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Sample records for cell msc paradigm

  1. Immunomodulation By Therapeutic Mesenchymal Stromal Cells (MSC) Is Triggered Through Phagocytosis of MSC By Monocytic Cells.

    Science.gov (United States)

    de Witte, Samantha F H; Luk, Franka; Sierra Parraga, Jesus M; Gargesha, Madhu; Merino, Ana; Korevaar, Sander S; Shankar, Anusha S; O'Flynn, Lisa; Elliman, Steve J; Roy, Debashish; Betjes, Michiel G H; Newsome, Philip N; Baan, Carla C; Hoogduijn, Martin J

    2018-04-01

    Mesenchymal stem or stromal cells (MSC) are under investigation as a potential immunotherapy. MSC are usually administered via intravenous infusion, after which they are trapped in the lungs and die and disappear within a day. The fate of MSC after their disappearance from the lungs is unknown and it is unclear how MSC realize their immunomodulatory effects in their short lifespan. We examined immunological mechanisms determining the fate of infused MSC and the immunomodulatory response associated with it. Tracking viable and dead human umbilical cord MSC (ucMSC) in mice using Qtracker beads (contained in viable cells) and Hoechst33342 (staining all cells) revealed that viable ucMSC were present in the lungs immediately after infusion. Twenty-four hours later, the majority of ucMSC were dead and found in the lungs and liver where they were contained in monocytic cells of predominantly non-classical Ly6C low phenotype. Monocytes containing ucMSC were also detected systemically. In vitro experiments confirmed that human CD14 ++ /CD16 - classical monocytes polarized toward a non-classical CD14 ++ CD16 + CD206 + phenotype after phagocytosis of ucMSC and expressed programmed death ligand-1 and IL-10, while TNF-α was reduced. ucMSC-primed monocytes induced Foxp3 + regulatory T cell formation in mixed lymphocyte reactions. These results demonstrate that infused MSC are rapidly phagocytosed by monocytes, which subsequently migrate from the lungs to other body sites. Phagocytosis of ucMSC induces phenotypical and functional changes in monocytes, which subsequently modulate cells of the adaptive immune system. It can be concluded that monocytes play a crucial role in mediating, distributing, and transferring the immunomodulatory effect of MSC. Stem Cells 2018;36:602-615. © AlphaMed Press 2018.

  2. Mesenchymal stem cell 1 (MSC1-based therapy attenuates tumor growth whereas MSC2-treatment promotes tumor growth and metastasis.

    Directory of Open Access Journals (Sweden)

    Ruth S Waterman

    Full Text Available Currently, there are many promising clinical trials using mesenchymal stem cells (MSCs in cell-based therapies of numerous diseases. Increasingly, however, there is a concern over the use of MSCs because they home to tumors and can support tumor growth and metastasis. For instance, we established that MSCs in the ovarian tumor microenvironment promoted tumor growth and favored angiogenesis. In parallel studies, we also developed a new approach to induce the conventional mixed pool of MSCs into two uniform but distinct phenotypes we termed MSC1 and MSC2.Here we tested the in vitro and in vivo stability of MSC1 and MSC2 phenotypes as well as their effects on tumor growth and spread. In vitro co-culture of MSC1 with various cancer cells diminished growth in colony forming units and tumor spheroid assays, while conventional MSCs or MSC2 co-culture had the opposite effect in these assays. Co-culture of MSC1 and cancer cells also distinctly affected their migration and invasion potential when compared to MSCs or MSC2 treated samples. The expression of bioactive molecules also differed dramatically among these samples. MSC1-based treatment of established tumors in an immune competent model attenuated tumor growth and metastasis in contrast to MSCs- and MSC2-treated animals in which tumor growth and spread was increased. Also, in contrast to these groups, MSC1-therapy led to less ascites accumulation, increased CD45+leukocytes, decreased collagen deposition, and mast cell degranulation.These observations indicate that the MSC1 and MSC2 phenotypes may be convenient tools for the discovery of critical components of the tumor stroma. The continued investigation of these cells may help ensure that cell based-therapy is used safely and effectively in human disease.

  3. TLR4 plays a crucial role in MSC-induced inhibition of NK cell function

    Energy Technology Data Exchange (ETDEWEB)

    Lu, Ying [No. 307 Hospital of the Chinese People' s Liberation Army, Beijing (China); Liu, Jin; Liu, Yang; Qin, Yaru [Beijing Institute of Radiation Medicine, Beijing (China); Luo, Qun [No. 307 Hospital of the Chinese People' s Liberation Army, Beijing (China); Wang, Quanli, E-mail: 13691110351@163.com [No. 307 Hospital of the Chinese People' s Liberation Army, Beijing (China); Duan, Haifeng, E-mail: duanhf0720@163.com [Beijing Institute of Radiation Medicine, Beijing (China)

    2015-08-21

    Mesenchymal stem cells (MSC) are a kind of stromal cell within the tumor microenvironment. In our research, MSC derived from acute myeloid leukemia patients' bone marrow (AML-MSC) and lung cancer tissues (LC-MSC) as well as normal bone marrow-derived MSC (BM-MSC) cultured in conditioned medium of HeLa cells were found to have higher expressions of Toll-like receptor (TLR4) mRNA compared with BM-MSC. The sorted TLR4-positive MSC (TLR4+ MSC) differed in cytokine (interleukin-6, interleukin-8, and monocyte chemoattractant protein-1) secretion from those of unsorted MSC. MSC was reported to inhibit natural killer (NK) cell proliferation and function. In this research, we confirmed that TLR4+ MSC aggravate this suppression. Furthermore, when TLR4 in the sorted cells were stimulated by LPS or following blocked by antibody, the suppression on NK cell proliferation and cytotoxicity were more intensive or recovered respectively. Compared to unsorted MSC, NKG2D receptor expression on NK cells were also inhibited by TLR4+ MSC. These findings suggest that activation of TLR4 pathway is important for TLR4+ MSC and MSC to obstruct anti-tumor immunity by inhibiting NK cell function, which may provide a potential stroma-targeted tumor therapy. - Highlights: • TLR4+ MSC inhibit NK cell proliferation in vivo and in vitro. • TLR4+ MSC inhibit NKG2D expression on NK cells and NK cell cytotoxicity. • The distinguished cytokine expression of TLR4+ MSC may contribute to the inhibition on NK cell function.

  4. The Effect of Gender on Mesenchymal Stem Cell (MSC Efficacy in Neonatal Hyperoxia-Induced Lung Injury.

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    Ibrahim Sammour

    Full Text Available Mesenchymal stem cells (MSC improve alveolar and vascular structures in experimental models of bronchopulmonary dysplasia (BPD. Female MSC secrete more anti-inflammatory and pro-angiogenic factors as compared to male MSC. Whether the therapeutic efficacy of MSC in attenuating lung injury in an experimental model of BPD is influenced by the sex of the donor MSC or recipient is unknown. Here we tested the hypothesis that female MSC would have greater lung regenerative properties than male MSC in experimental BPD and this benefit would be more evident in males.To determine whether intra-tracheal (IT administration of female MSC to neonatal rats with experimental BPD has more beneficial reparative effects as compared to IT male MSC.Newborn Sprague-Dawley rats exposed to normoxia (RA or hyperoxia (85% O2 from postnatal day (P 2- P21 were randomly assigned to receive male or female IT bone marrow (BM-derived green fluorescent protein (GFP+ MSC (1 x 106 cells/50 μl, or Placebo on P7. Pulmonary hypertension (PH, vascular remodeling, alveolarization, and angiogenesis were assessed at P21. PH was determined by measuring right ventricular systolic pressure (RVSP and pulmonary vascular remodeling was evaluated by quantifying the percentage of muscularized peripheral pulmonary vessels. Alveolarization was evaluated by measuring mean linear intercept (MLI and radial alveolar count (RAC. Angiogenesis was determined by measuring vascular density. Data are expressed as mean ± SD, and analyzed by ANOVA.There were no significant differences in the RA groups. Exposure to hyperoxia resulted in a decrease in vascular density and RAC, with a significant increase in MLI, RVSP, and the percentage of partially and fully muscularized pulmonary arterioles. Administration of both male and female MSC significantly improved vascular density, alveolarization, RVSP, percent of muscularized vessels and alveolarization. Interestingly, the improvement in PH and vascular

  5. Therapeutic use of human mesenchymal stem cells (MSC) for the treatment of radio-induced diseases

    International Nuclear Information System (INIS)

    Mouiseddine, Moubarak

    2008-05-01

    Ionising radiation can induce toxic effects on body. They provoke physiological modifications of tissues and organs which can be lethal. Total body irradiation or local abdominal irradiation can induce serious complications. Intestine is the first tissue concerned by these side effects. Radiation induces malabsorption of the intestine and lost of it integrity. Radio-induced physiopathological effects on intestine could lead to distant effects on other tissues and organs such as liver. The actual treatments have a limited efficiency or are not adapted to gastrointestinal damages. Indeed, in this type of lesions, the heterogeneous systems which are concerned and the gravity of lesions complicates the medical care. Our purpose is to show that cell therapy using human mesenchymal stem cells (MSC) constitutes resolution in this type of illness. The works which are presented in this thesis show that MSC are multi-potent and have heterogeneous expression of molecules. These cells are able to establish themselves in many organs and tissues after injection into irradiated body. Thus we have shown that MSC can prevent the small intestine from radio-induced damages. Indeed we demonstrate that through their actions on gut, MSC can indirectly restore hepatic integrity. (author)

  6. Granulocyte-like myeloid derived suppressor cells (G-MDSC) are increased in multiple myeloma and are driven by dysfunctional mesenchymal stem cells (MSC).

    Science.gov (United States)

    Giallongo, Cesarina; Tibullo, Daniele; Parrinello, Nunziatina L; La Cava, Piera; Di Rosa, Michelino; Bramanti, Vincenzo; Di Raimondo, Cosimo; Conticello, Concetta; Chiarenza, Annalisa; Palumbo, Giuseppe A; Avola, Roberto; Romano, Alessandra; Di Raimondo, Francesco

    2016-12-27

    Granulocytic-Myeloid-derived suppressor cells (G-MDSC) are increased in Multiple Myeloma (MM) patients but the mechanisms of G-MDSC generation are still unknown. There are many evidences of the role of mesenchymal stem cells (MSC) in promoting MM cell growth, survival and drug-resistance. We here used a specific experimental model in vitro to evaluate the ability of MSC to induce G-MDSC. We found that although MSC derived from healthy donors (HD), MGUS and MM were able to generate the same amount of MDSC, only MM-MSC-educated G-MDSC exhibited suppressive ability. In addition, in comparison with MSC derived from HD, MM-MSC produce higher amount of immune-modulatory factors that could be involved in MDSC induction. Compared to G-MDSC obtained from co-culture models with MSC from healthy subjects, both MGUS and MM-MSC-educated G-MDSC showed increase of immune-modulatory factors. However, only MM-MSC educated G-MDSC 1) up-regulated immune-suppressive factors as ARG1 and TNFα, 2) expressed higher levels of PROK2, important in angiogenesis and inflammatory process, and 3) showed ability to digest bone matrix.Our data demonstrate that MM-MSC are functionally different from healthy subjects and MGUS-MSC, supporting an evolving concept regarding the contribution of MM-MSC to tumor development and progression.

  7. Optimasi Penambahan Colcemid pada Karyotyping Kultur Mecenchymal Stem Cells (MSC Mencit

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    Ratih Rinendyaputri

    2016-02-01

    Full Text Available AbstractControl of the genetic stability of stem cells prior to the conduct of therapy is essential to prevent effects such as stem cell transformation. Karyotyping is a conventional technique to conduct an analysis of the number and structure of chromosomes. The analysis can only be performed on metaphase stage that needs to be optimized to get the cell at that stage because the length of the cell cycle are different in the each cell types. This study aims to obtain an optimal time to get MSC at metaphase stage. The study was conducted at the stem cell laboratory of Center for Biomedical and Basic Technology of Health. The event begins with isolation using flushing technique at the femur and tibia of mice. Furthermore, the culture in vitro and induction colcemid 0,25μg/ml for 8,16 and 24 hours to get the MSC at metaphase stage. KCl solution with a concentration of 0.075 M and 0,045 M used as a solvent hipotonis. Results showed that 16 hours of induction colcemid 0,25μg/ml in 0.075 M KCl solution usage percentage of MSC who are at metaphase stage and do the highest analysis (p<0.05. In this study 16 hours induction colcemid 0,25μg/ml is the optimal time to obtain metaphase stage of the MSC from bone marrow of mice.Keywords: mecenchymal stem cell, karyotyping, colcemidAbstrakKontrol terhadap stabilitas genetik pada sel punca sebelum pelaksanan terapi merupakan hal yang penting untuk mencegah efek seperti transformasi sel punca yang dapat terjadi. Secara konvensional dapat dilakukan karyotyping untuk melakukan analisis terhadap jumlah dan struktur kromosom. Analisis hanya dapat dilakukan pada tahap metafase sehingga perlu dilakukan optimasi untuk mendapatkan sel pada tahap tersebut mengingat panjang siklus sel setiap jenis sel berbeda. Penelitian ini bertujuan untuk memperoleh waktu yang optimal untuk mendapatkan MSC pada tahap metafase. Penelitian dilakukan di Laboratorium stem cell Pusat Biomedis dan Teknologi Dasar Kesehatan Badan Litbangkes

  8. Cell therapy medicinal product regulatory framework in Europe and its application for MSC based therapy development

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    Janis eAncans

    2012-08-01

    Full Text Available Advanced therapy medicinal products (ATMPs, including cell therapy products, form a new class of medicines in the European Union. Since ATMPs are at the forefront of scientific innovation in medicine, specific regulatory framework has been developed for these medicines and implemented from 2009. The Committee for Advanced Therapies (CAT has been established at European Medicines Agency (EMA for centralized classification, certification and evaluation procedures, and other ATMP related tasks. Guidance documents, initiatives and interaction platforms are available to make the new framework more accessible for small and medium-sized enterprises, academia, hospitals and foundations. Good understanding of centralised and national components of the regulatory system is required to plan product development. It is in the best interests of cell therapy developers to utilise provided resources starting with the preclinical stage. Whilst there have not been mesenchymal stem cell (MSC based medicine authorisations in the EU, three MSC products have received marketing approval in other regions since 2011. Information provided on regulatory requirements, procedures and initiatives is aimed to facilitate MSC based medicinal product development and authorisation in the EU.

