical interaction topology. Simulating the model in the computer faithfully reproduces the known activity sequence of regulatory proteins along the cell cycle of the living cell. Contrary to existing differential equation models, no parameters enter the model except the structure of the regulatory circuitry. The dynamical properties of the model indicate that the biological dynamical sequence is robustly implemented in the regulatory network, with the biological stationary state G1 corresponding to the dominant attractor in state space, and with the biological regulatory sequence being a strongly attractive trajectory. Comparing the fission yeast cell-cycle model to a similar model of the corresponding network in S. cerevisiae, a remarkable difference in circuitry, as well as dynamics is observed. While the latter operates in a strongly damped mode, driven by external excitation, the S. pombe network represents an auto-excited system with external damping.

  19. Differential Protein Network Analysis of the Immune Cell Lineage

    Directory of Open Access Journals (Sweden)

    Trevor Clancy

    2014-01-01

    Full Text Available Recently, the Immunological Genome Project (ImmGen completed the first phase of the goal to understand the molecular circuitry underlying the immune cell lineage in mice. That milestone resulted in the creation of the most comprehensive collection of gene expression profiles in the immune cell lineage in any model organism of human disease. There is now a requisite to examine this resource using bioinformatics integration with other molecular information, with the aim of gaining deeper insights into the underlying processes that characterize this immune cell lineage. We present here a bioinformatics approach to study differential protein interaction mechanisms across the entire immune cell lineage, achieved using affinity propagation applied to a protein interaction network similarity matrix. We demonstrate that the integration of protein interaction networks with the most comprehensive database of gene expression profiles of the immune cells can be used to generate hypotheses into the underlying mechanisms governing the differentiation and the differential functional activity across the immune cell lineage. This approach may not only serve as a hypothesis engine to derive understanding of differentiation and mechanisms across the immune cell lineage, but also help identify possible immune lineage specific and common lineage mechanism in the cells protein networks.

  20. Myocardial infarction in singapore: ethnic variation in evidence-based therapy and its association with socioeconomic status, social network size and perceived stress level.

    Science.gov (United States)

    Hein, Thet; Loo, Germaine; Tai, Bee-Choo; Phua, Qian-Hui; Chan, Mark Y; Poh, Kian-Keong; Chia, Boon-Lock; Richards, Mark; Lee, Chi-Hang

    2013-12-01

    Singapore is a multiethnic Asian country comprising predominantly Chinese, Malays, and Indians. We sought to study the disparities in evidence-based therapy for people from these three ethnic groups who were admitted to hospital with ST-segment elevation myocardial infarction (STEMI). We also examined its association with socioeconomic level and social network size and the influence on psychological stress level. In a prospective study, patients admitted with STEMI were recruited for a questionnaire survey. Relevant demographic and clinical data were collected. A total of 364 patients were recruited and categorised based on ethnicity: Chinese (222 patients), Malays (72 patients), and Indians (70 patients). Malays and Indians were significantly younger than Chinese at the time of presentation with STEMI. Malays had significantly more children than the Chinese and Indians. Malays were in the lowest socioeconomic class, based on education level (P ≤ .02) and residential type (P ≤ .003). Most (87%) patients were treated with primary percutaneous coronary intervention. There were no significant differences between Chinese, Malays, and Indians in accessibility to primary percutaneous coronary intervention, symptom-to-balloon time, door-to-balloon time, and prescription of evidence-based medications. Malays had larger social networks for information support (P ≤ .05) and financial support (P ≤ .04) than Chinese and Indians. There were no significant differences between the three ethnic groups in satisfaction with social support. The perceived stress level was higher among Malays and Indians than Chinese. Although Malays were underprivileged in the socioeconomic level, no significant difference in healthcare disparities were observed among the three ethnic groups. This may be a reflection of the advancement in Singapore's healthcare system. The lower socioeconomic level may also explain the higher perceived stress level in Malays. Copyright © 2013 Australian and

  1. Impact of the Type of First Medical Contact within a Guideline-Conform ST-Elevation Myocardial Infarction Network: A Prospective Observational Registry Study.

    Directory of Open Access Journals (Sweden)

    Roman Pfister

    Full Text Available The impact of type of first medical contact (FMC in the setting of a guideline conform metropolitan ST-elevation myocardial infarction (STEMI network providing obligatory primary percutaneous coronary intervention (PCI is unclear.3,312 patients were prospectively included between 2006 and 2012 into a registry accompanying the "Cologne Infarction Model" STEMI network, with 68.4% primarily presenting to emergency medical service (EMS, 17.6% to non-PCI-capable hospitals, and 14.0% to PCI-capable hospitals. Median contact-to-balloon time differed significantly by FMC with 89 minutes (IQR 72-115 for EMS, 107 minutes (IQR 85-148 for non-PCI- and 65 minutes (IQR 48-91 for PCI-capable hospitals (p < 0.001. TIMI-flow grade III and in-hospital mortality were 75.7% and 10.4% in EMS, 70.3% and 8.6% in non-PCI capable hospital and 84.4% and 5.6% in PCI-capable hospital presenters, respectively (p both < 0.01. The association of FMC with in-hospital mortality was not significant after adjustment for baseline characteristics, but risk of TIMI-flow grade < III remained significantly increased in patients presenting to non-PCI capable hospitals.Despite differences in treatment delay by type of FMC in-hospital mortality did not differ significantly. The increased risk of TIMI-flow grade < III in patients presenting to non PCI-capable hospitals needs further study.

  2. Emergence of Critical Behavior in β-Cell Network

    Science.gov (United States)

    Westacott, Matthew; Hraha, Thomas; McClatchey, Mason; Pozzoli, Marina; Benninger, Richard

    2014-03-01

    The β-cell is a cell type located in the Islet of Langerhans, a micro-organ of the pancreas which maintains glucose homeostasis through secretion of insulin. An electrophysiological process governing insulin release occurs through initial uptake of blood glucose and generation of ATP which inhibits the ATP sensitive potassium channel (K-ATP) causing membrane depolarization (activation). Neighboring β-cells are electrically coupled through gap junctions which allow passage of cationic molecules, creating a network of coupled electrical oscillators. Cells exhibiting hyperpolzarized (inactive) membrane potential affect behavior of neighboring cells by electrically suppressing their depolarization. Here we observe critical behavior between global active-inactive states by increasing the number of inactive elements with the K-ATP inhibitor Diazoxide and a tunable ATP insensitive transgenic mouse model. We show this behavior occurs due to from cell-cell coupling as mice lacking β-cell gap junctions show no critical behavior. Also, a computational β-cell model was expanded to construct a coupled β-cell network and we show this model replicates the critical behavior seen in-vitro.While electrical activity of single β-cells is well studied these data highlight a newly defined characteristic of their emergent multicellular behavior within the Islet of Langerhans and may elucidate pathophysiology of Diabetes due to mutations in the K-ATP channel.

  3. Social structures in Russia : cells and networks

    OpenAIRE

    Yefimov, Vladimir

    2001-01-01

    Russian companies heirs of Soviet enterprises are not Western-style companies, a significant difference is that they represent the basic structures of social life in the USSR : cells. The Soviet cellular system itself has deep roots in the history of Russia. The principal social structure of pre-revolutionary Russia was the rural community. In the late 1950s, Soviet society began to move away from the classic model. Cells gradually lose their exclusive role in the functioning of society. New ...

  4. Early Beneficial Effects of Bone Marrow Derived Mesenchymal Stem Cells Overexpressing Akt on Cardiac Metabolism after Myocardial Infarction

    Science.gov (United States)

    Gnecchi, Massimiliano; He, Huamei; Melo, Luis G; Noiseux, Nicolas; Morello, Fulvio; de Boer, Rudolf; Zhang, Lunan; Pratt, Richard E; Dzau, Victor J; Ingwall, Joanne S

    2010-01-01

    Background Administration of mesenchymal stem cells (MSCs) is an effective therapy to repair cardiac damage after myocardial infarction (MI) in experimental models. However, the mechanisms of action still need to be elucidated. Our group has recently suggested that MSCs mediate their therapeutic effects primarily via paracrine cytoprotective action. Furthermore, we have shown that MSCs overexpressing Akt1 (Akt-MSCs) exert even greater cytoprotection than unmodified MSCs. Thus far, little has been reported on the metabolic characteristics of infarcted hearts treated with stem cells. Here we hypothesize that Akt-MSC administration may influence the metabolic processes involved in cardiac adaptation and repair after MI. Methods and Results MI was performed in rats randomised in four groups: sham group and animals treated with control MSCs, Akt-MSCs or phosphate buffer solution (PBS). High energy metabolism and basal 2-deoxy-glucose (2-DG) uptake were evaluated on isolated hearts using phosphorous-31 nuclear magnetic resonance spectroscopy at 72 hours and two weeks after MI. Treatment with Akt-MSCs spared phosphocreatine stores and significantly limited the increase in 2-DG uptake in the residual intact myocardium compared to the PBS or the MSC treated animals. Furthermore, Akt-MSC treated hearts had normal pH, whereas low pH was measured in the PBS and MSC groups. Correlative analysis indicated that functional recovery after MI was inversely related to the rate of 2-DG uptake. Conclusion We conclude that administration of MSCs overexpressing Akt at the time of infarction results in preservation of normal metabolism and pH in the surviving myocardium. PMID:19353525

  5. [Efficacy of cyclosporine A-nanoparticles emulsion combined with stem cell transplantation therapy for acute myocardial infarction].

    Science.gov (United States)

    Yin, Qiao-xiang; Wang, Heng; Pei, Zhi-yong; Zhao, Yu-sheng

    2013-08-01

    To evaluate the efficacy of cyclosporine A-nanoparticles emulsion (CsA-NP) combined with adipose tissue-derived stem cells (ASCs)transplantation therapy for acute myocardial infarction (AMI) in a miniswine model. CsA-NP emulsion was prepared by the high-pressure homogenization method. Models were performed by coronary angioplasty for percutaneous balloon occlusion of left anterior descending artery (LAD). A total of 17 miniswines survived after AMI were divided into four groups: control group (n=5), CsA-NP group (n=4), ASCs group (n=4), and CsA-NP+ASCs group (n=4). ASCs or saline were delivered by intracoronary injection one week after AMI.Before cell transplantation and 8 weeks after cell transplantation, delayed-enhanced magnetic resonance imaging (DE-MRI) was performed to evaluate cardiac function and viability. The infarcted myocardium and implanted cells were histologically studied. Eight weeks after treatment, the left ventricular ejection fraction (LVEF)significantly increased in the CsA-NP+ASCs group when compared with the ASCs group [(53.6 ± 2.4)% vs. (48.3 ± 1.8)%, P<0.05]; meanwhile, the infarct size significantly decreased [(6.2 ± 1.7)cm(3) vs.(7.5 ± 0.6) cm(3), P<0.05] and the thickness of the ventricular wall significantly increased (P<0.05). Histology showed that the number of surviving cells increased nearly by three times in the CsA-NP+ASCs group, and the expressions of the cardiomyocyte specific markers (cTnT and α-actin) were detected. Histological samples also showed that CsA-NP+ASCs group reduced fibrotic tissue, and down-regulated the activation of Caspase-3. The CsA-NP+ASCs combination therapy can enhance the viability of ASCs by improving LVEF and preventing LV expansion, which may be explained that CsA-NP has the anti-apoptotic effect and can promote the survivals and proliferation of ASCs.

  6. Cell tracking and therapy evaluation of bone marrow monocytes and stromal cells using SPECT and CMR in a canine model of myocardial infarction

    Directory of Open Access Journals (Sweden)

    Merrifield Peter

    2009-04-01

    Full Text Available Abstract Background The clinical application of stem cell therapy for myocardial infarction will require the development of methods to monitor treatment and pre-clinical assessment in a large animal model, to determine its effectiveness and the optimum cell population, route of delivery, timing, and flow milieu. Objectives To establish a model for a in vivo tracking to monitor cell engraftment after autologous transplantation and b concurrent measurement of infarct evolution and remodeling. Methods We evaluated 22 dogs (8 sham controls, 7 treated with autologous bone marrow monocytes, and 7 with stromal cells using both imaging of 111Indium-tropolone labeled cells and late gadolinium enhancement CMR for up to12 weeks after a 3 hour coronary occlusion. Hearts were also examined using immunohistochemistry for capillary density and presence of PKH26 labeled cells. Results In vivo Indium imaging demonstrated an effective biological clearance half-life from the injection site of ~5 days. CMR demonstrated a pattern of progressive infarct shrinkage over 12 weeks, ranging from 67–88% of baseline values with monocytes producing a significant treatment effect. Relative infarct shrinkage was similar through to 6 weeks in all groups, following which the treatment effect was manifest. There was a trend towards an increase in capillary density with cell treatment. Conclusion This multi-modality approach will allow determination of the success and persistence of engraftment, and a correlation of this with infarct size shrinkage, regional function, and left ventricular remodeling. There were overall no major treatment effects with this particular model of transplantation immediately post-infarct.

  7. [Detection of damaged myocardial cells in histological sections by photochemical fluorochroming].

    Science.gov (United States)

    Tsimmerman, V G; Tsellarius, Iu G

    1976-01-01

    The effect of photochemical fluorochromizing used in the method suggested consists in the following: after the exposure of sections to short-wave ultraviolet irradiation the preparations start to fluorescence intensively in the visible region with the long-wave the myocardium of mice, dogs and section materials showed that following photochemical fluorochroming the intensity of lumenescence of damaged cells of the myocardium increased markedly as compared with that of intact cells. The authors recommend to use the described method in diagnosis of early stages of ischemic lesions of the myocardium.

  8. Cell-specific synaptic plasticity induced by network oscillations.

    Science.gov (United States)

    Zarnadze, Shota; Bäuerle, Peter; Santos-Torres, Julio; Böhm, Claudia; Schmitz, Dietmar; Geiger, Jörg Rp; Dugladze, Tamar; Gloveli, Tengis

    2016-05-24

    Gamma rhythms are known to contribute to the process of memory encoding. However, little is known about the underlying mechanisms at the molecular, cellular and network levels. Using local field potential recording in awake behaving mice and concomitant field potential and whole-cell recordings in slice preparations we found that gamma rhythms lead to activity-dependent modification of hippocampal networks, including alterations in sharp wave-ripple complexes. Network plasticity, expressed as long-lasting increases in sharp wave-associated synaptic currents, exhibits enhanced excitatory synaptic strength in pyramidal cells that is induced postsynaptically and depends on metabotropic glutamate receptor-5 activation. In sharp contrast, alteration of inhibitory synaptic strength is independent of postsynaptic activation and less pronounced. Further, we found a cell type-specific, directionally biased synaptic plasticity of two major types of GABAergic cells, parvalbumin- and cholecystokinin-expressing interneurons. Thus, we propose that gamma frequency oscillations represent a network state that introduces long-lasting synaptic plasticity in a cell-specific manner.

  9. CXCR4 Antagonist TG-0054 Mobilizes Mesenchymal Stem Cells, Attenuates Inflammation, and Preserves Cardiac Systolic Function in a Porcine Model of Myocardial Infarction.

    Science.gov (United States)

    Hsu, Wan-Tseng; Jui, Hsiang-Yiang; Huang, Ying-Huey; Su, Mao-Yuan M; Wu, Yen-Wen; Tseng, Wen-Yih I; Hsu, Ming-Chu; Chiang, Bor-Luen; Wu, Kenneth K; Lee, Chii-Ming

    2015-01-01

    Interaction between chemokine stromal cell-derived factor 1 and the CXC chemokine receptor 4 (CXCR4) governs the sequestration and mobilization of bone marrow stem cells. We investigated the therapeutic potential of TG-0054, a novel CXCR4 antagonist, in attenuating cardiac dysfunction after myocardial infarction (MI). In miniature pigs (minipigs), TG-0054 mobilized CD34(+)CXCR4(+), CD133(+)CXCR4(+), and CD271(+)CXCR4(+) cells into peripheral circulation. After isolation and expansion, TG-0054-mobilized CD271(+) cells were proved to be mesenchymal stem cells (designated CD271-MSCs) since they had trilineage differentiation potential, surface markers of MSCs, and immunosuppressive effects on allogeneic lymphocyte proliferation. MI was induced in 22 minipigs using balloon occlusion of the left anterior descending coronary artery, followed by intravenous injections of 2.85 mg/kg of TG-0054 or saline at 3 days and 7 days post-MI. Serial MRI analyses revealed that TG-0054 treatment prevented left ventricular (LV) dysfunction at 12 weeks after MI (change of LV ejection fraction from baseline, -1.0 ± 6.2% in the TG-0054 group versus -7.9 ± 5.8% in the controls). The preserved cardiac function was accompanied by a significant decrease in the myocardial expression of TNF-α, IL-1β, and IL-6 at 7 days post-MI. Moreover, the plasma levels of TNF-α, IL-1β, and IL-6 were persistently suppressed by the TG-0054 treatment. Infusion of TG-0054-mobilized CD271-MSCs reduced both myocardial and plasma cytokine levels in a pattern, which is temporally correlated with TG-0054 treatment. This study demonstrated that TG-0054 improves the impaired LV contractility following MI, at least in part, by mobilizing MSCs to attenuate the postinfarction inflammation. This insight may facilitate exploring novel stem cell-based therapy for treating post-MI heart failure.

  10. Regionalized sequence of myocardial cell growth and proliferation characterizes early chamber formation

    NARCIS (Netherlands)

    Soufan, Alexandre T.; van den Berg, Gert; Ruijter, Jan M.; de Boer, Piet A. J.; van den Hoff, Maurice J. B.; Moorman, Antoon F. M.

    2006-01-01

    Increase in cell size and proliferation of myocytes are key processes in cardiac morphogenesis, yet their regionalization during development of the heart has been described only anecdotally. We have made quantitative reconstructions of embryonic chicken hearts ranging in stage from the fusion of the

  11. Effects of sildenafil and/or muscle derived stem cells on myocardial infarction

    Directory of Open Access Journals (Sweden)

    Wang Judy SC

    2012-08-01

    Full Text Available Abstract Background Previous studies have shown that long-term oral daily PDE 5 inhibitors (PDE5i counteract fibrosis, cell loss, and the resulting dysfunction in tissues of various rat organs and that implantation of skeletal muscle-derived stem cells (MDSC exerts some of these effects. PDE5i and stem cells in combination were found to be more effective in non-MI cardiac repair than each treatment separately. We have now investigated whether sildenafil at lower doses and MDSC, alone or in combination are effective to attenuate LV remodeling after MI in rats. Methods MI was induced in rats by ligature of the left anterior descending coronary artery. Treatment groups were: “Series A”: 1 untreated; 2 oral sildenafil 3 mg/kg/day from day 1; and “Series B”: intracardiac injection at day 7 of: 3 saline; 4 rat MDSC (106 cells; 5 as #4, with sildenafil as in #2. Before surgery, and at 1 and 4 weeks, the left ventricle ejection fraction (LVEF was measured. LV sections were stained for collagen, myofibroblasts, apoptosis, cardiomyocytes, and iNOS, followed by quantitative image analysis. Western blots estimated angiogenesis and myofibroblast accumulation, as well as potential sildenafil tachyphylaxis by PDE 5 expression. Zymography estimated MMPs 2 and 9 in serum. Results As compared to untreated MI rats, sildenafil improved LVEF, reduced collagen, myofibroblasts, and circulating MMPs, and increased cardiac troponin T. MDSC replicated most of these effects and stimulated cardiac angiogenesis. Concurrent MDSC/sildenafil counteracted cardiomyocyte and endothelial cells loss, but did not improve LVEF or angiogenesis, and upregulated PDE 5. Conclusions Long-term oral sildenafil, or MDSC given separately, reduce the MI fibrotic scar and improve left ventricular function in this rat model. The failure of the treatment combination may be due to inducing overexpression of PDE5.

  12. Modelling and control of cell reaction networks

    NARCIS (Netherlands)

    S. Jha; J.H. van Schuppen (Jan)

    2001-01-01

    textabstractThe project aims at a study of the nonlinear systems arising in the biochemical processes occuring inside a cell. The cellular regulation has been formulated in the more familiar framework used in control and system theory in terms of inputs as the variables which can be influenced

  13. Intramyocardial Injection of Pig Pluripotent Stem Cells Improves Left Ventricular Function and Perfusion: A Study in a Porcine Model of Acute Myocardial Infarction.

    Directory of Open Access Journals (Sweden)

    Xiaorong Li

    Full Text Available Induced pluripotent stem (iPS cells have the potential to differentiate to various types of cardiovascular cells to repair an injured heart. The potential therapeutic benefits of iPS cell based treatment have been established in small-animal models of myocardial infarction (MI. We hypothesize that porcine iPS (piPS cell transplantation may be an effective treatment for MI. After a 90-minute occlusion of the left anterior descending artery in a porcine model, undifferentiated piPS cells or PBS were injected into the ischemic myocardium. Cardiac function, myocardial perfusion and cell differentiation were investigated. One week after piPS cell delivery, global left ventricular ejection fraction (LVEF significantly decreased in both the iPS group and the PBS group compared to the Sham group (p<0.05, respectively. Six weeks after piPS cell delivery, LVEF of the iPS group significantly improved compared to the PBS group (56.68% vs. 50.93%, p = 0.04 but was still lower than the Sham group. Likewise, the piPS cell transplantation improved the regional perfusion compared to the PBS injection (19.67% vs. 13.67%, p = 0.02. The infarct area was significantly smaller in the iPS group than the PBS group (12.04% vs. 15.98% p = 0.01. PiPS cells engrafted into the myocardium can differentiate into vessel cells, which result in increased formation of new vessels in the infarcted heart. Direct intramyocardial injection of piPS cells can decrease infarct size and improve left ventricular function and perfusion for an immunosuppressed porcine AMI model.

  14. Direct Adaptive Aircraft Control Using Dynamic Cell Structure Neural Networks

    Science.gov (United States)

    Jorgensen, Charles C.

    1997-01-01

    A Dynamic Cell Structure (DCS) Neural Network was developed which learns topology representing networks (TRNS) of F-15 aircraft aerodynamic stability and control derivatives. The network is integrated into a direct adaptive tracking controller. The combination produces a robust adaptive architecture capable of handling multiple accident and off- nominal flight scenarios. This paper describes the DCS network and modifications to the parameter estimation procedure. The work represents one step towards an integrated real-time reconfiguration control architecture for rapid prototyping of new aircraft designs. Performance was evaluated using three off-line benchmarks and on-line nonlinear Virtual Reality simulation. Flight control was evaluated under scenarios including differential stabilator lock, soft sensor failure, control and stability derivative variations, and air turbulence.

  15. Overexpression of angiopoietin-1 increases CD133+/c-kit+ cells and reduces myocardial apoptosis in db/db mouse infarcted hearts.

    Directory of Open Access Journals (Sweden)

    Heng Zeng

    Full Text Available Hematopoietic progenitor CD133(+/c-kit(+ cells have been shown to be involved in myocardial healing following myocardial infarction (MI. Previously we demonstrated that angiopoietin-1(Ang-1 is beneficial in the repair of diabetic infarcted hearts. We now investigate whether Ang-1 affects CD133(+/c-kit(+ cell recruitment to the infarcted myocardium thereby mediating cardiac repair in type II (db/db diabetic mice. db/db mice were administered either adenovirus Ang-1 (Ad-Ang-1 or Ad-β-gal systemically immediately after ligation of the left anterior descending coronary artery (LAD. Overexpression of Ang-1 resulted in a significant increase in CXCR-4/SDF-1α expression and promoted CD133(+/c-kit(+, CD133(+/CXCR-4(+ and CD133(+/SDF-1α(+ cell recruitment into ischemic hearts. Overexpression of Ang-1 led to significant increases in number of CD31(+ and smooth muscle-like cells and VEGF expression in bone marrow (BM. This was accompanied by significant decreases in cardiac apoptosis and fibrosis and an increase in myocardial capillary density. Ang-1 also upregulated Jagged-1, Notch3 and apelin expression followed by increases in arteriole formation in the infarcted myocardium. Furthermore, overexpression of Ang-1 resulted in a significant improvement of cardiac functional recovery after 14 days of ischemia. Our data strongly suggest that Ang-1 attenuates cardiac apoptosis and promotes cardiac repair by a mechanism involving in promoting CD133(+/c-kit(+ cells and angiogenesis in diabetic db/db mouse infarcted hearts.

  16. Dynamic Enhanced Inter-Cell Interference Coordination for Realistic Networks

    DEFF Research Database (Denmark)

    Pedersen, Klaus I.; Alvarez, Beatriz Soret; Barcos, Sonia

    2016-01-01

    ICIC configuration leads to modest gains, whereas the set of proposed fast dynamic eICIC algorithms result in capacity gains on the order of 35-120% depending on the local environment characteristics. These attractive gains together with the simplicity of the proposed solutions underline the practical relevance...... area. Rather than the classical semi-static and network-wise configuration, the importance of having highly dynamic and distributed mechanisms that are able to adapt to local environment conditions is revealed. We propose two promising cell association algorithms: one aiming at pure load balancing...... and an opportunistic approach exploiting the varying cell conditions. Moreover, an autonomous fast distributed muting algorithm is presented, which is simple, robust, and well suited for irregular network deployments. Performance results for realistic network deployments show that the traditional semi-static e...

  17. Primary Cilia, Signaling Networks and Cell Migration

    DEFF Research Database (Denmark)

    Veland, Iben Rønn

    on formation of the primary cilium and CDE at the pocket region. The ciliary protein Inversin functions as a molecular switch between canonical and non-canonical Wnt signaling. In paper II, we show that Inversin and the primary cilium control Wnt signaling and are required for polarization and cell migration....... A number of central Wnt components localize to the fibroblast primary cilium, including the Wnt5a-receptor, Fzd3, and Dvl proteins. Inversin-deficient MEFs have an elevated expression of canonical Wnt-associated genes and proteins, in addition to dysregulation of components in non-canonical Wnt signaling......, which leads to uncontrolled cell movements. Together, the results obtained from my PhD studies reflect the high level of complexity within signaling systems regulated by the primary cilium that control cellular processes during embryonic development and in tissue homeostasis. As such, this dissertation...

  18. In vitro three-dimensional coculturing poly3-hydroxybutyrate-co-3-hydroxyhexanoate with mouse-induced pluripotent stem cells for myocardial patch application.

    Science.gov (United States)

    Shijun, Xu; Junsheng, Mu; Jianqun, Zhang; Ping, Bo

    2016-03-01

    Identifying a suitable polymeric biomaterial for myocardial patch repair following myocardial infarction, cerebral infarction, and cartilage injury is essential. This study aimed to investigate the effect of the novel polymer material, poly3-hydroxybutyrate-co-3-hydroxyhexanoate, on the adhesion, proliferation, and differentiation of mouse-induced pluripotent stem cells in vitro. Mouse-induced pluripotent stem cells were isolated, expanded, and cultured on either two-dimensional or three-dimensional poly3-hydroxybutyrate-co-3-hydroxyhexanoate films (membranes were perforated to imitate three-dimensional space). Following attachment onto the films, mouse-induced pluripotent stem cell morphology was visualized using scanning electron microscopy. Cell vitality was detected using the Cell Counting Kit-8 assay and cell proliferation was observed using fluorescent 4',6-diamidino-2-phenylindole (DAPI) staining. Mouse-induced pluripotent stem cells were induced into cardiomyocytes by differentiation medium containing vitamin C. A control group in the absence of an inducer was included. Mouse-induced pluripotent stem cell survival and differentiation were observed using immunofluorescence and flow cytometry, respectively. Mouse-induced pluripotent stem cells growth, proliferation, and differentiation were observed on both two-dimensional and three-dimensional poly3-hydroxybutyrate-co-3-hydroxyhexanoate films. Vitamin C markedly improved the efficiency of mouse-induced pluripotent stem cells differentiation into cardiomyocytes on poly3-hydroxybutyrate-co-3-hydroxyhexanoate films. Three-dimensional culture was better at promoting mouse-induced pluripotent stem cell proliferation and differentiation compared with two-dimensional culture. © The Author(s) 2016.

  19. Transplantation of platelet gel spiked with cardiosphere-derived cells boosts structural and functional benefits relative to gel transplantation alone in rats with myocardial infarction

    Science.gov (United States)

    Cheng, Ke; Shen, Deliang; Smith, Jeremy; Galang, Giselle; Sun, Baiming; Zhang, Jinying; Marbán, Eduardo

    2012-01-01

    The emerging field of stem cell therapy and biomaterials has begun to provide promising strategies for the treatment of ischemic cardiomyopathy. Platelet gel and cardiosphere-derived cells (CDCs) are known to be beneficial when transplanted separately post-myocardial infarction (MI). We hypothesize that pre-seeding platelet gel with CDCs can enhance therapeutic efficacy. Platelet gel and CDCs were derived from venous blood and heart biopsies of syngeneic rats, respectively. In vitro, the viability, growth, and morphology of CDCs cultured in platelet gel were characterized. When delivered into infarcted rat hearts, platelet gel pre-seeded with CDCs was more efficiently populated with endogenous cardiomyocytes and endothelial cells than platelet gel alone. Recruitment of endogeous c-kit positive cells was enhanced in the hearts treated with gel with CDC. At 3 weeks, the hearts treated with CDC-seeded platelet gel exhibited the greatest attenuation of adverse left ventricular (LV) remodeling and the highest cardiac function (i.e., LV ejection fraction) as compared to hearts transplanted with gel only or vehicle controls. Histological analysis revealed that, though some transplanted CDCs differentiated into cardiomyocytes and endothelial cells in the recipients’ hearts, most of the incremental benefit arose from CDC-mediated endogenous repair. Pre-seeding platelet gel with CDCs enhanced the functional benefit of biomaterial therapy for treating myocardial infarction. PMID:22243801

  20. Validation of contrast-enhanced magnetic resonance imaging to monitor regenerative efficacy after cell therapy in a porcine model of convalescent myocardial infarction.

    Science.gov (United States)

    Malliaras, Konstantinos; Smith, Rachel R; Kanazawa, Hideaki; Yee, Kristine; Seinfeld, Jeffrey; Tseliou, Eleni; Dawkins, James F; Kreke, Michelle; Cheng, Ke; Luthringer, Daniel; Ho, Chak-Sum; Blusztajn, Agnieszka; Valle, Ileana; Chowdhury, Supurna; Makkar, Raj R; Dharmakumar, Rohan; Li, Debiao; Marbán, Linda; Marbán, Eduardo

    2013-12-24

    Magnetic resonance imaging (MRI) in the CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction (CADUCEUS) trial revealed that cardiosphere-derived cells (CDCs) decrease scar size and increase viable myocardium after myocardial infarction (MI), but MRI has not been validated as an index of regeneration after cell therapy. We tested the validity of contrast-enhanced MRI in quantifying scarred and viable myocardium after cell therapy in a porcine model of convalescent MI. Yucatan minipigs underwent induction of MI and 2-3 weeks later were randomized to receive intracoronary infusion of 12.5×10(6) mismatched allogeneic CDCs or vehicle. Allogeneic CDCs induced mild local mononuclear infiltration but no systemic immunogenicity. MRI revealed that allogeneic CDCs attenuated remodeling, improved global and regional function, decreased scar size, and increased viable myocardium compared with placebo 2 months post-treatment. Extensive histological analysis validated quantitatively the MRI measurements of scar size, scar mass, and viable mass. CDCs neither altered gadolinium contrast myocardial kinetics nor induced changes in vascular density or architecture in viable and scarred myocardium. Histology demonstrated that CDCs lead to cardiomyocyte hyperplasia in the border zone, consistent with the observed stimulation of endogenous regenerative mechanisms (cardiomyocyte cycling, upregulation of endogenous progenitors, angiogenesis). Contrast-enhanced MRI accurately measures scarred and viable myocardium after cell therapy in a porcine model of convalescent MI. MRI represents a useful tool for assessing dynamic changes in the infarct and monitoring regenerative efficacy.