  9. Mesenchymal Stem Cells (MSC Regulate Activation of Granulocyte-Like Myeloid Derived Suppressor Cells (G-MDSC in Chronic Myeloid Leukemia Patients.

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    Cesarina Giallongo

    Full Text Available It is well known that mesenchymal stem cells (MSC have a role in promotion of tumor growth, survival and drug-resistance in chronic myeloid leukemia (CML. Recent reports indicated that a subpopulation of myeloid cells, defined as granulocyte-like myeloid-derived suppressor cells (G-MDSC is increased in these patients. So far, the role of MSC in MDSC expansion and activation into the BM microenvironment remains unexplored. To address this question, here we use a specific experimental model in vitro, co-culturing MSC with peripheral blood mononucleated cells (PBMC from normal individuals, in order to generate MSC-educated G-MDSC. Although MSC of healthy donors (HD and CML patients were able to generate the same amount of MDSC, only CML-MSC-educated G-MDSC exhibited suppressive ability on autologous T lymphocytes. In addition, compared with HD-MSC, CML-MSC over-expressed some immunomodulatory factors including TGFβ, IL6 and IL10, that could be involved in MDSC activation. CML-MSC-educated G-MDSC expressed higher levels of ARG1, TNFα, IL1β, COX2 and IL6 than G-MDSC isolated from co-culture with HD-MSC. Our data provide evidence that CML-MSC may play a critical role in tumor microenvironment by orchestrating G-MDSC activation and regulating T lymphocytes-mediated leukemia surveillance, thus contributing to CML immune escape.

  10. Mesenchymal Stem Cells (MSC) Regulate Activation of Granulocyte-Like Myeloid Derived Suppressor Cells (G-MDSC) in Chronic Myeloid Leukemia Patients.

    Science.gov (United States)

    Giallongo, Cesarina; Romano, Alessandra; Parrinello, Nunziatina Laura; La Cava, Piera; Brundo, Maria Violetta; Bramanti, Vincenzo; Stagno, Fabio; Vigneri, Paolo; Chiarenza, Annalisa; Palumbo, Giuseppe Alberto; Tibullo, Daniele; Di Raimondo, Francesco

    2016-01-01

    It is well known that mesenchymal stem cells (MSC) have a role in promotion of tumor growth, survival and drug-resistance in chronic myeloid leukemia (CML). Recent reports indicated that a subpopulation of myeloid cells, defined as granulocyte-like myeloid-derived suppressor cells (G-MDSC) is increased in these patients. So far, the role of MSC in MDSC expansion and activation into the BM microenvironment remains unexplored. To address this question, here we use a specific experimental model in vitro, co-culturing MSC with peripheral blood mononucleated cells (PBMC) from normal individuals, in order to generate MSC-educated G-MDSC. Although MSC of healthy donors (HD) and CML patients were able to generate the same amount of MDSC, only CML-MSC-educated G-MDSC exhibited suppressive ability on autologous T lymphocytes. In addition, compared with HD-MSC, CML-MSC over-expressed some immunomodulatory factors including TGFβ, IL6 and IL10, that could be involved in MDSC activation. CML-MSC-educated G-MDSC expressed higher levels of ARG1, TNFα, IL1β, COX2 and IL6 than G-MDSC isolated from co-culture with HD-MSC. Our data provide evidence that CML-MSC may play a critical role in tumor microenvironment by orchestrating G-MDSC activation and regulating T lymphocytes-mediated leukemia surveillance, thus contributing to CML immune escape.

  11. Differential effects of platelet rich plasma and washed platelets on the proliferation of mouse MSC cells.

    Science.gov (United States)

    Duan, Jianmin; Kuang, Wei; Tan, Jiali; Li, Hongtao; Zhang, Yi; Hirotaka, Kikuchi; Tadashi, Katayama

    2011-04-01

    Multipotent mesenchymal stem cell (MSC) therapies are being tested clinically for a variety of disorders. However, despite the remarkable clinical advancements in this field, most applications still use traditional culture media containing fetal bovine serum. Platelet-rich plasma (PRP) appears as a novel application for tissue engineering and its effect on bone healing is thought to be mainly dependent on the proliferation promoting function, with the molecular mechanisms largely unknown. In this study, mouse osteogenic progenitor mesenchymal stem cells (MSCs) were cultured in PRP or washed platelet (WPLT)-treated wells or in untreated wells, and analyzed on cycloxygenase 2 (COX2) expression (qRT-PCR), cell growth (MTT assay) and cell differentiation (alkaline phosphatase activity). The results showed that PRP and WPLT stimulated cell growth similarly in the first 6 days, together with the steady induction of COX2 and PGE2. 10 μmol/l celecoxib (an inhibitor of COX2) significantly inhibited the pro-proliferation effects. Interestingly, WPLT had stronger effects than PRP in proliferation at the later time points (6-9 days). ALP activity assay and collagen 1a expression revealed PRP had a mild but statistically significant pro-differentiation effect, while no obvious effects observed in WLPT group. In summary, PRP stimulates initial growth of MSCs in a COX2 partially dependent manner and the less obvious osteogenic differentiation promoting effects of WPLT strongly indicates WPLT rather than the PRP should be the optional choice for expanding MSCs in vitro for clinical use.

  12. The histopathology of a human mesenchymal stem cell experimental tumor model: support for an hMSC origin for Ewing's sarcoma?

    DEFF Research Database (Denmark)

    Burns, J S; Abdallah, B M; Schrøder, Henrik Daa

    2008-01-01

    -forming potential of early passage hMSC-TERT20 cells, tumors derived from late passage cells expressed early biomarkers of osteogenesis. However, hMSC-TERT20 cells were heterogeneous for alpha smooth muscle actin (ASMA) expression and one out of six hMSC-TERT20 derived single cell clones was strongly ASMA positive....... Tumors from this ASMA+ clone had distinctive vascular qualities with hot spots of high CD34+ murine endothelial cell density, together with CD34- regions with a branching periodic acid Schiff reaction pattern. Such clone-specific differences in host vascular response provide novel models to explore...

  13. Cell therapy medicinal product regulatory framework in Europe and its application for MSC-based therapy development

    Science.gov (United States)

    Ancans, Janis

    2012-01-01

    Advanced therapy medicinal products (ATMPs), including cell therapy products, form a new class of medicines in the European Union. Since the ATMPs are at the forefront of scientific innovation in medicine, specific regulatory framework has been developed for these medicines and implemented from 2009. The Committee for Advanced Therapies (CAT) has been established at the European Medicines Agency (EMA) for centralized classification, certification and evaluation procedures, and other ATMP-related tasks. Guidance documents, initiatives, and interaction platforms are available to make the new framework more accessible for small- and medium-sized enterprises, academia, hospitals, and foundations. Good understanding of the centralized and national components of the regulatory system is required to plan product development. It is in the best interests of the cell therapy developers to utilize the resources provided starting with the pre-clinical stage. Whilst there have been no mesenchymal stem cell (MSC)-based medicine authorizations in the EU, three MSC products have received marketing approval in other regions since 2011. The information provided on the regulatory requirements, procedures, and initiatives is aimed at facilitating MSC-based medicinal product development and authorization in the EU. PMID:22912639

  14. Hypoxia pretreatment and EPO-modification enhance the protective effects of MSC on neuron-like PC12 cells in a similar way.

    Science.gov (United States)

    Feng, Jinli; Wang, Wei

    2017-01-08

    Mesenchymal stem cells (MSC) based cell transplantation therapy is proved to be an attractive strategy with great potential for improvement of hypoxia induced neural damage. In the present study, MSCs were co-culture with PC12 to investigate its protective effects against hypoxia pretreatment, and the Lactate dehydrogenase (LDH) release assay, MTT and Anexin V staining were performed to analysis the cellular damage or apoptotic. RT-PCR and Western blotting were further used to investigate the underlying mechanism. The results indicate that hypoxia treatment results in the decrease of PC12 cell viability, yet co-culture with MSC could protect the PC12 from hypoxia induced damage. Hypoxia pre-activated or EPO transduced MSC with up-regulated erythropoietin (EPO) expression could further enhance MSC's protective effect against hypoxia induced cell damage, which was associated with high level of anti-apoptotic p-Akt and ration Bcl-2/Bax, and decreased Caspase 3 in PC12. Taken together, these data suggests high levels of MSC-mediated cyto-protection is closely tied to high gene expression levels of EPO. The up-regulation of EPO for enhanced MSC-mediated cyto-protection may has great potential for the MSC cellular therapy of neural or neuronal injuries induced by hypoxia. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Therapeutic effect of transplanted human Wharton's jelly stem cell-derived oligodendrocyte progenitor cells (hWJ-MSC-derived OPCs) in an animal model of multiple sclerosis.

    Science.gov (United States)

    Mikaeili Agah, Elmira; Parivar, Kazem; Joghataei, Mohammad Taghi

    2014-04-01

    Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS). A potential new therapeutic approach for MS is cell transplantation which may promote remyelination. We transplanted human Wharton's jelly stem cell-derived oligodendrocyte progenitor cells (hWJ-MSC-derived OPCs) into the brain ventricles of mice induced with experimental autoimmune encephalomyelitis (EAE), the animal model of MS. We studied the effect of the transplanted OPCs on the functional and pathological manifestations of the disease. Transplanted hWJ-MSC-derived OPCs significantly reduced the clinical signs of EAE. Histological examinations showed that remyelination was significantly increased after transplantation. These results suggest that hWJ-MSC-derived OPCs promote the regeneration of myelin sheaths in the brain.

  16. Treatment of radio-induced colorectal lesions with Mesenchymal Stromal Cells (MSC): part of the inflammatory process

    International Nuclear Information System (INIS)

    Bessout, R.

    2012-01-01

    Throughout the last decades, radiotherapy established as a major tool in the treatment of abdomino-pelvic cancers. Despite great technological evolutions, radiotherapy remains associated with side effects that can sometimes be really harmful, this being mainly due to the toxicity of ionizing radiations for healthy tissues surrounding the tumor. As part of abdomino-pelvic radio-therapies, these side effects mainly affect the gastrointestinal tract, which is very sensitive to radiations. The development of curative treatments thus became a priority. Mesenchymal stem cells (MSC) showed their immunomodulatory ability as well as their ability to regenerate tissue in many models. During my thesis, we aimed at giving rise to the therapeutic advantage brought by MSC in the treatment of radioinduced damage as well as the underlying molecular mechanisms. Our results allowed us to demonstrate the efficiency of our treatment with an effect both on the colic epithelial structure and on its contractile functions. We demonstrated that this therapeutical efficiency depends on two processes. Stimulation of the epithelial proliferation through the Wnt pathway allows the epithelial regeneration process to be enhanced. The increased local corticosterone secretion allows the number and the activation state of T lymphocytes to diminish. Our results moreover suggest the existence of a link between the two observed phenomenons thus providing with a new proof of the combinatory effects of MSC therapy. (author)

  17. NK Cell Regulatory Property is Involved in the Protective Role of MSC-Derived Extracellular Vesicles in Renal Ischemic Reperfusion Injury.

    Science.gov (United States)

    Zou, Xiangyu; Gu, Di; Zhang, Guangyuan; Zhong, Liang; Cheng, Zhongliang; Liu, Guohua; Zhu, Yingjian

    2016-11-01

    Immunomodulation has been regarded as an important therapeutic aspect of mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) in renal ischemic reperfusion injury (IRI), and the specific mechanism still unclear. Here, we attempt to test the function of human MSC-EVs on renal IRI by targeting the natural killer (NK) cells and to investigate the possible mechanism. Data indicated that EVs decreased NK cells in spleen and ischemic kidney. Both the EVs and antibody-dependent depletion of NK cells displayed a protective role in IRI rats. Moreover, the splenectomy model was established to evaluate the role of spleen in this process. It showed that the NK cell regulatory ability and renal protective effects by EVs still exist without spleen, which is unlike MSC properties published previously. Further, the down-regulation of chemokines in injured kidney and the delivery of RNAs through EVs in vitro were also observed. Through the microRNA array test, various inflammation-related microRNAs highly expressed in MSC-EVs compared with fibroblast EVs were tested. Thus, these results indicated that MSC-EVs could ameliorate renal ischemic reperfusion injury by decreasing NK cells and the spleen is not necessary in this process. The regulation of chemokines in injured kidney was the other factor, and the transfer of various microRNAs in the MSC-EVs may be involved. This provides direction for future clinical applications.

  18. Therapeutic potential of mesenchymal stromal cells and MSC conditioned medium in Amyotrophic Lateral Sclerosis (ALS--in vitro evidence from primary motor neuron cultures, NSC-34 cells, astrocytes and microglia.

    Directory of Open Access Journals (Sweden)

    Hui Sun

    Full Text Available Administration of mesenchymal stromal cells (MSC improves functional outcome in the SOD1G93A mouse model of the degenerative motor neuron disorder amyotrophic lateral sclerosis (ALS as well as in models of other neurological disorders. We have now investigated the effect of the interaction between MSC and motor neurons (derived from both non-transgenic and mutant SOD1G93A transgenic mice, NSC-34 cells and glial cells (astrocytes, microglia (derived again from both non-transgenic and mutant SOD1G93A ALS transgenic mice in vitro. In primary motor neurons, NSC-34 cells and astrocytes, MSC conditioned medium (MSC CM attenuated staurosporine (STS - induced apoptosis in a concentration-dependent manner. Studying MSC CM-induced expression of neurotrophic factors in astrocytes and NSC-34 cells, we found that glial cell line-derived neurotrophic factor (GDNF and ciliary neurotrophic factor (CNTF gene expression in astrocytes were significantly enhanced by MSC CM, with differential responses of non-transgenic and mutant astrocytes. Expression of Vascular Endothelial Growth Factor (VEGF in NSC-34 cells was significantly upregulated upon MSC CM-treatment. MSC CM significantly reduced the expression of the cytokines TNFα and IL-6 and iNOS both in transgenic and non-transgenic astrocytes. Gene expression of the neuroprotective chemokine Fractalkine (CX3CL1 was also upregulated in mutant SOD1G93A transgenic astrocytes by MSC CM treatment. Correspondingly, MSC CM increased the respective receptor, CX3CR1, in mutant SOD1G93A transgenic microglia. Our data demonstrate that MSC modulate motor neuronal and glial response to apoptosis and inflammation. MSC therefore represent an interesting candidate for further preclinical and clinical evaluation in ALS.