  1. Effect of intramyocardial delivery of autologous bone marrow mononuclear stem cells on the regional myocardial perfusion. NOGA-guided subanalysis of the MYSTAR prospective randomised study.

    Science.gov (United States)

    Charwat, Silvia; Lang, Irene; Dettke, Markus; Graf, Senta; Nyolczas, Noemi; Hemetsberger, Rayyan; Zamini, Sholeh; Khorsand, Aliasghar; Sochor, Heinz; Maurer, Gerald; Glogar, Dietmar; Gyöngyösi, Mariann

    2010-03-01

    The aim of the sub-study of the MYSTAR randomised trial was to analyse the changes in myocardial perfusion in NOGA-defined regions of interest (ROI) with intramyocardial injections of autologous bone marrow mononuclear cells (BM-MNC) using an elaborated transformation algorithm. Patients with recent first acute myocardial infarction (AMI) and left ventricular (LV) ejection fraction (EF) between 30-45% received BM-MNC by intramyocardial followed by intracoronary injection 68 +/- 34 days post-AMI (pooled data of MYSTAR). NOGA-guided endocardial mapping and 99m-Sestamibi-SPECT (single photon emission computer tomography) were performed at baseline and at three months follow-up (FUP). ROI was delineated as a best polygon by connecting of injection points of NOGA polar maps. ROIs were projected onto baseline and FUP polar maps of SPECT calculating the perfusion severity of ROI. Infarct size was decreased (from 27.2 +/- 10.7% to 24.1 +/- 11.5%, por=5% improvement in perfusion defect severity received a significantly higher number of intramyocardial BM-MNC. In conclusion, combined cardiac BM-MNC delivery induces significant improvement in myocardial viability and perfusion in the intramyocardially injected area.

  2. Inferring cell-scale signalling networks via compressive sensing.

    Directory of Open Access Journals (Sweden)

    Lei Nie

    Full Text Available Signalling network inference is a central problem in system biology. Previous studies investigate this problem by independently inferring local signalling networks and then linking them together via crosstalk. Since a cellular signalling system is in fact indivisible, this reductionistic approach may have an impact on the accuracy of the inference results. Preferably, a cell-scale signalling network should be inferred as a whole. However, the holistic approach suffers from three practical issues: scalability, measurement and overfitting. Here we make this approach feasible based on two key observations: 1 variations of concentrations are sparse due to separations of timescales; 2 several species can be measured together using cross-reactivity. We propose a method, CCELL, for cell-scale signalling network inference from time series generated by immunoprecipitation using Bayesian compressive sensing. A set of benchmark networks with varying numbers of time-variant species is used to demonstrate the effectiveness of our method. Instead of exhaustively measuring all individual species, high accuracy is achieved from relatively few measurements.

  3. Energy Efficiency Challenges of 5G Small Cell Networks

    Science.gov (United States)

    Ge, Xiaohu; Yang, Jing; Gharavi, Hamid; Sun, Yang

    2017-01-01

    The deployment of a large number of small cells poses new challenges to energy efficiency, which has often been ignored in fifth generation (5G) cellular networks. While massive multiple-input multiple outputs (MIMO) will reduce the transmission power at the expense of higher computational cost, the question remains as to which computation or transmission power is more important in the energy efficiency of 5G small cell networks. Thus, the main objective in this paper is to investigate the computation power based on the Landauer principle. Simulation results reveal that more than 50% of the energy is consumed by the computation power at 5G small cell base stations (BSs). Moreover, the computation power of 5G small cell BS can approach 800 watt when the massive MIMO (e.g., 128 antennas) is deployed to transmit high volume traffic. This clearly indicates that computation power optimization can play a major role in the energy efficiency of small cell networks. PMID:28757670

  4. Proteomics-based network analysis characterizes biological processes and pathways activated by preconditioned mesenchymal stem cells in cardiac repair mechanisms.

    Science.gov (United States)

    Di Silvestre, Dario; Brambilla, Francesca; Scardoni, Giovanni; Brunetti, Pietro; Motta, Sara; Matteucci, Marco; Laudanna, Carlo; Recchia, Fabio A; Lionetti, Vincenzo; Mauri, Pierluigi

    2017-05-01

    We have demonstrated that intramyocardial delivery of human mesenchymal stem cells preconditioned with a hyaluronan mixed ester of butyric and retinoic acid (MSCp+) is more effective in preventing the decay of regional myocardial contractility in a swine model of myocardial infarction (MI). However, the understanding of the role of MSCp+ in proteomic remodeling of cardiac infarcted tissue is not complete. We therefore sought to perform a comprehensive analysis of the proteome of infarct remote (RZ) and border zone (BZ) of pigs treated with MSCp+ or unconditioned stem cells. Heart tissues were analyzed by MudPIT and differentially expressed proteins were selected by a label-free approach based on spectral counting. Protein profiles were evaluated by using PPI networks and their topological analysis. The proteomic remodeling was largely prevented in MSCp+ group. Extracellular proteins involved in fibrosis were down-regulated, while energetic pathways were globally up-regulated. Cardioprotectant pathways involved in the production of keto acid metabolites were also activated. Additionally, we found that new hub proteins support the cardioprotective phenotype characterizing the left ventricular BZ treated with MSCp+. In fact, the up-regulation of angiogenic proteins NCL and RAC1 can be explained by the increase of capillary density induced by MSCp+. Our results show that angiogenic pathways appear to be uniquely positioned to integrate signaling with energetic pathways involving cardiac repair. Our findings prompt the use of proteomics-based network analysis to optimize new approaches preventing the post-ischemic proteomic remodeling that may underlie the limited self-repair ability of adult heart. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. An artificial neural network to safely reduce the number of ambulance ECGs transmitted for physician assessment in a system with prehospital detection of ST elevation myocardial infarction

    Directory of Open Access Journals (Sweden)

    Forberg Jakob L

    2012-02-01

    Full Text Available Abstract Background Pre-hospital electrocardiogram (ECG transmission to an expert for interpretation and triage reduces time to acute percutaneous coronary intervention (PCI in patients with ST elevation Myocardial Infarction (STEMI. In order to detect all STEMI patients, the ECG should be transmitted in all cases of suspected acute cardiac ischemia. The aim of this study was to examine the ability of an artificial neural network (ANN to safely reduce the number of ECGs transmitted by identifying patients without STEMI and patients not needing acute PCI. Methods Five hundred and sixty ambulance ECGs transmitted to the coronary care unit (CCU in routine care were prospectively collected. The ECG interpretation by the ANN was compared with the diagnosis (STEMI or not and the need for an acute PCI (or not as determined from the Swedish coronary angiography and angioplasty register. The CCU physician's real time ECG interpretation (STEMI or not and triage decision (acute PCI or not were registered for comparison. Results The ANN sensitivity, specificity, positive and negative predictive values for STEMI was 95%, 68%, 18% and 99%, respectively, and for a need of acute PCI it was 97%, 68%, 17% and 100%. The area under the ANN's receiver operating characteristics curve for STEMI detection was 0.93 (95% CI 0.89-0.96 and for predicting the need of acute PCI 0.94 (95% CI 0.90-0.97. If ECGs where the ANN did not identify a STEMI or a need of acute PCI were theoretically to be withheld from transmission, the number of ECGs sent to the CCU could have been reduced by 64% without missing any case with STEMI or a need of immediate PCI. Conclusions Our ANN had an excellent ability to predict STEMI and the need of acute PCI in ambulance ECGs, and has a potential to safely reduce the number of ECG transmitted to the CCU by almost two thirds.

  6. Novel nano-network cathodes for solid oxide fuel cells

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Fei [Laboratory for Renewable Clean Energy, Department of Materials Science and Engineering, University of Science and Technology of China, Hefei 230026, Anhui (China); Department of Mechanical Engineering, University of South Carolina, Columbia, SC 29208 (United States); Wang, Zhiyong; Liu, Mingfei; Zhang, Lei; Xia, Changrong [Laboratory for Renewable Clean Energy, Department of Materials Science and Engineering, University of Science and Technology of China, Hefei 230026, Anhui (China); Chen, Fanglin [Department of Mechanical Engineering, University of South Carolina, Columbia, SC 29208 (United States)

    2008-10-15

    A novel nano-network of Sm{sub 0.5}Sr{sub 0.5}CoO{sub 3-{delta}} (SSC) is successfully fabricated as the cathodes for intermediate-temperature solid oxide fuel cells (SOFCs) operated at 500-600 C. The cathode is composed of SSC nanowires formed from nanobeads of less than 50 nm thus exhibiting high surface area and porosity, forming straight path for oxygen ion and electron transportation, resulting in high three-phase boundaries, and consequently showing remarkably high electrode performance. An anode-supported cell with the nano-network cathode demonstrates a peak power density of 0.44 W cm{sup -2} at 500 C and displays exceptional performance with cell operating time. The result suggests a new direction to significantly improve the SOFC performance. (author)

  7. Network Representation of Multi-Cell Accelerating Structures

    CERN Document Server

    Raguin, J Y

    2001-01-01

    The analysis of the electrodynamic properties of a complete multi-cell accelerating structure using electromagnetic numerical simulation codes is presently at the edge of existing computer capabilities. To overcome this limitation, a network representation is proposed which derives the overall scattering transfer matrix of such multi-cell structures from single-cell data calculated using the commercial finite-element code HFSS. For a constant-impedance structure, computation of the eigenvalues of this matrix allows dispersion diagrams to be obtained. In the more general case, this formalism leads to a representation of the coupled-chain of cavities as a set of cascaded non identical multipoles.

  8. On the Virtual Cell Transmission in Ultra Dense Networks

    Directory of Open Access Journals (Sweden)

    Xiaopeng Zhu

    2016-10-01

    Full Text Available Ultra dense networks (UDN are identified as one of the key enablers for 5G, since they can provide an ultra high spectral reuse factor exploiting proximal transmissions. By densifying the network infrastructure equipment, it is highly possible that each user will have one or more dedicated serving base station antennas, introducing the user-centric virtual cell paradigm. However, due to irregular deployment of a large amount of base station antennas, the interference environment becomes rather complex, thus introducing severe interferences among different virtual cells. This paper focuses on the downlink transmission scheme in UDN where a large number of users and base station antennas is uniformly spread over a certain area. An interference graph is first created based on the large-scale fadings to give a potential description of the interference relationship among the virtual cells. Then, base station antennas and users in the virtual cells within the same maximally-connected component are grouped together and merged into one new virtual cell cluster, where users are jointly served via zero-forcing (ZF beamforming. A multi-virtual-cell minimum mean square error precoding scheme is further proposed to mitigate the inter-cluster interference. Additionally, the interference alignment framework is proposed based on the low complexity virtual cell merging to eliminate the strong interference between different virtual cells. Simulation results show that the proposed interference graph-based virtual cell merging approach can attain the average user spectral efficiency performance of the grouping scheme based on virtual cell overlapping with a smaller virtual cell size and reduced signal processing complexity. Besides, the proposed user-centric transmission scheme greatly outperforms the BS-centric transmission scheme (maximum ratio transmission (MRT in terms of both the average user spectral efficiency and edge user spectral efficiency. What is more

  9. Clinical outcome after stem cell mobilization with granulocyte-colony-stimulating factor after acute ST-elevation myocardial infarction:

    DEFF Research Database (Denmark)

    Ripa, Rasmus S; Jørgensen, Erik; Kastrup, Jens

    2013-01-01

    Background. Granulocyte-colony-stimulating factor (G-CSF) has been investigated in trials aiming to promote recovery of myocardial function after myocardial infarction. Long-term safety-data have never been reported. A few studies indicated an increased risk of in-stent re-stenosis. We aimed to i.......8; 0.3). Conclusions. We found no indication of increased risk of adverse events up to 5 years after G-CSF treatment. These results support the continued investigation of G-CSF for cardiac therapy....

  10. Primary Cilia, Signaling Networks and Cell Migration

    DEFF Research Database (Denmark)

    Veland, Iben Rønn

    composition of receptors and signal components in the cilium to regulate cellular processes such as transcriptional control or cytoskeletal reorganization. This dissertation focuses on selected signaling systems regulated by the primary cilium, including the PDGFRα, TGFβ and Wnt pathways, and how......, which leads to uncontrolled cell movements. Together, the results obtained from my PhD studies reflect the high level of complexity within signaling systems regulated by the primary cilium that control cellular processes during embryonic development and in tissue homeostasis. As such, this dissertation......-dependent regulation of signal transduction. Upon ligand-binding and activation in the cilium, TGFβ receptors accumulate and are internalized at the ciliary base together with Smad2/3 transcription factors that are phosphorylated here and translocated to the nucleus for target gene expression. These processes depend...

  11. Hierarchical Feedback Modules and Reaction Hubs in Cell Signaling Networks

    Science.gov (United States)

    Xu, Jianfeng; Lan, Yueheng

    2015-01-01

    Despite much effort, identification of modular structures and study of their organizing and functional roles remain a formidable challenge in molecular systems biology, which, however, is essential in reaching a systematic understanding of large-scale cell regulation networks and hence gaining capacity of exerting effective interference to cell activity. Combining graph theoretic methods with available dynamics information, we successfully retrieved multiple feedback modules of three important signaling networks. These feedbacks are structurally arranged in a hierarchical way and dynamically produce layered temporal profiles of output signals. We found that global and local feedbacks act in very different ways and on distinct features of the information flow conveyed by signal transduction but work highly coordinately to implement specific biological functions. The redundancy embodied with multiple signal-relaying channels and feedback controls bestow great robustness and the reaction hubs seated at junctions of different paths announce their paramount importance through exquisite parameter management. The current investigation reveals intriguing general features of the organization of cell signaling networks and their relevance to biological function, which may find interesting applications in analysis, design and control of bio-networks. PMID:25951347

  12. Validation of Contrast-Enhanced MRI to Monitor Regenerative Efficacy after Cell Therapy in a Porcine Model of Convalescent Myocardial Infarction

    Science.gov (United States)

    Malliaras, Konstantinos; Smith, Rachel R.; Kanazawa, Hideaki; Yee, Kristine; Seinfeld, Jeffrey; Tseliou, Eleni; Dawkins, James F.; Kreke, Michelle; Cheng, Ke; Luthringer, Daniel; Ho, Chak-Sum; Blusztajn, Agnieszka; Valle, Ileana; Chowdhury, Supurna; Makkar, Raj R.; Dharmakumar, Rohan; Li, Debiao; Marbán, Linda; Marbán, Eduardo

    2014-01-01

    Background Magnetic Resonance Imaging (MRI) in the CADUCEUS trial revealed that cardiosphere-derived cells (CDCs) decrease scar size and increase viable myocardium post-myocardial infarction (MI), but MRI has not been validated as an index of regeneration after cell therapy. We tested the validity of contrast-enhanced MRI in quantifying scarred and viable myocardium after cell therapy in a porcine model of convalescent MI. Methods and Results Yucatan minipigs underwent induction of MI and 2-3 weeks later were randomized to receive intracoronary infusion of 12.5×106 mismatched allogeneic CDCs or vehicle. Allogeneic CDCs induced mild local mononuclear infiltration but no systemic immunogenicity. MRI revealed that allogeneic CDCs attenuated remodeling, improved global and regional function, decreased scar size and increased viable myocardium compared to placebo 2 months post-treatment. Extensive histological analysis validated quantitatively the MRI measurements of scar size, scar mass and viable mass. CDCs neither altered gadolinium contrast myocardial kinetics, nor induced changes in vascular density or architecture in viable and scarred myocardium. Histology demonstrated that CDCs lead to cardiomyocyte hyperplasia in the border zone, consistent with the observed stimulation of endogenous regenerative mechanisms (cardiomyocyte cycling, upregulation of endogenous progenitors, angiogenesis). Conclusions Contrast-enhanced MRI accurately measures scarred and viable myocardium after cell therapy in a porcine model of convalescent MI. MRI represents a useful tool for assessing dynamic changes in the infarct and monitoring regenerative efficacy. PMID:24061088

  13. Ticagrelor Attenuates Apoptosis of Lung and Myocardial Cells Induced by Abdominal Aorta Ischemia/Reperfusion.

    Science.gov (United States)

    Findik, Orhan; Kunt, Atike Tekeli; Yazir, Yusufhan; Yardimoğlu, Melda; Yilmaz, Seda Güleç; Aydin, Ufuk; Rençber, Selenay Furat; Baris, Ozgur; Balci, Canan; Isbir, Turgay

    2016-01-01

    This study aimed to analyze the effect of ticagrelor pretreatment on the prevention of lung and heart injury induced by abdominal aorta ischemia and reperfusion (I/R) and also to determine the effective dose. Thirty-five male Sprague-Dawley rats weighing 350-400 g were randomized into five groups. The animals received ticagrelor at doses of 7.5 mg/kg, 15 mg/kg and 25 mg/kg or normal saline 0.1 ml/kg orally via gastric gavage before the ischemic period. In the control and study groups, I/R injury was induced by clamping the aorta infrarenally for 2 hs, followed by 4 h of reperfusion. After sacrifice, hearts and lungs of the animals were extracted for both histopathological and biochemical analysis. There was a significant difference between the animals that received 7.5 mg/kg and 25 mg/kg and 15 mg/kg and 25 mg/kg dose of ticagrelor regarding tissue malondealdehyde (MDA), and glutathione reductase levels in both lung and heart Ticagrelor treatment at 25 mg/kg led to significant cardiac remodeling activity and normal lung architecture against I/R induced injury. The number of TdT-mediated dUTP nick-end labeling (TUNEL)-positive cells in alveolar epithelium and myocytes were increased in the sections from saline (I/R) group rats, and decreased following 25 mg/kg ticagrelor treatment. Ticagrelor dose-dependently inhibits platelet aggregation, increases cyclooxygenase-2 and also inhibits cellular uptake of adenosine all resulting in attenuation of I/R injury. Ticagrelor at 25 mg/kg was determined as the dose effective against I/R-induced injury in lung and heart in Sprague-Dawley rats in the present study. Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  14. Human embryonic stem cell-derived neuronal cells form spontaneously active neuronal networks in vitro.

    Science.gov (United States)

    Heikkilä, Teemu J; Ylä-Outinen, Laura; Tanskanen, Jarno M A; Lappalainen, Riikka S; Skottman, Heli; Suuronen, Riitta; Mikkonen, Jarno E; Hyttinen, Jari A K; Narkilahti, Susanna

    2009-07-01

    The production of functional human embryonic stem cell (hESC)-derived neuronal cells is critical for the application of hESCs in treating neurodegenerative disorders. To study the potential functionality of hESC-derived neurons, we cultured and monitored the development of hESC-derived neuronal networks on microelectrode arrays. Immunocytochemical studies revealed that these networks were positive for the neuronal marker proteins beta-tubulin(III) and microtubule-associated protein 2 (MAP-2). The hESC-derived neuronal networks were spontaneously active and exhibited a multitude of electrical impulse firing patterns. Synchronous bursts of electrical activity similar to those reported for hippocampal neurons and rodent embryonic stem cell-derived neuronal networks were recorded from the differentiated cultures until up to 4 months. The dependence of the observed neuronal network activity on sodium ion channels was examined using tetrodotoxin (TTX). Antagonists for the glutamate receptors NMDA [D(-)-2-amino-5-phosphonopentanoic acid] and AMPA/kainate [6-cyano-7-nitroquinoxaline-2,3-dione], and for GABAA receptors [(-)-bicuculline methiodide] modulated the spontaneous electrical activity, indicating that pharmacologically susceptible neuronal networks with functional synapses had been generated. The findings indicate that hESC-derived neuronal cells can generate spontaneously active networks with synchronous communication in vitro, and are therefore suitable for use in developmental and drug screening studies, as well as for regenerative medicine.

  15. Myocardial infarction : early diagnosis and cardioprotective strategies

    NARCIS (Netherlands)

    Oerlemans, M.I.F.J.

    2012-01-01

    In this thesis, we have investigated novel diagnostic and cardioprotective strategies to limit myocardial cell death and improve cardiac function after myocardial infarction. We demonstrated a new way to speed up the diagnosis of acute MI by using very small pieces of RNA (microRNAs). Using these

  16. Cell diversity and network dynamics in photosensitive human brain organoids

    Science.gov (United States)

    Quadrato, Giorgia; Nguyen, Tuan; Macosko, Evan Z.; Sherwood, John L.; Yang, Sung Min; Berger, Daniel; Maria, Natalie; Scholvin, Jorg; Goldman, Melissa; Kinney, Justin; Boyden, Edward S.; Lichtman, Jeff; Williams, Ziv M.; McCarroll, Steven A.; Arlotta, Paola

    2017-01-01

    In vitro models of the developing brain such as 3D brain organoids offer an unprecedented opportunity to study aspects of human brain development and disease. However, it remains undefined what cells are generated within organoids and to what extent they recapitulate the regional complexity, cellular diversity, and circuit functionality of the brain. Here, we analyzed gene expression in over 80,000 individual cells isolated from 31 human brain organoids. We find that organoids can generate a broad diversity of cells, which are related to endogenous classes, including cells from the cerebral cortex and the retina. Organoids could be developed over extended periods (over 9 months) enabling unprecedented levels of maturity including the formation of dendritic spines and of spontaneously-active neuronal networks. Finally, neuronal activity within organoids could be controlled using light stimulation of photoreceptor-like cells, which may offer ways to probe the functionality of human neuronal circuits using physiological sensory stimuli. PMID:28445462

  17. An Arabidopsis gene regulatory network for secondary cell wall synthesis.

    Science.gov (United States)

    Taylor-Teeples, M; Lin, L; de Lucas, M; Turco, G; Toal, T W; Gaudinier, A; Young, N F; Trabucco, G M; Veling, M T; Lamothe, R; Handakumbura, P P; Xiong, G; Wang, C; Corwin, J; Tsoukalas, A; Zhang, L; Ware, D; Pauly, M; Kliebenstein, D J; Dehesh, K; Tagkopoulos, I; Breton, G; Pruneda-Paz, J L; Ahnert, S E; Kay, S A; Hazen, S P; Brady, S M

    2015-01-29

    The plant cell wall is an important factor for determining cell shape, function and response to the environment. Secondary cell walls, such as those found in xylem, are composed of cellulose, hemicelluloses and lignin and account for the bulk of plant biomass. The coordination between transcriptional regulation of synthesis for each polymer is complex and vital to cell function. A regulatory hierarchy of developmental switches has been proposed, although the full complement of regulators remains unknown. Here we present a protein-DNA network between Arabidopsis thaliana transcription factors and secondary cell wall metabolic genes with gene expression regulated by a series of feed-forward loops. This model allowed us to develop and validate new hypotheses about secondary wall gene regulation under abiotic stress. Distinct stresses are able to perturb targeted genes to potentially promote functional adaptation. These interactions will serve as a foundation for understanding the regulation of a complex, integral plant component.

  18. Sox17-Mediated XEN Cell Conversion Identifies Dynamic Networks Controlling Cell-Fate Decisions in Embryo-Derived Stem Cells

    Directory of Open Access Journals (Sweden)

    Angela C.H. McDonald

    2014-10-01

    Full Text Available Little is known about the gene regulatory networks (GRNs distinguishing extraembryonic endoderm (ExEn stem (XEN cells from those that maintain the extensively characterized embryonic stem cell (ESC. An intriguing network candidate is Sox17, an essential transcription factor for XEN derivation and self-renewal. Here, we show that forced Sox17 expression drives ESCs toward ExEn, generating XEN cells that contribute to ExEn when placed back into early mouse embryos. Transient Sox17 expression is sufficient to drive this fate change during which time cells transit through distinct intermediate states prior to the generation of functional XEN-like cells. To orchestrate this conversion process, Sox17 acts in autoregulatory and feedforward network motifs, regulating dynamic GRNs directing cell fate. Sox17-mediated XEN conversion helps to explain the regulation of cell-fate changes and reveals GRNs regulating lineage decisions in the mouse embryo.

  19. E2/ER β Enhances Calcineurin Protein Degradation and PI3K/Akt/MDM2 Signal Transduction to Inhibit ISO-Induced Myocardial Cell Apoptosis

    Directory of Open Access Journals (Sweden)

    Kuan-Ho Lin

    2017-04-01

    Full Text Available Secretion of multifunctional estrogen and its receptor has been widely considered as the reason for markedly higher frequency of heart disease in men than in women. 17β-Estradiol (E2, for instance, has been reported to prevent development of cardiac apoptosis via activation of estrogen receptors (ERs. In addition, protein phosphatase such as protein phosphatase 1 (PP1 and calcineurin (PP2B are also involved in cardiac hypertrophy and cell apoptosis signaling. However, the mechanism by which E2/ERβ suppresses apoptosis is not fully understood, and the role of protein phosphatase in E2/ERβ action also needs further investigation. In this study, we observed that E2/ERβ inhibited isoproterenol (ISO-induced myocardial cell apoptosis, cytochrome c release and downstream apoptotic markers. Moreover, we found that E2/ERβ blocks ISO-induced apoptosis in H9c2 cells through the enhancement of calcineurin protein degradation through PI3K/Akt/MDM2 signaling pathway. Our results suggest that supplementation with estrogen and/or overexpression of estrogen receptor β gene may prove to be effective means to treat stress-induced myocardial damage.

  20. Comparative cell cycle transcriptomics reveals synchronization of developmental transcription factor networks in cancer cells

    Science.gov (United States)

    Johard, Helena; Mahdessian, Diana; Fedr, Radek; Marks, Carolyn; Medalová, Jiřina; Souček, Karel; Lundberg, Emma; Linnarsson, Sten; Bryja, Vítězslav; Sekyrova, Petra; Altun, Mikael; Andäng, Michael

    2017-01-01

    The cell cycle coordinates core functions such as replication and cell division. However, cell-cycle-regulated transcription in the control of non-core functions, such as cell identity maintenance through specific transcription factors (TFs) and signalling pathways remains unclear. Here, we provide a resource consisting of mapped transcriptomes in unsynchronized HeLa and U2OS cancer cells sorted for cell cycle phase by Fucci reporter expression. We developed a novel algorithm for data analysis that enables efficient visualization and data comparisons and identified cell cycle synchronization of Notch signalling and TFs associated with development. Furthermore, the cell cycle synchronizes with the circadian clock, providing a possible link between developmental transcriptional networks and the cell cycle. In conclusion we find that cell cycle synchronized transcriptional patterns are temporally compartmentalized and more complex than previously anticipated, involving genes, which control cell identity and development. PMID:29228002

  1. Time course of VCAM-1 expression in reperfused myocardial infarction in swine and its relation to retention of intracoronary administered bone marrow-derived mononuclear cells.

    Directory of Open Access Journals (Sweden)

    André Uitterdijk

    Full Text Available Intracoronary infusion of autologous bone marrow-derived mononuclear cells (BMMNC, after acute myocardial infarction (AMI, has been shown to improve myocardial function. However, therapeutic efficacy is limited, possibly because cell retention rates are low, suggesting that optimization of cell retention might increase therapeutic efficacy. Since retention of injected BMMNC is observed only within infarcted, but not remote, myocardium, we hypothesized that adhesion molecules on activated endothelium following reperfusion are essential. Consequently, we investigated the role of vascular cell adhesion molecule 1 (VCAM-1 in BMMNC retention in swine undergoing reperfused AMI produced by 120 min of percutaneous left circumflex coronary occlusion.VCAM-1 expression in the infarct and remote region was quantified at 1, 3, 7, 14, and 35 days, post-reperfusion (n≥6 swine per group. Since expression levels were significantly higher at 3 days (2.41±0.62% than at 7 days (0.98±0.28%; p<0.05, we compared the degree of cell retention at those time points in a follow-up study, in which an average of 43·106 autologous BMMNCs were infused intracoronary at 3, or 7 days, post-reperfusion (n = 6 swine per group and retention was histologically quantified one hour after intracoronary infusion of autologous BMMNCs. Although VCAM-1 expression correlated with retention of BMMNC within each time point, overall BMMNC retention was similar at day 3 and day 7 (2.3±1.3% vs. 3.1±1.4%, p = 0.72. This was not due to the composition of infused bone marrow cell fractions (analyzed with flow cytometry; n = 5 per group, as cell composition of the infused BMMNC fractions was similar.These findings suggest that VCAM-1 expression influences to a small degree, but is not the principal determinant of, BMMNC retention.

  2. Time course of VCAM-1 expression in reperfused myocardial infarction in swine and its relation to retention of intracoronary administered bone marrow-derived mononuclear cells.

    Science.gov (United States)

    Uitterdijk, André; Groenendijk, Bianca C W; Gorsse-Bakker, Charlotte; Panasewicz, Anna; Sneep, Stefan; Tempel, Dennie; van de Kamp, Esther H; Merkus, Daphne; van der Giessen, Willem J; Duncker, Dirk J

    2017-01-01

    Intracoronary infusion of autologous bone marrow-derived mononuclear cells (BMMNC), after acute myocardial infarction (AMI), has been shown to improve myocardial function. However, therapeutic efficacy is limited, possibly because cell retention rates are low, suggesting that optimization of cell retention might increase therapeutic efficacy. Since retention of injected BMMNC is observed only within infarcted, but not remote, myocardium, we hypothesized that adhesion molecules on activated endothelium following reperfusion are essential. Consequently, we investigated the role of vascular cell adhesion molecule 1 (VCAM-1) in BMMNC retention in swine undergoing reperfused AMI produced by 120 min of percutaneous left circumflex coronary occlusion. VCAM-1 expression in the infarct and remote region was quantified at 1, 3, 7, 14, and 35 days, post-reperfusion (n≥6 swine per group). Since expression levels were significantly higher at 3 days (2.41±0.62%) than at 7 days (0.98±0.28%; p<0.05), we compared the degree of cell retention at those time points in a follow-up study, in which an average of 43·106 autologous BMMNCs were infused intracoronary at 3, or 7 days, post-reperfusion (n = 6 swine per group) and retention was histologically quantified one hour after intracoronary infusion of autologous BMMNCs. Although VCAM-1 expression correlated with retention of BMMNC within each time point, overall BMMNC retention was similar at day 3 and day 7 (2.3±1.3% vs. 3.1±1.4%, p = 0.72). This was not due to the composition of infused bone marrow cell fractions (analyzed with flow cytometry; n = 5 per group), as cell composition of the infused BMMNC fractions was similar. These findings suggest that VCAM-1 expression influences to a small degree, but is not the principal determinant of, BMMNC retention.

  3. The mechanics of microtubule networks in cell division.

    Science.gov (United States)

    Forth, Scott; Kapoor, Tarun M

    2017-06-05

    The primary goal of a dividing somatic cell is to accurately and equally segregate its genome into two new daughter cells. In eukaryotes, this process is performed by a self-organized structure called the mitotic spindle. It has long been appreciated that mechanical forces must be applied to chromosomes. At the same time, the network of microtubules in the spindle must be able to apply and sustain large forces to maintain spindle integrity. Here we consider recent efforts to measure forces generated within microtubule networks by ensembles of key proteins. New findings, such as length-dependent force generation, protein clustering by asymmetric friction, and entropic expansion forces will help advance models of force generation needed for spindle function and maintaining integrity. © 2017 Forth and Kapoor.

  4. Distribution of mitochondrial nucleoids upon mitochondrial network fragmentation and network reintegration in HEPG2 cells.

    Science.gov (United States)

    Tauber, Jan; Dlasková, Andrea; Šantorová, Jitka; Smolková, Katarína; Alán, Lukáš; Špaček, Tomáš; Plecitá-Hlavatá, Lydie; Jabůrek, Martin; Ježek, Petr

    2013-03-01

    Mitochondrial DNA (mtDNA) is organized in nucleoids in complex with accessory proteins, proteins of mtDNA replication and gene expression machinery. A robust mtDNA genome is represented by hundreds to thousands of nucleoids in cell mitochondrion. Detailed information is lacking about the dynamics of nucleoid distribution within the mitochondrial network upon physiological and pathological events. Therefore, we used confocal microscopy to study mitochondrial nucleoid redistribution upon mitochondrial fission and following reintegration of the mitochondrial network. Fission was induced by oxidative stress at respiration inhibition by rotenone or upon elimination of the protonmotive force by uncoupling or upon canceling its electrical component, ΔΨ(m), by valinomycin; and by silencing of mitofusin MFN2. Agent withdrawal resulted in concomitant mitochondrial network reintegration. We found two major principal morphological states: (i) a tubular state of the mitochondrial network with equidistant nucleoid spacing, 1.10±0.2 nucleoids per μm, and (ii) a fragmented state of solitary spheroid objects in which several nucleoids were clustered. We rarely observed singular mitochondrial fragments with a single nucleoid inside and very seldom we observed empty fragments. Reintegration of fragments into the mitochondrial network re-established the tubular state with equidistant nucleoid spacing. The two major morphological states coexisted at intermediate stages. These observations suggest that both mitochondrial network fission and reconnection of the disintegrated network are nucleoid-centric, i.e., fission and new mitochondrial tubule formation are initiated around nucleoids. Analyses of combinations of these morphological icons thus provide a basis for a future mitochondrial morphology diagnostics. Copyright © 2012 Elsevier Ltd. All rights reserved.

  5. Meta-Analysis of Cell-based CaRdiac stUdiEs (ACCRUE) in patients with acute myocardial infarction based on individual patient data

    DEFF Research Database (Denmark)

    Gyöngyösi, Mariann; Wojakowski, Wojciech; Lemarchand, Patricia

    2015-01-01

    therapy after acute myocardial infarction (AMI), including individual patient data from 12 randomized trials (ASTAMI, Aalst, BOOST, BONAMI, CADUCEUS, FINCELL, REGENT, REPAIR-AMI, SCAMI, SWISS-AMI, TIME, LATE-TIME; n=1252). METHODS AND RESULTS: The primary end point was freedom from combined major adverse......RATIONALE: The meta-Analysis of Cell-based CaRdiac study is the first prospectively declared collaborative multinational database, including individual data of patients with ischemic heart disease treated with cell therapy. OBJECTIVE: We analyzed the safety and efficacy of intracoronary cell...... cardiac and cerebrovascular events (including all-cause death, AMI recurrance, stroke, and target vessel revascularization). The secondary end point was freedom from hard clinical end points (death, AMI recurrence, or stroke), assessed with random-effects meta-analyses and Cox regressions for interactions...

  6. Evidence for grid cells in a human memory network.

    Science.gov (United States)

    Doeller, Christian F; Barry, Caswell; Burgess, Neil

    2010-02-04

    Grid cells in the entorhinal cortex of freely moving rats provide a strikingly periodic representation of self-location which is indicative of very specific computational mechanisms. However, the existence of grid cells in humans and their distribution throughout the brain are unknown. Here we show that the preferred firing directions of directionally modulated grid cells in rat entorhinal cortex are aligned with the grids, and that the spatial organization of grid-cell firing is more strongly apparent at faster than slower running speeds. Because the grids are also aligned with each other, we predicted a macroscopic signal visible to functional magnetic resonance imaging (fMRI) in humans. We then looked for this signal as participants explored a virtual reality environment, mimicking the rats' foraging task: fMRI activation and adaptation showing a speed-modulated six-fold rotational symmetry in running direction. The signal was found in a network of entorhinal/subicular, posterior and medial parietal, lateral temporal and medial prefrontal areas. The effect was strongest in right entorhinal cortex, and the coherence of the directional signal across entorhinal cortex correlated with spatial memory performance. Our study illustrates the potential power of combining single-unit electrophysiology with fMRI in systems neuroscience. Our results provide evidence for grid-cell-like representations in humans, and implicate a specific type of neural representation in a network of regions which supports spatial cognition and also autobiographical memory.

  7. Nickel-cadmium battery cell reversal from resistive network effects

    Science.gov (United States)

    Zimmerman, A. H.

    1985-07-01

    During the individual cell short-down procedures often used for storing or reconditioning nickel-cadmium (Ni-Cd) batteries, it is possible for significant reversal of the lowest capacity cells to occur. The reversal is caused by the finite resistance of the common current-carrying leads in the resistive network that is generally used during short-down. A model is developed to evaluate the extent of such a reversal in any specific battery, and the model is verified by means of data from the short-down of a f-cell, 3.5-Ah battery. Computer simulations of short-down on a variety of battery configurations indicate the desirability of controlling capacity imbalances arising from cell configuration and battery management, limiting variability in the short-down resistors, minimizing lead resistances, and optimizing lead configurations.

  8. Intra-myocardial injection of both growth factors and heart derived Sca-1+/CD31- cells attenuates post-MI LV remodeling more than does cell transplantation alone: neither intervention enhances functionally significant cardiomyocyte regeneration.

    Directory of Open Access Journals (Sweden)

    Xiaohong Wang

    Full Text Available Insulin-like growth factor 1 (IGF-1 and hepatocyte growth factor (HGF are two potent cell survival and regenerative factors in response to myocardial injury (MI. We hypothesized that simultaneous delivery of IGF+HGF combined with Sca-1+/CD31- cells would improve the outcome of transplantation therapy in response to the altered hostile microenvironment post MI. One million adenovirus nuclear LacZ-labeled Sca-1+/CD31- cells were injected into the peri-infarction area after left anterior descending coronary artery (LAD ligation in mice. Recombinant mouse IGF-1+HGF was added to the cell suspension prior to the injection. The left ventricular (LV function was assessed by echocardiography 4 weeks after the transplantation. The cell engraftment, differentiation and cardiomyocyte regeneration were evaluated by histological analysis. Sca-1+/CD31- cells formed viable grafts and improved LV ejection fraction (EF (Control, 54.5+/-2.4; MI, 17.6+/-3.1; Cell, 28.2+/-4.2, n = 9, P<0.01. IGF+HGF significantly enhanced the benefits of cell transplantation as evidenced by increased EF (38.8+/-2.2; n = 9, P<0.01 and attenuated adverse structural remodeling. Furthermore, IGF+HGF supplementation increased the cell engraftment rate, promoted the transplanted cell survival, enhanced angiogenesis, and minimally stimulated endogenous cardiomyocyte regeneration in vivo. The in vitro experiments showed that IGF+HGF treatment stimulated Sca-1+/CD31- cell proliferation and inhibited serum free medium induced apoptosis. Supperarray profiling of Sca-1+/CD31- cells revealed that Sca-1+/CD31- cells highly expressed various trophic factor mRNAs and IGF+HGF treatment altered the mRNAs expression patterns of these cells. These data indicate that IGF-1+HGF could serve as an adjuvant to cell transplantation for myocardial repair by stimulating donor cell and endogenous cardiac stem cell survival, regeneration and promoting angiogenesis.

  9. Multimodality Molecular Imaging of Cardiac Cell Transplantation: Part I. Reporter Gene Design, Characterization, and Optical in Vivo Imaging of Bone Marrow Stromal Cells after Myocardial Infarction

    Science.gov (United States)

    Parashurama, Natesh; Ahn, Byeong-Cheol; Ziv, Keren; Ito, Ken; Paulmurugan, Ramasamy; Willmann, Jürgen K.; Chung, Jaehoon; Ikeno, Fumiaki; Swanson, Julia C.; Merk, Denis R.; Lyons, Jennifer K.; Yerushalmi, David; Teramoto, Tomohiko; Kosuge, Hisanori; Dao, Catherine N.; Ray, Pritha; Patel, Manishkumar; Chang, Ya-fang; Mahmoudi, Morteza; Cohen, Jeff Eric; Goldstone, Andrew Brooks; Habte, Frezghi; Bhaumik, Srabani; Yaghoubi, Shahriar; Robbins, Robert C.; Dash, Rajesh; Yang, Phillip C.; Brinton, Todd J.; Yock, Paul G.; McConnell, Michael V.

    2016-01-01

    Purpose To use multimodality reporter-gene imaging to assess the serial survival of marrow stromal cells (MSC) after therapy for myocardial infarction (MI) and to determine if the requisite preclinical imaging end point was met prior to a follow-up large-animal MSC imaging study. Materials and Methods Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care. Mice (n = 19) that had experienced MI were injected with bone marrow–derived MSC that expressed a multimodality triple fusion (TF) reporter gene. The TF reporter gene (fluc2-egfp-sr39ttk) consisted of a human promoter, ubiquitin, driving firefly luciferase 2 (fluc2), enhanced green fluorescent protein (egfp), and the sr39tk positron emission tomography reporter gene. Serial bioluminescence imaging of MSC-TF and ex vivo luciferase assays were performed. Correlations were analyzed with the Pearson product-moment correlation, and serial imaging results were analyzed with a mixed-effects regression model. Results Analysis of the MSC-TF after cardiac cell therapy showed significantly lower signal on days 8 and 14 than on day 2 (P = .011 and P = .001, respectively). MSC-TF with MI demonstrated significantly higher signal than MSC-TF without MI at days 4, 8, and 14 (P = .016). Ex vivo luciferase activity assay confirmed the presence of MSC-TF on days 8 and 14 after MI. Conclusion Multimodality reporter-gene imaging was successfully used to assess serial MSC survival after therapy for MI, and it was determined that the requisite preclinical imaging end point, 14 days of MSC survival, was met prior to a follow-up large-animal MSC study. © RSNA, 2016 Online supplemental material is available for this article. PMID:27308957

  10. The problem of colliding networks and its relation to cell fusion and cancer.

    Science.gov (United States)

    Koulakov, Alexei A; Lazebnik, Yuri

    2012-11-07

    Cell fusion, a process that merges two or more cells into one, is required for normal development and has been explored as a tool for stem cell therapy. It has also been proposed that cell fusion causes cancer and contributes to its progression. These functions rely on a poorly understood ability of cell fusion to create new cell types. We suggest that this ability can be understood by considering cells as attractor networks whose basic property is to adopt a set of distinct, stable, self-maintaining states called attractors. According to this view, fusion of two cell types is a collision of two networks that have adopted distinct attractors. To learn how these networks reach a consensus, we model cell fusion computationally. To do so, we simulate patterns of gene activities using a formalism developed to simulate patterns of memory in neural networks. We find that the hybrid networks can assume attractors that are unrelated to parental attractors, implying that cell fusion can create new cell types by nearly instantaneously moving cells between attractors. We also show that hybrid networks are prone to assume spurious attractors, which are emergent and sporadic network states. This finding means that cell fusion can produce abnormal cell types, including cancerous types, by placing cells into normally inaccessible spurious states. Finally, we suggest that the problem of colliding networks has general significance in many processes represented by attractor networks, including biological, social, and political phenomena. Copyright © 2012 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  11. Regenerative healing following foetal myocardial infarction.

    Science.gov (United States)

    Herdrich, Benjamin J; Danzer, Enrico; Davey, Marcus G; Allukian, Myron; Englefield, Virginia; Gorman, Joseph H; Gorman, Robert C; Liechty, Kenneth W

    2010-12-01

    The adult response to myocardial infarction results in inflammation, scar formation, left ventricular dilatation, and loss of regional and global function. Regenerative scarless healing has been demonstrated in foetal dermis and tendon and is associated with diminished inflammation. We hypothesised that following foetal myocardial infarction, there would be minimal inflammation, regenerative healing, and preservation of function. Anteroapical myocardial infarction encompassing 20% of the left ventricle was created in adult or early gestation foetal sheep. Myocardial function was serially assessed using quantitative echocardiography. Infarct architecture was examined histologically for evidence of scar formation. Cellular inflammation, cellular proliferation, and apoptosis were assessed using immunohistochemistry. In the adult sheep 4 weeks following myocardial infarction, there was a significant decline in ejection fraction (EF) (41±7.4% to 26±7.4%, p<0.05), and the akinetic myocardial segment increased in size (6.9±0.8 cm to 7.9±1.1 cm, p<0.05). By contrast, there was no decline in the foetal EF (53±8.1% to 55±8.8%) and no akinetic foetal myocardial segment 4 weeks post-infarction. The foetal infarcts lacked an inflammatory cell infiltrate and healed with minimal fibrosis, compared with the adults. Foetal infarcts also demonstrated 5-bromo-2'-deoxyuridine (BrdU)+ proliferating cells, including cardiomyocytes, within the infarct. These data demonstrate that the foetal response to myocardial infarction is dramatically different from the adult and is characterised by minimal inflammation, lack of fibrosis, myocardial proliferation and restoration of cardiac function. Diminished inflammation is associated with foetal regenerative cardiac healing following injury. Understanding the mechanisms involved in foetal myocardial regeneration may lead to applications to alter the adult response following myocardial infarction. Copyright © 2010 European Association for

  12. Regenerative healing following fetal myocardial infarction

    Science.gov (United States)

    Herdrich, Benjamin J.; Danzer, Enrico; Davey, Marcus G.; Allukian, Myron; Englefield, Virginia; Gorman, Joseph H.; Gorman, Robert C.; Liechty, Kenneth W.

    2010-01-01

    Objectives The adult response to myocardial infarction results in inflammation, scar formation, left ventricular dilatation, and loss of regional and global function. Regenerative scarless healing has been demonstrated in fetal dermis and tendon and is associated with diminished inflammation. We hypothesized that following fetal myocardial infarction there would be minimal inflammation, regenerative healing, and preservation of function. Methods Anteroapical myocardial infarction encompassing 20% of the left ventricle were created in adult or early gestation fetal sheep. Myocardial function was serially assessed using quantitative echocardiography. Infarct architecture was examined histologically for evidence of scar formation. Cellular inflammation, cellular proliferation, and apoptosis were assessed using immunohistochemistry. Results In the adult sheep 4 weeks following myocardial infarction, there was a significant decline in ejection fraction (41±7.4% to 26±7.4%, p<0.05), and the akinetic myocardial segment increased in size (6.9±0.8 cm to 7.9±1.1 cm, p<0.05). In contrast, there was no decline in the fetal ejection fraction (53±8.1% to 55±8.8%) and no akinetic fetal myocardial segment 4 weeks post-infarction. The fetal infarcts lacked an inflammatory cell infiltrate and healed with minimal fibrosis, compared to the adults. Fetal infarcts also demonstrated BrdU+ proliferating cells, including cardiomyocytes, within the infarct. Conclusions These data demonstrate that the fetal response to myocardial infarction is dramatically different than the adult and is characterized by minimal inflammation, lack of fibrosis, myocardial proliferation, and restoration of cardiac function. Diminished inflammation is associated with fetal regenerative cardiac healing following injury. Understanding the mechanisms involved in fetal myocardial regeneration may lead to applications to alter the adult response following myocardial infarction. PMID:20452780

  13. Acute myocardial infarction is associated with endothelial glycocalyx and cell damage and a parallel increase in circulating catecholamines

    DEFF Research Database (Denmark)

    Ostrowski, Sisse R; Pedersen, Sune H; Jensen, Jan S

    2013-01-01

    INTRODUCTION: Excessive sympathoadrenal activation in critical illness contributes directly to organ damage, and high concentrations of catecholamines damage the vascular endothelium. This study investigated associations between potential drivers of sympathoadrenal activation, circulating...... catecholamines and biomarkers of endothelial damage and outcome in ST segment elevation myocardial infarction (STEMI)-patients, hypothesizing that the catecholamine surge would reflect shock degree and correlate with biomarkers of endothelial damage. METHODS: This was a prospective study of 678 consecutive STEMI...

  14. Meta-analysis reveals conserved cell cycle transcriptional network across multiple human cell types.

    Science.gov (United States)

    Giotti, Bruno; Joshi, Anagha; Freeman, Tom C

    2017-01-05

    Cell division is central to the physiology and pathology of all eukaryotic organisms. The molecular machinery underpinning the cell cycle has been studied extensively in a number of species and core aspects of it have been found to be highly conserved. Similarly, the transcriptional changes associated with this pathway have been studied in different organisms and different cell types. In each case hundreds of genes have been reported to be regulated, however there seems to be little consensus in the genes identified across different studies. In a recent comparison of transcriptomic studies of the cell cycle in different human cell types, only 96 cell cycle genes were reported to be the same across all studies examined. Here we perform a systematic re-examination of published human cell cycle expression data by using a network-based approach to identify groups of genes with a similar expression profile and therefore function. Two clusters in particular, containing 298 transcripts, showed patterns of expression consistent with cell cycle occurrence across the four human cell types assessed. Our analysis shows that there is a far greater conservation of cell cycle-associated gene expression across human cell types than reported previously, which can be separated into two distinct transcriptional networks associated with the G 1 /S-S and G 2 -M phases of the cell cycle. This work also highlights the benefits of performing a re-analysis on combined datasets.

  15. Neural network adapted to wound cell analysis in surgical patients.

    Science.gov (United States)

    Viljanto, Jouko; Koski, Antti

    2011-01-01

    Assessment of the real state of wound healing of closed surgical wounds is uncertain both clinically and from conventional laboratory tests. Therefore, a novel approach based on early analysis of exactly timed wound cells, computerized further with an artificial neural network, was developed. At the end of routine surgery performed on 481 children under 18 years of age, a specific wound drain Cellstick™ was inserted subcutaneously between the wound edges to harvest wound cells. The Cellsticks™ were removed from 1 to 50 hours, mainly at hour 3 or 24 postsurgery. Immediately, the cellular contents were washed out using a pump constructed for the purpose. After cytocentrifugation, the cells were stained and counted differentially. Based on their relative proportions at selected time intervals, an artificial self-organizing neural map was developed. This was further transformed to a unidirectional linear graph where each node represents one set of relative cell quantities. As early as 3 hours, but more precisely 24 hours after surgery, the location of the nodes on this graph showed individually the patients' initial speed of wound inflammatory cell response. Similarly, timed Cellstick™ specimens from new surgical patients could be analyzed, computerized, and compared with these node values to assess their initial speed in wound inflammatory cell response. Location of the node on the graph does not express the time lapse after surgery but the speed of wound inflammatory cell response in relation to that of other patients. © 2011 by the Wound Healing Society.

  16. The Orchestra of Myocardial Regeneration

    NARCIS (Netherlands)

    Siddiqi, S.

    2014-01-01

    A glimpse on previous and current literature ignites the recognition of the luxurious era that cardiac science has reached. In particular, the past fifteen years have provided tremendous advancements in the field of myocardial biology with the characterization of cardiac stem cells, reprogramming of

  17. Bone marrow mesenchymal stromal cells with CD47 high expression via the signal transducer and activators of transcription signaling pathway preventing myocardial fibrosis.

    Science.gov (United States)

    Deng, Wei; Chen, Qing-Wei; Li, Xing-Sheng; Yuan, Zhong-Ming; Li, Gui-Qiong; Ke, Da-Zhi; Wang, Li; Wu, Zhi-Qing; Luo, Shi-Lan

    2015-01-01

    This study was initiated to investigate the efficacy of myocardial fibrosis intervention via signal transducer and activators of transcription (STAT) signaling using bone marrow (BM) mesenchymal stromal cells (MSC) in which being over-expressed with the aid of bispecific antibody (BiAb) and ultrasound-mediated microbubbles (MB). BiAb was prepared and combined with isolated MSC with CD47 overexpression from male mice and trans-fused into female mice with isoproterenol-induced myocardial fibrosis via the tail vein, followed by MB. This study included five groups. Five weeks after treatment, expression levels of the sex-determining region of Y-chromosome (SRY), matrix metalloproteinases (MMP)-9, tissue inhibitor of metalloproteinase (TIMP)-1 and vascular endothelial growth factor (VEGF) in myocardium were detected by fluorescent quantitative real-time polymerase chain reaction (qRT-PCR). The protein expression of signal transducer and activators of transcription (STAT) 1 and STAT 3 was detected by Western blot. The highest homing number of MSC was in the CD47 + MSC + BiAb + MB group, second highest in the CD47 + MSC + BiAb group, and lowest in MSC alone. Compared with the Control group, CD47 + MSC + BiAb + MB, CD47 + MSC + BiAb, CD47 + MSC and MSC groups had decreased levels of MMP-9, TIMP-1, STAT 1 and collagen deposition, and increased levels of STAT 3. Up regulated STAT 3 and down regulated TIMP-1 were significantly different in CD47 + MSC + BiAb + MB compared with CD47 + MSC or CD47 + MSC + BiAb. CD47 can enhance the homing rate and repairing efficacy of MSC. MSC can improve MMP-TIMP expression in injured myocardium and interfere with myocardial fibrosis after homing, a mechanism that may be related to the STAT-mediated signaling pathway.

  18. Angiotensin II receptor blockers suppress the release of stromal cell-derived factor-1α from infarcted myocardium in patients with acute myocardial infarction.

    Science.gov (United States)

    Yoshizaki, Toru; Uematsu, Manabu; Obata, Jun-Ei; Nakamura, Takamitsu; Fujioka, Daisuke; Watanabe, Kazuhiro; Nakamura, Kazuto; Kugiyama, Kiyotaka

    2018-04-01

    Although angiotensin II receptor blockers (ARBs) have been shown to have anti-inflammatory effects on infarcted myocardium in experimental models, little is known in humans. Stromal cell-derived factor-1α (SDF-1α), a pro-inflammatory chemokine, is released from infarcted tissue in patients with acute myocardial infarction (AMI). This study examined whether ARBs suppress SDF-1α production in the infarcted lesion in patients with AMI. SDF-1α levels were measured by enzyme-linked immunosorbent assays in plasma obtained from the aortic root (AO) and the anterior interventricular vein (AIV) in 50 patients with an anterior AMI. Measurement of SDF-1α levels and left ventriculography were repeated at discharge and 6 months after AMI. Patients were divided into 2 groups according to treatment with ARBs, which were administered at the discretion of the attending physician after admission. The AIV-AO gradient of SDF-1α, reflecting SDF-1α release from the infarcted myocardial region, decreased between the time of discharge and 6 months after AMI in patients taking an ARB. In contrast, the SDF-1α transcardiac gradient did not change in patients not taking an ARB. Among the clinical parameters tested, only the use of ARBs was significantly associated with percent changes in the SDF-1α transcardiac gradient from the time of discharge to 6 months after AMI in a linear regression analysis (r=-0.31, p=0.03). The SDF-1α transcardiac gradient 6 months after AMI was inversely correlated with the percent change in left ventricular (LV) ejection fraction (r=-0.52, pinfarcted myocardial region, which was associated with improvement in LV dysfunction and adverse remodeling in AMI survivors. Copyright © 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

  19. Secretome of apoptotic peripheral blood cells (APOSEC) attenuates microvascular obstruction in a porcine closed chest reperfused acute myocardial infarction model: role of platelet aggregation and vasodilation.

    Science.gov (United States)

    Hoetzenecker, K; Assinger, A; Lichtenauer, M; Mildner, M; Schweiger, T; Starlinger, P; Jakab, A; Berényi, E; Pavo, N; Zimmermann, M; Gabriel, C; Plass, C; Gyöngyösi, M; Volf, I; Ankersmit, H J

    2012-09-01

    Although epicardial blood flow can be restored by an early intervention in most cases, a lack of adequate reperfusion at the microvascular level is often a limiting prognostic factor of acute myocardial infarction (AMI). Our group has recently found that paracrine factors secreted from apoptotic peripheral blood mononuclear cells (APOSEC) attenuate the extent of myocardial injury. The aim of this study was to determine the influence of APOSEC on microvascular obstruction (MVO) in a porcine AMI model. A single dose of APOSEC was intravenously injected in a closed chest reperfused infarction model. MVO was determined by magnetic resonance imaging and cardiac catheterization. Role of platelet function and vasodilation were monitored by means of ELISA, flow cytometry, aggregometry, western blot and myographic experiments in vitro and in vivo. Treatment of AMI with APOSEC resulted in a significant reduction of MVO. Platelet activation markers were reduced in plasma samples obtained during AMI, suggesting an anti-aggregatory capacity of APOSEC. This finding was confirmed by in vitro tests showing that activation and aggregation of both porcine and human platelets were significantly impaired by co-incubation with APOSEC, paralleled by vasodilator-stimulated phosphoprotein (VASP)-mediated inhibition of platelets. In addition, APOSEC evidenced a significant vasodilatory capacity on coronary arteries via p-eNOS and iNOS activation. Our data give first evidence that APOSEC reduces the extent of MVO during AMI, and suggest that modulation of platelet activation and vasodilation in the initial phase after myocardial infarction contributes to the improved long-term outcome in APOSEC treated animals.

  20. How pathogens use linear motifs to perturb host cell networks

    KAUST Repository

    Via, Allegra

    2015-01-01

    Molecular mimicry is one of the powerful stratagems that pathogens employ to colonise their hosts and take advantage of host cell functions to guarantee their replication and dissemination. In particular, several viruses have evolved the ability to interact with host cell components through protein short linear motifs (SLiMs) that mimic host SLiMs, thus facilitating their internalisation and the manipulation of a wide range of cellular networks. Here we present convincing evidence from the literature that motif mimicry also represents an effective, widespread hijacking strategy in prokaryotic and eukaryotic parasites. Further insights into host motif mimicry would be of great help in the elucidation of the molecular mechanisms behind host cell invasion and the development of anti-infective therapeutic strategies.

  1. Cell type specific alterations in interchromosomal networks across the cell cycle.

    Directory of Open Access Journals (Sweden)

    Andrew J Fritz

    2014-10-01

    Full Text Available The interchromosomal organization of a subset of human chromosomes (#1, 4, 11, 12, 16, 17, and 18 was examined in G1 and S phase of human WI38 lung fibroblast and MCF10A breast epithelial cells. Radial positioning of the chromosome territories (CTs was independent of gene density, but size dependent. While no changes in radial positioning during the cell cycle were detected, there were stage-specific differences between cell types. Each CT was in close proximity (interaction with a similar number of other CT except the gene rich CT17 which had significantly more interactions. Furthermore, CT17 was a member of the highest pairwise CT combinations with multiple interactions. Major differences were detected in the pairwise interaction profiles of MCF10A versus WI38 including cell cycle alterations from G1 to S. These alterations in interaction profiles were subdivided into five types: overall increase, overall decrease, switching from 1 to ≥2 interactions, vice versa, or no change. A global data mining program termed the chromatic median determined the most probable overall association network for the entire subset of CT. This probabilistic interchromosomal network was nearly completely different between the two cell lines. It was also strikingly altered across the cell cycle in MCF10A, but only slightly in WI38. We conclude that CT undergo multiple and preferred interactions with other CT in the nucleus and form preferred -albeit probabilistic- interchromosomal networks. This network of interactions is altered across the cell cycle and between cell types. It is intriguing to consider the relationship of these alterations to the corresponding changes in the gene expression program across the cell cycle and in different cell types.

  2. A Comprehensive Nuclear Receptor Network for Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Ralf Kittler

    2013-02-01

    Full Text Available In breast cancer, nuclear receptors (NRs play a prominent role in governing gene expression, have prognostic utility, and are therapeutic targets. We built a regulatory map for 24 NRs, six chromatin state markers, and 14 breast-cancer-associated transcription factors (TFs that are expressed in the breast cancer cell line MCF-7. The resulting network reveals a highly interconnected regulatory matrix where extensive crosstalk occurs among NRs and other breast -cancer-associated TFs. We show that large numbers of factors are coordinately bound to highly occupied target regions throughout the genome, and these regions are associated with active chromatin state and hormone-responsive gene expression. This network also provides a framework for stratifying and predicting patient outcomes, and we use it to show that the peroxisome proliferator-activated receptor delta binds to a set of genes also regulated by the retinoic acid receptors and whose expression is associated with poor prognosis in breast cancer.

  3. Detection of silent cells, synchronization and modulatory activity in developing cellular networks.

    Science.gov (United States)

    Hjorth, Johannes J J; Dawitz, Julia; Kroon, Tim; Pires, Johny; Dassen, Valerie J; Berkhout, Janna A; Emperador Melero, Javier; Nadadhur, Aish G; Alevra, Mihai; Toonen, Ruud F; Heine, Vivi M; Mansvelder, Huibert D; Meredith, Rhiannon M

    2016-04-01

    Developing networks in the immature nervous system and in cellular cultures are characterized by waves of synchronous activity in restricted clusters of cells. Synchronized activity in immature networks is proposed to regulate many different developmental processes, from neuron growth and cell migration, to the refinement of synapses, topographic maps, and the mature composition of ion channels. These emergent activity patterns are not present in all cells simultaneously within the network and more immature "silent" cells, potentially correlated with the presence of silent synapses, are prominent in different networks during early developmental periods. Many current network analyses for detection of synchronous cellular activity utilize activity-based pixel correlations to identify cellular-based regions of interest (ROIs) and coincident cell activity. However, using activity-based correlations, these methods first underestimate or ignore the inactive silent cells within the developing network and second, are difficult to apply within cell-dense regions commonly found in developing brain networks. In addition, previous methods may ignore ROIs within a network that shows transient activity patterns comprising both inactive and active periods. We developed analysis software to semi-automatically detect cells within developing neuronal networks that were imaged using calcium-sensitive reporter dyes. Using an iterative threshold, modulation of activity was tracked within individual cells across the network. The distribution pattern of both inactive and active, including synchronous cells, could be determined based on distance measures to neighboring cells and according to different anatomical layers. © 2015 Wiley Periodicals, Inc.

  4. Dual isotope simultaneous imaging to evaluate the effects of intracoronary bone marrow-derived mesenchymal stem cells on perfusion and metabolism in canines with acute myocardial infarction.