  19. Differential MSC activation leads to distinct mononuclear leukocyte binding mechanisms

    Science.gov (United States)

    Kota, Daniel J.; Dicarlo, Bryan; Hetz, Robert A.; Smith, Philippa; Cox, Charles S.; Olson, Scott D.

    2014-04-01

    Advances in the field of Multipotent Mesenchymal Stromal cell (MSC) biology have demonstrated that MSCs can improve disease outcome when `activated' to exert immunomodulatory effects. However, the precise mechanisms modulating MSC-immune cells interactions remain largely elusive. In here, we activated MSC based on a recent polarization paradigm, in which MSCs can be polarized towards a pro- or anti-inflammatory phenotype depending on the Toll-like receptor stimulated, to dissect the mechanisms through which MSCs physically interact with and modulate leukocytes in this context. Our data show that MSCs activated through the Toll-like receptor (TLR) 4 pathway increased VCAM-1 and ICAM-1 dependent binding of leukocytes. On the other hand, TLR3 stimulation strongly increases leukocytes affinity to MSC comparatively, through the formation of cable-like hyaluronic acid structures. In addition, TLR4 activation elicited secretion of pro-inflammatory mediators by MSCs, whereas TLR3-activated MSCs displayed a milder pro-inflammatory phenotype, similar to inactivated MSCs. However, the differently activated MSCs maintained their ability to suppress leukocyte activation at similar levels in our in vitro model, and this immunomodulatory property was shown here to be partially mediated by prostaglandin. These results reinforce the concept that alternate activation profiles control MSC responses and may impact the therapeutic use of MSCs.

  20. Platelet-Derived Growth Factor-BB Protects Mesenchymal Stem Cells (MSCs) Derived From Immune Thrombocytopenia Patients Against Apoptosis and Senescence and Maintains MSC-Mediated Immunosuppression.

    Science.gov (United States)

    Zhang, Jia-Min; Feng, Fei-Er; Wang, Qian-Ming; Zhu, Xiao-Lu; Fu, Hai-Xia; Xu, Lan-Ping; Liu, Kai-Yan; Huang, Xiao-Jun; Zhang, Xiao-Hui

    2016-12-01

    : Immune thrombocytopenia (ITP) is characterized by platelet destruction and megakaryocyte dysfunction. Mesenchymal stem cells (MSCs) from ITP patients (MSC-ITP) do not exhibit conventional proliferative abilities and thus exhibit defects in immunoregulation, suggesting that MSC impairment might be a mechanism involved in ITP. Platelet-derived growth factor (PDGF) improves growth and survival in various cell types. Moreover, PDGF promotes MSC proliferation. The aim of the present study was to analyze the effects of PDGF-BB on MSC-ITP. We showed that MSC-ITP expanded more slowly and appeared flattened and larger. MSC-ITP exhibited increased apoptosis and senescence compared with controls. Both the intrinsic and extrinsic pathways account for the enhanced apoptosis. P53 and p21 expression were upregulated in MSC-ITP, but inhibition of p53 with pifithrin-α markedly inhibited apoptosis and senescence. Furthermore, MSCs from ITP patients showed a lower capacity for inhibiting the proliferation of activated T cells inducing regulatory T cells (Tregs) and suppressing the synthesis of anti-glycoprotein (GP)IIb-IIIa antibodies. PDGF-BB treatment significantly decreased the expression of p53 and p21 and increased survivin expression in MSC-ITP. In addition, the apoptotic rate and number of senescent cells in ITP MSCs were reduced. Their impaired ability for inhibiting activated T cells, inducing Tregs, and suppressing the synthesis of anti-GPIIb-IIIa antibodies was restored after PDGF-BB treatment. In conclusion, we have demonstrated that PDGF-BB protects MSCs derived from ITP patients against apoptosis, senescence, and immunomodulatory defects. This protective effect of PDGF-BB is likely mediated via the p53/p21 pathway, thus potentially providing a new therapeutic approach for ITP. Immune thrombocytopenia (ITP) is characterized by platelet destruction and megakaryocyte dysfunction. Platelet-derived growth factor (PDGF) improves growth and survival in various cell types

  1. HucMSC exosome-transported 14-3-3ζ prevents the injury of cisplatin to HK-2 cells by inducing autophagy in vitro.

    Science.gov (United States)

    Wang, Juanjuan; Jia, Haoyuan; Zhang, Bin; Yin, Lei; Mao, Fei; Yu, Jing; Ji, Cheng; Xu, Xiao; Yan, Yongmin; Xu, Wenrong; Qian, Hui

    2018-01-01

    On the basis of previous studies, exosomes secreted by human umbilical cord mesenchymal stromal cell (hucMSC-ex) could prevent and repair acute kidney injury induced by cisplatin in rats. However, its potential mechanism is still unclear. In the present study, the model with hucMSC-ex pretreated human renal tubular epithelial cell lines HK-2 that could prevent the injury of cisplatin was successfully established. First, we pretreated the HK-2 cells with hucMSC-ex for 24 h. Cisplatin was then used to injure HK-2 cells. Gain and loss of function study were used to explore the role of 14-3-3ζ. The expression level of proliferating cell nuclear antigen (PCNA) was analyzed by immunofluorescence assay and Western blot. The number of apoptotic cells was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling assay and flow cytometry analysis. The formation of autophagosomes was observed under super-resolution optical microscope. Western blot was used to analyze the expression levels of LC3B, P62, 14-3-3ζ and Bax. Pretreating cells with hucMSC-ex could prevent the injury of cisplatin by reducing the number of apoptotic cells and increasing the expression level of PCNA. Simultaneously, the autophagic level was up-regulated. The application of autophagic inhibitor 3-methyladenine (3-MA) could reverse the protective effect of hucMSC-ex. The overexpression of 14-3-3ζ enhanced the autophagic level and protected the injury of cisplatin. The knock-down of 14-3-3ζ could reduce the autophagic level and enhance the disadvantage of cisplatin. The enhanced injury of cisplatin was reversed when the knock-down of 14-3-3ζ was replenished with hucMSC-ex. 14-3-3ζ transported by hucMSC-ex may up-regulate autophagic level in HK-2 cells, which can prevent the injury of cisplatin. This discovery provides the new theoretical basis for the prevention of cisplatin-induced nephrotoxicity by hucMSC-ex. Copyright © 2017 International Society for Cellular Therapy. Published

  2. Quantification of Mesenchymal Stem Cell (MSC delivery to a target site using in vivo confocal microscopy.

    Directory of Open Access Journals (Sweden)

    Luke J Mortensen

    Full Text Available The ability to deliver cells to appropriate target tissues is a prerequisite for successful cell-based therapy. To optimize cell therapy it is therefore necessary to develop a robust method of in vivo cell delivery quantification. Here we examine Mesenchymal Stem Cells (MSCs labeled with a series of 4 membrane dyes from which we select the optimal dye combination for pair-wise comparisons of delivery to inflamed tissue in the mouse ear using confocal fluorescence imaging. The use of an optimized dye pair for simultaneous tracking of two cell populations in the same animal enables quantification of a test population that is referenced to an internal control population, thereby eliminating intra-subject variations and variations in injected cell numbers. Consistent results were obtained even when the administered cell number varied by more than an order of magnitude, demonstrating an ability to neutralize one of the largest sources of in vivo experimental error and to greatly reduce the number of cells required to evaluate cell delivery. With this method, we are able to show a small but significant increase in the delivery of cytokine pre-treated MSCs (TNF-α & IFN-γ compared to control MSCs. Our results suggest future directions for screening cell strategies using our in vivo cell delivery assay, which may be useful to develop methods to maximize cell therapeutic potential.

  3. Cellular Kinetics of Perivascular MSC Precursors

    Directory of Open Access Journals (Sweden)

    William C. W. Chen

    2013-01-01

    Full Text Available Mesenchymal stem/stromal cells (MSCs and MSC-like multipotent stem/progenitor cells have been widely investigated for regenerative medicine and deemed promising in clinical applications. In order to further improve MSC-based stem cell therapeutics, it is important to understand the cellular kinetics and functional roles of MSCs in the dynamic regenerative processes. However, due to the heterogeneous nature of typical MSC cultures, their native identity and anatomical localization in the body have remained unclear, making it difficult to decipher the existence of distinct cell subsets within the MSC entity. Recent studies have shown that several blood-vessel-derived precursor cell populations, purified by flow cytometry from multiple human organs, give rise to bona fide MSCs, suggesting that the vasculature serves as a systemic reservoir of MSC-like stem/progenitor cells. Using individually purified MSC-like precursor cell subsets, we and other researchers have been able to investigate the differential phenotypes and regenerative capacities of these contributing cellular constituents in the MSC pool. In this review, we will discuss the identification and characterization of perivascular MSC precursors, including pericytes and adventitial cells, and focus on their cellular kinetics: cell adhesion, migration, engraftment, homing, and intercellular cross-talk during tissue repair and regeneration.

  4. Effect of mesenchymal stromal cells (MSC) on chronic visceral hypersensitivity in a radio-induced colonic ulceration model in the rat

    International Nuclear Information System (INIS)

    Durand, Christelle

    2014-01-01

    Patients who undergo pelvic radiotherapy may develop significant incidence of undesirable chronic gastrointestinal complications resulting from radiation-induced damages around the tumour. Chronic visceral pain is one of the radiation-induced side effects that greatly affects the quality of life of 'cancer survivors'. The lack of effective analgesic treatment highlights the importance of novel and effective therapeutic strategies. In our laboratory, mesenchymal stromal cell (MSC) based approach showed beneficial immunomodulatory and regenerative effects in a rat model of irreversible radiationinduced colonic ulcers. The goal of my work was to assess the relevance of this model to study radiation-induced visceral persistent hypersensitivity and its modulation by MSC treatment. We first demonstrated that this model is associated with long-lasting visceral hypersensitivity and central neuronal sensitization. In this context we showed then that mast cells (MC) are involved in the mechanism of peripheral sensitization. Moreover, we suggested the implication of the neuro-mediator NO . in the pathophysiology of persistent radiation-induced visceral hypersensitivity. We also suggested that MSC treatment reversed radiation-induced hypersensitivity by a mechanism that in part may involve the modulation of MC activation and/or the decrease in the number of MC and nerve fiber interactions. In addition, MSC treatment reduced the percentage of nitrinergic neurons, increased after irradiation, and restored colonic muscular contractibility. Such processes may promote the therapeutic benefit of MSC observed in our study. In conclusion, this work provided new insights on the therapeutic benefit of MSC in our study model and a new argument in favour of their use in a future clinical trial to cure abdomino-pelvic radiotherapy side effects. (author) [fr

  5. The histopathology of a human mesenchymal stem cell experimental tumor model: support for an hMSC origin for Ewing's sarcoma?

    DEFF Research Database (Denmark)

    Burns, J S; Abdallah, B M; Schrøder, Henrik Daa

    2008-01-01

    , showed increased immunohistochemical staining for CyclinD1 and p21WAF1/Cip1, whereas p27Kip1 staining was reduced. Notably, spectral karyotyping showed that tumorigenic hMSC-TERT20 cells retained a normal diploid karyotype, with no detectable chromosome abnormalities. Consistent with the bone...

  6. Cytoplasmic Domain of MscS Interacts with Cell Division Protein FtsZ: A Possible Non-Channel Function of the Mechanosensitive Channel in Escherichia Coli.

    Directory of Open Access Journals (Sweden)

    Piotr Koprowski

    Full Text Available Bacterial mechano-sensitive (MS channels reside in the inner membrane and are considered to act as emergency valves whose role is to lower cell turgor when bacteria enter hypo-osmotic environments. However, there is emerging evidence that members of the Mechano-sensitive channel Small (MscS family play additional roles in bacterial and plant cell physiology. MscS has a large cytoplasmic C-terminal region that changes its shape upon activation and inactivation of the channel. Our pull-down and co-sedimentation assays show that this domain interacts with FtsZ, a bacterial tubulin-like protein. We identify point mutations in the MscS C-terminal domain that reduce binding to FtsZ and show that bacteria expressing these mutants are compromised in growth on sublethal concentrations of β-lactam antibiotics. Our results suggest that interaction between MscS and FtsZ could occur upon inactivation and/or opening of the channel and could be important for the bacterial cell response against sustained stress upon stationary phase and in the presence of β-lactam antibiotics.

  7. A Transient Cell-shielding Method for Viable MSC Delivery Within Hydrophobic Scaffolds Polymerized in situ

    Science.gov (United States)

    2015-03-27

    increasing alcohol concentrations (50e100%). Materials were air-dried and mounted to a specimen stub using carbon tape . Samples were sputter-coated with...Transplantability and therapeutic effects of bone marrow-derived mesen- chymal cells in children with osteogenesis imperfecta. Nat Med 1999;5: 309e13

  8. No Synergistic Effect of Cotransplantation of MSC and Ex Vivo TPO-Expanded CD34(+) Cord Blood Cells on Platelet Recovery and Bone Marrow Engraftment in NOD SCID Mice.

    Science.gov (United States)

    van der Garde, Mark; Brand, Anneke; Slot, Manon C; de Graaf-Dijkstra, Alice; Zwaginga, Jaap Jan; van Hensbergen, Yvette

    2015-06-15

    After cord blood (CB) transplantation, early platelet recovery in immune-deficient mice is obtained by expansion of CB CD34(+) cells with thrombopoietin (TPO) as single growth factor. Moreover, improvement of hematopoietic engraftment has been shown by cotransplantation of mesenchymal stem cells (MSC). We investigated whether a combination of both approaches would further enhance the outcome of CB transplantation in NOD SCID mice. NOD SCID mice were transplanted with either CB CD34(+) cells, CD34(+) cells with MSC, TPO-expanded CD34(+) cells or TPO-expanded CD34(+) cells with MSC. We analyzed human platelet recovery in the peripheral blood (PB) from day 4 after transplantation onward and human bone marrow (BM) engraftment at week 6. The different transplants were assessed in vitro for their migration capacity and expression of CXCR4. TPO expansion improved the early platelet recovery in the PB of the mice. Cotransplantation of MSC with CD34(+) cells improved BM engraftment and platelet levels in the PB 6 weeks after transplantation. Combining TPO expansion and MSC cotransplantation, however, neither resulted in a more efficient early platelet recovery, nor in a better BM engraftment, nor even very low or absent BM engraftment occurred. In vitro, MSC boosted the migration of CD34(+) cells, suggesting a possible mechanism for the increase in engraftment. Our results show that cotransplantation of MSC with TPO-expanded CD34(+) cells at most combines, but does not increase the separate advantages of these different strategies. A combination of both strategies even adds a risk of non engraftment.