    Science.gov (United States)

    Hao, Linjun; Hao, Jin; Fang, Wei; Han, Chunlei; Zhang, Kaixiu; Wang, Xuemei

    2015-07-01

    Stem cell therapy on acute myocardial infarction (AMI) has been performed for over a decade. In the present study, cardiac perfusion, metabolism and function in dogs with AMI treated by intracoronary injection of bone marrow-derived mesenchymal stem cells (MSCs) were evaluated by dual isotope simultaneous acquisition (DISA) of single positron emission computed tomography (SPECT). Dogs (n=12, 20-30 kg) were randomly assigned to two groups: A graft study (n=6) and control group (n=6). Bone marrow mesenchymal aspirate was collected 3 weeks before surgical procedure. Stem cells were induced by 5-azacytidine for differentiation into myocytes. The dog AMI model was produced by blocking the blood stream at 1/3 of the distinct left anterior descending coronary artery for 90 min. For dogs in the grafting group, MSCs were transplanted by intracoronary injection, and for the control group, 0.9% NaCl was injected instead. At 1 and 10 weeks after MSCs were grafted, respectively, SPECT DISA was performed for each dog in the two groups with 99mTc-SPECT MIBI (925 MBq) and 18F-FDG (222 MBq) for evaluation of myocardial perfusion and metabolism. After the dogs were sacrificed, heart tissue was stained by myocyte-specific antibodies for newborn vessels, troponin T and bromodeoxyuridine (BrdU). Following induction by 5-azacytidine, the morphological features with colony formation, microfilament, as well as atrial granules and positive stainings of α-actinin, myosin and troponin I demonstrated strongly that the MSCs differentiated into myocytes. The number of viable myocardial segments was 10 in the grafting group, which was significantly greater compared with the control group. The ejection fraction of the infarcted left ventricle (LVEF,%) increased from 53.80±9.58 to 70.00±7.52 (change, 16.20±2.93) at 1 and 10 weeks after MSCs engraftment, whilst in the control group, LVEF was 50.50±8.02 and 56.50±7.24 (change, 5.50±2.69), respectively. The LVEF difference was statistically

  5. Diverse Hormone Response Networks in 41 Independent Drosophila Cell Lines

    Directory of Open Access Journals (Sweden)

    Marcus Stoiber

    2016-03-01

    Full Text Available Steroid hormones induce cascades of gene activation and repression with transformative effects on cell fate . Steroid transduction plays a major role in the development and physiology of nearly all metazoan species, and in the progression of the most common forms of cancer. Despite the paramount importance of steroids in developmental and translational biology, a complete map of transcriptional response has not been developed for any hormone . In the case of 20-hydroxyecdysone (ecdysone in Drosophila melanogaster, these trajectories range from apoptosis to immortalization. We mapped the ecdysone transduction network in a cohort of 41 cell lines, the largest such atlas yet assembled. We found that the early transcriptional response mirrors the distinctiveness of physiological origins: genes respond in restricted patterns, conditional on the expression levels of dozens of transcription factors. Only a small cohort of genes is constitutively modulated independent of initial cell state. Ecdysone-responsive genes tend to organize into directional same-stranded units, with consecutive genes induced from the same strand. Here, we identify half of the ecdysone receptor heterodimer as the primary rate-limiting step in the response, and find that initial receptor isoform levels modulate the activated cohort of target transcription factors. This atlas of steroid response reveals organizing principles of gene regulation by a model type II nuclear receptor and lays the foundation for comprehensive and predictive understanding of the ecdysone transduction network in the fruit fly.

  6. A system of recurrent neural networks for modularising, parameterising and dynamic analysis of cell signalling networks.

    Science.gov (United States)

    Samarasinghe, S; Ling, H

    In this paper, we show how to extend our previously proposed novel continuous time Recurrent Neural Networks (RNN) approach that retains the advantage of continuous dynamics offered by Ordinary Differential Equations (ODE) while enabling parameter estimation through adaptation, to larger signalling networks using a modular approach. Specifically, the signalling network is decomposed into several sub-models based on important temporal events in the network. Each sub-model is represented by the proposed RNN and trained using data generated from the corresponding ODE model. Trained sub-models are assembled into a whole system RNN which is then subjected to systems dynamics and sensitivity analyses. The concept is illustrated by application to G1/S transition in cell cycle using Iwamoto et al. (2008) ODE model. We decomposed the G1/S network into 3 sub-models: (i) E2F transcription factor release; (ii) E2F and CycE positive feedback loop for elevating cyclin levels; and (iii) E2F and CycA negative feedback to degrade E2F. The trained sub-models accurately represented system dynamics and parameters were in good agreement with the ODE model. The whole system RNN however revealed couple of parameters contributing to compounding errors due to feedback and required refinement to sub-model 2. These related to the reversible reaction between CycE/CDK2 and p27, its inhibitor. The revised whole system RNN model very accurately matched dynamics of the ODE system. Local sensitivity analysis of the whole system model further revealed the most dominant influence of the above two parameters in perturbing G1/S transition, giving support to a recent hypothesis that the release of inhibitor p27 from Cyc/CDK complex triggers cell cycle stage transition. To make the model useful in a practical setting, we modified each RNN sub-model with a time relay switch to facilitate larger interval input data (≈20min) (original model used data for 30s or less) and retrained them that produced

  7. Acute myocardial infarction following a hornet sting

    Directory of Open Access Journals (Sweden)

    Cvetković-Matić Danica

    2009-01-01

    Full Text Available Background. The occurrence of an acute myocardial infarction following a hornet sting has been very rarely reported in the previous literature. Pathogenetic mechanisms include direct action of the venom components on the coronary endothelium and allergic reaction with mediators released from mast cells. The anaphylactic reaction and venom components can produce acute coronary artery thrombosis. Case report. We reported a 45-year-old man with acute myocardial infarction after a hornet sting in the presence of anaphylaxis. We also discussed clinical implications and pathophysiological mechanisms of acute myocardial infarction caused by hymenoptera sting. Conclusion. A case report of this unusual acute myocardial infarction highlights the potential acute myocardial ischemia associated with hymenoptera sting which requests early diagnosis, thorough cardiovascular evaluation and appropriate treatment.

  8. Heart dysfunction and fibrosis in rat treated with myocardial ...

    African Journals Online (AJOL)

    use

    2011-11-16

    Nov 16, 2011 ... damage and death associated with myocardial cells. (Thygesen et al., 2007). Even if other heart tissue ... good material for regenerative medicine and cell therapy research in MI and reperfusion. Thus, the aim of .... improve the condition of myocardial ischemia, stem cell therapy research, and regenerative ...

  9. Cache-enabled small cell networks: modeling and tradeoffs.

    Science.gov (United States)

    Baştuǧ, Ejder; Bennis, Mehdi; Kountouris, Marios; Debbah, Mérouane

    We consider a network model where small base stations (SBSs) have caching capabilities as a means to alleviate the backhaul load and satisfy users' demand. The SBSs are stochastically distributed over the plane according to a Poisson point process (PPP) and serve their users either (i) by bringing the content from the Internet through a finite rate backhaul or (ii) by serving them from the local caches. We derive closed-form expressions for the outage probability and the average delivery rate as a function of the signal-to-interference-plus-noise ratio (SINR), SBS density, target file bitrate, storage size, file length, and file popularity. We then analyze the impact of key operating parameters on the system performance. It is shown that a certain outage probability can be achieved either by increasing the number of base stations or the total storage size. Our results and analysis provide key insights into the deployment of cache-enabled small cell networks (SCNs), which are seen as a promising solution for future heterogeneous cellular networks.

  10. Information in a Network of Neuronal Cells: Effect of Cell Density and Short-Term Depression

    Directory of Open Access Journals (Sweden)

    Valentina Onesto

    2016-01-01

    Full Text Available Neurons are specialized, electrically excitable cells which use electrical to chemical signals to transmit and elaborate information. Understanding how the cooperation of a great many of neurons in a grid may modify and perhaps improve the information quality, in contrast to few neurons in isolation, is critical for the rational design of cell-materials interfaces for applications in regenerative medicine, tissue engineering, and personalized lab-on-a-chips. In the present paper, we couple an integrate-and-fire model with information theory variables to analyse the extent of information in a network of nerve cells. We provide an estimate of the information in the network in bits as a function of cell density and short-term depression time. In the model, neurons are connected through a Delaunay triangulation of not-intersecting edges; in doing so, the number of connecting synapses per neuron is approximately constant to reproduce the early time of network development in planar neural cell cultures. In simulations where the number of nodes is varied, we observe an optimal value of cell density for which information in the grid is maximized. In simulations in which the posttransmission latency time is varied, we observe that information increases as the latency time decreases and, for specific configurations of the grid, it is largely enhanced in a resonance effect.

  11. Information in a Network of Neuronal Cells: Effect of Cell Density and Short-Term Depression

    KAUST Repository

    Onesto, Valentina

    2016-05-10

    Neurons are specialized, electrically excitable cells which use electrical to chemical signals to transmit and elaborate information. Understanding how the cooperation of a great many of neurons in a grid may modify and perhaps improve the information quality, in contrast to few neurons in isolation, is critical for the rational design of cell-materials interfaces for applications in regenerative medicine, tissue engineering, and personalized lab-on-a-chips. In the present paper, we couple an integrate-and-fire model with information theory variables to analyse the extent of information in a network of nerve cells. We provide an estimate of the information in the network in bits as a function of cell density and short-term depression time. In the model, neurons are connected through a Delaunay triangulation of not-intersecting edges; in doing so, the number of connecting synapses per neuron is approximately constant to reproduce the early time of network development in planar neural cell cultures. In simulations where the number of nodes is varied, we observe an optimal value of cell density for which information in the grid is maximized. In simulations in which the posttransmission latency time is varied, we observe that information increases as the latency time decreases and, for specific configurations of the grid, it is largely enhanced in a resonance effect.

  12. Verifying cell loss requirements in high-speed communication networks

    Directory of Open Access Journals (Sweden)

    Kerry W. Fendick

    1998-01-01

    Full Text Available In high-speed communication networks it is common to have requirements of very small cell loss probabilities due to buffer overflow. Losses are measured to verify that the cell loss requirements are being met, but it is not clear how to interpret such measurements. We propose methods for determining whether or not cell loss requirements are being met. A key idea is to look at the stream of losses as successive clusters of losses. Often clusters of losses, rather than individual losses, should be regarded as the important “loss events”. Thus we propose modeling the cell loss process by a batch Poisson stochastic process. Successive clusters of losses are assumed to arrive according to a Poisson process. Within each cluster, cell losses do not occur at a single time, but the distance between losses within a cluster should be negligible compared to the distance between clusters. Thus, for the purpose of estimating the cell loss probability, we ignore the spaces between successive cell losses in a cluster of losses. Asymptotic theory suggests that the counting process of losses initiating clusters often should be approximately a Poisson process even though the cell arrival process is not nearly Poisson. The batch Poisson model is relatively easy to test statistically and fit; e.g., the batch-size distribution and the batch arrival rate can readily be estimated from cell loss data. Since batch (cluster sizes may be highly variable, it may be useful to focus on the number of batches instead of the number of cells in a measurement interval. We also propose a method for approximately determining the parameters of a special batch Poisson cell loss with geometric batch-size distribution from a queueing model of the buffer content. For this step, we use a reflected Brownian motion (RBM approximation of a G/D/1/C queueing model. We also use the RBM model to estimate the input burstiness given the cell loss rate. In addition, we use the RBM model to

  13. Classification of myocardial infarction

    DEFF Research Database (Denmark)

    Saaby, Lotte; Poulsen, Tina Svenstrup; Hosbond, Susanne Elisabeth

    2013-01-01

    The classification of myocardial infarction into 5 types was introduced in 2007 as an important component of the universal definition. In contrast to the plaque rupture-related type 1 myocardial infarction, type 2 myocardial infarction is considered to be caused by an imbalance between demand...... and supply of oxygen in the myocardium. However, no specific criteria for type 2 myocardial infarction have been established....

  14. Effects of mir-21 on Cardiac Microvascular Endothelial Cells After Acute Myocardial Infarction in Rats: Role of Phosphatase and Tensin Homolog (PTEN)/Vascular Endothelial Growth Factor (VEGF) Signal Pathway

    OpenAIRE

    Yang, Feng; Liu, Wenwei; Yan, Xiaojuan; Zhou, Hanyun; Zhang, Hongshen; Liu, Jianfei; Yu, Ming; Zhu, Xiaoshan; Ma, Kezhong

    2016-01-01

    Background This study investigated how miR-21 expression is reflected in acute myocardial infarction and explored the role of miR-21 and the PTEN/VEGF signaling pathway in cardiac microvascular endothelial cells. Material/Methods We used an in vivo LAD rat model to simulate acute myocardial infarction. MiR-21 mimics and miR-21 inhibitors were injected and transfected into model rats in order to alter miR-21 expression. Cardiac functions were evaluated using echocardiographic measurement, ELIS...

  15. Cell-type-specific predictive network yields novel insights into mouse embryonic stem cell self-renewal and cell fate.

    Directory of Open Access Journals (Sweden)

    Karen G Dowell

    Full Text Available Self-renewal, the ability of a stem cell to divide repeatedly while maintaining an undifferentiated state, is a defining characteristic of all stem cells. Here, we clarify the molecular foundations of mouse embryonic stem cell (mESC self-renewal by applying a proven Bayesian network machine learning approach to integrate high-throughput data for protein function discovery. By focusing on a single stem-cell system, at a specific developmental stage, within the context of well-defined biological processes known to be active in that cell type, we produce a consensus predictive network that reflects biological reality more closely than those made by prior efforts using more generalized, context-independent methods. In addition, we show how machine learning efforts may be misled if the tissue specific role of mammalian proteins is not defined in the training set and circumscribed in the evidential data. For this study, we assembled an extensive compendium of mESC data: ∼2.2 million data points, collected from 60 different studies, under 992 conditions. We then integrated these data into a consensus mESC functional relationship network focused on biological processes associated with embryonic stem cell self-renewal and cell fate determination. Computational evaluations, literature validation, and analyses of predicted functional linkages show that our results are highly accurate and biologically relevant. Our mESC network predicts many novel players involved in self-renewal and serves as the foundation for future pluripotent stem cell studies. This network can be used by stem cell researchers (at http://StemSight.org to explore hypotheses about gene function in the context of self-renewal and to prioritize genes of interest for experimental validation.

  16. Cell-type-specific predictive network yields novel insights into mouse embryonic stem cell self-renewal and cell fate.

    Science.gov (United States)

    Dowell, Karen G; Simons, Allen K; Wang, Zack Z; Yun, Kyuson; Hibbs, Matthew A

    2013-01-01

    Self-renewal, the ability of a stem cell to divide repeatedly while maintaining an undifferentiated state, is a defining characteristic of all stem cells. Here, we clarify the molecular foundations of mouse embryonic stem cell (mESC) self-renewal by applying a proven Bayesian network machine learning approach to integrate high-throughput data for protein function discovery. By focusing on a single stem-cell system, at a specific developmental stage, within the context of well-defined biological processes known to be active in that cell type, we produce a consensus predictive network that reflects biological reality more closely than those made by prior efforts using more generalized, context-independent methods. In addition, we show how machine learning efforts may be misled if the tissue specific role of mammalian proteins is not defined in the training set and circumscribed in the evidential data. For this study, we assembled an extensive compendium of mESC data: ∼2.2 million data points, collected from 60 different studies, under 992 conditions. We then integrated these data into a consensus mESC functional relationship network focused on biological processes associated with embryonic stem cell self-renewal and cell fate determination. Computational evaluations, literature validation, and analyses of predicted functional linkages show that our results are highly accurate and biologically relevant. Our mESC network predicts many novel players involved in self-renewal and serves as the foundation for future pluripotent stem cell studies. This network can be used by stem cell researchers (at http://StemSight.org) to explore hypotheses about gene function in the context of self-renewal and to prioritize genes of interest for experimental validation.

  17. Gene network inference using continuous time Bayesian networks: a comparative study and application to Th17 cell differentiation.

    Science.gov (United States)

    Acerbi, Enzo; Zelante, Teresa; Narang, Vipin; Stella, Fabio

    2014-12-11

    Dynamic aspects of gene regulatory networks are typically investigated by measuring system variables at multiple time points. Current state-of-the-art computational approaches for reconstructing gene networks directly build on such data, making a strong assumption that the system evolves in a synchronous fashion at fixed points in time. However, nowadays omics data are being generated with increasing time course granularity. Thus, modellers now have the possibility to represent the system as evolving in continuous time and to improve the models' expressiveness. Continuous time Bayesian networks are proposed as a new approach for gene network reconstruction from time course expression data. Their performance was compared to two state-of-the-art methods: dynamic Bayesian networks and Granger causality analysis. On simulated data, the methods comparison was carried out for networks of increasing size, for measurements taken at different time granularity densities and for measurements unevenly spaced over time. Continuous time Bayesian networks outperformed the other methods in terms of the accuracy of regulatory interactions learnt from data for all network sizes. Furthermore, their performance degraded smoothly as the size of the network increased. Continuous time Bayesian networks were significantly better than dynamic Bayesian networks for all time granularities tested and better than Granger causality for dense time series. Both continuous time Bayesian networks and Granger causality performed robustly for unevenly spaced time series, with no significant loss of performance compared to the evenly spaced case, while the same did not hold true for dynamic Bayesian networks. The comparison included the IRMA experimental datasets which confirmed the effectiveness of the proposed method. Continuous time Bayesian networks were then applied to elucidate the regulatory mechanisms controlling murine T helper 17 (Th17) cell differentiation and were found to be effective in

  18. Activation of Na+-K+-ATPase with DRm217 attenuates oxidative stress-induced myocardial cell injury via closing Na+-K+-ATPase/Src/Ros amplifier.

    Science.gov (United States)

    Yan, Xiaofei; Xun, Meng; Dou, Xiaojuan; Wu, Litao; Zhang, Fujun; Zheng, Jin

    2017-04-01

    Reduced Na+-K+-ATPase activity has close relationship with cardiomyocyte death. Reactive oxygen species (ROS) also plays an important role in cardiac cell damage. It has been proved that Na+-K+-ATPase and ROS form a feed-forward amplifier. The aim of this study was to explore whether DRm217, a proved Na+/K+-ATPase's DR-region specific monoclonal antibody and direct activator, could disrupt Na+-K+-ATPase/ROS amplifier and protect cardiac cells from ROS-induced injury. We found that DRm217 protected myocardial cells against hydrogen peroxide (H2O2)-induced cardiac cell injury and mitochondrial dysfunction. DRm217 also alleviated the effect of H2O2 on inhibition of Na+-K+-ATPase activity, Na+-K+-ATPase cell surface expression, and Src phosphorylation. H2O2-treatment increased intracellular ROS, mitochondrial ROS and induced intracellular Ca2+, mitochondrial Ca2+ overload. DRm217 closed Na+-K+-ATPase/ROS amplifier, alleviated Ca2+ accumulation and finally inhibited ROS and mitochondrial ROS generation. These novel results may help us to understand the important role of the Na+-K+-ATPase in oxidative stress and oxidative stress-related disease.

  19. Transient myocardial ischemia after myocardial infarction

    DEFF Research Database (Denmark)

    Mickley, H

    1995-01-01

    Ambulatory ST-segment monitoring is a relatively new device in the evaluation of myocardial ischemia. The method is unique in allowing us to continuously examine the patient over an extended period of time in a changing environmental milieu. In survivors of acute myocardial infarction the prevale...

  20. Dynamics and robustness of the cardiac progenitor cell induced pluripotent stem cell network during cell phenotypes transition.

    Science.gov (United States)

    Yao, Yuangen; Ma, Chengzhang; Deng, Haiyou; Liu, Quan; Cao, Wei; Gui, Rong; Feng, Tianquan; Yi, Ming

    2017-02-01

    Robustness is a fundamental characteristic of biological systems since all living systems need to adapt to internal or external perturbations, unpredictable environments, stochastic events and unreliable components, and so on. A long-term challenge in systems biology is to reveal the origin of robustness underlying molecular regulator network. In this study, a simple Boolean model is used to investigate the global dynamic properties and robustness of cardiac progenitor cell (CPC) induced pluripotent stem cell network that governs reprogramming and directed differentiation process. It is demonstrated that two major attractors correspond to source and target cell phenotypes, respectively, and two dominating attracting trajectories characterise the biological pathways between two major cell phenotypes. In particular, the experimentally observed transition between different cell phenotypes can be reproduced and explained theoretically. Furthermore, the robustness of major attractors and trajectories is largely maintained with respect to small perturbations to the network. Taken together, the CPC-induced pluripotent stem cell network is extremely robustly designed for their functions.

  1. Longitudinal monitoring adipose-derived stem cell survival by PET imaging hexadecyl-4-{sup 124}I-iodobenzoate in rat myocardial infarction model

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Min Hwan [Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); School of Life Sciences and Biotechnology, Korea University, Seoul (Korea, Republic of); Woo, Sang-Keun; Lee, Kyo Chul; An, Gwang Il [Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Pandya, Darpan [Department of Molecular Medicine, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University, Daegu (Korea, Republic of); Park, Noh Won; Nahm, Sang-Soep; Eom, Ki Dong [College of Veterinary Medicine, Konkuk University, Seoul (Korea, Republic of); Kim, Kwang Il; Lee, Tae Sup [Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Kim, Chan Wha [School of Life Sciences and Biotechnology, Korea University, Seoul (Korea, Republic of); Kang, Joo Hyun [Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Yoo, Jeongsoo, E-mail: yooj@knu.ac.kr [Department of Molecular Medicine, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University, Daegu (Korea, Republic of); Lee, Yong Jin, E-mail: yjlee@kirams.re.kr [Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2015-01-02

    Highlights: • We developed a safe, simple and appropriate stem cell labeling method with {sup 124}I-HIB. • ADSC survival can be monitored with PET in MI model via direct labeling. • Tracking of ADSC labeled with {sup 124}I-HIB was possible for 3 days in MI model using PET. • ADSC viability and differentiation were not affected by {sup 124}I-HIB labeling. • Survival of ADSC in living bodies can be longitudinally tracked with PET imaging. - Abstract: This study aims to monitor how the change of cell survival of transplanted adipose-derived stem cells (ADSCs) responds to myocardial infarction (MI) via the hexadecyl-4-{sup 124}I-iodobenzoate ({sup 124}I-HIB) mediated direct labeling method in vivo. Stem cells have shown the potential to improve cardiac function after MI. However, monitoring of the fate of transplanted stem cells at target sites is still unclear. Rat ADSCs were labeled with {sup 124}I-HIB, and radiolabeled ADSCs were transplanted into the myocardium of normal and MI model. In the group of {sup 124}I-HIB-labeled ADSC transplantation, in vivo imaging was performed using small-animal positron emission tomography (PET)/computed tomography (CT) for 9 days. Twenty-one days post-transplantation, histopathological analysis and apoptosis assay were performed. ADSC viability and differentiation were not affected by {sup 124}I-HIB labeling. In vivo tracking of the {sup 124}I-HIB-labeled ADSCs was possible for 9 and 3 days in normal and MI model, respectively. Apoptosis of transplanted cells increased in the MI model compared than that in normal model. We developed a direct labeling agent, {sup 124}I-HIB, and first tried to longitudinally monitor transplanted stem cell to MI. This approach may provide new insights on the roles of stem cell monitoring in living bodies for stem cell therapy from pre-clinical studies to clinical trials.

  2. Cardiac metabolism in myocardial ischemia.

    Science.gov (United States)

    Rosano, Giuseppe M C; Fini, Massimo; Caminiti, Giuseppe; Barbaro, Giuseppe

    2008-01-01

    Myocardial ischemia occurs for a mismatch between blood flow and metabolic requirements, when the rate of oxygen and metabolic substrates delivery to the myocardium is insufficient to meet the myocardial energy requirements for a given myocardial workload. During ischemia, substantial changes occur in cardiac energy metabolism, as a consequence of the reduced oxygen availability. Some of these metabolic changes are beneficial and may help the heart adapt to the ischemic condition. However, most of the changes are maladaptive and contribute to the severity of the ischemic injury leading stunned or hibernating myocardium, cell death and ultimately to contractile disfunction. Dramatic changes in cardiac metabolism and contractile function, also occur during myocardial reperfusion as a consequence of the generation of oxygen free radicals, loss of cation homeostasis, depletion of energy stores, and changes in subcellular activities. The reperfusion injury may cause in the death of cardiac myocytes that were still viable immediately before myocardial reperfusion. This form of myocardial injury, by itself can induce cardiomyocyte death and increase infarct size. During acute ischemia the relative substrate concentration is the prime factor defining preference and utilization rate. Allosteric enzyme regulation and protein phosphorylation cascades, partially controlled by hormones such as insulin, modulate the concentration effect; together they provide short-term adjustments of cardiac energy metabolism. The expression of metabolic genes is also dynamically regulated in response to developmental and (patho)physiological conditions, leading to long-term adjustments. Specific nuclear receptor transcription factors and co-activators regulate the expression of these genes. Understanding the functional role of these changes is critical for developing the concept of metabolic intervention for heart disease. The paper will review the alterations in energy metabolism that occur

  3. Transplantation and tracking of human-induced pluripotent stem cells in a pig model of myocardial infarction: assessment of cell survival, engraftment, and distribution by hybrid single photon emission computed tomography/computed tomography of sodium iodide symporter transgene expression.

    Science.gov (United States)

    Templin, Christian; Zweigerdt, Robert; Schwanke, Kristin; Olmer, Ruth; Ghadri, Jelena-Rima; Emmert, Maximilian Y; Müller, Ennio; Küest, Silke M; Cohrs, Susan; Schibli, Roger; Kronen, Peter; Hilbe, Monika; Reinisch, Andreas; Strunk, Dirk; Haverich, Axel; Hoerstrup, Simon; Lüscher, Thomas F; Kaufmann, Philipp A; Landmesser, Ulf; Martin, Ulrich

    2012-07-24

    Evaluation of novel cellular therapies in large-animal models and patients is currently hampered by the lack of imaging approaches that allow for long-term monitoring of viable transplanted cells. In this study, sodium iodide symporter (NIS) transgene imaging was evaluated as an approach to follow in vivo survival, engraftment, and distribution of human-induced pluripotent stem cell (hiPSC) derivatives in a pig model of myocardial infarction. Transgenic hiPSC lines stably expressing a fluorescent reporter and NIS (NIS(pos)-hiPSCs) were established. Iodide uptake, efflux, and viability of NIS(pos)-hiPSCs were assessed in vitro. Ten (±2) days after induction of myocardial infarction by transient occlusion of the left anterior descending artery, catheter-based intramyocardial injection of NIS(pos)-hiPSCs guided by 3-dimensional NOGA mapping was performed. Dual-isotope single photon emission computed tomographic/computed tomographic imaging was applied with the use of (123)I to follow donor cell survival and distribution and with the use of (99m)TC-tetrofosmin for perfusion imaging. In vitro, iodide uptake in NIS(pos)-hiPSCs was increased 100-fold above that of nontransgenic controls. In vivo, viable NIS(pos)-hiPSCs could be visualized for up to 15 weeks. Immunohistochemistry demonstrated that hiPSC-derived endothelial cells contributed to vascularization. Up to 12 to 15 weeks after transplantation, no teratomas were detected. This study describes for the first time the feasibility of repeated long-term in vivo imaging of viability and tissue distribution of cellular grafts in large animals. Moreover, this is the first report demonstrating vascular differentiation and long-term engraftment of hiPSCs in a large-animal model of myocardial infarction. NIS(pos)-hiPSCs represent a valuable tool to monitor and improve current cellular treatment strategies in clinically relevant animal models.

  4. Myocardial imaging. Coxsackie myocarditis

    Energy Technology Data Exchange (ETDEWEB)

    Wells, R.G.; Ruskin, J.A.; Sty, J.R.

    1986-09-01

    A 3-week-old male neonate with heart failure associated with Coxsackie virus infection was imaged with Tc-99m PYP and TI-201. The abnormal imaging pattern suggested myocardial infarction. Autopsy findings indicated that the cause was myocardial necrosis secondary to an acute inflammatory process. Causes of abnormal myocardial uptake of Tc-99m PYP in pediatrics include infarction, myocarditis, cardiomyopathy, bacterial endocarditis, and trauma. Myocardial imaging cannot provide a specific cause diagnosis. Causes of myocardial infarction in pediatrics are listed in Table 1.

  5. Troponin bound calcium in electron micrographs of myocardial cells as demonstrated by the potassium-antimonate technique.

    Science.gov (United States)

    Myklebust, R; Justesen, N P; Saetersdal, T S

    1975-10-13

    Following the K-antimonate reaction in atrial myocardial tissue, a pattern of evenly spaced cross striations of antimonate precipitates is demonstrated along the myofilaments. This spacing, found in both turtle and mouse atria, has a periodicity of about 400 A. In order to test the shifts of the antimonate reaction product in the tissue, a comparison is made between the localization of the antimonate precipitate as seen in viz. thin plastic sections and in cryo-ultra sections being dry-cut at -90 degree C from N2 frozen tissue. Preliminary results suggest only minor distributional differences in the sarcomeric pattern. On the basis of these tests, and, on the basis of previous studies by means of X-ray microanalysis, it is suggested that the periodic pattern of evenly spaced precipitates, reflects the localization of troponin bound calcium along the thin filaments during contraction.

  6. A validated regulatory network for Th17 cell specification

    Science.gov (United States)

    Ciofani, Maria; Madar, Aviv; Galan, Carolina; Sellars, Maclean; Mace, Kieran; Pauli, Florencia; Agarwal, Ashish; Huang, Wendy; Parkhurst, Christopher N.; Muratet, Michael; Newberry, Kim M.; Meadows, Sarah; Greenfield, Alex; Yang, Yi; Jain, Preti; Kirigin, Francis F.; Birchmeier, Carmen; Wagner, Erwin F.; Murphy, Kenneth M.; Myers, Richard M.; Bonneau, Richard; Littman, Dan R.

    2012-01-01

    Th17 cells have critical roles in mucosal defense and are major contributors to inflammatory disease. Their differentiation requires the nuclear hormone receptor RORγt working with multiple other essential transcription factors (TFs). We have used an iterative systems approach, combining genome-wide TF occupancy, expression profiling of TF mutants, and expression time series to delineate the Th17 global transcriptional regulatory network. We find that cooperatively-bound BATF and IRF4 contribute to initial chromatin accessibility, and with STAT3 initiate a transcriptional program that is then globally tuned by the lineage-specifying TF RORγt, which plays a focal deterministic role at key loci. Integration of multiple datasets allowed inference of an accurate predictive model that we computationally and experimentally validated, identifying multiple new Th17 regulators, including Fosl2, a key determinant of cellular plasticity. This interconnected network can be used to investigate new therapeutic approaches to manipulate Th17 functions in the setting of inflammatory disease. PMID:23021777

  7. Acute myocardial infarction: 'telomerasing' for cardioprotection

    OpenAIRE

    Sanchís-Gomar, Fabián; Lucía Mulas, Alejandro

    2015-01-01

    Reactivating the telomerase gene through gene therapy after acute myocardial infarction (AMI) has been recently reported to improve survival in mice. Given that regular physical exercise also activates this gene, therapeutic and lifestyle interventions targeting telomerase need to be explored as possible additions to the current armamentarium for myocardial regeneration. 9.292 JCR (2015) Q1, 17/289 Biochemistry & mollecular biology, 17/187 Cell biology, 8/124 Medicine, research & experimen...

  8. High power fuel cell simulator based on artificial neural network

    Energy Technology Data Exchange (ETDEWEB)

    Chavez-Ramirez, Abraham U.; Munoz-Guerrero, Roberto [Departamento de Ingenieria Electrica, CINVESTAV-IPN. Av. Instituto Politecnico Nacional No. 2508, D.F. CP 07360 (Mexico); Duron-Torres, S.M. [Unidad Academica de Ciencias Quimicas, Universidad Autonoma de Zacatecas, Campus Siglo XXI, Edif. 6 (Mexico); Ferraro, M.; Brunaccini, G.; Sergi, F.; Antonucci, V. [CNR-ITAE, Via Salita S. Lucia sopra Contesse 5-98126 Messina (Italy); Arriaga, L.G. [Centro de Investigacion y Desarrollo Tecnologico en Electroquimica S.C., Parque Tecnologico Queretaro, Sanfandila, Pedro Escobedo, Queretaro (Mexico)

    2010-11-15

    Artificial Neural Network (ANN) has become a powerful modeling tool for predicting the performance of complex systems with no well-known variable relationships due to the inherent properties. A commercial Polymeric Electrolyte Membrane fuel cell (PEMFC) stack (5 kW) was modeled successfully using this tool, increasing the number of test into the 7 inputs - 2 outputs-dimensional spaces in the shortest time, acquiring only a small amount of experimental data. Some parameters could not be measured easily on the real system in experimental tests; however, by receiving the data from PEMFC, the ANN could be trained to learn the internal relationships that govern this system, and predict its behavior without any physical equations. Confident accuracy was achieved in this work making possible to import this tool to complex systems and applications. (author)

  9. Determining the control networks regulating stem cell lineages in colonic crypts.

    Science.gov (United States)

    Yang, Jienian; Axelrod, David E; Komarova, Natalia L

    2017-09-21

    The question of stem cell control is at the center of our understanding of tissue functioning, both in healthy and cancerous conditions. It is well accepted that cellular fate decisions (such as divisions, differentiation, apoptosis) are orchestrated by a network of regulatory signals emitted by different cell populations in the lineage and the surrounding tissue. The exact regulatory network that governs stem cell lineages in a given tissue is usually unknown. Here we propose an algorithm to identify a set of candidate control networks that are compatible with (a) measured means and variances of cell populations in different compartments, (b) qualitative information on cell population dynamics, such as the existence of local controls and oscillatory reaction of the system to population size perturbations, and (c) statistics of correlations between cell numbers in different compartments. Using the example of human colon crypts, where lineages are comprised of stem cells, transit amplifying cells, and differentiated cells, we start with a theoretically known set of 32 smallest control networks compatible with tissue stability. Utilizing near-equilibrium stochastic calculus of stem cells developed earlier, we apply a series of tests, where we compare the networks' expected behavior with the observations. This allows us to exclude most of the networks, until only three, very similar, candidate networks remain, which are most compatible with the measurements. This work demonstrates how theoretical analysis of control networks combined with only static biological data can shed light onto the inner workings of stem cell lineages, in the absence of direct experimental assessment of regulatory signaling mechanisms. The resulting candidate networks are dominated by negative control loops and possess the following properties: (1) stem cell division decisions are negatively controlled by the stem cell population, (2) stem cell differentiation decisions are negatively

  10. Assessment of safety and efficacy of mesenchymal stromal cell therapy in preclinical models of acute myocardial infarction: a systematic review protocol

    Directory of Open Access Journals (Sweden)

    Carly C. Barron

    2017-11-01

    Full Text Available Abstract Background Despite advances in treatment, acute myocardial infarction (MI is still associated with significant morbidity and mortality, especially in patients with extensive damage and scar formation. Based on some promising preclinical studies, there is interest in the use of mesenchymal stromal cells (MSCs to promote cardiac repair after acute MI. However, there is a need for a systematic review of this evidence to summarize the efficacy and safety of MSCs in preclinical models of MI. This will better inform the translation of MSC therapy for acute MI and guide the design of a future clinical trial. Methods/design A systematic literature search of MEDLINE, Embase, and BIOSIS Previews will be conducted. We will identify comparative preclinical studies (randomized and non-randomized of myocardial infarction that include animals given MSC therapy versus a vehicle/placebo. The primary outcome will be left ventricular ejection fraction. Secondary and tertiary outcomes will include death, infarct size, measures of cardiac function, biochemical outcomes, and MSC retention and differentiation. Risk of bias will be assessed using the Cochrane Risk of Bias Tool. Subgroup analyses will be performed to measure how various sources of preclinical study heterogeneity affect the direction and magnitude of the primary outcome. We will meta-analyze data using inverse variance random effects modeling. Discussion This systematic review of preclinical evidence will provide a summary of the efficacy and safety of MSCs in animal models of MI. The results will help determine whether sufficient evidence exists to conduct a clinical trial in humans and inform its design.

  11. Long-term clinical results of autologous bone marrow CD 133+ cell transplantation in patients with ST-elevation myocardial infarction

    Science.gov (United States)

    Kirgizova, M. A.; Suslova, T. E.; Markov, V. A.; Karpov, R. S.; Ryabov, V. V.

    2015-11-01

    The aim of the study was investigate the long-term results of autologous bone marrow CD 133+ cell transplantation in patients with primary ST-Elevation Myocardial Infarction (STEMI). Methods and results: From 2006 to 2007, 26 patients with primary STEMI were included in an open randomized study. Patients were randomized to two groups: 1st - included patients underwent PCI and transplantation of autologous bone marrow CD 133+ cell (n = 10); 2nd - patients with only PCI (n = 16). Follow-up study was performed 7.70±0.42 years after STEMI and consisted in physical examination, 6-min walking test, Echo exam. Total and cardiovascular mortality in group 1 was lower (20% (n = 2) vs. 44% (n = 7), p = 0.1 and 22% (n = 2) vs. 25% (n = 4), (p=0.53), respectively). Analysis of cardiac volumetric parameters shows significant differences between groups: EDV of 100.7 ± 50.2 mL vs. 144.40±42.7 mL, ESV of 56.3 ± 37.8 mL vs. 89.7 ± 38.7 mL in 1st and 2nd groups, respectively. Data of the study showed positive effects of autologous bone marrow CD 133+ cell transplantation on the long-term survival of patients and structural status of the heart.

  12. Novel Mesenchymal Stem Cell Strategy in Alleviating Toll-Like Receptor-4, p53 and Nrf2 Signaling in Isoproterenol-Induced Myocardial Infarction in Rat Model.

    Science.gov (United States)

    Kadry, Mai O; Abdel-Megeed, Rehab M

    2017-11-06

    Mesenchymal stem cells (MSCs) are multipotent stromal cells that merit the differentiation into various cell types. The present study was designed to test the hypothesis that the cardioprotective effect of MSCs transplantation and digoxin treatment is mediated via the regulation of messenger RNA gene expression of pro-inflammatory cytokines and apoptotic markers. Myocardial infarction was induced in Wistar rats via isoproterenol injection in a dose of (85 mg/kg, subcutaneously, twice at an interval of 24 h). Four weeks post-MSCs transplantation and digoxin treatment a significant reduction in serum cardiac markers, aspartate aminotransferase, creatine kinase-MB and troponine II was observed. Meanwhile, isoproterenol significantly reduced the gene and protein expression of the oxidative stress marker nuclear-related factor-2 (Nrf2) with a concomitant elevation in (MDA) level and inflammatory markers toll-like receptor-4 (TLR-4), intercellular adhesion molecules (ICAMs) and (VCAM-1). Moreover, apoptotic marker (P53) was significantly down-regulated. This was confirmed by histopathological investigations. It was hypothesized that MSCs transplantation was superior over digoxin treatment regimen in improving heart function.

  13. The Influence of Hyaluronic Acid and Glioblastoma Cell Coculture on the Formation of Endothelial Cell Networks in Gelatin Hydrogels.

    Science.gov (United States)

    Ngo, Mai T; Harley, Brendan A

    2017-09-22

    Glioblastoma (GBM) is the most common and deadly form of brain cancer. Interactions between GBM cells and vasculature in vivo contribute to poor clinical outcomes, with GBM-induced vessel co-option, regression, and subsequent angiogenesis strongly influencing GBM invasion. Here, elements of the GBM perivascular niche are incorporated into a methacrylamide-functionalized gelatin hydrogel as a means to examine GBM-vessel interactions. The complexity of 3D endothelial cell networks formed from human umbilical vein endothelial cells and normal human lung fibroblasts as a function of hydrogel properties and vascular endothelial growth factor (VEGF) presentation is presented. While overall length and branching of the endothelial cell networks decrease with increasing hydrogel stiffness and incorporation of brain-mimetic hyaluronic acid, it can be separately altered by changing the vascular cell seeding density. It is shown that covalent incorporation of VEGF supports network formation as robustly as continuously available soluble VEGF. The impact of U87-MG GBM cells on the endothelial cell networks is subsequently investigated. GBM cells localize in proximity to the endothelial cell networks and hasten network regression in vitro. Together, this in vitro platform recapitulates the close association between GBM cells and vessel structures as well as elements of vessel co-option and regression preceding angiogenesis in vivo. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Signaling by Small GTPases at Cell-Cell junctions: Protein Interactions Building Control and Networks.

    Science.gov (United States)

    Braga, Vania

    2017-09-11

    A number of interesting reports highlight the intricate network of signaling proteins that coordinate formation and maintenance of cell-cell contacts. We have much yet to learn about how the in vitro binding data is translated into protein association inside the cells and whether such interaction modulates the signaling properties of the protein. What emerges from recent studies is the importance to carefully consider small GTPase activation in the context of where its activation occurs, which upstream regulators are involved in the activation/inactivation cycle and the GTPase interacting partners that determine the intracellular niche and extent of signaling. Data discussed here unravel unparalleled cooperation and coordination of functions among GTPases and their regulators in supporting strong adhesion between cells. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.

  15. Organizational structure and the periphery of the gene regulatory network in B-cell lymphoma.

    Science.gov (United States)

    de Matos Simoes, Ricardo; Tripathi, Shailesh; Emmert-Streib, Frank

    2012-05-14

    The physical periphery of a biological cell is mainly described by signaling pathways which are triggered by transmembrane proteins and receptors that are sentinels to control the whole gene regulatory network of a cell. However, our current knowledge about the gene regulatory mechanisms that are governed by extracellular signals is severely limited. The purpose of this paper is three fold. First, we infer a gene regulatory network from a large-scale B-cell lymphoma expression data set using the C3NET algorithm. Second, we provide a functional and structural analysis of the largest connected component of this network, revealing that this network component corresponds to the peripheral region of a cell. Third, we analyze the hierarchical organization of network components of the whole inferred B-cell gene regulatory network by introducing a new approach which exploits the variability within the data as well as the inferential characteristics of C3NET. As a result, we find a functional bisection of the network corresponding to different cellular components. Overall, our study allows to highlight the peripheral gene regulatory network of B-cells and shows that it is centered around hub transmembrane proteins located at the physical periphery of the cell. In addition, we identify a variety of novel pathological transmembrane proteins such as ion channel complexes and signaling receptors in B-cell lymphoma.

  16. Control of sleep by a network of cell cycle genes.

    Science.gov (United States)

    Afonso, Dinis J S; Machado, Daniel R; Koh, Kyunghee

    2015-01-01

    Sleep is essential for health and cognition, but the molecular and neural mechanisms of sleep regulation are not well understood. We recently reported the identification of TARANIS (TARA) as a sleep-promoting factor that acts in a previously unknown arousal center in Drosophila. tara mutants exhibit a dose-dependent reduction in sleep amount of up to ∼60%. TARA and its mammalian homologs, the Trip-Br (Transcriptional Regulators Interacting with PHD zinc fingers and/or Bromodomains) family of proteins, are primarily known as transcriptional coregulators involved in cell cycle progression, and contain a conserved Cyclin-A (CycA) binding homology domain. We found that tara and CycA synergistically promote sleep, and CycA levels are reduced in tara mutants. Additional data demonstrated that Cyclin-dependent kinase 1 (Cdk1) antagonizes tara and CycA to promote wakefulness. Moreover, we identified a subset of CycA expressing neurons in the pars lateralis, a brain region proposed to be analogous to the mammalian hypothalamus, as an arousal center. In this Extra View article, we report further characterization of tara mutants and provide an extended discussion of our findings and future directions within the framework of a working model, in which a network of cell cycle genes, tara, CycA, and Cdk1, interact in an arousal center to regulate sleep.

  17. CD8+ Tumor-Infiltrating T Cells Are Trapped in the Tumor-Dendritic Cell Network

    Directory of Open Access Journals (Sweden)

    Alexandre Boissonnas

    2013-01-01

    Full Text Available Chemotherapy enhances the antitumor adaptive immune T cell response, but the immunosuppressive tumor environment often dominates, resulting in cancer relapse. Antigen-presenting cells such as tumor-associated macrophages (TAMs and tumor dendritic cells (TuDCs are the main protagonists of tumor-infiltrating lymphocyte (TIL immuno-suppression. TAMs have been widely investigated and are associated with poor prognosis, but the immuno-suppressive activity of TuDCs is less well understood. We performed two-photon imaging of the tumor tissue to examine the spatiotemporal interactions between TILs and TuDCs after chemotherapy. In a strongly immuno-suppressive murine tumor model, cyclophosphamide-mediated chemotherapy transiently enhanced the antitumor activity of adoptively transferred ovalbumin-specific CD8+ T cell receptor transgenic T cells (OTI but barely affected TuDC compartment within the tumor. Time lapse imaging of living tumor tissue showed that TuDCs are organized as a mesh with dynamic interconnections. Once infiltrated into the tumor parenchyma, OTI T cells make antigen-specific and long-lasting contacts with TuDCs. Extensive analysis of TIL infiltration on histologic section revealed that after chemotherapy the majority of OTI T cells interact with TuDCs and that infiltration is restricted to TuDC-rich areas. We propose that the TuDC network exerts antigen-dependent unproductive retention that trap T cells and limit their antitumor effectiveness.

  18. Route of Delivery Modulates the Efficacy of Mesenchymal Stem Cell Therapy for Myocardial Infarction: A Meta-Analysis of Preclinical Studies and Clinical Trials.

    Science.gov (United States)

    Kanelidis, Anthony J; Premer, Courtney; Lopez, Juan; Balkan, Wayne; Hare, Joshua M

    2017-03-31

    Accumulating data support a therapeutic role for mesenchymal stem cell (MSC) therapy; however, there is no consensus on the optimal route of delivery. We tested the hypothesis that the route of MSC delivery influences the reduction in infarct size and improvement in left ventricular ejection fraction (LVEF). We performed a meta-analysis investigating the effect of MSC therapy in acute myocardial infarction (AMI) and chronic ischemic cardiomyopathy preclinical studies (58 studies; n=1165 mouse, rat, swine) which revealed a reduction in infarct size and improvement of LVEF in all animal models. Route of delivery was analyzed in AMI swine studies and clinical trials (6 clinical trials; n=334 patients). In AMI swine studies, transendocardial stem cell injection reduced infarct size (n=49, 9.4% reduction; 95% confidence interval, -15.9 to -3.0), whereas direct intramyocardial injection, intravenous infusion, and intracoronary infusion indicated no improvement. Similarly, transendocardial stem cell injection improved LVEF (n=65, 9.1% increase; 95% confidence interval, 3.7 to 14.5), as did direct intramyocardial injection and intravenous infusion, whereas intracoronary infusion demonstrated no improvement. In humans, changes of LVEF paralleled these results, with transendocardial stem cell injection improving LVEF (n=46, 7.0% increase; 95% confidence interval, 2.7 to 11.3), as did intravenous infusion, but again intracoronary infusion demonstrating no improvement. MSC therapy improves cardiac function in animal models of both AMI and chronic ischemic cardiomyopathy. The route of delivery seems to play a role in modulating the efficacy of MSC therapy in AMI swine studies and clinical trials, suggesting the superiority of transendocardial stem cell injection because of its reduction in infarct size and improvement of LVEF, which has important implications for the design of future studies. © 2016 American Heart Association, Inc.

  19. Predictors of ventricular remodelling in patients with reperfused acute myocardial infarction and left ventricular dysfunction candidates for bone marrow cell therapy: insights from the BONAMI trial

    Energy Technology Data Exchange (ETDEWEB)

    Manrique, Alain [Nuclear Medicine, CHU de Caen, Caen (France); Universite de Caen Normandie, EA 4650, Caen (France); CHU de Caen et GIP Cyceron, Caen cedex 6 (France); Lemarchand, Patricia; Delasalle, Beatrice; Lamirault, Guillaume; Trochu, Jean-Noel; Le Tourneau, Thierry [L' Institut du thorax, INSERM, UMR1087, Nantes (France); CNRS, UMR 6291, Nantes (France); Universite de Nantes, Nantes (France); CHU de Nantes, Nantes (France); Lairez, Olivier; Roncalli, Jerome [Institut CARDIOMET-Toulouse, Cardiac Imaging Center, CIC Biotherapies, CHU de Toulouse, Toulouse (France); Sportouch-Duckan, Catherine; Piot, Christophe [Universite Montpellier, Institut de Genomique Fonctionnelle, INSERM U661, CNRS UMR 5203, Montpellier (France); Clinique du Millenaire, Montpellier (France); Le Corvoisier, Philippe [Hopital Henri Mondor, INSERM, Centre d' Investigation Clinique 1430 et U955 equipe 3, Creteil (France); Neuder, Yannick [CHU de Grenoble, Pole Thorax et Vaisseaux, Grenoble (France); Richardson, Marjorie [CHRU Lille, Service d' Explorations Fonctionnelles Cardiovasculaires, Hopital Cardiologique, Lille (France); Lebon, Alain [CHU de Caen, Service de Cardiologie, Caen (France); Teiger, Emmanuel [Hopital Henri Mondor, AP-HP, Unite de Cardiologie Interventionnelle et Federation de Cardiologie, Creteil (France); Hossein-Foucher, Claude [Hopital Salengro CHRU de Lille, Service de Medecine Nucleaire, Lille (France); Universite de Lille 2, UFR de Medecine, Lille (France)

    2016-04-15

    Few data are available regarding the relation of left ventricular (LV) mechanical dyssynchrony to remodelling after acute myocardial infarction (MI) and stem cell therapy. We evaluated the 1-year time course of both LV mechanical dyssynchrony and remodelling in patients enrolled in the BONAMI trial, a randomized, multicenter controlled trial assessing cell therapy in patients with reperfused MI. Patients with acute MI and ejection fraction (EF) ≤ 45 % were randomized to cell therapy or to control and underwent thallium single-photon emission computed tomography (SPECT), radionuclide angiography, and echocardiography at baseline, 3 months, and 1 year. Eighty-three patients with a comprehensive 1-year follow-up were included. LV dyssynchrony was assessed by the standard deviation (SD) of the LV phase histogram using radionuclide angiography. Remodelling was defined as a 20 % increase in LV end-systolic volume index (LVESVI) at 1 year. At baseline, LVEF, wall motion score index, and perfusion defect size were significantly impaired in the 43 patients (52 %) with LV remodelling (all p < 0.001), without significant increase in LV mechanical dyssynchrony. During follow-up, there was a progressive increase in LV SD (p = 0.01). Baseline independent predictors of LV remodelling were perfusion SPECT defect size (p = 0.001), LVEF (p = 0.01) and a history of hypertension (p = 0.043). Bone marrow cell therapy did not affect the time-course of LV remodelling and dyssynchrony. LV remodelling 1 year after reperfused MI is associated with progressive LV dyssynchrony and is related to baseline infarct size and ejection fraction, without impact of cell therapy on this process. (orig.)

  20. MicroRNA Networks in Breast Cancer Cells.

    Science.gov (United States)

    Tahiri, Andliena; Aure, Miriam R; Kristensen, Vessela N

    2018-01-01

    A variety of molecular techniques can be used in order to unravel the molecular composition of cells. In particular, the microarray technology has been used to identify novel biomarkers that may be useful in the diagnosis, prognosis, or treatment of cancer. The microarray technology is ideal for biomarker discovery as it allows for the screening of a large number of molecules at once. In this review, we focus on microRNAs (miRNAs) which are key molecules in cells and regulate gene expression post-transcriptionally. miRNAs are small, single-stranded RNA molecules that bind to complementary mRNAs. Binding of miRNAs to mRNAs leads either to degradation, or translational inhibition of the target mRNA. Roughly one third of all the mRNAs are postulated to be regulated by miRNAs. miRNAs are known to be deregulated in different types of cancer, including breast cancer, and it has been demonstrated that deregulation of several miRNAs can be used as biological markers in cancer. miRNA expression can for example discriminate between normal, benign and malignant breast tissue, and between different breast cancer subtypes.In the post-genomic era, an important task of molecular biology is to understand gene regulation in the context of biological networks. Because miRNAs have such a pronounced role in cells, it is pivotal to understand the mechanisms that underlie their control, and to identify how miRNAs influence cancer development and progression.

  1. Mesenchymal Stem Cells Induce Expression of CD73 in Human Monocytes In Vitro and in a Swine Model of Myocardial Infarction In Vivo

    Directory of Open Access Journals (Sweden)

    Marta Monguió-Tortajada

    2017-11-01

    Full Text Available The ectoenzymes CD39 and CD73 regulate the purinergic signaling through the hydrolysis of adenosine triphosphate (ATP/ADP to AMP and to adenosine (Ado, respectively. This shifts the pro-inflammatory milieu induced by extracellular ATP to the anti-inflammatory regulation by Ado. Mesenchymal stem cells (MSCs have potent immunomodulatory capabilities, including monocyte modulation toward an anti-inflammatory phenotype aiding tissue repair. In vitro, we observed that human cardiac adipose tissue-derived MSCs (cATMSCs and umbilical cord MSCs similarly polarize monocytes toward a regulatory M2 phenotype, which maintained the expression of CD39 and induced expression of CD73 in a cell contact dependent fashion, correlating with increased functional activity. In addition, the local treatment with porcine cATMSCs using an engineered bioactive graft promoted the in vivo CD73 expression on host monocytes in a swine model of myocardial infarction. Our results suggest the upregulation of ectonucleotidases on MSC-conditioned monocytes as an effective mechanism to amplify the long-lasting immunomodulatory and healing effects of MSCs delivery.

  2. Reduction in infarct size, but no functional improvement after bone marrow cell administration in a porcine model of reperfused myocardial infarction.

    Science.gov (United States)

    Moelker, Amber D; Baks, Timo; van den Bos, E J; van Geuns, R J; de Feyter, P J; Duncker, Dirk J; van der Giessen, W J

    2006-12-01

    Stem cell therapy after myocardial infarction (MI) has been studied in models of permanent coronary occlusion. We studied the effect of intracoronary administration of unselected bone marrow (BM) and mononuclear cells (MNC) in a porcine model of reperfused MI. In 34 swine, the left circumflex coronary artery was balloon-occluded for 2 h followed by reperfusion. Ten swine without MI served as controls. All swine underwent magnetic resonance imaging (MRI) 1 week post-MI. The next day, 10 of the 30 surviving MI swine received BM, 10 other MI swine received MNC, and the remaining MI swine received medium intracoronary. Four weeks later, all swine underwent a follow-up MRI. One week after MI, end-diastolic volume (92+/-16 mL) and left ventricular (LV) weight (78+/-12 g) were greater, whereas ejection fraction (40+/-8%) was lower than in controls (69+/-11 mL, 62+/-13 g, and 53+/-6%). Injection of BM or MNC had no effect on the MI-induced changes in global or regional LV-function. However, there was a significant reduction in infarct size 4 weeks after MNC injection (-6+/-3%) compared with the medium (-3+/-5%). Intracoronary injection of BM or MNC in swine does not improve regional or global LV-function 4 weeks after injection. However, a reduction in infarct-size was noted after MNC injection.

  3. Proteomic patterns of cervical cancer cell lines, a network perspective.

    Science.gov (United States)

    Higareda-Almaraz, Juan Carlos; Enríquez-Gasca, María del Rocío; Hernández-Ortiz, Magdalena; Resendis-Antonio, Osbaldo; Encarnación-Guevara, Sergio

    2011-06-22

    Cervical cancer is a major mortality factor in the female population. This neoplastic is an excellent model for studying the mechanisms involved in cancer maintenance, because the Human Papilloma Virus (HPV) is the etiology factor in most cases. With the purpose of characterizing the effects of malignant transformation in cellular activity, proteomic studies constitute a reliable way to monitor the biological alterations induced by this disease. In this contextual scheme, a systemic description that enables the identification of the common events between cell lines of different origins, is required to distinguish the essence of carcinogenesis. With this study, we sought to achieve a systemic perspective of the common proteomic profile of six cervical cancer cell lines, both positive and negative for HPV, and which differ from the profile corresponding to the non-tumourgenic cell line, HaCaT. Our objectives were to identify common cellular events participating in cancer maintenance, as well as the establishment of a pipeline to work with proteomic-derived results. We analyzed by means of 2D SDS-PAGE and MALDI-TOF mass spectrometry the protein extracts of six cervical cancer cell lines, from which we identified a consensus of 66 proteins. We call this group of proteins, the "central core of cervical cancer". Starting from this core set of proteins, we acquired a PPI network that pointed, through topological analysis, to some proteins that may well be playing a central role in the neoplastic process, such as 14-3-3ζ. In silico overrepresentation analysis of transcription factors pointed to the overexpression of c-Myc, Max and E2F1 as key transcription factors involved in orchestrating the neoplastic phenotype. Our findings show that there is a "central core of cervical cancer" protein expression pattern, and suggest that 14-3-3ζ is key to determine if the cell proliferates or dies. In addition, our bioinformatics analysis suggests that the neoplastic phenotype is

  4. Proteomic patterns of cervical cancer cell lines, a network perspective

    Directory of Open Access Journals (Sweden)

    Resendis-Antonio Osbaldo

    2011-06-01

    Full Text Available Abstract Background Cervical cancer is a major mortality factor in the female population. This neoplastic is an excellent model for studying the mechanisms involved in cancer maintenance, because the Human Papilloma Virus (HPV is the etiology factor in most cases. With the purpose of characterizing the effects of malignant transformation in cellular activity, proteomic studies constitute a reliable way to monitor the biological alterations induced by this disease. In this contextual scheme, a systemic description that enables the identification of the common events between cell lines of different origins, is required to distinguish the essence of carcinogenesis. Results With this study, we sought to achieve a systemic perspective of the common proteomic profile of six cervical cancer cell lines, both positive and negative for HPV, and which differ from the profile corresponding to the non-tumourgenic cell line, HaCaT. Our objectives were to identify common cellular events participating in cancer maintenance, as well as the establishment of a pipeline to work with proteomic-derived results. We analyzed by means of 2D SDS-PAGE and MALDI-TOF mass spectrometry the protein extracts of six cervical cancer cell lines, from which we identified a consensus of 66 proteins. We call this group of proteins, the "central core of cervical cancer". Starting from this core set of proteins, we acquired a PPI network that pointed, through topological analysis, to some proteins that may well be playing a central role in the neoplastic process, such as 14-3-3ζ. In silico overrepresentation analysis of transcription factors pointed to the overexpression of c-Myc, Max and E2F1 as key transcription factors involved in orchestrating the neoplastic phenotype. Conclusions Our findings show that there is a "central core of cervical cancer" protein expression pattern, and suggest that 14-3-3ζ is key to determine if the cell proliferates or dies. In addition, our

  5. Concurrent hypermulticolor monitoring of CD31, CD34, CD45 and CD146 endothelial progenitor cell markers for acute myocardial infarction

    Energy Technology Data Exchange (ETDEWEB)

    Shim, Yumi [College of Pharmacy, Seoul National University, 1 Gwanak-Ro, Gwanak Gu, Seoul 151-742 (Korea, Republic of); Nam, Myung Hyun [Department of Laboratory Medicine, Korea University Ansan Hospital, Korea University College of Medicine (Korea, Republic of); Hyuk, Song Woo [Cardiology College of Medicine, Korea University (Korea, Republic of); Yoon, Soo Young [College of Medicine, Korea University, Seoul (Korea, Republic of); Song, Joon Myong, E-mail: jmsong@snu.ac.kr [College of Pharmacy, Seoul National University, 1 Gwanak-Ro, Gwanak Gu, Seoul 151-742 (Korea, Republic of)

    2015-01-01

    Highlights: • We observe EPCs and HPCs in patient for AMI diagnosis. • We detect two EPC subtypes using quantum dot and AOTF. • Quantum dot has narrower emission wavelength range than fluorescence dye. • AOTF provide smaller spectral interference than bandpass filters. • Quantum dot and AOTF are suitable for detecting large number of molecular markers concurrently. - Abstract: The circulating endothelial progenitor cells (EPCs) in blood of acute myocardial infarction (AMI) patient have been monitored in many previous studies. The number of circulating EPC increases in the blood of patients at onset of the AMI. EPC is originated from bone marrow. It performs vessel regeneration. There are many markers used for detecting EPC. Four of these markers, CD31, CD34, CD45, and CD146, were concurrently detected at the single cell level for the identification of EPC in the present preliminary study. The CD45 negative cell sorting was performed to peripheral blood mononuclear cells (PBMCs) acquired from four AMI patients with a magnetic bead sorter, since, EPCs expressed CD45 negative or dim. The resultant PBMC eluents were treated with quantum-antibody conjugates for the probing four different markers of EPCs and then applied to a high-content single cell imaging cytometer using acousto-optical tunable filter (AOTF). The use of quantum dot, with narrow emission wavelength range and AOTF enabling cellular image at a particular single wavelength, is very advantageous for accurate high-content AMI diagnosis based on simultaneous monitoring of many markers. The number of EPC increased as compared with control in three of four AMI patients. In this approach, two EPC subtypes were found, CD31(+), CD34(+), CD45(−/dim), CD146(−) as early outgrowth EPCs and CD31(+), CD34(+), CD45(−/dim), CD146(+) as late outgrowth EPCs. Patient 1 had CD31(+), CD34(+), CD45(−/dim), CD146(+) cells whose percentage was 4.21% of cells. Patient 2 had 2.38% of CD31(+), CD34(+), CD45(

  6. Graph Theory-Based Analysis of the Lymph Node Fibroblastic Reticular Cell Network.

    Science.gov (United States)

    Novkovic, Mario; Onder, Lucas; Bocharov, Gennady; Ludewig, Burkhard

    2017-01-01

    Secondary lymphoid organs have developed segregated niches that are able to initiate and maintain effective immune responses. Such global organization requires tight control of diverse cellular components, specifically those that regulate lymphocyte trafficking. Fibroblastic reticular cells (FRCs) form a densely interconnected network in lymph nodes and provide key factors necessary for T cell migration and retention, and foster subsequent interactions between T cells and dendritic cells. Development of integrative systems biology approaches has made it possible to elucidate this multilevel complexity of the immune system. Here, we present a graph theory-based analysis of the FRC network in murine lymph nodes, where generation of the network topology is performed using high-resolution confocal microscopy and 3D reconstruction. This approach facilitates the analysis of physical cell-to-cell connectivity, and estimation of topological robustness and global behavior of the network when it is subjected to perturbation in silico.