  9. No Synergistic Effect of Cotransplantation of MSC and Ex Vivo TPO-Expanded CD34+ Cord Blood Cells on Platelet Recovery and Bone Marrow Engraftment in NOD SCID Mice

    Science.gov (United States)

    van der Garde, Mark; Brand, Anneke; Slot, Manon C.; de Graaf-Dijkstra, Alice; van Hensbergen, Yvette

    2015-01-01

    After cord blood (CB) transplantation, early platelet recovery in immune-deficient mice is obtained by expansion of CB CD34+ cells with thrombopoietin (TPO) as single growth factor. Moreover, improvement of hematopoietic engraftment has been shown by cotransplantation of mesenchymal stem cells (MSC). We investigated whether a combination of both approaches would further enhance the outcome of CB transplantation in NOD SCID mice. NOD SCID mice were transplanted with either CB CD34+ cells, CD34+ cells with MSC, TPO-expanded CD34+ cells or TPO-expanded CD34+ cells with MSC. We analyzed human platelet recovery in the peripheral blood (PB) from day 4 after transplantation onward and human bone marrow (BM) engraftment at week 6. The different transplants were assessed in vitro for their migration capacity and expression of CXCR4. TPO expansion improved the early platelet recovery in the PB of the mice. Cotransplantation of MSC with CD34+ cells improved BM engraftment and platelet levels in the PB 6 weeks after transplantation. Combining TPO expansion and MSC cotransplantation, however, neither resulted in a more efficient early platelet recovery, nor in a better BM engraftment, nor even very low or absent BM engraftment occurred. In vitro, MSC boosted the migration of CD34+ cells, suggesting a possible mechanism for the increase in engraftment. Our results show that cotransplantation of MSC with TPO-expanded CD34+ cells at most combines, but does not increase the separate advantages of these different strategies. A combination of both strategies even adds a risk of non engraftment. PMID:25668618

  10. Serum-free human MSC medium supports consistency in human but not in equine adipose-derived multipotent mesenchymal stromal cell culture.

    Science.gov (United States)

    Schubert, Susanna; Brehm, Walter; Hillmann, Aline; Burk, Janina

    2018-01-01

    For clinical applications of multipotent mesenchymal stromal cells (MSCs), serum-free culture is preferable to standardize cell products and prevent contamination with pathogens. In contrast to human MSCs, knowledge on serum-free culture of large animal MSCs is limited, despite its relevance for preclinical studies and development of veterinary cellular therapeutics. This study aimed to evaluate the suitability of a commercially available serum-free human MSC medium for culturing equine adipose-derived MSCs in comparison with human adipose MSCs. Enzyme-free isolation by explant technique and expansion of equine and human cells in the serum-free medium were feasible. However, serum-free culture altered the morphology and complicated handling of equine MSCs, with cell aggregation and spontaneous detachment of multilayers, compared to culture in standard medium supplemented with fetal bovine serum. Furthermore, proliferation and the surface immunophenotype of equine cells were more variable compared to the controls and appeared to depend on the lot of the serum-free medium. Particularly the expression of CD90 was different between experimental groups (P cultured in serum-free medium (5.21-83.40%) compared to standard medium (86.20-99.50%). Additionally, small subpopulations expressing MSC exclusion markers such as CD14 (0.28-11.60%), CD34 (0.00-9.87%), CD45 (0.35-10.50%), or MHCII (0.00-3.67%) were found in equine samples after serum-free culture. In contrast, human samples displayed a more consistent morphology and a consistent CD29 + (98.60-99.90%), CD73 + (94.60-98.40%), CD90 + (99.60-99.90%), and CD105 + (97.40-99.80%) immunophenotype after culture in serum-free medium. The obtained data demonstrate that the serum-free medium was suitable for human MSC culture but did not lead to entirely satisfactory results in equine MSCs. This underlines that requirements regarding serum-free culture conditions are species-specific, indicating a need for serum-free media to

  11. Serum from postmenopausal women treated with a by-product of olive-oil extraction process stimulates osteoblastogenesis and inhibits adipogenesis in human mesenchymal stem-cells (MSC).

    Science.gov (United States)

    Casado-Díaz, Antonio; Túnez-Fiñana, Isaac; Mata-Granados, José María; Ruiz-Méndez, María Victoria; Dorado, Gabriel; Romero-Sánchez, María Concepción; Navarro-Valverde, Cristina; Quesada-Gómez, José Manuel

    2017-04-01

    Aging may enhance both oxidative stress and bone-marrow mesenchymal stem-cell (MSC) differentiation into adipocytes. That reduces osteoblastogenesis, thus favoring bone-mass loss and fracture, representing an important worldwide health-issue, mainly in countries with aging populations. Intake of antioxidant products may help to retain bone-mass density. Interestingly, a novel olive-pomace physical treatment to generate olive oil also yields by-products rich in functional antioxidants. Thus, diet of postmenopausal women was supplemented for two months with one of such by-products (distillate 6; D6), being rich in squalene. After treatment, serum from such women showed reduced both lipidic peroxidation and oxidized low-density lipoprotein (LDL). Besides, vitamin E and coenzyme Q10 levels increased. Furthermore, culture medium containing 10% of such serum both increased osteoblastogenesis and reduced adipogenesis in human MSC from bone marrow. Therefore, highly antioxidant by-products like D6 may represent a relevant source for development of functional products, for both prevention and treatment of degenerative pathologies associated with aging, like osteoporosis. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. The current landscape of the mesenchymal stromal cell secretome: A new paradigm for cell-free regeneration.

    Science.gov (United States)

    Konala, Vijay Bhaskar Reddy; Mamidi, Murali Krishna; Bhonde, Ramesh; Das, Anjan Kumar; Pochampally, Radhika; Pal, Rajarshi

    2016-01-01

    The unique properties of mesenchymal stromal/stem cells (MSCs) to self-renew and their multipotentiality have rendered them attractive to researchers and clinicians. In addition to the differentiation potential, the broad repertoire of secreted trophic factors (cytokines) exhibiting diverse functions such as immunomodulation, anti-inflammatory activity, angiogenesis and anti-apoptotic, commonly referred to as the MSC secretome, has gained immense attention in the past few years. There is enough evidence to show that the one important pathway by which MSCs participate in tissue repair and regeneration is through its secretome. Concurrently, a large body of MSC research has focused on characterization of the MSC secretome; this includes both soluble factors and factors released in extracellular vesicles, for example, exosomes and microvesicles. This review provides an overview of our current understanding of the MSC secretome with respect to their potential clinical applications. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  13. Electrostatics at the membrane define MscL channel mechanosensitivity and kinetics.

    Science.gov (United States)

    Zhong, Dalian; Blount, Paul

    2014-12-01

    The bacterial mechanosensitive channel of large conductance (MscL) serves as a biological emergency release valve, preventing the occurrence of cell lysis caused by acute osmotic stress. Its tractable nature allows it to serve as a paradigm for how a protein can directly sense membrane tension. Although much is known of the importance of the hydrophobicity of specific residues in channel gating, it has remained unclear whether electrostatics at the membrane plays any role. We studied MscL chimeras derived from functionally distinct orthologues: Escherichia coli and Staphylococcus aureus. Dissection of one set led to an observation that changing the charge of a single residue, K101, of E. coli (Ec)-MscL, effects a channel phenotype: when mutated to a negative residue, the channel is less mechanosensitive and has longer open dwell times. Assuming electrostatic interactions, we determined whether they are due to protein-protein or protein-lipid interactions by performing site-directed mutagenesis elsewhere in the protein and reconstituting channels into defined lipids, with and without negative head groups. We found that although both interactions appear to play some role, the primary determinant of the channel phenotype seems to be protein-lipid electrostatics. The data suggest a model for the role of electrostatic interactions in the dynamics of MscL gating. © FASEB.

  14. Deep tissue single cell MSC ablation using a fiber laser source to evaluate therapeutic potential in osteogenesis imperfecta

    Science.gov (United States)

    Tehrani, Kayvan F.; Pendleton, Emily G.; Lin, Charles P.; Mortensen, Luke J.

    2016-04-01

    Osteogenesis imperfecta (OI) is a currently uncurable disease where a mutation in collagen type I yields brittle bones. One potential therapy is transplantation of mesenchymal stem cells (MSCs), but controlling and enhancing transplanted cell survival has proven challenging. Therefore, we use a 2- photon imaging system to study individual transplanted cells in the living bone marrow. We ablated cells deep in the bone marrow and observed minimal collateral damage to surrounding tissue. Future work will evaluate the local impact of transplanted MSCs on bone deposition in vivo.

  15. Regenerative Endodontics in light of the stem cell paradigm

    Science.gov (United States)

    Rosa, Vinicius; Botero, Tatiana M.; Nör, Jacques E.

    2013-01-01

    Stem cells play a critical role in development and in tissue regeneration. The dental pulp contains a small sub-population of stem cells that are involved in the response of the pulp to caries progression. Specifically, stem cells replace odontoblasts that have undergone cell death as a consequence of the cariogenic challenge. Stem cells also secrete factors that have the potential to enhance pulp vascularization and provide the oxygen and nutrients required for the dentinogenic response that is typically observed in teeth with deep caries. However, the same angiogenic factors that are required for dentin regeneration may ultimately contribute to the demise of the pulp by enhancing vascular permeability and interstitial pressure. Recent studies focused on the biology of dental pulp stem cells revealed that the multipotency and angiogenic capacity of these cells could be exploited therapeutically in dental pulp tissue engineering. Collectively, these findings suggest new treatment paradigms in the field of Endodontics. The goal of this review is to discuss the potential impact of dental pulp stem cells to Regenerative Endodontics. PMID:21726222

  16. Phenotypic modulation of auto-reactive cells by insertion of tolerogenic molecules via MSC-derived exosomes.

    Science.gov (United States)

    Mokarizadeh, Aram; Delirezh, Nowruz; Morshedi, Ahhmad; Mosayebi, Ghasem; Farshid, Amir-Abbas; Dalir-Naghadeh, Bahram

    2012-01-01

    Auto-reactive cells-mediated immune responses are responsible for the current tissue damages during autoimmunity. Accordingly, functional modulation of auto-reactive cells has been a pivotal aim in many of recent studies. In the current study, we investigated the possibility for insertion of regulatory molecules onto auto-reactive cells through exosomal nano-shuttles as a novel approach for phenotype modification of auto-reactive cells. The exosomes were isolated from supernatant of mesenchymal stem cells culture. Resultant exosomes co-cultured with lymphocytes were harvested from established EAE mice in the presence of antigenic MOG35-55 peptide. After 24 hr, insertion of exosomal tolerogenic molecules (PD-L1, TGF-β, galectin-1) onto auto-reactive cells were explored through flow cytometry. The potency of exosomal inserted membrane molecules to modulate phenotype of auto-reactive lymphocytes was assessed upon ELISA test for their-derived cytokines IFN-γ and IL-17. Incorporation of exosomal molecules into lymohocytes' membrane was confirmed by flow cytometric analyses for surface levels of mentioned molecules. Additionally, the decreased secretion of IFN-γ and IL-17 were detected in exosome pre-treated lymphocytes upon stimulation with MOG peptide. Mesenchymal stem cells -derived exosomes showed to be efficient organelles for insertion of bioactive tolerogenic molecules onto auto-reactive cells and modulation of their phenotypes.

  17. Mesenchymal stem cell therapy: Two steps forward, one step back

    Science.gov (United States)

    Ankrum, James; Karp, Jeffrey M.

    2010-01-01

    Mesenchymal stem cell (MSC) therapy is poised to establish a new clinical paradigm; however, recent trials have produced mixed results. Although MSC were originally considered to treat connective tissue defects, preclinical studies revealed potent immunomodulatory properties that prompted the use of MSC to treat numerous inflammatory conditions. Unfortunately, although clinical trials have met safety endpoints, efficacy has not been demonstrated. We believe the challenge to demonstrate efficacy can be attributed in part to an incomplete understanding of the fate of MSC following infusion. Here, we highlight the clinical status of MSC therapy and discuss the importance of cell-tracking techniques, which have advanced our understanding of the fate and function of systemically infused MSC and might improve clinical application. PMID:20335067

  18. Streptomycin potency is dependent on MscL channel expression

    Science.gov (United States)

    Iscla, Irene; Wray, Robin; Wei, Shuguang; Posner, Bruce; Blount, Paul

    2014-09-01

    The antibiotic streptomycin is widely used in the treatment of microbial infections. The primary mechanism of action is inhibition of translation by binding to the ribosome, but how it enters the bacterial cell is unclear. Early in the study of this antibiotic, a mysterious streptomycin-induced potassium efflux preceding any decrease in viability was observed; it was speculated that this changed the electrochemical gradient such that streptomycin better accessed the cytoplasm. Here we use a high-throughput screen to search for compounds targeting the mechanosensitive channel of large conductance (MscL) and find dihydrostreptomycin among the ‘hits’. Furthermore, we find that MscL is not only necessary for the previously described streptomycin-induced potassium efflux, but also directly increases MscL activity in electrophysiological studies. The data suggest that gating MscL is a novel mode of action of dihydrostreptomycin, and that MscL’s large pore may provide a mechanism for cell entry.

  19. GMP-compliant isolation and large-scale expansion of bone marrow-derived MSC.

    Directory of Open Access Journals (Sweden)

    Natalie Fekete

    Full Text Available BACKGROUND: Mesenchymal stromal cells (MSC have gained importance in tissue repair, tissue engineering and in immunosupressive therapy during the last years. Due to the limited availability of MSC in the bone marrow, ex vivo amplification prior to clinical application is requisite to obtain therapeutic applicable cell doses. Translation of preclinical into clinical-grade large-scale MSC expansion necessitates precise definition and standardization of all procedural parameters including cell seeding density, culture medium and cultivation devices. While xenogeneic additives such as fetal calf serum are still widely used for cell culture, its use in the clinical context is associated with many risks, such as prion and viral transmission or adverse immunological reactions against xenogeneic components. METHODS AND FINDINGS: We established animal-free expansion protocols using platelet lysate as medium supplement and thereby could confirm its safety and feasibility for large-scale MSC isolation and expansion. Five different GMP-compliant standardized protocols designed for the safe, reliable, efficient and economical isolation and expansion of MSC was performed and MSC obtained were analyzed for differentiation capacity by qPCR and histochemistry. Expression of standard MSC markers as defined by the International Society for Cellular Therapy as well as expression of additional MSC markers and of various chemokine and cytokine receptors was analysed by flow cytometry. Changes of metabolic markers and cytokines in the medium were addressed using the LUMINEX platform. CONCLUSIONS: The five different systems for isolation and expansion of MSC described in this study are all suitable to produce at least 100 millions of MSC, which is commonly regarded as a single clinical dose. Final products are equal according to the minimal criteria for MSC defined by the ISCT. We showed that chemokine and integrin receptors analyzed had the same expression pattern

  20. Stem cells: A new paradigm in periodontal regeneration

    Directory of Open Access Journals (Sweden)

    Marawar Pramod P, Shinde Sagar K, Mani Ameet M, Patil Ishwardas D

    2013-04-01

    Full Text Available Stem cells are a unique type of cell that forms the basis of the development, growth and survival of a living organism. Though the term is often used to describe controversial embryonic stem cells, there are many different types of stem cells, classified by their original location and/or method of formation. Stem cells are undifferentiated cells that go on developing into any of more than 200 type of cells that adult Human body hold. Now a days stem cells have significant use in regenerative periodontal therapy. Recently, reports have begun to emerge demonstrating that populations of adult stem cells reside in the periodontal ligament of humans and other animals. This opens the way for new cell-based therapies for periodontal regeneration.This review provides an overview of adult human stem cells and their potential use in periodontal regeneration.

  1. Hungarian medical physics MSc education

    International Nuclear Information System (INIS)

    Legrady, D.; Czifrus, Z.; Zarand, P.; Aszodi, A.; Pesznyak, C.; Major, T.

    2012-01-01

    The medical physics specialisation aims at providing high level interdisciplinary theoretical and practical knowledge and readily applicable skills, which can put into action in both the clinical and the R and D field. The first competence based gradual medical physics course in the B.Sc./M.Sc. system in Hungary was launched two years ago at the Faculty of Natural Sciences of Budapest University of Technology and Economics managed by the Institute of Nuclear Techniques. The MSc programme was compiled on the base of EFOMP, IPEM, AAPM and IAEA recommendations. The course curriculum comprises fundamental physical subjects (atomic and molecular physics, nuclear physics and particle physics) as well as fundamental medical knowledge (anatomy, physiology and radiobiology) required for subjects of diagnostic and therapy. Students of this MSc branch may chose further subjects from a 'compulsory optional' set of subjects, which contains medical imaging, X-ray diagnostics, radiation therapy, magnetic resonance imaging, radiation protection, Monte Carlo calculation and its clinical applications, ultrasound diagnostics and nuclear medicine. (authors)

  2. Transcriptome Analyses of Mosaic (MSC Mitochondrial Mutants of Cucumber in a Highly Inbred Nuclear Background

    Directory of Open Access Journals (Sweden)

    Tomasz L. Mróz

    2018-03-01

    Full Text Available Cucumber (Cucumis sativus L. has a large, paternally transmitted mitochondrial genome. Cucumber plants regenerated from cell cultures occasionally show paternally transmitted mosaic (MSC phenotypes, characterized by slower growth, chlorotic patterns on the leaves and fruit, lower fertility, and rearrangements in their mitochondrial DNAs (mtDNAs. MSC lines 3, 12, and 16 originated from different cell cultures all established using the highly inbred, wild-type line B. These MSC lines possess different rearrangements and under-represented regions in their mtDNAs. We completed RNA-seq on normalized and non-normalized cDNA libraries from MSC3, MSC12, and MSC16 to study their nuclear gene-expression profiles relative to inbred B. Results from both libraries indicated that gene expression in MSC12 and MSC16 were more similar to each other than MSC3. Forty-one differentially expressed genes (DEGs were upregulated and one downregulated in the MSC lines relative to B. Gene functional classifications revealed that more than half of these DEGs are associated with stress-response pathways. Consistent with this observation, we detected elevated levels of hydrogen peroxide throughout leaf tissue in all MSC lines compared to wild-type line B. These results demonstrate that independently produced MSC lines with different mitochondrial polymorphisms show unique and shared nuclear responses. This study revealed genes associated with stress response that could become selection targets to develop cucumber cultivars with increased stress tolerance, and further support of cucumber as a model plant to study nuclear-mitochondrial interactions.

  3. TOR and paradigm change: cell growth is controlled.

    Science.gov (United States)

    Hall, Michael N

    2016-09-15

    This year marks the 25th anniversary of the discovery of target of rapamycin (TOR), a highly conserved kinase and central controller of cell growth. In this Retrospective, I briefly describe the discovery of TOR and the subsequent elucidation of its cellular role. I place particular emphasis on an article by Barbet et al. from 1996, the first suggesting that TOR controls cell growth in response to nutrients. © 2016 Hall. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

  4. Different Culture Media Affect Proliferation, Surface Epitope Expression, and Differentiation of Ovine MSC

    Directory of Open Access Journals (Sweden)

    Carina Adamzyk

    2013-01-01

    Full Text Available Orthopedic implants including engineered bone tissue are commonly tested in sheep. To avoid rejection of heterologous or xenogeneic cells, autologous cells are preferably used, that is, ovine mesenchymal stem cells (oMSC. Unlike human MSC, ovine MSC are not well studied regarding isolation, expansion, and characterization. Here we investigated the impact of culture media composition on growth characteristics, differentiation, and surface antigen expression of oMSC. The culture media varied in fetal calf serum (FCS content and in the addition of supplements and/or additional epidermal growth factor (EGF. We found that FCS strongly influenced oMSC proliferation and that specific combinations of supplemental factors (MCDB-201, ITS-plus, dexamethasone, and L-ascorbic acid determined the expression of surface epitopes. We compared two published protocols for oMSC differentiation towards the osteogenic, adipogenic, and chondrogenic fate and found (i considerable donor to donor variations, (ii protocol-dependent variations, and (iii variations resulting from the preculture medium composition. Our results indicate that the isolation and culture of oMSC in different growth media are highly variable regarding oMSC phenotype and behaviour. Furthermore, variations from donor to donor critically influence growth rate, surface marker expression, and differentiation.

  5. The nucleolus: a paradigm for cell proliferation and aging

    Directory of Open Access Journals (Sweden)

    Comai L.

    1999-01-01

    Full Text Available The nucleolus is the cellular site of ribosome biosynthesis. At this site, active ribosomal DNA (rDNA genes are rapidly transcribed by RNA polymerase I (pol I molecules. Recent advances in our understanding of the pol I transcription system have indicated that regulation of ribosomal RNA (rRNA synthesis is a critical factor in cell growth. Importantly, the same signaling networks that control cell growth and proliferation and are deregulated in cancer appear to control pol I transcription. Therefore, the study of the biochemical basis for growth regulation of pol I transcription can provide basic information about the nuclear signaling network. Hopefully, this information may facilitate the search for drugs that can inhibit the growth of tumor cells by blocking pol I activation. In addition to its function in ribosome biogenesis, recent studies have revealed the prominent role of the nucleolus in cell senescence. These findings have stimulated a new wave of research on the functional relationship between the nucleolus and aging. The aim of this review is to provide an overview of some current topics in the area of nucleolus biology, and it has been written for a general readership.

  6. New paradigms for metabolic modeling of human cells

    DEFF Research Database (Denmark)

    Mardinoglu, Adil; Nielsen, Jens

    2015-01-01

    review recent work on reconstruction of GEMs for human cell/tissue types and cancer, and the use of GEMs for identification of metabolic changes occurring in response to disease development. We further discuss how GEMs can be used for the development of efficient therapeutic strategies. Finally......Abnormalities in cellular functions are associated with the progression of human diseases, often resulting in metabolic reprogramming. GEnome-scale metabolic Models (GEMs) have enabled studying global metabolic reprogramming in connection with disease development in a systematic manner. Here we...

  7. Effects of platelet rich plasma and chondrocyte co-culture on MSC chondrogenesis, hypertrophy and pathological responses

    OpenAIRE

    Ramezanifard, Rouhallah; Kabiri, Mahboubeh; Hanaee Ahvaz, Hana

    2017-01-01

    Regarding the inadequate healing capability of cartilage tissue, cell-based therapy is making the future of cartilage repair and regeneration. Mesenchymal stem cells (MSC) have shown great promise in cartilage regeneration. However, a yet-unresolved issue is the emergence of hypertrophic and pathologic markers during in vitro MSC chondrogenesis. Articular chondrocytes (AC) can suppress the undesired hypertrophy when co-cultured with MSC. On the other hand, platelet rich plasma (PRP), is consi...

  8. USING OF MSC WITH DIFFERENT ONTOGENETIC MATURITY FOR CORRECTION OF CHRONIC FIBROSING LIVER DAMAGE

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    M. Y. Shagidulin

    2013-01-01

    Full Text Available Aim. To compare the effectiveness of MSC with different degree of ontogenetic maturity (MSC bone marrow – MSC BM and MSC umbilical cord – MSC UC on regenerative processes in injured liver. Methods. In 4 groups of experiments on Wistar rats (n = 80 with a model of fibrotic toxic liver damage (FLD it was studied the effect of MSCs with different degree of ontogenetic maturity on recovery processes at the regeneration of damaged liver: 1 gr. – Control, 2 gr. and 3 gr. introduction of MSC BM, included in Sphero®GEL-long in doses of 2.5 ×106 and 5.0 x 106 cells, respectively, and 4 gr. – introduction of MSC UC in the form of cell-spheroids (8–10 × 105 cells. The cells were injected into the damaged liver in 7 days after the end of FDL-modeling. The effect of cell therapy was studied during 180 days. The effectiveness of corrective therapy was evaluated by the results of functional and morphological investigations of livers (histological control of parenchymal and nonparenchy- mal liver tissue. Results. MSC BM in both doses and MSC UC contributed to a more rapid normalization of liver enzyme indices compared with the control (1 gr., but the differences in the rate of recovery of disturbed enzymatic liver functions between groups 2, 3 and 4 – were absent. In 90 days after the cell application it was determined a more pronounced recovery activity of cells in groups 3 and 4; in 180 days the more pronounced activation of recovery processes was observed in group 3; but in group 4 the sclerotic processes were more pro- nounced in this period. Conclusion. For the induction of recovery processes in damage liver it is advisable not to use the MSC UC, but to use MSC BM in the Sphero®GEL, because MSC BM exert not only local but also systemic immune-regulatory effect, increasing the pool of T-reg. cells, which are additional carriers of regenera- tion information in organism. 

  9. Safety assessment of bone marrow derived MSC grown in platelet-rich plasma

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    Shoji Fukuda

    2015-06-01

    Full Text Available The injection of endothelial progenitor cells and mononuclear cells derived from bone marrow at the ischemic region of peripheral artery disease patients is reported to be effective for therapeutic angiogenesis; however, these cell therapies require large amounts of bone marrow to obtain sufficient numbers of cells. To solve this problem, we attempted to culture bone-marrow-derived mesenchymal stem cells (BM-MSC, which are supposed to secrete several cytokines that promote angiogenesis. We also focused on using platelet-rich plasma (PRP as a supplement for cell culture instead of fetal bovine serum. Human BM-MSC obtained from healthy volunteers expanded rapidly when cultured with 10% PRP prepared from their own blood. FACS analysis revealed that these cultured human MSC were homogeneous populations, and chromosomal analysis showed a normal karyotype. Moreover, the angiogenetic effect was apparent two weeks after human BM-MSC were injected into the ischemic muscle in SCID mice. Tumor formation was not detected three months after injection into SCID mice either subcutaneously or intramuscularly. To simulate clinical settings, canine BM-MSC were grown with canine PRP and injected into their ischemic muscles. We confirmed that donor cells existed in situ two and six weeks after operation without any side effects. These results suggest that cultured human BM-MSC can be a promising cell source for therapeutic angiogenesis.

  10. Breaking Out of the Cell: On The Benefits of a New Spreadsheet User-Interaction Paradigm

    OpenAIRE

    Hellman, Ziv

    2008-01-01

    Contemporary spreadsheets are plagued by a profusion of errors, auditing difficulties, lack of uniform development methodologies, and barriers to easy comprehension of the underlying business models they represent. This paper presents a case that most of these difficulties stem from the fact that the standard spreadsheet user-interaction paradigm - the 'cell-matrix' approach - is appropriate for spreadsheet data presentation but has significant drawbacks with respect to spreadsheet creation, ...