  7. Relationship between preparation of cells for therapy and cell quality using artificial neural network analysis.

    Science.gov (United States)

    Dhondalay, Gopal Krishna; Lawrence, Katherine; Ward, Stephen; Ball, Graham; Hoare, Michael

    2014-10-01

    The successful preparation of cells for therapy depends on the characterization of causal factors affecting cell quality. Ultra scale-down methods are used to characterize cells in terms of their response to process engineering causal factors of hydrodynamic shear stress and time. This response is in turn characterized in terms of causal factors relating to variations as may naturally occur during cell preparation, i.e., passage number, generation number, time of the final passage stage and hold time in formulation medium. To investigate the influence of all of these causal factors we have adopted a non-linear, multivariate predictive artificial neural network (ANN) based modeling approach to help create clearer insights into their effect on cell membrane integrity and surface marker content. A prostate cancer cell line candidate for cancer therapy (P4E6) was used and cell surface markers CD9, CD147 and HLA A-C were investigated. All causal factors studied were found to be significant in establishing an ANN model for the prediction of cell quality parameters with the extent of exposure to shear stress being the most significant and then passage number (range 57-66) and generation number (range 10-19) determining most strongly the cells' resistance to shear stress. Both the operation of the final cell passage and the hold time of the cells in a formulation buffer also determine the cells' resistance to shear stress. The processing parameters related to cell handling after preparation, i.e., shear stress and time of exposure were found to be the most influential affecting cell quality. CD9 surface marker loss was the most sensitive indicator of the effects of shear stress followed by loss of membrane integrity and then HLA A-C, while CD147 remained unaffected by shear stress or even prone to increase. Also greater stability of cell surface marker presence was noted for cells generated at greater passage numbers or generation numbers or for reduction in hold time in

  8. Off-hour primary percutaneous coronary angioplasty does not affect outcome of patients with ST-Segment elevation acute myocardial infarction treated within a regional network for reperfusion: The REAL (Registro Regionale Angioplastiche dell'Emilia-Romagna) registry.

    Science.gov (United States)

    Casella, Gianni; Ottani, Filippo; Ortolani, Paolo; Guastaroba, Paolo; Santarelli, Andrea; Balducelli, Marco; Menozzi, Alberto; Magnavacchi, Paolo; Sangiorgi, Giuseppe Massimo; Manari, Antonio; De Palma, Rossana; Marzocchi, Antonio

    2011-03-01

    This study aims to evaluate whether results of "off-hours" and "regular-hours" primary angioplasty (primary percutaneous coronary intervention [pPCI]) are comparable in an unselected population of patients with ST-segment elevation acute myocardial infarction treated within a regional network organization. Conflicting results exist on the outcome of off-hours pPCI. We analyzed in-hospital and 1-year cardiac mortality among 3,072 consecutive ST-segment elevation myocardial infarction (STEMI) patients treated with pPCI between January 1, 2004, and June 30, 2006, during regular-hours (weekdays 8:00 AM to 8:00 PM) and off-hours (weekdays 8:01 PM to 7:59 AM, weekends, and holidays) within the STEMI Network of the Italian Region Emilia-Romagna (28 hospitals: 19 spoke and 9 hub interventional centers). Fifty-three percent of patients were treated off-hours. Baseline findings were comparable, although regular-hours patients were older and had more incidences of multivessel disease. Median pain-to-balloon (195 min, interquartile range [IQR]: 140 to 285 vs. 186 min, IQR: 130 to 280 min; p = 0.03) and door-to-balloon time (88 min, IQR: 60 to 122 vs. 77 min, IQR: 48 to 116 min; p < 0.0001) were longer for off-hours pPCI. However, unadjusted in-hospital (5.8% off-hours vs. 7.2% regular-hours, p = 0.11) and 1-year cardiac mortality (8.4% off-hours vs. 10.3% regular-hours, p = 0.08) were comparable. At multivariate analysis, off-hours pPCI did not predict an adverse outcome either for the overall population (odds ratio [OR]: 0.70, 95% confidence interval [CI]: 0.49 to 1.01) or for patients directly admitted to the interventional center (OR: 0.79, 95% CI: 0.52 to 1.20). When pPCI is performed within an efficient STEMI network focused on reperfusion, the clinical effectiveness of either off-hours or regular-hours pPCI is comparable. Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  9. Regulatory networks define phenotypic classes of human stem cell lines

    OpenAIRE

    Müller, Franz-Josef; Laurent, Louise C.; Kostka, Dennis; Ulitsky, Igor; Williams, Roy; Lu, Christina; Park, In-Hyun; Rao, Mahendra?S.; Shamir, Ron; Schwartz, Philip H.; Schmidt, Nils O.; Loring, Jeanne F.

    2008-01-01

    Stem cells are defined as self-renewing cell populations that can differentiate into multiple distinct cell types. However, hundreds of different human cell lines from embryonic, fetal, and adult sources have been called stem cells, even though they range from pluripotent cells, typified by embryonic stem cells, which are capable of virtually unlimited proliferation and differentiation, to adult stem cell lines, which can generate a far more limited repertory of differentiated cell types. The...

  10. Effects of mir-21 on Cardiac Microvascular Endothelial Cells After Acute Myocardial Infarction in Rats: Role of Phosphatase and Tensin Homolog (PTEN)/Vascular Endothelial Growth Factor (VEGF) Signal Pathway

    Science.gov (United States)

    Yang, Feng; Liu, Wenwei; Yan, Xiaojuan; Zhou, Hanyun; Zhang, Hongshen; Liu, Jianfei; Yu, Ming; Zhu, Xiaoshan; Ma, Kezhong

    2016-01-01

    Background This study investigated how miR-21 expression is reflected in acute myocardial infarction and explored the role of miR-21 and the PTEN/VEGF signaling pathway in cardiac microvascular endothelial cells. Material/Methods We used an in vivo LAD rat model to simulate acute myocardial infarction. MiR-21 mimics and miR-21 inhibitors were injected and transfected into model rats in order to alter miR-21 expression. Cardiac functions were evaluated using echocardiographic measurement, ELISA, and Masson staining. In addition, lenti-PTEN and VEGF siRNA were transfected into CMEC cells using standard procedures for assessing the effect of PTEN and VEGE on cell proliferation, apoptosis, and angiogenesis. MiR-21, PTEN, and VEGF expressions were examined by RT-PCR and Western blot. The relationship between miR-21 and PTEN was determined by the luciferase activity assay. Results We demonstrated that miR-21 bonded with the 3′-UTR of PTEN and suppressed PTEN expressions. Established models significantly induced cardiac infarct volume and endothelial injury marker expressions as well as miR-21 and PTEN expressions (Pcell proliferation, apoptosis, and angiogenesis (P<0.05). Conclusions MiR-21 exerts protective effects on endothelial injury through the PTEN/VEGF pathway after acute myocardial infarction. PMID:27708252

  11. Dynamics of the cell-cycle network under genome-rewiring perturbations.

    Science.gov (United States)

    Katzir, Yair; Elhanati, Yuval; Averbukh, Inna; Braun, Erez

    2013-12-01

    The cell-cycle progression is regulated by a specific network enabling its ordered dynamics. Recent experiments supported by computational models have shown that a core of genes ensures this robust cycle dynamics. However, much less is known about the direct interaction of the cell-cycle regulators with genes outside of the cell-cycle network, in particular those of the metabolic system. Following our recent experimental work, we present here a model focusing on the dynamics of the cell-cycle core network under rewiring perturbations. Rewiring is achieved by placing an essential metabolic gene exclusively under the regulation of a cell-cycle's promoter, forcing the cell-cycle network to function under a multitasking challenging condition; operating in parallel the cell-cycle progression and a metabolic essential gene. Our model relies on simple rate equations that capture the dynamics of the relevant protein-DNA and protein-protein interactions, while making a clear distinction between these two different types of processes. In particular, we treat the cell-cycle transcription factors as limited 'resources' and focus on the redistribution of resources in the network during its dynamics. This elucidates the sensitivity of its various nodes to rewiring interactions. The basic model produces the correct cycle dynamics for a wide range of parameters. The simplicity of the model enables us to study the interface between the cell-cycle regulation and other cellular processes. Rewiring a promoter of the network to regulate a foreign gene, forces a multitasking regulatory load. The higher the load on the promoter, the longer is the cell-cycle period. Moreover, in agreement with our experimental results, the model shows that different nodes of the network exhibit variable susceptibilities to the rewiring perturbations. Our model suggests that the topology of the cell-cycle core network ensures its plasticity and flexible interface with other cellular processes, without a

  12. Intracoronary infusion of encapsulated glucagon-like peptide-1-eluting mesenchymal stem cells preserves left ventricular function in a porcine model of acute myocardial infarction.

    Science.gov (United States)

    de Jong, Renate; van Hout, Gerardus P J; Houtgraaf, Jaco H; Kazemi, Kushan; Wallrapp, Christine; Lewis, Andrew; Pasterkamp, Gerard; Hoefer, Imo E; Duckers, Henricus J

    2014-10-01

    Engraftment and survival of stem cells in the infarcted myocardium remain problematic in cell-based therapy for cardiovascular disease. To overcome these issues, encapsulated mesenchymal stem cells (eMSCs) were developed that were transfected to produce glucagon-like peptide-1, an incretin hormone with known cardioprotective effects, alongside MSC endogenous paracrine factors. This study was designed to investigate the efficacy of different doses of intracoronary infusion of eMSC in a porcine model of acute myocardial infarction (AMI). One hundred pigs were subjected to a moderate AMI (posterolateral AMI; n=50) or a severe AMI (anterior AMI; n=50), whereupon surviving animals (n=36 moderate, n=33 severe) were randomized to receive either intracoronary infusion of 3 incremental doses of eMSC or Ringers' lactate control. Cardiac function was assessed using invasive hemodynamics, echocardiography, and histological analysis. A trend was observed in the moderate AMI model, whereas in the severe AMI model, left ventricular ejection fraction improved by +9.3% (P=0.004) in the best responding eMSC group, because of a preservation of left ventricular end-systolic volume. Arteriolar density increased 3-fold in the infarct area (8.4±0.9/mm(2) in controls versus 22.2±2.6/mm(2) in eMSC group; P<0.001). Although not statistically significant, capillary density was 30% higher in the border zone (908.1±99.7/mm(2) in control versus 1209.0±64.6/mm(2) in eMSC group; P=ns). eMSCs enable sustained local delivery of cardioprotective proteins to the heart, thereby enhancing angiogenesis and preserving contractile function in an animal AMI model. © 2014 American Heart Association, Inc.

  13. Myocardial Fibrosis in Athletes.

    NARCIS (Netherlands)

    Schoor, F.R. van de; Aengevaeren, V.L.; Hopman, M.T.E.; Oxborough, D.L.; George, K.P.; Thompson, P.D.; Eijsvogels, T.M.H.

    2016-01-01

    Myocardial fibrosis (MF) is a common phenomenon in the late stages of diverse cardiac diseases and is a predictive factor for sudden cardiac death. Myocardial fibrosis detected by magnetic resonance imaging has also been reported in athletes. Regular exercise improves cardiovascular health, but

  14. Engineered Microvasculature in PDMS Networks Using Endothelial Cells Derived from Human Induced Pluripotent Stem Cells

    Science.gov (United States)

    Sivarapatna, Amogh; Ghaedi, Mahboobe; Xiao, Yang; Han, Edward; Aryal, Binod; Zhou, Jing; Fernandez-Hernando, Carlos; Qyang, Yibing; Hirschi, Karen K.

    2017-01-01

    In this study, we used a polydimethylsiloxane (PDMS)-based platform for the generation of intact, perfusion-competent microvascular networks in vitro. COMSOL Multiphysics, a finite-element analysis and simulation software package, was used to obtain simulated velocity, pressure, and shear stress profiles. Transgene-free human induced pluripotent stem cells (hiPSCs) were differentiated into partially arterialized endothelial cells (hiPSC-ECs) in 5 d under completely chemically defined conditions, using the small molecule glycogen synthase kinase 3β inhibitor CHIR99021 and were thoroughly characterized for functionality and arterial-like marker expression. These cells, along with primary human umbilical vein endothelial cells (HUVECs), were seeded in the PDMS system to generate microvascular networks that were subjected to shear stress. Engineered microvessels had patent lumens and expressed VE-cadherin along their periphery. Shear stress caused by flowing medium increased the secretion of nitric oxide and caused endothelial cells s to align and to redistribute actin filaments parallel to the direction of the laminar flow. Shear stress also caused significant increases in gene expression for arterial markers Notch1 and EphrinB2 as well as antithrombotic markers Kruppel-like factor 2 (KLF-2)/4. These changes in response to shear stress in the microvascular platform were observed in hiPSC-EC microvessels but not in microvessels that were derived from HUVECs, which indicated that hiPSC-ECs may be more plastic in modulating their phenotype under flow than are HUVECs. Taken together, we demonstrate the feasibly of generating intact, engineered microvessels in vitro, which replicate some of the key biological features of native microvessels. PMID:28901188

  15. Method of derivation and differentiation of mouse embryonic stem cells generating synchronous neuronal networks.

    Science.gov (United States)

    Gazina, Elena V; Morrisroe, Emma; Mendis, Gunarathna D C; Michalska, Anna E; Chen, Joseph; Nefzger, Christian M; Rollo, Benjamin N; Reid, Christopher A; Pera, Martin F; Petrou, Steven

    2018-01-01

    Stem cells-derived neuronal cultures hold great promise for in vitro disease modelling and drug screening. However, currently stem cells-derived neuronal cultures do not recapitulate the functional properties of primary neurons, such as network properties. Cultured primary murine neurons develop networks which are synchronised over large fractions of the culture, whereas neurons derived from mouse embryonic stem cells (ESCs) display only partly synchronised network activity and human pluripotent stem cells-derived neurons have mostly asynchronous network properties. Therefore, strategies to improve correspondence of derived neuronal cultures with primary neurons need to be developed to validate the use of stem cell-derived neuronal cultures as in vitro models. By combining serum-free derivation of ESCs from mouse blastocysts with neuronal differentiation of ESCs in morphogen-free adherent culture we generated neuronal networks with properties recapitulating those of mature primary cortical cultures. After 35days of differentiation ESC-derived neurons developed network activity very similar to that of mature primary cortical neurons. Importantly, ESC plating density was critical for network development. Compared to the previously published methods this protocol generated more synchronous neuronal networks, with high similarity to the networks formed in mature primary cortical culture. We have demonstrated that ESC-derived neuronal networks recapitulating key properties of mature primary cortical networks can be generated by optimising both stem cell derivation and differentiation. This validates the approach of using ESC-derived neuronal cultures for disease modelling and in vitro drug screening. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Aspirin protects human coronary artery endothelial cells against atherogenic electronegative LDL via an epigenetic mechanism: a novel cytoprotective role of aspirin in acute myocardial infarction.

    Science.gov (United States)

    Chang, Po-Yuan; Chen, Yi-Jie; Chang, Fu-Hsiung; Lu, Jonathan; Huang, Wen-Huei; Yang, Tzu-Ching; Lee, Yuan-Teh; Chang, Shwu-Fen; Lu, Shao-Chun; Chen, Chu-Huang

    2013-07-01

    L5 is the most negatively charged subfraction of human low-density lipoprotein (LDL) and is the only subfraction of LDL capable of inducing apoptosis in cultured vascular endothelial cells (ECs) by inhibiting fibroblast growth factor-2 (FGF2) transcription. We examined whether plasma L5 levels are elevated in patients with ST-segment elevation myocardial infarction (STEMI) and whether aspirin provides epigenetic protection of human coronary artery ECs (HCAECs) exposed to L5. Plasma L5 levels were compared between patients with STEMI (n = 10) and control subjects with chest pain syndrome but a normal coronary arteriogram (n = 5). L5 was isolated from the plasma of STEMI patients and control subjects, and apoptosis, FGF2 expression, and FGF2 promoter methylation were examined in HCAECs treated with L5 and aspirin. Plasma L5 levels were significantly higher in STEMI patients than in control subjects (P aspirin (0.2 mM) attenuated the adverse effects of L5 on HCAEC survival, FGF2 expression, and FGF2 promoter methylation. In contrast, high concentrations of aspirin (≥1.0 mM) accentuated the effects of L5. Our results show that L5 levels are significantly increased in STEMI patients. Furthermore, L5 impairs HCAEC function through CpG methylation of the FGF2 promoter, which is suppressed in the presence of low-concentration aspirin. Our results provide evidence of a novel mechanism of aspirin in the prevention of MI.

  17. Ultrasound-Targeted Microbubble Destruction Improves the Migration and Homing of Mesenchymal Stem Cells after Myocardial Infarction by Upregulating SDF-1/CXCR4: A Pilot Study.

    Science.gov (United States)

    Li, Lu; Wu, Shengzheng; Liu, Zheng; Zhuo, Zhongxiong; Tan, Kaibin; Xia, Hongmei; Zhuo, Lisha; Deng, Xiaojun; Gao, Yunhua; Xu, Yali

    2015-01-01

    Mesenchymal stem cell (MSC) therapy shows considerable promise for the treatment of myocardial infarction (MI). However, the inefficient migration and homing of MSCs after systemic infusion have limited their therapeutic applications. Ultrasound-targeted microbubble destruction (UTMD) has proven to be promising to improve the homing of MSCs to the ischemic myocardium, but the concrete mechanism remains unclear. We hypothesize that UTMD promotes MSC homing by upregulating SDF-1/CXCR4, and this study was aimed at exploring this potential mechanism. We analyzed SDF-1/CXCR4 expression after UTMD treatment in vitro and in vivo and counted the number of homing MSCs in MI areas. The in vitro results demonstrated that UTMD not only led to elevated secretion of SDF-1 but also resulted in an increased proportion of MSCs that expressed surface CXCR4. The in vivo findings show an increase in the number of homing MSCs and higher expression of SDF-1/CXCR4 in the UTMD combined with MSCs infusion group compared to other groups. In conclusion, UTMD can increase SDF-1 expression in the ischemic myocardium and upregulate the expression of surface CXCR4 on MSCs, which provides a molecular mechanism for the homing of MSCs assisted by UTMD via SDF-1/CXCR4 axis.

  18. Ultrasound-Targeted Microbubble Destruction Improves the Migration and Homing of Mesenchymal Stem Cells after Myocardial Infarction by Upregulating SDF-1/CXCR4: A Pilot Study

    Directory of Open Access Journals (Sweden)

    Lu Li

    2015-01-01

    Full Text Available Mesenchymal stem cell (MSC therapy shows considerable promise for the treatment of myocardial infarction (MI. However, the inefficient migration and homing of MSCs after systemic infusion have limited their therapeutic applications. Ultrasound-targeted microbubble destruction (UTMD has proven to be promising to improve the homing of MSCs to the ischemic myocardium, but the concrete mechanism remains unclear. We hypothesize that UTMD promotes MSC homing by upregulating SDF-1/CXCR4, and this study was aimed at exploring this potential mechanism. We analyzed SDF-1/CXCR4 expression after UTMD treatment in vitro and in vivo and counted the number of homing MSCs in MI areas. The in vitro results demonstrated that UTMD not only led to elevated secretion of SDF-1 but also resulted in an increased proportion of MSCs that expressed surface CXCR4. The in vivo findings show an increase in the number of homing MSCs and higher expression of SDF-1/CXCR4 in the UTMD combined with MSCs infusion group compared to other groups. In conclusion, UTMD can increase SDF-1 expression in the ischemic myocardium and upregulate the expression of surface CXCR4 on MSCs, which provides a molecular mechanism for the homing of MSCs assisted by UTMD via SDF-1/CXCR4 axis.

  19. Relationship of Endothelial Cell-Specific Molecule 1 Level in Stress Hyperglycemia Patients With Acute ST-Segment Elevation Myocardial Infarction: A Pilot Study.

    Science.gov (United States)

    Qiu, Chongrong; Sui, Jian; Zhang, Qian; Wei, Peng; Wang, Peng; Fu, Qiang

    2016-10-01

    Endothelial cell-specific molecule 1 ([ESM-1], endocan) is a new biomarker of endothelial dysfunction, which may be involved in the pathogenesis of atherosclerosis and stress hyperglycemia in patients with acute ST-segment elevation myocardial infarction (STEMI). Therefore, we investigated serum ESM-1 levels in patients with stress hyperglycemia having STEMI; 105 patients with STEMI and 33 individuals as a control group were included in the study. The patients were followed up for 3 months and major adverse cardiac events (MACEs) were recorded. Serum ESM-1 level was significantly higher in patients with stress hyperglycemia patients having STEMI (P levels correlated positively with glucose levels (r = .21, P levels >1.01 ng/mL (odds ratio 3.01, 95% confidence interval 1.05-8.64, P stress hyperglycemia having STEMI, admission glucose levels are associated with ESM-1 levels, and ESM-1 is an independent predictor of MACEs. An ESM-1 level >1.01 ng/mL is likely to predict a greater risk of MACEs. © The Author(s) 2015.

  20. Acute myocardial infarction.

    Science.gov (United States)

    Reed, Grant W; Rossi, Jeffrey E; Cannon, Christopher P

    2017-01-14

    Acute myocardial infarction has traditionally been divided into ST elevation or non-ST elevation myocardial infarction; however, therapies are similar between the two, and the overall management of acute myocardial infarction can be reviewed for simplicity. Acute myocardial infarction remains a leading cause of morbidity and mortality worldwide, despite substantial improvements in prognosis over the past decade. The progress is a result of several major trends, including improvements in risk stratification, more widespread use of an invasive strategy, implementation of care delivery systems prioritising immediate revascularisation through percutaneous coronary intervention (or fibrinolysis), advances in antiplatelet agents and anticoagulants, and greater use of secondary prevention strategies such as statins. This seminar discusses the important topics of the pathophysiology, epidemiological trends, and modern management of acute myocardial infarction, focusing on the recent advances in reperfusion strategies and pharmacological treatment approaches. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Computational modeling of acute myocardial infarction.

    Science.gov (United States)

    Sáez, P; Kuhl, E

    2016-01-01

    Myocardial infarction, commonly known as heart attack, is caused by reduced blood supply and damages the heart muscle because of a lack of oxygen. Myocardial infarction initiates a cascade of biochemical and mechanical events. In the early stages, cardiomyocytes death, wall thinning, collagen degradation, and ventricular dilation are the immediate consequences of myocardial infarction. In the later stages, collagenous scar formation in the infarcted zone and hypertrophy of the non-infarcted zone are auto-regulatory mechanisms to partly correct for these events. Here we propose a computational model for the short-term adaptation after myocardial infarction using the continuum theory of multiplicative growth. Our model captures the effects of cell death initiating wall thinning, and collagen degradation initiating ventricular dilation. Our simulations agree well with clinical observations in early myocardial infarction. They represent a first step toward simulating the progression of myocardial infarction with the ultimate goal to predict the propensity toward heart failure as a function of infarct intensity, location, and size.

  2. Passaged neural stem cell-derived neuronal networks for a portable biosensor.

    Science.gov (United States)

    O'Shaughnessy, Thomas J; Liu, Jinny L; Ma, Wu

    2009-04-15

    We have previously demonstrated a portable biosensor that utilizes networks of mammalian neurons on microelectrode arrays (MEAs) as the sensing element. These neuronal cultures on MEAs are derived from primary neuronal tissues and are short-lived. In order to extend the shelf life of neuronal networks for use in a fieldable sensor technology, a renewable source of networks is needed. Neural stem and progenitor cells are capable of self-renewal and differentiation into functional neuronal networks. The purpose of this study was to develop a strategy for growing passaged neural stem and progenitor cells on MEAs under controlled conditions to produce differentiated neurons and glia comprising functional neuronal networks. Primary and passaged neuroepithelial stem and progenitor cells dissociated from embryonic day 13 rat cortex were seeded on MEAs and maintained with serum-free medium containing basic fibroblast growth factor (bFGF) combined with brain-derived neurotrophic factor (BDNF). These culture conditions lead to abundant neurons, with astrocytes as supportive cells, forming synaptically linked networks of neurons. Spontaneous action potentials were best recorded from networks derived from primary or passaged progenitor cells 4-5 weeks after initial culture. The passaged progenitor cell-derived networks on MEAs responded to the GABA(A) antagonist bicuculline, the NMDA glutamate inhibitor APV, and the non-NMDA glutamate antagonist CNQX indicating active synapses were present. Passaged neural stem and progenitor cell-derived networks on MEAs have properties similar to networks derived from primary neuronal cultures and can serve as a renewable supply of sensor elements for detection of environmental threats.

  3. Review Paper: Myocardial Rupture After Acute Myocardial Infarction ...

    African Journals Online (AJOL)

    Myocardial rupture complications after acute myocardial infarction are infrequent but lethal. They mainly involve rupture of the ventricular free wall, ventricular septum, papillary muscle, or combined. We compare features of different kinds of myocardial ruptures after acute myocardial infarction by reviewing the clinical ...

  4. A Cut Cell Method for Simulating Spatial Models of Biochemical Reaction Networks in Arbitrary Geometries.

    Science.gov (United States)

    Strychalski, Wanda; Adalsteinsson, David; Elston, Timothy C

    2010-01-01

    Cells use signaling networks consisting of multiple interacting proteins to respond to changes in their environment. In many situations, such as chemotaxis, spatial and temporal information must be transmitted through the network. Recent computational studies have emphasized the importance of cellular geometry in signal transduction, but have been limited in their ability to accurately represent complex cell morphologies. We present a finite volume method that addresses this problem. Our method uses Cartesian cut cells and is second order in space and time. We use our method to simulate several models of signaling systems in realistic cell morphologies obtained from live cell images and examine the effects of geometry on signal transduction.

  5. HIF-2α and Oct4 have synergistic effects on survival and myocardial repair of very small embryonic-like mesenchymal stem cells in infarcted hearts.

    Science.gov (United States)

    Zhang, Shaoheng; Zhao, Lan; Wang, Jiahong; Chen, Nannan; Yan, Jian; Pan, Xin

    2017-01-12

    Poor cell survival and limited functional benefits have restricted mesenchymal stem cell (MSC) efficacy for treating myocardial infarction (MI), suggesting that a better understanding of stem cell biology is needed. The transcription factor HIF-2α is an essential regulator of the transcriptional response to hypoxia, which can interact with embryonic stem cells (ESCs) transcription factor Oct4 and modulate its signaling. Here, we obtained very small embryonic-like mesenchymal stem cells (vselMSCs) from MI patients, which possessed the very small embryonic-like stem cells' (VSELs) morphology as well as ESCs' pluripotency. Using microarray analysis, we compared HIF-2α-regulated gene profiles in vselMSCs with ESC profiles and determined that HIF-2α coexpressed Oct4 in vselMSCs similarly to ESCs. However, this coexpression was absent in unpurified MSCs (uMSCs). Under hypoxic condition, vselMSCs exhibited stronger survival, proliferation and differentiation than uMSCs. Transplantation of vselMSCs caused greater improvement in cardiac function and heart remodeling in the infarcted rats. We further demonstrated that HIF-2α and Oct4 jointly regulate their relative downstream gene expressions, including Bcl2 and Survivin; the important pluripotent markers Nanog, Klf4, and Sox2; and Ang-1, bFGF, and VEGF, promoting angiogenesis and engraftment. Importantly, these effects were generally magnified by upregulation of HIF-2α and Oct4 induced by HIF-2α or Oct4 overexpression, and the greatest improvements were elicited after co-overexpressing HIF-2α and Oct4; overexpressing one transcription factor while silencing the other canceled this increase, and HIF-2α or Oct4 silencing abolished these effects. Together, these findings demonstrated that HIF-2α in vselMSCs cooperated with Oct4 in survival and function. The identification of the cooperation between HIF-2α and Oct4 will lead to deeper characterization of the downstream targets of this interaction in vselMSCs and will

  6. Intracoronary artery transplantation of cardiomyoblast-like cells from human adipose tissue-derived multi-lineage progenitor cells improve left ventricular dysfunction and survival in a swine model of chronic myocardial infarction

    Energy Technology Data Exchange (ETDEWEB)

    Okura, Hanayuki [The Center for Medical Engineering and Informatics, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0879 (Japan); Department of Somatic Stem Cell Therapy and Health Policy, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation, 2-2 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Saga, Ayami; Soeda, Mayumi [Department of Somatic Stem Cell Therapy and Health Policy, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation, 2-2 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Miyagawa, Shigeru; Sawa, Yoshiki [Department of Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0879 (Japan); Daimon, Takashi [Division of Biostatistics, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501 (Japan); Ichinose, Akihiro [Department of Plastic Surgery, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, Hyogo (Japan); Matsuyama, Akifumi, E-mail: akifumi-matsuyama@umin.ac.jp [The Center for Medical Engineering and Informatics, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0879 (Japan); Department of Plastic Surgery, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, Hyogo (Japan); RIKEN Program for Drug Discovery and Medical Technology Platforms, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045 (Japan)

    2012-09-07

    Highlights: Black-Right-Pointing-Pointer We administered human CLCs in a swine model of MI via intracoronary artery. Black-Right-Pointing-Pointer Histological studies demonstrated engraftment of hCLCs into the scarred myocardium. Black-Right-Pointing-Pointer Echocardiography showed rescue of cardiac function in the hCLCs transplanted swine. Black-Right-Pointing-Pointer Transplantation of hCLCs is an effective therapeutics for cardiac regeneration. -- Abstract: Transplantation of human cardiomyoblast-like cells (hCLCs) from human adipose tissue-derived multi-lineage progenitor cells improved left ventricular function and survival of rats with myocardial infarction. Here we examined the effect of intracoronary artery transplantation of human CLCs in a swine model of chronic heart failure. Twenty-four pigs underwent balloon-occlusion of the first diagonal branch followed by reperfusion, with a second balloon-occlusion of the left ascending coronary artery 1 week later followed by reperfusion. Four weeks after the second occlusion/reperfusion, 17 of the 18 surviving animals with severe chronic MI (ejection fraction <35% by echocardiography) were immunosuppressed then randomly assigned to receive either intracoronary artery transplantation of hCLCs hADMPCs or placebo lactic Ringer's solution with heparin. Intracoronary artery transplantation was followed by the distribution of DiI-stained hCLCs into the scarred myocardial milieu. Echocardiography at post-transplant days 4 and 8 weeks showed rescue and maintenance of cardiac function in the hCLCs transplanted group, but not in the control animals, indicating myocardial functional recovery by hCLCs intracoronary transplantation. At 8 week post-transplantation, 7 of 8 hCLCs transplanted animals were still alive compared with only 1 of the 5 control (p = 0.0147). Histological studies at week 12 post-transplantation demonstrated engraftment of the pre DiI-stained hCLCs into the scarred myocardium and their expression of

  7. A Microfluidic Pore Network Approach to Investigate Water Transport in Fuel Cell Porous Transport Layers

    OpenAIRE

    Bazylak, A.; Berejnov, V.; Markicevic, B.; Sinton, D.; Djilali, N.