  11. Galectin-1 and galectin-3 expression in equine mesenchymal stromal cells (MSCs, synovial fibroblasts and chondrocytes, and the effect of inflammation on MSC motility

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    Heidi L. Reesink

    2017-11-01

    Full Text Available Abstract Background Mesenchymal stromal cells (MSCs can be used intra-articularly to quell inflammation and promote cartilage healing; however, mechanisms by which MSCs mitigate joint disease remain poorly understood. Galectins, a family of β-galactoside binding proteins, regulate inflammation, adhesion and cell migration in diverse cell types. Galectin-1 and galectin-3 are proposed to be important intra-articular modulators of inflammation in both osteoarthritis and rheumatoid arthritis. Here, we asked whether equine bone marrow-derived MSCs (BMSCs express higher levels of galectin-1 and -3 relative to synovial fibroblasts and chondrocytes and if an inflammatory environment affects BMSC galectin expression and motility. Methods Equine galectin-1 and -3 gene expression was quantified using qRT-PCR in cultured BMSCs, synoviocytes and articular chondrocytes, in addition to synovial membrane and articular cartilage tissues. Galectin gene expression, protein expression, and protein secretion were measured in equine BMSCs following exposure to inflammatory cytokines (IL-1β 5 and 10 ng/mL, TNF-α 25 and 50 ng/mL, or LPS 0.1, 1, 10 and 50 μg/mL. BMSC focal adhesion formation was assessed using confocal microscopy, and BMSC motility was quantified in the presence of inflammatory cytokines (IL-1β or TNF-α and the pan-galectin inhibitor β-lactose (100 and 200 mM. Results Equine BMSCs expressed 3-fold higher galectin-1 mRNA levels as compared to cultured synovial fibroblasts (p = 0.0005 and 30-fold higher galectin-1 (p < 0.0001 relative to cultured chondrocytes. BMSC galectin-1 mRNA expression was significantly increased as compared to carpal synovial membrane and articular cartilage tissues (p < 0.0001. IL-1β and TNF-α treatments decreased BMSC galectin gene expression and impaired BMSC motility in dose-dependent fashion but did not alter galectin protein expression. β-lactose abrogated BMSC focal adhesion formation and inhibited

  12. Galectin-1 and galectin-3 expression in equine mesenchymal stromal cells (MSCs), synovial fibroblasts and chondrocytes, and the effect of inflammation on MSC motility.

    Science.gov (United States)

    Reesink, Heidi L; Sutton, Ryan M; Shurer, Carolyn R; Peterson, Ryan P; Tan, Julie S; Su, Jin; Paszek, Matthew J; Nixon, Alan J

    2017-11-02

    Mesenchymal stromal cells (MSCs) can be used intra-articularly to quell inflammation and promote cartilage healing; however, mechanisms by which MSCs mitigate joint disease remain poorly understood. Galectins, a family of β-galactoside binding proteins, regulate inflammation, adhesion and cell migration in diverse cell types. Galectin-1 and galectin-3 are proposed to be important intra-articular modulators of inflammation in both osteoarthritis and rheumatoid arthritis. Here, we asked whether equine bone marrow-derived MSCs (BMSCs) express higher levels of galectin-1 and -3 relative to synovial fibroblasts and chondrocytes and if an inflammatory environment affects BMSC galectin expression and motility. Equine galectin-1 and -3 gene expression was quantified using qRT-PCR in cultured BMSCs, synoviocytes and articular chondrocytes, in addition to synovial membrane and articular cartilage tissues. Galectin gene expression, protein expression, and protein secretion were measured in equine BMSCs following exposure to inflammatory cytokines (IL-1β 5 and 10 ng/mL, TNF-α 25 and 50 ng/mL, or LPS 0.1, 1, 10 and 50 μg/mL). BMSC focal adhesion formation was assessed using confocal microscopy, and BMSC motility was quantified in the presence of inflammatory cytokines (IL-1β or TNF-α) and the pan-galectin inhibitor β-lactose (100 and 200 mM). Equine BMSCs expressed 3-fold higher galectin-1 mRNA levels as compared to cultured synovial fibroblasts (p = 0.0005) and 30-fold higher galectin-1 (p < 0.0001) relative to cultured chondrocytes. BMSC galectin-1 mRNA expression was significantly increased as compared to carpal synovial membrane and articular cartilage tissues (p < 0.0001). IL-1β and TNF-α treatments decreased BMSC galectin gene expression and impaired BMSC motility in dose-dependent fashion but did not alter galectin protein expression. β-lactose abrogated BMSC focal adhesion formation and inhibited BMSC motility. Equine BMSCs constitutively

  13. Combined MSC and GLP-1 Therapy Modulates Collagen Remodeling and Apoptosis following Myocardial Infarction

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    Elizabeth J. Wright

    2016-01-01

    Full Text Available Background. Mesenchymal stem cells (MSCs and glucagon-like peptide-1 (GLP-1 are being tested as treatment strategies for myocardial infarction (MI; however, their mechanisms in the heart are not fully understood. Methods. We examined the effects of MSCs, either native, or engineered to secrete a GLP-1 fusion protein (MSCs ± GLP-1, on human cardiomyocyte apoptosis in vitro. The effect on cardiac remodeling when encapsulated in alginate beads (CellBeads-MSC and CellBeads-MSC + GLP-1 was also evaluated in a pig MI model, whereby pigs were treated with Empty Beads, CellBeads-MSC, or CellBeads-MSC + GLP-1 and sacrificed at one or four weeks following MI. Results. MSC + GLP-1 conditioned media demonstrated antiapoptotic effects on ischaemic human cardiomyocytes in vitro. In vivo, qRT-PCR revealed large changes in the expression of several genes involved in extracellular matrix remodeling, which were altered following MSC ± GLP treatment. After four weeks, infarcted areas were imaged using atomic force microscopy, demonstrating significant alterations between groups in the structure of collagen fibrils and resulting scar. Conclusions. These data demonstrate that MSCs ± GLP-1 exhibit modulatory effects on healing post-MI, affecting both apoptosis and collagen scar formation. These data support the premise that both MSCs and GLP-1 could be beneficial in MI treatment.

  14. Infusion of Trx-1-overexpressing hucMSC prolongs the survival of acutely irradiated NOD/SCID mice by decreasing excessive inflammatory injury.

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    JiangWei Hu

    Full Text Available A protective reagent for ARI should have the ability to repair injured tissue caused by radiation and prevent continuous damage from secondary risk factors. Trx-1 was explored as a candidate therapy for ARI, as it scavenges reactive oxygen species, regulates cell growth and differentiation, participates in immune reactions, and inhibits apoptosis by acting inside and/or outside cells. Trx-1 can also decrease excessive inflammation in ARI by regulating the creation of inflamed media, by inhibiting the activation of complement, and by reducing the chemotaxis, adhesion, and migration of inflammatory cells. As effectively and stably expressing exogenous genes in the long term and regulating immune inflammation and tissue repair, MSC are a good choice for Trx-1 gene therapy. In this study, Trx-1-overexpressing hucMSC-Trx-1 were obtained by adenoviral vector-mediated infection. We first measured the redox capacity of hucMSC-Trx-1 with an antioxidant capacity (T-AOC assay, a hydrogen peroxide (H2O2 content determination assay in vivo, a H2O2-induced oxidation hemolysis assay, and a lipid peroxidation assay in vitro. Then, we measured survival time, the protection of the hematopoietic system, and the regulation of inflammation in important organs in three treatment groups of NOD/SCID mice (treated with hucMSC-Trx-1, with hucMSC, and with saline that were exposed to 4.5 Gy (60Co-γ-ray radiation. The hucMSC-Trx-1 group achieved superior antioxidation results, protecting bone marrow hematopoietic stem cells (Lin(-CD117(+: hucMSC-Trx-1 vs. hucMSC, P<0.05; hucMSC-Trx-1 vs. NS, P<0.01, promoting the formation of red blood cells and hemoglobin (hucMSC-Trx-1 vs. hucMSC or NS, P<0.05, reducing inflammation and damage in important organs (Bone marrow and lung: hucMSC-Trx-1 vs. NS, P<0.01; hucMSC-Trx-1 vs. hucMSC, P<0.05. Liver and intestine: hucMSC-Trx-1 vs. NS, P<0.05; hucMSC-Trx-1 vs. hucMSC, P<0.05, and prolonging survival (hucMSC-Trx-1 vs. hucMSC or NS, P<0

  15. Pharmacophore-based screening of differentially-expressed PGF, DDIT4, COMP and CHI3L1 from hMSC cell lines reveals five novel therapeutic compounds for primary osteoporosis

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    Catherine Jessica Lai

    2016-06-01

    Full Text Available As many societies age, primary osteoporosis (PO is increasingly a major health problem. Current drug treatments such as alendronate and risedronate have known side effects. We took an agnostic empirical approach to find PO therapeutic compounds. We examined 13,548,960 probe data-points from mesenchymal stromal cell (hMSC lines and found that PGF, DDIT4, and COMP to be up-regulated, and CHI3L1, down-regulated. We then identified their druggable domains. For the up-regulated differentially-expressed genes, we used protein–protein interactions to find residue clusters as binding surfaces. We then employed pharmacophore models to screen 15,407,096 conformations of 22,723,923 compounds, which identified (6R,9R-6-(2-furyl-9-(1H-indol-3-yl-2-(trifluoromethyl-5,6,7, 9-tetrahydro-4H[1,2,4]triazolo[5,1],(2S-N1-[2-[2-(methylamino-2-oxo-ethyl]phenyl]-N2-phenylpyrrolidine-1,2-dicarboxamide, and 2-furyl-(1H-indol-3-yl-methyl-BLAHone as candidate compounds. For the down-regulated CH13L1, we relied on genome-wide disease signatures to identify (11alpha-9-fluoro-11,17,21-trihydroxypregn-4-ene-3,20-dione and Genistein as candidate compounds. Our approach differs from previous research as we did not confine our drug targets to hypothesized compounds in the existing literature. Instead, we allowed the full expression profile of PO cell lines to reveal the most desirable targets. Second, our differential gene analysis revealed both up- and down-regulated genes, in contrast to the literature, which has focused on inhibiting only up-regulated genes. Third, our virtual screening universe of 22,723,923 compounds was more than 100 times larger than those in the known literature.

  16. A new antibiotic with potent activity targets MscL.

    Science.gov (United States)

    Iscla, Irene; Wray, Robin; Blount, Paul; Larkins-Ford, Jonah; Conery, Annie L; Ausubel, Frederick M; Ramu, Soumya; Kavanagh, Angela; Huang, Johnny X; Blaskovich, Mark A; Cooper, Matthew A; Obregon-Henao, Andres; Orme, Ian; Tjandra, Edwin S; Stroeher, Uwe H; Brown, Melissa H; Macardle, Cindy; van Holst, Nick; Ling Tong, Chee; Slattery, Ashley D; Gibson, Christopher T; Raston, Colin L; Boulos, Ramiz A

    2015-07-01

    The growing problem of antibiotic-resistant bacteria is a major threat to human health. Paradoxically, new antibiotic discovery is declining, with most of the recently approved antibiotics corresponding to new uses for old antibiotics or structurally similar derivatives of known antibiotics. We used an in silico approach to design a new class of nontoxic antimicrobials for the bacteria-specific mechanosensitive ion channel of large conductance, MscL. One antimicrobial of this class, compound 10, is effective against methicillin-resistant Staphylococcus aureus with no cytotoxicity in human cell lines at the therapeutic concentrations. As predicted from in silico modeling, we show that the mechanism of action of compound 10 is at least partly dependent on interactions with MscL. Moreover we show that compound 10 cured a methicillin-resistant S. aureus infection in the model nematode Caenorhabditis elegans. Our work shows that compound 10, and other drugs that target MscL, are potentially important therapeutics against antibiotic-resistant bacterial infections.

  17. Primary Spinal Germ Cell Tumors: A Case Analysis and Review of Treatment Paradigms

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    Joshua J. Loya

    2013-01-01

    Full Text Available Objective. Primary intramedullary spinal germ cell tumors are exceedingly rare. As such, there are no established treatment paradigms. We describe our management for spinal germ cell tumors and a review of the literature. Clinical Presentation. We describe the case of a 45-year-old man with progressive lower extremity weakness and sensory deficits. He was found to have enhancing intramedullary mass lesions in the thoracic spinal cord, and pathology was consistent with an intramedullary germ cell tumor. A video presentation of the case and surgical approach is provided. Conclusion. As spinal cord germinomas are highly sensitive to radiation and chemotherapy, a patient can be spared radical surgery. Diverse treatment approaches exist across institutions. We advocate biopsy followed by local radiation, with or without adjuvant chemotherapy, as the optimal treatment for these tumors. Histological findings have prognostic value if syncytiotrophoblastic giant cells (STGCs are found, which are associated with a higher rate of recurrence. The recurrence rate in STGC-positive spinal germinomas is 33% (2/6, whereas it is only 8% in STGC-negative tumors (2/24. We advocate limited volume radiotherapy combined with systemic chemotherapy in patients with high risk of recurrence. To reduce endocrine and neurocognitive side effects, cranio-spinal radiation should be used as a last resort in patients with recurrence.

  18. In vivo MR detection of fluorine-labeled human MSC using the bSSFP sequence.

    Science.gov (United States)

    Ribot, Emeline J; Gaudet, Jeffrey M; Chen, Yuhua; Gilbert, Kyle M; Foster, Paula J

    2014-01-01

    Mesenchymal stem cells (MSC) are used to restore deteriorated cell environments. There is a need to specifically track these cells following transplantation in order to evaluate different methods of implantation, to follow their migration within the body, and to quantify their accumulation at the target. Cellular magnetic resonance imaging (MRI) using fluorine-based nanoemulsions is a great means to detect these transplanted cells in vivo because of the high specificity for fluorine detection and the capability for precise quantification. This technique, however, has low sensitivity, necessitating improvement in MR sequences. To counteract this issue, the balanced steady-state free precession (bSSFP) imaging sequence can be of great interest due to the high signal-to-noise ratio (SNR). Furthermore, it can be applied to obtain 3D images within short acquisition times. In this paper, bSSFP provided accurate quantification of samples of the perfluorocarbon Cell Sense-labeled cells in vitro. Cell Sense was internalized by human MSC (hMSC) without adverse alterations in cell viability or differentiation into adipocytes/osteocytes. The bSSFP sequence was applied in vivo to track and quantify the signals from both Cell Sense-labeled and iron-labeled hMSC after intramuscular implantation. The fluorine signal was observed to decrease faster and more significantly than the volume of iron-associated voids, which points to the advantage of quantifying the fluorine signal and the complexity of quantifying signal loss due to iron.

  19. MSC-derived Extracellular Vesicles Attenuate Immune Responses in Two Autoimmune Murine Models: Type 1 Diabetes and Uveoretinitis

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    Taeko Shigemoto-Kuroda

    2017-05-01

    Full Text Available Accumulating evidence shows that extracellular vesicles (EVs produced by mesenchymal stem/stromal cells (MSCs exert their therapeutic effects in several disease models. We previously demonstrated that MSCs suppress autoimmunity in models of type 1 diabetes (T1D and experimental autoimmune uveoretinitis (EAU. Therefore, here, we investigated the therapeutic potential of MSC-derived EVs using our established mouse models for autoimmune diseases affecting the pancreas and the eye: T1D and EAU. The data demonstrate that MSC-derived EVs effectively prevent the onset of disease in both T1D and EAU. In addition, the mixed lymphocyte reaction assay with MSC-derived EVs indicated that EVs inhibit activation of antigen-presenting cells and suppress development of T helper 1 (Th1 and Th17 cells. These results raise the possibility that MSC-derived EVs may be an alternative to cell therapy for autoimmune disease prevention.

  20. Phenotypic, Functional, and Safety Control at Preimplantation Phase of MSC-Based Therapy.

    Science.gov (United States)

    Lech, Wioletta; Figiel-Dabrowska, Anna; Sarnowska, Anna; Drela, Katarzyna; Obtulowicz, Patrycja; Noszczyk, Bartlomiej Henryk; Buzanska, Leonora; Domanska-Janik, Krystyna

    2016-01-01

    Mesenchymal stem cells (MSC) exhibit enormous heterogeneity which can modify their regenerative properties and therefore influence therapeutic effectiveness as well as safety of these cells transplantation. In addition the high phenotypic plasticity of MSC population makes it enormously sensitive to any changes in environmental properties including fluctuation in oxygen concentration. We have shown here that lowering oxygen level far below air atmosphere has a beneficial impact on various parameters characteristic for umbilical cord Wharton Jelly- (WJ-) MSC and adipose tissue- (AD-) derived MSC cultures. This includes their cellular composition, rate of proliferation, and maintenance of stemness properties together with commitment to cell differentiation toward mesodermal and neural lineages. In addition, the culture genomic stability increased significantly during long-term cell passaging and eventually protected cells against spontaneous transformation. Also by comparing of two routinely used methods of MSCs isolation (mechanical versus enzymatic) we have found substantial divergence arising between cell culture properties increasing along the time of cultivation in vitro. Thus, in this paper we highlight the urgent necessity to develop the more sensitive and selective methods for prediction and control cells fate and functioning during the time of growth in vitro.

  1. Phenotypic, Functional, and Safety Control at Preimplantation Phase of MSC-Based Therapy

    Science.gov (United States)

    Lech, Wioletta; Figiel-Dabrowska, Anna; Drela, Katarzyna; Obtulowicz, Patrycja; Noszczyk, Bartlomiej Henryk; Buzanska, Leonora

    2016-01-01

    Mesenchymal stem cells (MSC) exhibit enormous heterogeneity which can modify their regenerative properties and therefore influence therapeutic effectiveness as well as safety of these cells transplantation. In addition the high phenotypic plasticity of MSC population makes it enormously sensitive to any changes in environmental properties including fluctuation in oxygen concentration. We have shown here that lowering oxygen level far below air atmosphere has a beneficial impact on various parameters characteristic for umbilical cord Wharton Jelly- (WJ-) MSC and adipose tissue- (AD-) derived MSC cultures. This includes their cellular composition, rate of proliferation, and maintenance of stemness properties together with commitment to cell differentiation toward mesodermal and neural lineages. In addition, the culture genomic stability increased significantly during long-term cell passaging and eventually protected cells against spontaneous transformation. Also by comparing of two routinely used methods of MSCs isolation (mechanical versus enzymatic) we have found substantial divergence arising between cell culture properties increasing along the time of cultivation in vitro. Thus, in this paper we highlight the urgent necessity to develop the more sensitive and selective methods for prediction and control cells fate and functioning during the time of growth in vitro. PMID:27651796

  2. Pathogenesis of childhood idiopathic nephrotic syndrome: a paradigm shift from T-cells to podocytes.

    Science.gov (United States)

    Kaneko, Kazunari; Tsuji, Shoji; Kimata, Takahisa; Kitao, Tetsuya; Yamanouchi, Sohsaku; Kato, Shogo

    2015-02-01

    Nephrotic syndrome is the most common cause of kidney disease in children, but its pathogenesis remains unclear. This article reviews the novel aspects of the mechanisms underlying massive proteinuria in minimal-change disease, which is the most common form of childhood nephrotic syndrome. This article integrates the findings of a PubMed database search for English language articles published in the past 40 years (from September 1974 to February 2014) using the key words "pathogenesis", "minimal change nephrotic syndrome" or "idiopathic nephrotic syndrome". Unknown humoral factors associated with T-cell dysfunction have been thought to play an important role in the pathogenesis of minimal-change disease. However, recent findings are changing this paradigm, i.e., visceral glomerular epithelial cells (podocytes) may be involved via expression of molecules such as CD80 and angiopoietin-like 4. Recent evidence suggests that minimal-change disease results from interactions between humoral factors and dysfunctional podocytes. In addition to immunosuppressant drugs that target lymphocytes, a biological agent such as an antibody against the abnormal molecule(s) expressed by podocytes may provide novel drug treatment for minimal-change disease.

  3. Thermodynamic Paradigm for Solution Demixing Inspired by Nuclear Transport in Living Cells.

    Science.gov (United States)

    Wang, Ching-Hao; Mehta, Pankaj; Elbaum, Michael

    2017-04-14

    Living cells display a remarkable capacity to compartmentalize their functional biochemistry. A particularly fascinating example is the cell nucleus. Exchange of macromolecules between the nucleus and the surrounding cytoplasm does not involve traversing a lipid bilayer membrane. Instead, large protein channels known as nuclear pores cross the nuclear envelope and regulate the passage of other proteins and RNA molecules. Beyond simply gating diffusion, the system of nuclear pores and associated transport receptors is able to generate substantial concentration gradients, at the energetic expense of guanosine triphosphate hydrolysis. In contrast to conventional approaches to demixing such as reverse osmosis and dialysis, the biological system operates continuously, without application of cyclic changes in pressure or solvent exchange. Abstracting the biological paradigm, we examine this transport system as a thermodynamic machine of solution demixing. Building on the construct of free energy transduction and biochemical kinetics, we find conditions for the stable operation and optimization of the concentration gradients as a function of dissipation in the form of entropy production.

  4. MSC/ECM Cellular Complexes Induce Periodontal Tissue Regeneration.

    Science.gov (United States)

    Takewaki, M; Kajiya, M; Takeda, K; Sasaki, S; Motoike, S; Komatsu, N; Matsuda, S; Ouhara, K; Mizuno, N; Fujita, T; Kurihara, H

    2017-08-01

    Transplantation of mesenchymal stem cells (MSCs), which possess self-renewing properties and multipotency, into a periodontal defect is thought to be a useful option for periodontal tissue regeneration. However, developing more reliable and predictable implantation techniques is still needed. Recently, we generated clumps of an MSC/extracellular matrix (ECM) complex (C-MSC), which consisted of cells and self-produced ECM. C-MSCs can regulate their cellular functions in vitro and can be grafted into a defect site, without any artificial scaffold, to induce bone regeneration. Accordingly, this study aimed to evaluate the effect of C-MSC transplantation on periodontal tissue regeneration in beagle dogs. Seven beagle dogs were employed to generate a premolar class III furcation defect model. MSCs isolated from dog ilium were seeded at a density of 7.0 × 10 4 cells/well into 24-well plates and cultured in growth medium supplemented with 50 µg/mL ascorbic acid for 4 d. To obtain C-MSCs, confluent cells were scratched using a micropipette tip and were then torn off as a cellular sheet. The sheet was rolled up to make round clumps of cells. C-MSCs were maintained in growth medium or osteoinductive medium (OIM) for 5 or 10 d. The biological properties of C-MSCs were evaluated in vitro, and their periodontal tissue regenerative activity was tested by using a dog class III furcation defect model. Immunofluorescence analysis revealed that type I collagen fabricated the form of C-MSCs. OIM markedly elevated calcium deposition in C-MSCs at day 10, suggesting its osteogenic differentiation capacity. Both C-MSCs and C-MSCs cultured with OIM transplantation without an artificial scaffold into the dog furcation defect induced periodontal tissue regeneration successfully compared with no graft, whereas osteogenic-differentiated C-MSCs led to rapid alveolar bone regeneration. These findings suggested that the use of C-MSCs refined by self-produced ECM may represent a novel

  5. A new paradigm for the role of smooth muscle cells in the human cervix.

    Science.gov (United States)

    Vink, Joy Y; Qin, Sisi; Brock, Clifton O; Zork, Noelia M; Feltovich, Helen M; Chen, Xiaowei; Urie, Paul; Myers, Kristin M; Hall, Timothy J; Wapner, Ronald; Kitajewski, Jan K; Shawber, Carrie J; Gallos, George

    2016-10-01

    % cervical smooth muscle cells that were randomly scattered in the tissue. In organ bath studies, oxytocin stimulated the internal os to contract with more than double the force of the external os (1341 ± 693 vs 523 ± 536 integrated grams × seconds, respectively, P = .009). Nifedipine significantly decreased cervical tissue muscle force compared to timed vehicle control (oxytocin alone) at doses of 10(-5) mol/L (vehicle 47% ± 15% vs oxytocin + nifedipine 24% ± 16%, P = .007), 10(-4) mol/L (vehicle 46% ± 16% vs oxytocin + nifedipine -4% ± 20%, P = .003), and 10(-3) mol/L (vehicle 42% ± 14% vs oxytocin + nifedipine -15% ± 18%, P = .0006). The half maximal inhibitory concentration for nifedipine was 1.35 × 10(-5) mol/L. Our findings suggest a new paradigm for cervical tissue morphology-one that includes the possibility of a specialized sphincter at the internal os. This new paradigm introduces novel avenues to further investigate potential mechanisms of normal and premature cervical remodeling. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. An improved ontological representation of dendritic cells as a paradigm for all cell types

    Directory of Open Access Journals (Sweden)

    Mungall Chris

    2009-02-01

    Full Text Available Abstract Background Recent increases in the volume and diversity of life science data and information and an increasing emphasis on data sharing and interoperability have resulted in the creation of a large number of biological ontologies, including the Cell Ontology (CL, designed to provide a standardized representation of cell types for data annotation. Ontologies have been shown to have significant benefits for computational analyses of large data sets and for automated reasoning applications, leading to organized attempts to improve the structure and formal rigor of ontologies to better support computation. Currently, the CL employs multiple is_a relations, defining cell types in terms of histological, functional, and lineage properties, and the majority of definitions are written with sufficient generality to hold across multiple species. This approach limits the CL's utility for computation and for cross-species data integration. Results To enhance the CL's utility for computational analyses, we developed a method for the ontological representation of cells and applied this method to develop a dendritic cell ontology (DC-CL. DC-CL subtypes are delineated on the basis of surface protein expression, systematically including both species-general and species-specific types and optimizing DC-CL for the analysis of flow cytometry data. We avoid multiple uses of is_a by linking DC-CL terms to terms in other ontologies via additional, formally defined relations such as has_function. Conclusion This approach brings benefits in the form of increased accuracy, support for reasoning, and interoperability with other ontology resources. Accordingly, we propose our method as a general strategy for the ontological representation of cells. DC-CL is available from http://www.obofoundry.org.

  7. NSAIDS inhibit in vitro MSC chondrogenesis but not osteogenesis: implications for mechanism of bone formation inhibition in man.

    Science.gov (United States)

    Pountos, Ippokratis; Giannoudis, Peter V; Jones, Elena; English, Anne; Churchman, Sarah; Field, Sarah; Ponchel, Frederique; Bird, Howard; Emery, Paul; McGonagle, Dennis

    2011-03-01

    The non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for analgesia but may inhibit bone formation. We investigated whether the reported NSAID effect on bone is related to inhibition of bone marrow mesenchymal stem cell (MSC) proliferation and osteogenic and chondrogenic differentiation and evaluated both cyclooxygenase (COX)-1 and COX-2 specific drugs. The effects of seven COX-1 and COX-2 inhibitors on MSC proliferation and osteogenic and chondrogenic differentiation were tested using Vybrant, sodium 3'-[1-(phenylaminocarbonyl)- 3,4-tetrazolium]-bis (4-methoxy-6-nitro) benzene sulfonic acid hydrate (XTT), functional and quantitative assays of MSC differentiation. The MSC expression of COX-1 and COX-2 and prostaglandin E2 (PGE-2) levels were evaluated serially during lineage differentiation by quantitative PCR and ELISA. None of the NSAIDs at broad range of concentration (range 10(-3) to 100 μg/ml) significantly affected MSC proliferation. Surprisingly, MSC osteogenic differentiation inhibition was not evident. However, NSAIDs affected chondrogenic potential with a reduction in sulphated glycosaminoglycans (sGAG) content by 45% and 55% with diclofenac and ketorolac, respectively (P NSAIDs may inhibit bone formation via blockage of MSC chondrogenic differentiation which is an important intermediate phase in normal endochondral bone formation. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

  8. TACT: A Set of MSC/PATRAN- and MSC/NASTRAN- based Modal Correlation Tools

    Science.gov (United States)

    Marlowe, Jill M.; Dixon, Genevieve D.

    1998-01-01

    This paper describes the functionality and demonstrates the utility of the Test Analysis Correlation Tools (TACT), a suite of MSC/PATRAN Command Language (PCL) tools which automate the process of correlating finite element models to modal survey test data. The initial release of TACT provides a basic yet complete set of tools for performing correlation totally inside the PATRAN/NASTRAN environment. Features include a step-by-step menu structure, pre-test accelerometer set evaluation and selection, analysis and test result export/import in Universal File Format, calculation of frequency percent difference and cross-orthogonality correlation results using NASTRAN, creation and manipulation of mode pairs, and five different ways of viewing synchronized animations of analysis and test modal results. For the PATRAN-based analyst, TACT eliminates the repetitive, time-consuming and error-prone steps associated with transferring finite element data to a third-party modal correlation package, which allows the analyst to spend more time on the more challenging task of model updating. The usefulness of this software is presented using a case history, the correlation for a NASA Langley Research Center (LaRC) low aspect ratio research wind tunnel model. To demonstrate the improvements that TACT offers the MSC/PATRAN- and MSC/DIASTRAN- based structural analysis community, a comparison of the modal correlation process using TACT within PATRAN versus external third-party modal correlation packages is presented.