    2008-01-01

    Pore network modelling has traditionally been used to study displacement processes in idealized porous media related to geological flows, with applications ranging from groundwater hydrology to enhanced oil recovery. Very recently, pore network modelling has been applied to model the gas diffusion layer (GDL) of a polymer electrolyte membrane (PEM) fuel cell. Discrete pore network models have the potential to elucidate transport phenomena in the GDL with high computational efficiency, in cont...

  8. From genomes to in silico cells via metabolic networks

    DEFF Research Database (Denmark)

    Borodina, Irina; Nielsen, Jens

    2005-01-01

    Genome-scale metabolic models are the focal point of systems biology as they allow the collection of various data types in a form suitable for mathematical analysis. High-quality metabolic networks and metabolic networks with incorporated regulation have been successfully used for the analysis of...

  9. The prognostic value of admission red cell distribution width-to-platelet ratio in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.

    Science.gov (United States)

    Pusuroglu, Hamdi; Cakmak, Huseyin Altug; Akgul, Ozgur; Erturk, Mehmet; Surgit, Ozgur; Akkaya, Emre; Bulut, Umit; Yildirim, Aydin

    2015-10-01

    Red cell distribution width (RDW) is a measure of variation in the size of circulating red blood cells. Recent studies have reported a strong independent relation between elevated RDW and short- and long-term prognosis in various disorders. The aim of the present study was to investigate the relationship between admission RDW-to-platelet ratio (RPR) and in-hospital and long-term prognosis in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). A total of 470 consecutive patients with a diagnosis of STEMI who underwent primary PCI were included in this prospective study. The patients were divided into two groups based on their admission RPR: high (>0.061) RPR group and low (≤0.061) RPR group. The patients were followed for adverse clinical outcomes in-hospital and for up to one year after discharge. In-hospital cardiovascular mortality, major adverse cardiovascular events (MACE), advanced heart failure and cardiogenic shock were significantly higher in the high RPR group (p<0.05). All-cause and cardiovascular mortality, MACE, fatal reinfarction, advanced heart failure, and rehospitalization for cardiac cause were more frequent in the high RPR group in one-year follow-up (p<0.05). High RPR was found to be a significant independent predictor of one-year cardiovascular mortality in multivariate analysis (p=0.003, OR: 3.106, 95% CI: 1.456-6.623). RPR is an inexpensive and readily available biomarker that provides an additional level of risk stratification beyond that provided by conventional risk parameters in predicting long-term MACE and cardiovascular mortality in STEMI. Copyright © 2015 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

  10. Transplantation of adipose tissue-derived stem cells improves cardiac contractile function and electrical stability in a rat myocardial infarction model.

    Science.gov (United States)

    Gautam, Milan; Fujita, Daiki; Kimura, Kazuhiro; Ichikawa, Hinako; Izawa, Atsushi; Hirose, Masamichi; Kashihara, Toshihide; Yamada, Mitsuhiko; Takahashi, Masafumi; Ikeda, Uichi; Shiba, Yuji

    2015-04-01

    The transplantation of adipose tissue-derived stem cells (ADSCs) improves cardiac contractility after myocardial infarction (MI); however, little is known about the electrophysiological consequences of transplantation. The purpose of this study was to clarify whether the transplantation of ADSCs increases or decreases the incidence of ventricular tachyarrhythmias (VT) in a rat model of MI. MI was induced experimentally by permanent occlusion of the left anterior descending artery of Lewis rats. ADSCs were harvested from GFP-transgenic rats, and were cultured until passage four. ADSCs (10×10(6)) resuspended in 100μL saline or pro-survival cocktail (PSC), which enhances cardiac graft survival, were injected directly into syngeneic rat hearts 1week after MI. The recipients of ADSCs suspended in PSC had a larger graft area compared with those receiving ASDCs suspended in saline at 1week post-transplantation (number of graft cells/section: 148.7±10.6 vs. 22.4±3.4, ptransplanted with ASDCs in PSC. ADSCs were transplanted into infarcted hearts, and the mechanical and electrophysiological functions were assessed. Echocardiography revealed that ADSC recipients had improved contractile function compared with those receiving PSC vehicle (fractional shortening: 21.1±0.9 vs. 14.1±1.2, ptransplantation, VT was induced via in vivo programmed electrical stimulation. The recipients of ADSCs showed a significantly lower incidence of induced VT compared with the control (31.3% vs. 83.3%, ptransplantation, we performed ex vivo optical mapping using a voltage sensitive dye, and found that ADSC transplantation decreased conduction velocity and its dispersion in the peri-infarct area. These results suggest that ADSC transplantation improved cardiac mechanical and electrophysiological functions in subacute MI. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Adiabatic superconducting cells for ultra-low-power artificial neural networks

    Directory of Open Access Journals (Sweden)

    Andrey E. Schegolev

    2016-10-01

    Full Text Available We propose the concept of using superconducting quantum interferometers for the implementation of neural network algorithms with extremely low power dissipation. These adiabatic elements are Josephson cells with sigmoid- and Gaussian-like activation functions. We optimize their parameters for application in three-layer perceptron and radial basis function networks.

  12. Histochemical and immunohistochemical analyses of the myocardial scar fallowing acute myocardial infarction

    Directory of Open Access Journals (Sweden)

    Tatić Vujadin

    2012-01-01

    Full Text Available Background/Aim. The heart has traditionally been considered as a static organ without capacity of regeneration after trauma. Currently, the more and more often asked question is whether the heart has any intrinsic capacities to regenerate myocytes after myocardial infarction. The aim of this study was to present the existence of the preserved muscle fibers in the myocardial scar following myocardial infarction as well as the presence of numerous cells of various size and form that differently reacted to the used immunohistochemical antibodies. Methods. Histological, histochemical and immunohistochemical analyses of myocardial sections taken from 177 patients who had died of acute myocardial infarction and had the myocardial scar following myocardial infarction, were carried out. More sections taken both from the site of acute infarction and scar were examined by the following methods: hematoxylin-eosin (HE, periodic acid schiff (PAS, PAS-diastasis, Masson trichrom, Malory, van Gieson, vimentin, desmin, myosin, myoglobin, alpha actin, smoth muscle actin (SMA, p53, leukocyte common antigen (LCA, proliferating cell nuclear antigen (PCNA, Ki-67, actin HHF35, CD34, CD31, CD45, CD45Ro, CD8, CD20. Results. In all sections taken from the scar region, larger or smaller islets of the preserved muscle fibers with the signs of hypertrophy were found. In the scar, a large number of cells of various size and form: spindle, oval, elongated with abundant cytoplasm, small with one nucleus and cells with scanty cytoplasm, were found. The present cells differently reacted to histochemical and immunohistochemical methods. Large oval cells showed negative reaction to lymphocytic and leukocytic markers, and positive to alpha actin, actin HHF35, Ki-67, myosin, myoglobin and desmin. Elongated cells were also positive to those markers. Small mononuclear cells showed positive reaction to lymphocytic markers. Endothelial and smooth muscle cells in the blood vessel walls

  13. Cell growth and cell cycle in Saccharomyces cerevisiae: basic regulatory design and protein-protein interaction network.

    Science.gov (United States)

    Alberghina, Lilia; Mavelli, Gabriella; Drovandi, Guido; Palumbo, Pasquale; Pessina, Stefania; Tripodi, Farida; Coccetti, Paola; Vanoni, Marco

    2012-01-01

    In this review we summarize the major connections between cell growth and cell cycle in the model eukaryote Saccharomyces cerevisiae. In S. cerevisiae regulation of cell cycle progression is achieved predominantly during a narrow interval in the late G1 phase known as START (Pringle and Hartwell, 1981). At START a yeast cell integrates environmental and internal signals (such as nutrient availability, presence of pheromone, attainment of a critical size, status of the metabolic machinery) and decides whether to enter a new cell cycle or to undertake an alternative developmental program. Several signaling pathways, that act to connect the nutritional status to cellular actions, are briefly outlined. A Growth & Cycle interaction network has been manually curated. More than one fifth of the edges within the Growth & Cycle network connect Growth and Cycle proteins, indicating a strong interconnection between the processes of cell growth and cell cycle. The backbone of the Growth & Cycle network is composed of middle-degree nodes suggesting that it shares some properties with HOT networks. The development of multi-scale modeling and simulation analysis will help to elucidate relevant central features of growth and cycle as well as to identify their system-level properties. Confident collaborative efforts involving different expertises will allow to construct consensus, integrated models effectively linking the processes of cell growth and cell cycle, ultimately contributing to shed more light also on diseases in which an altered proliferation ability is observed, such as cancer. Copyright © 2011 Elsevier Inc. All rights reserved.

  14. Terapias celulares do miocárdio com células da medula óssea: critérios de qualidade e perspectivas Myocardial cell therapy with bone marrow cells: criteria for quality and future perspectives

    Directory of Open Access Journals (Sweden)

    Maria Isabel D. Rossi

    2009-05-01

    Full Text Available A terapia celular pode ser uma nova opção terapêutica para pacientes cardíacos, modificando o processo de remodelamento cardíaco e prevenindo a falência cardíaca pós-infarto. Estudos clínicos até o presente usaram células mononucleadas de medula óssea, isoladas por centrifugação em gradiente de densidade a partir de aspirados de medula óssea da crista ilíaca. Embora esta nova estratégia revolucionária pareça ser segura e melhorar a função cardíaca, resultados negativos surgiram desafiando o futuro de terapias baseadas em células para o reparo cardíaco. Aqui discutimos alguns resultados laboratoriais que podem explicar, pelo menos parcialmente, as diferenças obtidas em protocolos similares. Uma análise da correlação entre a composição celular da fração mononuclear do aspirado da medula óssea e o êxito clínico da terapia indicou que os linfócitos não favorecem o reparo do miocárdio. Uma seleção negativa eliminando as linhagens do sistema imunitário pode ser proposta para melhorar a terapia celular do miocárdio.Cell therapy may provide a novel therapeutic option for cardiac patients, modifying myocardium remodeling processes and preventing post-infarction heart failure. Currently clinical studies predominantly use bone marrow mononuclear cells isolated by density gradient centrifugation of iliac crest bone marrow aspirates. Although this revolutionary new strategy seems to be safe and to improve myocardial function, negative data have emerged challenging the future of cell-based therapy for heart repair. Here we discuss some laboratory data that might explain, at least in part, variations in outcomes using similar protocols. Analysis of the correlation between the cell composition of the mononuclear fraction of bone marrow aspirates and the clinical outcome of the therapy has indicated that cells of the lymphocyte lineage are not beneficial in myocardial regeneration. A proposal of selection to eliminate

  15. Periodontitis and myocardial hypertrophy.

    Science.gov (United States)

    Suzuki, Jun-Ichi; Sato, Hiroki; Kaneko, Makoto; Yoshida, Asuka; Aoyama, Norio; Akimoto, Shouta; Wakayama, Kouji; Kumagai, Hidetoshi; Ikeda, Yuichi; Akazawa, Hiroshi; Izumi, Yuichi; Isobe, Mitsuaki; Komuro, Issei

    2017-04-01

    There is a deep relationship between cardiovascular disease and periodontitis. It has been reported that myocardial hypertrophy may be affected by periodontitis in clinical settings. Although these clinical observations had some study limitations, they strongly suggest a direct association between severity of periodontitis and left ventricular hypertrophy. However, the detailed mechanisms between myocardial hypertrophy and periodontitis have not yet been elucidated. Recently, we demonstrated that periodontal bacteria infection is closely related to myocardial hypertrophy. In murine transverse aortic constriction models, a periodontal pathogen, Aggregatibacter actinomycetemcomitans markedly enhanced cardiac hypertrophy with matrix metalloproteinase-2 activation, while another pathogen Porphyromonas gingivalis (P.g.) did not accelerate these pathological changes. In the isoproterenol-induced myocardial hypertrophy model, P.g. induced myocardial hypertrophy through Toll-like receptor-2 signaling. From our results and other reports, regulation of chronic inflammation induced by periodontitis may have a key role in the treatment of myocardial hypertrophy. In this article, we review the pathophysiological mechanism between myocardial hypertrophy and periodontitis.

  16. In situ analysis of tyrosine phosphorylation networks by FLIM on cell arrays.

    Science.gov (United States)

    Grecco, Hernán E; Roda-Navarro, Pedro; Girod, Andreas; Hou, Jian; Frahm, Thomas; Truxius, Dina C; Pepperkok, Rainer; Squire, Anthony; Bastiaens, Philippe I H

    2010-06-01

    Extracellular stimuli are transduced inside the cell by posttranslational modifications (PTMs), such as phosphorylation, of proteins in signaling networks. Insight into the structure of these networks requires quantification of PTM levels in individual cells. Fluorescence resonance energy transfer (FRET) measured by fluorescence lifetime imaging microscopy (FLIM) is a powerful tool to image PTM levels in situ. FLIM on cell arrays that express fluorescent protein fusions can quantify tyrosine phosphorylation patterns in large networks in individual cells. We identified tyrosine kinase substrates by imaging their phosphorylation levels after inhibition of protein tyrosine phosphatases. Analysis of the correlation between protein phosphorylation and expression levels at single cell resolution allowed us to identify positive feedback motifs. Using FLIM on cell arrays (CA-FLIM), we uncovered components that transduce signals from epidermal growth factor receptor.

  17. Cardiac Telocytes in Regeneration of Myocardium After Myocardial Infarction.

    Science.gov (United States)

    Zhaofu, Liao; Dongqing, Cai

    2016-01-01

    Recent research progress has revealed that a novel type of interstitial cells termed cardiac telocytes (CTs) is found in the interstitium of the heart. We demonstrated that CTs are distributed both longitudinally and within the cross network in the myocardium and that the density of CTs in the atrium-atria and base of the myocardium is higher than that in the middle of the myocardium, while the density of CTs in the epicardium is higher than that in the endocardium. In addition, we documented, for the first time, that the network of CTs in the infarct zone of the myocardium is destroyed during myocardial infarction (MI). This fact shows that, in addition to the death of cardiac myocytes, the previously unrecognized death of CTs is an important mechanism that contributes to the structural damage and poor healing and regeneration observed in the infarcted myocardium. Furthermore, we demonstrated, for the first time, that transplantation of CTs in cases of MI decreases the infarct size and improves myocardial function. The mechanisms behind the beneficial effects of CT transplantation are increased angiogenesis at the infarct site and the border zone, decreased fibrosis in the infarct and non-infarct zones, improved pathological reconstruction of the left ventricle, and increased regeneration of CTs in the infarct zone. Our findings reveal that CTs can be specifically identified by the following characteristics: very small cell bodies, extreme prolongation with some dilation, predisposition to cell death under ischemia, and expression of molecular markers such as c-Kit, CD34, vimentin, and PDGFR-β. CTs act as a structural and functional niche microenvironment in the myocardium and play an essential role in maintaining the integrity of the myocardium and in the regeneration of damaged myocardium.

  18. Grid cells used for Surface-Water Network for the Central Valley Hydrologic Model

    Data.gov (United States)

    U.S. Geological Survey, Department of the Interior — This digital dataset contains the segment and reaches for the surface-water network by model cell for the Central Valley Hydrologic Model (CVHM). The Central Valley...

  19. Photoluminescent Mesoporous Silicon Nanoparticles with siCCR2 Improve the Effects of Mesenchymal Stromal Cell Transplantation after Acute Myocardial Infarction.

    Science.gov (United States)

    Lu, Wenbin; Xie, ZhuoYing; Tang, Yong; Bai, Ling; Yao, Yuyu; Fu, Cong; Ma, Genshan

    2015-01-01

    Despite the benefits of mesenchymal stromal cell (MSC) transplantation in cardiac tissue, detailed in vivo observations have shown that MSCs only survive for a brief period after transplantation due to harsh microenvironmental conditions, including ischemia, inflammation and anoikis, in the infarcted myocardium. Thus, new strategies are needed to enhance MSC survival and inhibit cardiac remodeling. Studies have now demonstrated that chemokine [C-C motif] ligand 2 (CCL2) and its cognate receptor C-C chemokine receptor 2 (CCR2) promote excessive Ly6C(high) inflammatory monocyte infiltration at the infarct in response to ischemic myocardial injury. Therefore, decreasing the activities of these monocytes immediately after acute myocardial infarction (AMI) could be beneficial for AMI patients. This study tested the hypothesis that therapeutic siRNA-loaded photoluminescent mesoporous silicon nanoparticles (PMSNs) targeting CCR2 expression in Ly6C(high) inflammatory monocytes decrease the accumulation of these cells in the infarct, improve the efficacy of MSC transplantation and attenuate myocardial remodeling. PMSNs carrying therapeutic siCCR2 were first synthesized without the inclusion of fluorescent materials or dyes. After AMI BALB/c mice were established, 10(5) 5-ethynyl-2'- deoxyuridine (EdU)-labeled MSCs suspended in 100 µl of phosphate buffered saline (PBS) were injected into the border zone of the infarct of each mouse. PMSNs-siCCR2 (25 µg/g) were also intravenously injected via the tail vein immediately following AMI induction. Control mice were injected with an equal amount of PMSNs without siCCR2. PMSNs-siCCR2 were examined in vivo using near-infrared imaging technology. The therapeutic effects of PMSNs-siCCR2 for MSC transplantation were determined at the mRNA, protein and functional levels. PMSNs-siCCR2 circulated freely in vivo and were cleared in a relatively short period of time (t(½)=37 min) with no evidence of toxicity. The therapeutic PMSNs-siCCR2

  20. Prompt bone marrow-derived mesenchymal stem cell therapy enables early porcine heart function recovery from acute myocardial infarction.

    Science.gov (United States)

    Fan, Chang-Qing; Leu, Steve; Sheu, Jiunn-Jye; Zhen, Yen-Yi; Tsai, Tzu-Hsien; Chen, Yung-Lung; Chung, Sheng-Ying; Chai, Han-Tan; Sun, Cheuk-Kwan; Yang, Jenq-Lin; Chang, Hsueh-Wen; Ko, Sheung-Fat; Yip, Hon-Kan

    2014-01-01

    Impact of early bone marrow-derived mesenchymal stem cell (BMDMSC) implantation on left ventricular (LV) function after AMI was studied.Twelve mini-pigs were equally divided into placebo (AMI through left coronary artery ligation) and cell-treated groups [BMDMSCs (3.0 × 10(7)) implanted into infarct area (IA)] with myocardium harvested by post-AMI day 90. Six healthy animals served as controls.On post-AMI day 90, magnetic resonance imaging showed a lower LV ejection fraction but higher LV dimensions in the placebo group (P < 0.003) that also had increased IAs but reduced wall thickness (P < 0.005). Pro-apoptotic gene expressions (Bax, caspase-3) and apoptotic nucleus number in IAs and peri-IAs were highest in the placebo group (P < 0.001). Inflammatory biomarker expressions (MMP-9, oxidized protein, CD40+ cells) were highest, whereas those of angiogenesis (VEGF, CD31+ cells, SDF-1α, CXCR4) and myocardium-preservation (connexin43, troponin-I, cytochrome-C) were lowest in the placebo group (P < 0.01).BMDMSC implantation preserved LV function and alleviated remodeling at post-AMI day 90.

  1. Breast cancer stem cells, cytokine networks, and the tumor microenvironment

    National Research Council Canada - National Science Library

    Korkaya, Hasan; Liu, Suling; Wicha, Max S

    2011-01-01

    .... These cancer stem cells (CSCs) are regulated by complex interactions with the components of the tumor microenvironment - including mesenchymal stem cells, adipocytes, tumor associated fibroblasts, endothelial cells, and immune...

  2. Backhaul-Aware Interference Management in the Uplink of Wireless Small Cell Networks

    OpenAIRE

    Samarakoon, Sumudu; Bennis, Mehdi; Saad, Walid; Latva-Aho, Matti

    2013-01-01

    The design of distributed mechanisms for interference management is one of the key challenges in emerging wireless small cell networks whose backhaul is capacity limited and heterogeneous (wired, wireless and a mix thereof). In this paper, a novel, backhaul-aware approach to interference management in wireless small cell networks is proposed. The proposed approach enables macrocell user equipments (MUEs) to optimize their uplink performance, by exploiting the presence of neighboring small cel...

  3. In vitro membrane reconstitution of the T cell receptor proximal signaling network

    OpenAIRE

    Hui, Enfu; Vale, Ronald D.

    2014-01-01

    T-cell receptor (TCR) phosphorylation is controlled by a complex network that includes Lck, a Src family kinase (SFK), the tyrosine phosphatase CD45, and the Lck-inhibitory kinase Csk. How these competing phosphorylation and dephosphorylation reactions are modulated to produce T-cell triggering is not fully understood. Here we reconstituted this signaling network using purified enzymes on liposomes, recapitulating the membrane environment in which they normally interact. We demonstrate that L...

  4. A Terrestrial Microbial Fuel Cell for Powering a Single-Hop Wireless Sensor Network

    OpenAIRE

    Daxing Zhang; Yingmin Zhu; Witold Pedrycz; Yongxian Guo

    2016-01-01

    Microbial fuel cells (MFCs) are envisioned as one of the most promising alternative renewable energy sources because they can generate electric current continuously while treating waste. Terrestrial Microbial Fuel Cells (TMFCs) can be inoculated and work on the use of soil, which further extends the application areas of MFCs. Energy supply, as a primary influential factor determining the lifetime of Wireless Sensor Network (WSN) nodes, remains an open challenge in sensor networks. In theory, ...

  5. [Research progress of myocardial tissue engineering scaffold materials].

    Science.gov (United States)

    Fang, Yibing; Liao, Bin

    2011-03-01

    To review the current status and problems in the developing scaffolds for the myocardial tissue engineering application. The literature concerning the myocardial tissue engineering scaffold in recent years was reviewed extensively and summarized. As one of three elements for tissue engineering, a proper scaffold is very important for the proliferation and differentiation of the seeding cells. The naturally derived and synthetic extracellular matrix (ECM) materials aim to closely resemble the in vivo microenvironment by acting as an active component of the developing tissue construct in myocardial tissue engineering. With the advent and continuous refinement of cell removal techniques, a new class of native ECM has emerged with some striking advantages. Through using the principle of composite scaffold, computers and other high-technology nano-polymer technology, surface modification of traditional biological materials in myocardial tissue engineering are expected to provide ideal myocardial scaffolds.

  6. Stromal Cell Networks Regulate Lymphocyte Entry, Migration, and Territoriality in Lymph Nodes

    Science.gov (United States)

    Bajénoff, Marc; Egen, Jackson; Koo, Lily Y.; Laugier, Jean Pierre; Brau, Frédéric; Glaichenhaus, Nicolas; Germain, Ronald N.

    2009-01-01

    Summary Following entry into lymph nodes (LNs), B cells migrate to follicles, whereas T cells remain in the paracortex, with each lymphocyte type showing apparently random migration within these distinct areas. Other than chemokines, the factors contributing to this spatial segregation and to the observed patterns of lymphocyte movement are poorly characterized. By combining confocal, electron, and intravital microscopy, we show here that the fibroblastic reticular cell (FRC) network regulates naïve T cell access to the paracortex and also supports and defines the limits of T cell movement within this domain, whereas a distinct follicular dendritic cell (FDC) network similarly serves as the substratum for movement of follicular B cells. These results highlight the central role of stromal microanatomy in orchestrating cell migration within the LN. PMID:17112751

  7. Providing optimal regional care for ST-segment elevation myocardial infarction: a prospective cohort study of patients in the Hamilton Niagara Haldimand Brant Local Health Integration Network.

    Science.gov (United States)

    Mercuri, Mathew; Welsford, Michelle; Schwalm, Jon-David; Mehta, Shamir R; Rao-Melacini, Purnima; Sheth, Tej; Rokoss, Michael; Jolly, Sanjit S; Velianou, James L; Natarajan, Madhu K

    2015-01-01

    Although considered the evidence-based best therapy for ST-segment elevation myocardial infarction (STEMI), many patients do not receive primary percutaneous coronary intervention (PCI) because of health care resource distribution and constraints. This study describes the clinical management and outcomes of all patients identified with STEMI within a region, including those who did not receive primary PCI. This study used a prospective cohort design. Patients presenting with STEMI to PCI- and non-PCI-capable hospitals in one integrated health region in Ontario were included in the study. The primary objective was to examine use of reperfusion strategies and timeliness of care. Secondary objectives included determining (through regression models) which variables were associated with mortality within 90 days, and describing patient uptake of risk-reducing therapies and activities post-STEMI. Between Apr. 1, 2010, and Mar. 31, 2013, data were collected on 2247 consecutive patients presenting with STEMI. Patients presenting to the PCI-capable hospital were more likely to receive primary PCI (82.5% v. 65.2%, p < 0.001) and be treated within optimal treatment times. However, there was no appreciable difference in mortality at 90 days post-STEMI between patients presenting to PCI- and non-PCI-capable hospitals (7.8% v. 7.5%, p = 0.82), even after adjustment for acuity on presentation. Despite recognized risk factors, many patients were not taking evidence-based medications for risk factor modification before STEMI. A systematic approach to regional STEMI care focusing on timely access to the best available therapies, rather than the type of reperfusion provided alone, can yield favourable outcomes.

  8. An Experimental Study of Advanced Receivers in a Practical Dense Small Cells Network

    DEFF Research Database (Denmark)

    Assefa, Dereje; Berardinelli, Gilberto; Tavares, Fernando Menezes Leitão

    2016-01-01

    been obtained using a software defined radio (SDR) testbed network with 12 testbed nodes, configured as either access point or user equipment. Each node features a 4 X 4$ or a 2 X 2 MIMO configuration. The results demonstrate that advanced receivers with a larger MIMO antenna configuration...... leads to significant limitations on the network throughput in such deployments. In addition, network densification introduces difficulty in network deployment. This paper presents a study on the benefits of advanced receiver in a practical uncoordinated dense small cells deployment. Our aim is to show...... that advanced receivers can alleviate the need for detailed cell planning. To this end we adopt a hybrid simulation evaluation approach where propagation data are obtained from experimental analysis, and by which we analyse how MIMO constellation and network size impacts to the aim. The experimental data have...

  9. Sparse Regression Based Structure Learning of Stochastic Reaction Networks from Single Cell Snapshot Time Series.

    Directory of Open Access Journals (Sweden)

    Anna Klimovskaia

    2016-12-01

    Full Text Available Stochastic chemical reaction networks constitute a model class to quantitatively describe dynamics and cell-to-cell variability in biological systems. The topology of these networks typically is only partially characterized due to experimental limitations. Current approaches for refining network topology are based on the explicit enumeration of alternative topologies and are therefore restricted to small problem instances with almost complete knowledge. We propose the reactionet lasso, a computational procedure that derives a stepwise sparse regression approach on the basis of the Chemical Master Equation, enabling large-scale structure learning for reaction networks by implicitly accounting for billions of topology variants. We have assessed the structure learning capabilities of the reactionet lasso on synthetic data for the complete TRAIL induced apoptosis signaling cascade comprising 70 reactions. We find that the reactionet lasso is able to efficiently recover the structure of these reaction systems, ab initio, with high sensitivity and specificity. With only 6000 possible reactions and over 102000 network topologies. In conjunction with information rich single cell technologies such as single cell RNA sequencing or mass cytometry, the reactionet lasso will enable large-scale structure learning, particularly in areas with partial network structure knowledge, such as cancer biology, and thereby enable the detection of pathological alterations of reaction networks. We provide software to allow for wide applicability of the reactionet lasso.

  10. Long-term effectiveness of early administration of glycoprotein IIb/IIIa agents to real-world patients undergoing primary percutaneous interventions: results of a registry study in an ST-elevation myocardial infarction network.

    Science.gov (United States)

    Ortolani, Paolo; Marzocchi, Antonio; Marrozzini, Cinzia; Palmerini, Tullio; Saia, Francesco; Taglieri, Nevio; Baldazzi, Federica; Dall'Ara, Gianni; Nardini, Paola; Gianstefani, Silvia; Guastaroba, Paolo; Grilli, Roberto; Branzi, Angelo

    2009-01-01

    To evaluate the clinical impact of early administration of glycoprotein IIb/IIIa agents (IIb/IIIa agents) in the context of a dedicated hub and spoke network allowing very prompt pharmacological/mechanical interventions. Using a prospective database, we conducted a cohort study of ST-elevation myocardial infarction (STEMI) patients (n = 1124) undergoing primary percutaneous coronary interventions (PPCIs) and IIb/IIIa agents administration (period, 2003-2006). Comparisons were planned between patients receiving early IIb/IIIa agents administration (in hub/spoke centre emergency departments or during ambulance transfer; early group, n = 380) or delayed administration (in the catheterization laboratory; late group, n = 744). The primary outcome measure was long-term overall mortality/re-infarction. Baseline characteristics of the two groups were largely comparable. Angiographically, early group patients more often achieved pre-PPCI TIMI Grade 2-3 and TIMI Grade 3 flow. Clinically, the early administration group experienced lower 2-year risk of unadjusted mortality/re-infarction (17 vs. 23%; P = 0.01). After adjustment for potential confounders, early administration was associated with favourable outcome in the overall population (HR = 0.71, P = 0.03) and in high-risk subgroups (TIMI risk index >25, HR = 0.64, P = 0.02; Killip class >1, HR = 0.54, P = 0.01). In patients treated by PPCI within a STEMI network setting, early administration of IIb/IIIa agents may provide long-term clinical benefits. Notably, these results appeared magnified in high-risk patients.

  11. Injection of composite with bone marrow-derived mesenchymal stem cells and a novel synthetic hydrogel after myocardial infarction: A protective role in left ventricle function

    Directory of Open Access Journals (Sweden)

    Jinling Chen

    2014-04-01

    Full Text Available A number of studies have shown that the transplantation of bone marrow-derived mesenchymal stem cells (BMSCs into the thinned infarct wall improves regional wall motion. In this study, we hypothesized that the injection of biomaterials and MSCs into the infarcted myocardium can preserve left ventricular (LV function. To test this hypothesis, anterior acute myocardial infarction (AMI was induced in 34 rabbits and BMSCs with hydrogel composite were prepared. One week after inducing AMI, 28 of the 34 rabbits were divided into four groups (Groups A–D; three rabbits were used for bone marrow aspiration, and three rabbits died and all received an epicardial injection. Group A received BMSCs with hydrogel composite marked by 5-bromodeoxyuridine (BrdU; Group B received BMSCs only marked by BrdU; Group C received hydrogel only marked by BrdU; and Group D was the control group, which received fetal bovine serum. Echocardiography was performed before AMI was induced, 1 week after AMI, and 4 weeks after the epicardial injection. The results were compared with those before AMI, and the rabbits of all the four groups had significantly larger LV end-diastolic diameter (LVDd, thinner anterior wall (AW, lower LV ejection fraction (LVEF, lower VS and VE (p<0.05 1 week after AMI, which were more significant in Group A (p<0.05. Compared with 1 week after AMI, Group A and Group B had significantly smaller LVDd, thicker AW, larger LVEF, larger VS and VE (p<0.05 4 weeks after the epicardial injection, which were more significant in Group A (p<0.05; however, there was no significant difference in Group C and Group D. These results suggested that BMSCs with hydrogel composite could serve as an injectable biomaterial that prevents LV remodeling and dilation, and improves local systolic and diastolic function after AMI.

  12. Autologous bone marrow cell implantation attenuates left ventricular remodeling and improves heart function in porcine myocardial infarction: an echocardiographic, six-month angiographic, and molecular-cellular study.

    Science.gov (United States)

    Leu, Steve; Sun, Cheuk-Kwan; Sheu, Jiunn-Jye; Chang, Li-Teh; Yuen, Chun-Man; Yen, Chia-Hung; Chiang, Chiang-Hua; Ko, Sheung-Fat; Pei, Sung-Nan; Chua, Sarah; Youssef, Ali A; Wu, Chiung-Jen; Yip, Hon-Kan

    2011-07-15

    We investigated the potential benefits and the underlying mechanisms of autologous bone marrow-derived mononuclear cell (BMDMNC) implantation in a porcine model of acute anterior wall myocardial infarction (AAWMI) by studying 6-month left ventricular (LV) function and LV remodeling. After being aspirated from the iliac crest and cultured for 1 week, BMDMNCs were implanted immediately after AAWMI induction through the left anterior descending artery ligation. Thirty male mini-pigs (16-18 kg) were equally divided into group 1 [AAWMI plus saline injection into infarct-ischemia area (IA)], group 2 (AAWMI plus 3.0 × 10⁷ BMDMNC transplantation into non-IA), group 3 (AAWMI plus 3.0 × 10⁷ BMDMNC transplantation into IA), group 4 (sham control plus 3.0 × 10⁷ BMDMNC transplantation into LV myocardium), and group 5 (normal control). By day 90, echocardiography demonstrated an increased LV end-diastolic and end-systolic dimensions but reduced LV ejection fraction (LVEF) in groups 1 and 2 than in other groups (all p infarct area, the number of small vessels and mRNA expressions of endothelial nitric oxide synthase, Bcl-2, interleukin (IL)-10, and peroxisome proliferator-activated receptor-γ coactivator-1α were lower, whereas the number of apoptotic nuclei, caspase-3, Bax, endothelin-1, IL-8, and matrix metalloproteinase was higher in groups 1 and 2 than in other groups (all p < 0.01). Autologous BMDMNC transplantation into IA rather non-IA improves LV function and reduces LV remodeling via eliciting a broad-spectrum of molecular-cellular defensive mechanisms. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  13. Three dimensional fusion of electromechanical mapping and magnetic resonance imaging for real-time navigation of intramyocardial cell injections in a porcine model of chronic myocardial infarction.

    Science.gov (United States)

    van Slochteren, F J; van Es, R; Gyöngyösi, M; van der Spoel, T I G; Koudstaal, S; Leiner, T; Doevendans, P A; Chamuleau, S A J

    2016-05-01

    For cardiac regenerative therapy intramyocardial catheter guided cell transplantations are targeted to the infarct border zone (IBZ) i.e. the closest region of viable myocardium in the vicinity of the infarct area. For optimal therapeutic effect this area should be accurately identified. However late gadolinium enhanced magnetic resonance imaging (LGE-MRI) is the gold standard technique to determine the infarct size and location, electromechanical mapping (EMM) is used to guide percutaneous intramyocardial injections to the IBZ. Since EMM has a low spatial resolution, we aim to develop a practical and accurate technique to fuse EMM with LGE-MRI to guide intramyocardial injections. LGE-MRI and EMM were obtained in 17 pigs with chronic myocardial infarction created by balloon occlusion of LCX and LAD coronary arteries. LGE-MRI and EMM datasets were registered using our in-house developed 3D CartBox image registration software toolbox to assess: (1) the feasibility of the 3D CartBox toolbox, (2) the EMM values measured in the areas with a distinct infarct transmurality (IT), and (3) the highest sensitivity and specificity of the EMM to assess IT and define the IBZ. Registration of LGE-MRI and EMM resulted in a mean error of 3.01 ± 1.94 mm between the LGE-MRI mesh and EMM points. The highest sensitivity and specificity were found for UV <9.4 mV and bipolar voltage <1.2 mV to respectively identify IT of ≥5 and ≥97.5 %. The 3D CartBox image registration toolbox enables registration of EMM data on pre-acquired MRI during the EMM guided procedure and allows physicians to easily guide injections to the most optimal injection location for cardiac regenerative therapy and harness the full therapeutic effect of the therapy.

  14. Sensorimotor Functional and Structural Networks after Intracerebral Stem Cell Grafts in the Ischemic Mouse Brain.

    Science.gov (United States)

    Green, Claudia; Minassian, Anuka; Vogel, Stefanie; Diedenhofen, Michael; Beyrau, Andreas; Wiedermann, Dirk; Hoehn, Mathias

    2018-02-14

    Past investigations on stem cell-mediated recovery after stroke have limited their focus on the extent and morphological development of the ischemic lesion itself over time or on the integration capacity of the stem cell graft ex vivo However, an assessment of the long-term functional and structural improvement in vivo is essential to reliably quantify the regenerative capacity of cell implantation after stroke. We induced ischemic stroke in nude mice and implanted human neural stem cells (H9 derived) into the ipsilateral cortex in the acute phase. Functional and structural connectivity changes of the sensorimotor network were noninvasively monitored using magnetic resonance imaging for 3 months after stem cell implantation. A sharp decrease of the functional sensorimotor network extended even to the contralateral hemisphere, persisting for the whole 12 weeks of observation. In mice with stem cell implantation, functional networks were stabilized early on, pointing to a paracrine effect as an early supportive mechanism of the graft. This stabilization required the persistent vitality of the stem cells, monitored by bioluminescence imaging. Thus, we also observed deterioration of the early network stabilization upon vitality loss of the graft after a few weeks. Structural connectivity analysis showed fiber-density increases between the cortex and white matter regions occurring predominantly on the ischemic hemisphere. These fiber-density changes were nearly the same for both study groups. This motivated us to hypothesize that the stem cells can influence, via early paracrine effect, the functional networks, while observed structural changes are mainly stimulated by the ischemic event. SIGNIFICANCE STATEMENT In recent years, research on strokes has made a shift away from a focus on immediate ischemic effects and towards an emphasis on the long-range effects of the lesion on the whole brain. Outcome improvements in stem cell therapies also require the understanding of

  15. Design Principles of Regulatory Networks: Searching for the Molecular Algorithms of the Cell

    Science.gov (United States)

    Lim, Wendell A.; Lee, Connie M.; Tang, Chao

    2013-01-01

    A challenge in biology is to understand how complex molecular networks in the cell execute sophisticated regulatory functions. Here we explore the idea that there are common and general principles that link network structures to biological functions, principles that constrain the design solutions that evolution can converge upon for accomplishing a given cellular task. We describe approaches for classifying networks based on abstract architectures and functions, rather than on the specific molecular components of the networks. For any common regulatory task, can we define the space of all possible molecular solutions? Such inverse approaches might ultimately allow the assembly of a design table of core molecular algorithms that could serve as a guide for building synthetic networks and modulating disease networks. PMID:23352241

  16. Pore Network Modeling of Multiphase Transport in Polymer Electrolyte Membrane Fuel Cell Gas Diffusion Layers

    Science.gov (United States)

    Fazeli, Mohammadreza

    In this thesis, pore network modeling was used to study how the microstructure of the polymer electrolyte membrane (PEM) fuel cell gas diffusion layer (GDL) influences multiphase transport within the composite layer. An equivalent pore network of a GDL was used to study the effects of GDL/catalyst layer condensation points and contact quality on the spatial distribution of liquid water in the GDL. Next, pore networks extracted from synchrotron-based micro-computed tomography images of compressed GDLs were employed to simulate liquid water transport in GDL materials over a range of compression pressures, and favorable GDL compression values for preferred liquid water distributions were found for two commercially available GDL materials. Finally, a technique was developed for calculating the oxygen diffusivity in carbon paper substrates with a microporous layer (MPL) coating through pore network modeling. A hybrid network was incorporated into the pore network model, and effective diffusivity predictions of MPL coated GDL materials were obtained.

  17. Design principles of regulatory networks: searching for the molecular algorithms of the cell.

    Science.gov (United States)

    Lim, Wendell A; Lee, Connie M; Tang, Chao

    2013-01-24

    A challenge in biology is to understand how complex molecular networks in the cell execute sophisticated regulatory functions. Here we explore the idea that there are common and general principles that link network structures to biological functions, principles that constrain the design solutions that evolution can converge upon for accomplishing a given cellular task. We describe approaches for classifying networks based on abstract architectures and functions, rather than on the specific molecular components of the networks. For any common regulatory task, can we define the space of all possible molecular solutions? Such inverse approaches might ultimately allow the assembly of a design table of core molecular algorithms that could serve as a guide for building synthetic networks and modulating disease networks. Copyright © 2013 Elsevier Inc. All rights reserved.

  18. A Network Model to Describe the Terminal Differentiation of B Cells.

    Directory of Open Access Journals (Sweden)

    Akram Méndez

    2016-01-01

    Full Text Available Terminal differentiation of B cells is an essential process for the humoral immune response in vertebrates and is achieved by the concerted action of several transcription factors in response to antigen recognition and extracellular signals provided by T-helper cells. While there is a wealth of experimental data regarding the molecular and cellular signals involved in this process, there is no general consensus regarding the structure and dynamical properties of the underlying regulatory network controlling this process. We developed a dynamical model of the regulatory network controlling terminal differentiation of B cells. The structure of the network was inferred from experimental data available in the literature, and its dynamical behavior was analyzed by modeling the network both as a discrete and a continuous dynamical systems. The steady states of these models are consistent with the patterns of activation reported for the Naive, GC, Mem, and PC cell types. Moreover, the models are able to describe the patterns of differentiation from the precursor Naive to any of the GC, Mem, or PC cell types in response to a specific set of extracellular signals. We simulated all possible single loss- and gain-of-function mutants, corroborating the importance of Pax5, Bcl6, Bach2, Irf4, and Blimp1 as key regulators of B cell differentiation process. The model is able to represent the directional nature of terminal B cell differentiation and qualitatively describes key differentiation events from a precursor cell to terminally differentiated B cells.

  19. Chromatin states modify network motifs contributing to cell-specific functions

    Science.gov (United States)

    Zhao, Hongying; Liu, Tingting; Liu, Ling; Zhang, Guanxiong; Pang, Lin; Yu, Fulong; Fan, Huihui; Ping, Yanyan; Wang, Li; Xu, Chaohan; Xiao, Yun; Li, Xia

    2015-01-01

    Epigenetic modification can affect many important biological processes, such as cell proliferation and apoptosis. It can alter chromatin conformation and contribute to gene regulation. To investigate how chromatin states associated with network motifs, we assembled chromatin state-modified regulatory networks by combining 269 ChIP-seq data and chromatin states in four cell types. We found that many chromatin states were significantly associated with network motifs, especially for feedforward loops (FFLs). These distinct chromatin state compositions contribute to different expression levels and translational control of targets in FFLs. Strikingly, the chromatin state-modified FFLs were highly cell-specific and, to a large extent, determined cell-selective functions, such as the embryonic stem cell-specific bivalent modification-related FFL with an important role in poising developmentally important genes for expression. Besides, comparisons of chromatin state-modified FFLs between cancerous/stem and primary cell lines revealed specific type of chromatin state alterations that may act together with motif structural changes cooperatively contribute to cell-to-cell functional differences. Combination of these alterations could be helpful in prioritizing candidate genes. Together, this work highlights that a dynamic epigenetic dimension can help network motifs to control cell-specific functions. PMID:26169043

  20. Plasma-derived extracellular vesicles contain predictive biomarkers and potential therapeutic targets for Myocardial Ischemic (MI) injury

    NARCIS (Netherlands)

    Cheow, Esther Sok Hwee; Cheng, Woo Chin; Lee, Chuen Neng; De Kleijn, Dominique; Sorokin, Vitaly; Sze, Siu Kwan

    2016-01-01

    Myocardial infarction (MI) triggers a potent inflammatory response via the release of circulatory mediators, including extracellular vesicles (EVs) by damaged cardiac cells, necessary for myocardial healing. Timely repression of inflammatory response are critical to prevent and minimize cardiac

  1. LGN Directs Interphase Endothelial Cell Behavior via the Microtubule Network.

    Directory of Open Access Journals (Sweden)

    Catherine E Wright

    Full Text Available Angiogenic sprouts require coordination of endothelial cell (EC behaviors as they extend and branch. Microtubules influence behaviors such as cell migration and cell-cell interactions via regulated growth and shrinkage. Here we investigated the role of the mitotic polarity protein LGN in EC behaviors and sprouting angiogenesis. Surprisingly, reduced levels of LGN did not affect oriented division of EC within a sprout, but knockdown perturbed overall sprouting. At the cell level, LGN knockdown compromised cell-cell adhesion and migration. EC with reduced LGN levels also showed enhanced growth and stabilization of microtubules that correlated with perturbed migration. These results fit a model whereby LGN influences interphase microtubule dynamics in endothelial cells to regulate migration, cell adhesion, and sprout extension, and reveal a novel non-mitotic role for LGN in sprouting angiogenesis.

  2. Robust organizational principles of protrusive biopolymer networks in migrating living cells.

    Directory of Open Access Journals (Sweden)

    Björn Stuhrmann

    Full Text Available Cell migration is associated with the dynamic protrusion of a thin actin-based cytoskeletal extension at the cell front, which has been shown to consist of two different substructures, the leading lamellipodium and the subsequent lamellum. While the formation of the lamellipodium is increasingly well understood, organizational principles underlying the emergence of the lamellum are just beginning to be unraveled. We report here on a 1D mathematical model which describes the reaction-diffusion processes of a polarized actin network in steady state, and reproduces essential characteristics of the lamellipodium-lamellum system. We observe a steep gradient in filament lengths at the protruding edge, a local depolymerization maximum a few microns behind the edge, as well as a differential dominance of the network destabilizer ADF/cofilin and the stabilizer tropomyosin. We identify simple and robust organizational principles giving rise to the derived network characteristics, uncoupled from the specifics of any molecular implementation, and thus plausibly valid across cell types. An analysis of network length dependence on physico-chemical system parameters implies that to limit array treadmilling to cellular dimensions, network growth has to be truncated by mechanisms other than aging-induced depolymerization, e.g., by myosin-associated network dissociation at the transition to the cell body. Our work contributes to the analytical understanding of the cytoskeletal extension's bisection into lamellipodium and lamellum and sheds light on how cells organize their molecular machinery to achieve motility.

  3. Shape-dependent control of cell growth, differentiation, and apoptosis: switching between attractors in cell regulatory networks

    Science.gov (United States)

    Huang, S.; Ingber, D. E.

    2000-01-01

    Development of characteristic tissue patterns requires that individual cells be switched locally between different phenotypes or "fates;" while one cell may proliferate, its neighbors may differentiate or die. Recent studies have revealed that local switching between these different gene programs is controlled through interplay between soluble growth factors, insoluble extracellular matrix molecules, and mechanical forces which produce cell shape distortion. Although the precise molecular basis remains unknown, shape-dependent control of cell growth and function appears to be mediated by tension-dependent changes in the actin cytoskeleton. However, the question remains: how can a generalized physical stimulus, such as cell distortion, activate the same set of genes and signaling proteins that are triggered by molecules which bind to specific cell surface receptors. In this article, we use computer simulations based on dynamic Boolean networks to show that the different cell fates that a particular cell can exhibit may represent a preprogrammed set of common end programs or "attractors" which self-organize within the cell's regulatory networks. In this type of dynamic network model of information processing, generalized stimuli (e.g., mechanical forces) and specific molecular cues elicit signals which follow different trajectories, but eventually converge onto one of a small set of common end programs (growth, quiescence, differentiation, apoptosis, etc.). In other words, if cells use this type of information processing system, then control of cell function would involve selection of preexisting (latent) behavioral modes of the cell, rather than instruction by specific binding molecules. Importantly, the results of the computer simulation closely mimic experimental data obtained with living endothelial cells. The major implication of this finding is that current methods used for analysis of cell function that rely on characterization of linear signaling pathways or

  4. The Athena trials: Autologous adipose-derived regenerative cells for refractory chronic myocardial ischemia with left ventricular dysfunction.

    Science.gov (United States)

    Henry, Timothy D; Pepine, Carl J; Lambert, Charles R; Traverse, Jay H; Schatz, Richard; Costa, Marco; Povsic, Thomas J; David Anderson, R; Willerson, James T; Kesten, Steven; Perin, Emerson C

    2017-02-01

    To assess safety and feasibility of autologous adipose-derived regenerative cells (ADRCs), for treatment of chronic ischemic cardiomyopathy patients. Preclinical and early clinical trials suggest ADRCs have excellent potential for ischemic conditions. The Athena program consisted of two parallel, prospective, randomized (2:1, active: placebo), double-blind trials assessing intramyocardial (IM) ADRC delivery [40-million, n = 28 (ATHENA) and 80-million (ATHENA II) cells, n = 3]). Patients with an EF ≥20% but ≤45%, multivessel coronary artery disease (CAD) not amenable to revascularization, inducible ischemia, and symptoms of either angina (CCS II-IV) or heart failure (NYHA Class II-III) on maximal medical therapy were enrolled. All patients underwent fat harvest procedure (≤450 mL adipose), on-site cell processing (Celution® System, Cytori Therapeutics), electromechanical mapping, and IM delivery of ADRCs or placebo. Enrollment was terminated prematurely due to non-ADRC-related adverse events and subsequent prolonged enrollment time. Thirty-one patients (17-ADRCs, 14-placebo) mean age 65 ± 8 years, baseline LVEF(%) 31.1 ± 8.7 (ADRC), 31.8 ± 7.7 (placebo) were enrolled. Change in V0 2 max favored ADRCs (+45.4 ± 222 vs. -9.5 ± 137 mL/min) but there was no difference in left ventricular function or volumes. At 12-months, heart failure hospitalizations occurred in 2/17 (11.7%) [ADRC] and 3/14 (21.4%) [placebo]. Differences in NYHA and CCS classes favored ADRCs at 12-months with significant improvement in MLHFQ (-21.6 + 13.9 vs. -5.5 + 23.8, P = 0.038). A small volume fat harvest, automated local processing, and IM delivery of autologous ADRCs is feasible with suggestion of benefit in "no option" CAD patients. Although the sample size is limited, the findings support feasibility and scalability for treatment of ischemic cardiomyopathy with ADRCs. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  5. Low Modulus Silicone Elastomer Networks with Desirable Viscoelastic Properties for Cell Mobility Studies

    Science.gov (United States)

    Albert, Julie N. L.; Genzer, Jan

    2013-03-01

    Biocompatible silicone elastomer networks provide a versatile platform for studying the effect of compliance on cell movement. In conventional network formation schemes, poly(dimethylsiloxane) (PDMS) is cross-linked via reactive end groups, and the modulus of the material is controlled by the ratio of polymer to cross-linker. However, low modulus networks fabricated in this manner are imperfect and insufficiently cross-linked with high soluble fractions and reduced elasticity, especially as the network modulus approaches that of soft tissues (on the order of 10 kPa). In order to overcome these limitations, we synthesized PDMS chains in which vinylmethylsiloxane units were incorporated every ~15-20 kDa along the polymer backbone. We then cross-linked the polymer through the vinyl groups using hydrosilylation chemistry. The resultant networks exhibited lower soluble fractions and lower viscous dissipation/greater elasticity as compared to equivalent-modulus networks fabricated by the conventional end-group cross-linking scheme. We attribute the mechanical properties of our networks to the presence of network-bound free chain ends that effectively plasticize the network to lower the modulus without compromising network elasticity.

  6. Comprehensive Mapping of Pluripotent Stem Cell Metabolism Using Dynamic Genome-Scale Network Modeling

    Directory of Open Access Journals (Sweden)

    Sriram Chandrasekaran

    2017-12-01

    Full Text Available Summary: Metabolism is an emerging stem cell hallmark tied to cell fate, pluripotency, and self-renewal, yet systems-level understanding of stem cell metabolism has been limited by the lack of genome-scale network models. Here, we develop a systems approach to integrate time-course metabolomics data with a computational model of metabolism to analyze the metabolic state of naive and primed murine pluripotent stem cells. Using this approach, we find that one-carbon metabolism involving phosphoglycerate dehydrogenase, folate synthesis, and nucleotide synthesis is a key pathway that differs between the two states, resulting in differential sensitivity to anti-folates. The model also predicts that the pluripotency factor Lin28 regulates this one-carbon metabolic pathway, which we validate using metabolomics data from Lin28-deficient cells. Moreover, we identify and validate metabolic reactions related to S-adenosyl-methionine production that can differentially impact histone methylation in naive and primed cells. Our network-based approach provides a framework for characterizing metabolic changes influencing pluripotency and cell fate. : Chandrasekaran et al. use computational modeling, metabolomics, and metabolic inhibitors to discover metabolic differences between various pluripotent stem cell states and infer their impact on stem cell fate decisions. Keywords: systems biology, stem cell biology, metabolism, genome-scale modeling, pluripotency, histone methylation, naive (ground state, primed state, cell fate, metabolic network

  7. Quantitative studies of subdiffusion in living cells and actin networks

    DEFF Research Database (Denmark)

    Munteanu, Emilia-Laura; Olsen, Anja Lea; Tolic-Nørrelykke, Iva Marija

    2006-01-01

    of optical tweezers data, primarily baed on the power spectra of time series of postions for trapped spherical objects. The majority of precise studies in the literature are performed on in vitro systems, whereas in the present work, an example of an in vivo system is presented for which precise power...... spectral analysis is both useful and necessary. The biological system is the cytoplasm of fission yeast, S. pombe, in which we observe subdiffusion of lipid granuli. in a search for the cause of subdiffusion, we chemically disrupt the actin network in the cytoplasm and further consider in vitro networks...

  8. A system mathematical model of a cell-cell communication network in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Shao, Hongwei; He, Ying; Li, King C P; Zhou, Xiaobo

    2013-03-01

    Amyotrophic lateral sclerosis (ALS) is a devastating and chronic neurodegenerative disease without any known cure. In the brain and spinal cord of both patients and animal models with ALS, neuroinflammation is a prominent pathological hallmark which is characterized by infiltrating T cells at sites of motor neuron injury. Their presence in mutant Cu(2+)/Zn(2+) superoxide dismutase (mSOD1) induced ALS plays an important role in shifting the response of microglia from neuroprotective to neurotoxic. In order to better understand how these cells and their communication network collectively modulate the disease progression, we have established a mathematical model integrating diverse cells and cytokines. According to the experimental data sets, we first refined this model by identifying a link between TGFβ and M1 microglia which can produce an optimized model to fit data sets better. Then based on this model, parameters were estimated using genetic algorithm. Sensitivity analysis of these parameters identified several factors such as the release rate of IFNγ by T helper 1 (Th1) cells, which may be related to the heterogeneity between the patients with different survival times. Furthermore, the tests on T cell based therapeutic strategies indicated that elimination of Th1 cells is the most effective approach extending survival time. This confirmed the dominant role of Th1 cells in leading the rapid disorder in the later stage of ALS. For the therapies targeting cytokines, injection of IL6 can essentially augment the neuroprotective response and extend the life effectively by elevating the level of IL4, a neuroprotective cytokine, while directly injected IL4 will decay rapidly in the ALS microenvironment and cannot provide a persistent protective effect. On the other hand, in spite of the attractive effect of direct elimination of mSOD1 or self-antigen, it is difficult to implement in CNS. As an alternative, elimination of IFNγ can be chosen as another effective

  9. c-kit positive cells and networks in tooth germs of human midterm fetuses.

    Science.gov (United States)

    Didilescu, Andreea Cristiana; Pop, Florinel; Rusu, Mugurel Constantin

    2013-12-01

    Numerous studies have attempted to characterize the dental pulp stem cells. However, studies performed on prenatal human tissues have not been performed to evaluate the in situ characterization and topography of progenitor cells. We aimed to perform such a study using of antibodies for CD117/c-kit and multiplex antibody for Ki67+ caspase 3. Antibodies were applied on samples dissected from five human midterm fetuses. Positive CD117/c-kit labeling was found in mesenchymal derived tissues, such as the dental follicle and the dental papilla. The epithelial tissues, that is, dental lamina, enamel organ and oral epithelia, also displayed isolated progenitor cells which were CD117/c-kit positive. Interestingly, CD117/c-kit positive cells of mesenchymal derived tissues extended multiple prolongations building networks; the most consistent of such networks were those of the dental follicle and the perivascular networks of the dental papilla. However, the mantle of the dental papilla was also positive for CD117/c-kit positive stromal networks. The CD117/c-kit cell populations building networks appeared mostly with a Ki67 negative phenotype. The results suggest that CD117/c-kit progenitor cells of the prenatal tooth germ tissues might be involved in intercellular signaling. Copyright © 2013 Elsevier GmbH. All rights reserved.

  10. Dynamic assembly of ultrasoft colloidal networks enables cell invasion within restrictive fibrillar polymers

    Science.gov (United States)

    Douglas, Alison M.; Fragkopoulos, Alexandros A.; Gaines, Michelle K.; Lyon, L. Andrew; Fernandez-Nieves, Alberto; Barker, Thomas H.

    2017-01-01

    In regenerative medicine, natural protein-based polymers offer enhanced endogenous bioactivity and potential for seamless integration with tissue, yet form weak hydrogels that lack the physical robustness required for surgical manipulation, making them difficult to apply in practice. The use of higher concentrations of protein, exogenous cross-linkers, and blending synthetic polymers has all been applied to form more mechanically robust networks. Each relies on generating a smaller network mesh size, which increases the elastic modulus and robustness, but critically inhibits cell spreading and migration, hampering tissue regeneration. Here we report two unique observations; first, that colloidal suspensions, at sufficiently high volume fraction (ϕ), dynamically assemble into a fully percolated 3D network within high-concentration protein polymers. Second, cells appear capable of leveraging these unique domains for highly efficient cell migration throughout the composite construct. In contrast to porogens, the particles in our system remain embedded within the bulk polymer, creating a network of particle-filled tunnels. Whereas this would normally physically restrict cell motility, when the particulate network is created using ultralow cross-linked microgels, the colloidal suspension displays viscous behavior on the same timescale as cell spreading and migration and thus enables efficient cell infiltration of the construct through the colloidal-filled tunnels.

  11. Application of metal nanowire networks on hydrogenated amorphous silicon thin film solar cells

    Science.gov (United States)

    Xie, Shouyi; Hou, Guofu; Chen, Peizhuan; Jia, Baohua; Gu, Min

    2017-02-01

    We demonstrate the application of metal nanowire (NW) networks as a transparent electrode on hydrogenated amorphous Si (a-Si:H) solar cells. We first systematically investigate the optical performances of the metal NW networks on a-Si:H solar cells in different electrode configurations through numerical simulations to fully understand the mechanisms to guide the experiments. The theoretically optimized configuration is discovered to be metal NWs sandwiched between a 40 nm indium tin oxide (ITO) layer and a 20 nm ITO layer. The overall performances of the solar cells integrated with the metal NW networks are experimentally studied. It has been found the experimentally best performing NW integrated solar cell deviates from the theoretically predicated design due to the performance degradation induced by the fabrication complicity. A 6.7% efficiency enhancement was achieved for the solar cell with metal NW network integrated on top of a 60 nm thick ITO layer compared to the cell with only the ITO layer due to enhanced electrical conductivity by the metal NW network.

  12. Pattern formation in B-cell immune networks : Domains and dots in shape-space

    NARCIS (Netherlands)

    Noest, A.J.; Takumi, K.; Boer, R.J. de

    1997-01-01

    The immune system contains many types of B-cells, which can activate each other if the shapes and surface properties of their receptors (or antibodies) match well. The dynamics of the resulting network is analysed using a recently derived B-cell activation function which captures the effects of the

  13. Global phosphoproteome profiling reveals unanticipated networks responsive to cisplatin treatment of embryonic stem cells

    DEFF Research Database (Denmark)

    Pines, Alex; Kelstrup, Christian D; Vrouwe, Mischa G

    2011-01-01

    (stable isotope labeling by amino acids in cell culture)-labeled murine embryonic stem cells with the anticancer drug cisplatin. Network and pathway analyses indicated that processes related to the DNA damage response and cytoskeleton organization were significantly affected. Although the ATM (ataxia...

  14. Gender and age peculiarities of content changes of protein C, von Willebrand factor, vascular cell adhesion molecules sVCAM-1 in patients with acute left ventricle Q-wave myocardial infarction

    Directory of Open Access Journals (Sweden)

    S. M. Kyselov

    2015-04-01

    Full Text Available Markers of hemostasis have an influence on the state of postinfarction remodeling processes. Aim. In order to study the gender and age peculiarities, to determine the predictive value of the protein C, von Willebrand factor and vascular cell adhesion molecules sVCAM-1 concentration, we examined 76 patients with acute Q-wave myocardial infarction. Methods and results. On the 1st day of the disease, higher concentrations of protein C were detected in young women, vascular cell adhesion molecules sVCAM-1 - in men of any age. On the 10th day of the disease, both in men and women increase in the content of protein C, reducing the concentration of von Willebrand factor and vascular cell adhesion molecules sVCAM-1 were detected. Conclusion. Protein C has the highest prognostic potential in relation to the formation of heart aneurysm after Q-wave myocardial infarction in women of young age, and von Willebrand factor and vascular cell adhesion molecules sVCAM-1 - in older men.

  15. TIME Trial: Effect of Timing of Stem Cell Delivery Following ST-Elevation Myocardial Infarction on the Recovery of Global and Regional Left Ventricular Function: Final 2-Year Analysis.

    Science.gov (United States)

    Traverse, Jay H; Henry, Timothy D; Pepine, Carl J; Willerson, James T; Chugh, Atul; Yang, Phillip C; Zhao, David X M; Ellis, Stephen G; Forder, John R; Perin, Emerson C; Penn, Marc S; Hatzopoulos, Antonis K; Chambers, Jeffrey C; Baran, Kenneth W; Raveendran, Ganesh; Gee, Adrian P; Taylor, Doris A; Moyé, Lem; Ebert, Ray F; Simari, Robert D

    2018-02-02

    The TIME trial (Timing in Myocardial Infarction Evaluation) was the first cell therapy trial sufficiently powered to determine if timing of cell delivery after ST-segment-elevation myocardial infarction affects recovery of left ventricular (LV) function. To report the 2-year clinical and cardiac magnetic resonance imaging results and their modification by microvascular obstruction. TIME was a randomized, double-blind, placebo-controlled trial comparing 150 million bone marrow mononuclear cells versus placebo in 120 patients with anterior ST-segment-elevation myocardial infarctions resulting in LV dysfunction. Primary end points included changes in global (LV ejection fraction) and regional (infarct and border zone) function. Secondary end point