  9. Combined enzyme/prodrug treatment by genetically engineered AT-MSC exerts synergy and inhibits growth of MDA-MB-231 induced lung metastases.

    Science.gov (United States)

    Matuskova, Miroslava; Kozovska, Zuzana; Toro, Lenka; Durinikova, Erika; Tyciakova, Silvia; Cierna, Zuzana; Bohovic, Roman; Kucerova, Lucia

    2015-04-09

    Metastatic spread of tumor cells remains a serious problem in cancer treatment. Gene-directed enzyme/prodrug therapy mediated by tumor-homing genetically engineered mesenchymal stromal cells (MSC) represents a promising therapeutic modality for elimination of disseminated cells. Efficacy of gene-directed enzyme/prodrug therapy can be improved by combination of individual systems. We aimed to define the combination effect of two systems of gene therapy mediated by MSC, and evaluate the ability of systemically administered genetically engineered mesenchymal stromal cells to inhibit the growth of experimental metastases derived from human breast adenocarcinoma cells MDA-MB-231/EGFP. Human adipose tissue-derived mesenchymal stromal cells (AT-MSC) were retrovirally transduced with fusion yeast cytosine deaminase::uracil phosphoribosyltransferase (CD::UPRT) or with Herpes simplex virus thymidine kinase (HSVtk). Engineered MSC were cocultured with tumor cells in the presence of prodrugs 5-fluorocytosin (5-FC) and ganciclovir (GCV). Combination effect of these enzyme/prodrug approaches was calculated. SCID/bg mice bearing experimental lung metastases were treated with CD::UPRT-MSC, HSVtk-MSC or both in combination in the presence of respective prodrug(s). Treatment efficiency was evaluated by EGFP-positive cell detection by flow cytometry combined with real-time PCR quantification of human cells in mouse organs. Results were confirmed by histological and immunohistochemical examination. We demonstrated various extent of synergy depending on tested cell line and experimental setup. The strongest synergism was observed on breast cancer-derived cell line MDA-MB-231/EGFP. Systemic administration of CD::UPRT-MSC and HSVtk-MSC in combination with 5-FC and GCV inhibited growth of MDA-MB-231 induced lung metastases. Combined gene-directed enzyme/prodrug therapy mediated by MSC exerted synergic cytotoxic effect and resulted in high therapeutic efficacy in vivo.

  10. Student performance in a newly developed MSc programme

    DEFF Research Database (Denmark)

    Richelsen, Ann Bettina

    2011-01-01

    other than DTUs and allow qualified students to enter the MSc programmes. The focus of the present work is a comparison of how international and Danish students perform within specific modules of the MSc curriculum in Engineering Design and Applied Mechanics at Technical University of Denmark...

  11. Optimization and translation of MSC-based hyaluronic acid hydrogels for cartilage repair

    Science.gov (United States)

    Erickson, Isaac E.

    2011-12-01

    Traumatic injury and disease disrupt the ability of cartilage to carry joint stresses and, without an innate regenerative response, often lead to degenerative changes towards the premature development of osteoarthritis. Surgical interventions have yet to restore long-term mechanical function. Towards this end, tissue engineering has been explored for the de novo formation of engineered cartilage as a biologic approach to cartilage repair. Research utilizing autologous chondrocytes has been promising, but clinical limitations in their yield have motivated research into the potential of mesenchymal stem cells (MSCs) as an alternative cell source. MSCs are multipotent cells that can differentiate towards a chondrocyte phenotype in a number of biomaterials, but no combination has successfully recapitulated the native mechanical function of healthy articular cartilage. The broad objective of this thesis was to establish an MSC-based tissue engineering approach worthy of clinical translation. Hydrogels are a common class of biomaterial used for cartilage tissue engineering and our initial work demonstrated the potential of a photo-polymerizable hyaluronic acid (HA) hydrogel to promote MSC chondrogenesis and improved construct maturation by optimizing macromer and MSC seeding density. The beneficial effects of dynamic compressive loading, high MSC density, and continuous mixing (orbital shaker) resulted in equilibrium modulus values over 1 MPa, well in range of native tissue. While compressive properties are crucial, clinical translation also demands that constructs stably integrate within a defect. We utilized a push-out testing modality to assess the in vitro integration of HA constructs within artificial cartilage defects. We established the necessity for in vitro pre-maturation of constructs before repair to achieve greater integration strength and compressive properties in situ. Combining high MSC density and gentle mixing resulted in integration strength over 500 k

  12. Shenghua Decoction reduces uterine bleeding and regulates T-cell paradigm in human deciduas of RU486 medical abortion.

    Science.gov (United States)

    Li, Xia; Zhang, Meng; Wang, Bin; Li, Yuzhu; Wang, Li; Zhao, Xiangzhong; Zhou, Xianbin; Guo, Yuqi; Jiang, Guosheng; Yao, Chengfang

    2013-12-12

    Excessive uterine bleeding is the most common and problematic side effect of RU486 medical abortion. Shenghua Decoction (SHD) is a well-known traditional Chinese herbal prescription for reducing uterine bleeding induced by RU486 medical abortion. However, its therapeutic mechanism still remains unclear. The Th1/Th2/Th17/Treg paradigm plays an important role in achieving maternal-fetal immunotolerance and its bias participates in RU486-induced abortion. Our previous research on mice demonstrated that the uterine bleeding volume is negatively related to the proportions of Th1 and Th17 cells whereas positively related to the proportions of Th2 and Treg cells. Additionally, Th1-type cytokine inducing effect was identified in our previous study. Therefore, it was hypothesized that SHD reduced the uterine bleeding in RU486 medical abortion by inducing Th1/Th2/Th17/Treg paradigm bias. The purpose of this study was to determine the regulatory effect and the mechanism of SHD on human decidual Th1/Th2/Th17/Treg paradigm for alleviating uterine bleeding in RU486 medical abortion. 90 women within seven weeks of a normal intrauterine pregnancy, who elected for termination of pregnancy, were divided into three groups; vacuum aspiration group, RU486 group, and SHD-RU486 group. Duration of uterine bleeding was recorded and volume of uterine bleeding was measured by the method of alkaline hematin photometric. To determine the regulatory effect of SHD on Th1/Th2/Th17/Treg paradigm, the proportions of Th1/Th2/Th17/Treg cells in the decidua of different groups were analyzed using a FACS calibur. Correlation was analyzed in order to demonstrate the relationship between the Th1/Th2/Th17/Treg paradigm and the uterine bleeding in RU486 medical abortion. Moreover, to elucidate the mechanism underlying the T-cell paradigm regulating of SHD, the mRNA and protein expressions of subset-specific transcription factors (T-bet, GATA-3, RORγt, and Foxp3) for the differentiation of Th1/Th2/Th17

  13. HucMSC exosomes-delivered 14-3-3ζ enhanced autophagy via modulation of ATG16L in preventing cisplatin-induced acute kidney injury.

    Science.gov (United States)

    Jia, Haoyuan; Liu, Wanzhu; Zhang, Bin; Wang, Juanjuan; Wu, Peipei; Tandra, Nitin; Liang, Zhaofeng; Ji, Cheng; Yin, Lei; Hu, Xinyuan; Yan, Yongmin; Mao, Fei; Zhang, Xu; Yu, Jing; Xu, Wenrong; Qian, Hui

    2018-01-01

    The clinical application of cisplatin is restricted by its side effects of nephrotoxicity. Human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-ex) have an important effect in tissue injury repair. Our previous work discovered that pretreatment with human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-ex) alleviated cisplatin-induced acute kidney injury (AKI) by activating autophagy both in vitro and in vivo . In this study, we further explored the mechanisms of hucMSC-ex in autophagy for preventing cisplatin-induced nephrotoxicity. We discovered that 14-3-3ζ was contained in hucMSC-ex, and knockdown and overexpression 14-3-3ζ reduced and enhanced the autophagic activity respectively. Furthermore, Knockdown of 14-3-3ζ alleviated the preventive effect of hucMSC-ex. In contrast, overexpression of 14-3-3ζ enhanced the effect. Further results confirmed that hucMSC-ex increased ATG16L expression and that 14-3-3ζ interacted with ATG16L, promoting the localization of ATG16L at autophagosome precursors. In this study, we revealed that hucMSC-ex-delivered 14-3-3ζ interacted with ATG16L to activate autophagy. Our findings suggest that 14-3-3ζ is a novel mechanism for MSC-exosomes-activated autophagy and provides a new strategy for the prevention of cisplatin-induced nephrotoxicity.

  14. Mechanical strain downregulates C/EBPβ in MSC and decreases endoplasmic reticulum stress.

    Directory of Open Access Journals (Sweden)

    Maya Styner

    Full Text Available Exercise prevents marrow mesenchymal stem cell (MSC adipogenesis, reversing trends that accompany aging and osteoporosis. Mechanical input, the in-vitro analogue to exercise, limits PPARγ expression and adipogenesis in MSC. We considered whether C/EBPβ might be mechanoresponsive as it is upstream to PPARγ, and also is known to upregulate endoplasmic reticulum (ER stress. MSC (C3H10T1/2 pluripotent cells as well as mouse marrow-derived MSC were cultured in adipogenic media and a daily mechanical strain regimen was applied. We demonstrate herein that mechanical strain represses C/EBPβ mRNA (0.6-fold ±0.07, p<0.05 and protein (0.4-fold ±0.1, p<0.01 in MSC. SiRNA silencing of β-catenin prevented mechanical repression of C/EBPβ. C/EBPβ overexpression did not override strain's inhibition of adipogenesis, which suggests that mechanical control of C/EBPβ is not the primary site at which adipogenesis is regulated. Mechanical inhibition of C/EBPβ, however, might be critical for further processes that regulate MSC health. Indeed, overexpression of C/EBPβ in MSC induced ER stress evidenced by a dose-dependent increase in the pro-apoptotic CHOP (protein 4-fold ±0.5, p<0.05 and a threshold reduction in the chaperone BiP (protein 0.6-fold ±0.1, p = 0.2; mRNA 0.3-fold ±0.1, p<0.01. ChIP-seq demonstrated a significant association between C/EBPβ and both CHOP and BiP genes. The strain regimen, in addition to decreasing C/EBPβ mRNA (0.5-fold ±0.09, p<0.05, expanded ER capacity as measured by an increase in BiP mRNA (2-fold ±0.2, p<0.05 and protein. Finally, ER stress induced by tunicamycin was ameliorated by mechanical strain as demonstrated by decreased C/EBPβ, increased BiP and decreased CHOP protein expression. Thus, C/EBPβ is a mechanically responsive transcription factor and its repression should counter increases in marrow fat as well as improve skeletal resistance to ER stress.

  15. Nanotechnology convergence and modeling paradigm of sustainable energy system using polymer electrolyte membrane fuel cell as a benchmark example

    Energy Technology Data Exchange (ETDEWEB)

    Chung, Pil Seung; So, Dae Sup; Biegler, Lorenz T.; Jhon, Myung S., E-mail: mj3a@andrew.cmu.edu [Carnegie Mellon University, Department of Chemical Engineering (United States)

    2012-08-15

    Developments in nanotechnology have led to innovative progress and converging technologies in engineering and science. These demand novel methodologies that enable efficient communications from the nanoscale all the way to decision-making criteria for actual production systems. In this paper, we discuss the convergence of nanotechnology and novel multi-scale modeling paradigms by using the fuel cell system as a benchmark example. This approach includes complex multi-phenomena at different time and length scales along with the introduction of an optimization framework for application-driven nanotechnology research trends. The modeling paradigm introduced here covers the novel holistic integration from atomistic/molecular phenomena to meso/continuum scales. System optimization is also discussed with respect to the reduced order parameters for a coarse-graining procedure in multi-scale model integration as well as system design. The development of a hierarchical multi-scale paradigm consolidates the theoretical analysis and enables large-scale decision-making of process level design, based on first-principles, and therefore promotes the convergence of nanotechnology to sustainable energy technologies.

  16. Nanotechnology convergence and modeling paradigm of sustainable energy system using polymer electrolyte membrane fuel cell as a benchmark example

    Science.gov (United States)

    Chung, Pil Seung; So, Dae Sup; Biegler, Lorenz T.; Jhon, Myung S.

    2012-08-01

    Developments in nanotechnology have led to innovative progress and converging technologies in engineering and science. These demand novel methodologies that enable efficient communications from the nanoscale all the way to decision-making criteria for actual production systems. In this paper, we discuss the convergence of nanotechnology and novel multi-scale modeling paradigms by using the fuel cell system as a benchmark example. This approach includes complex multi-phenomena at different time and length scales along with the introduction of an optimization framework for application-driven nanotechnology research trends. The modeling paradigm introduced here covers the novel holistic integration from atomistic/molecular phenomena to meso/continuum scales. System optimization is also discussed with respect to the reduced order parameters for a coarse-graining procedure in multi-scale model integration as well as system design. The development of a hierarchical multi-scale paradigm consolidates the theoretical analysis and enables large-scale decision-making of process level design, based on first-principles, and therefore promotes the convergence of nanotechnology to sustainable energy technologies.

  17. Nanotechnology convergence and modeling paradigm of sustainable energy system using polymer electrolyte membrane fuel cell as a benchmark example

    International Nuclear Information System (INIS)

    Chung, Pil Seung; So, Dae Sup; Biegler, Lorenz T.; Jhon, Myung S.

    2012-01-01

    Developments in nanotechnology have led to innovative progress and converging technologies in engineering and science. These demand novel methodologies that enable efficient communications from the nanoscale all the way to decision-making criteria for actual production systems. In this paper, we discuss the convergence of nanotechnology and novel multi-scale modeling paradigms by using the fuel cell system as a benchmark example. This approach includes complex multi-phenomena at different time and length scales along with the introduction of an optimization framework for application-driven nanotechnology research trends. The modeling paradigm introduced here covers the novel holistic integration from atomistic/molecular phenomena to meso/continuum scales. System optimization is also discussed with respect to the reduced order parameters for a coarse-graining procedure in multi-scale model integration as well as system design. The development of a hierarchical multi-scale paradigm consolidates the theoretical analysis and enables large-scale decision-making of process level design, based on first-principles, and therefore promotes the convergence of nanotechnology to sustainable energy technologies.

  18. Reversibility of cellular aging by reprogramming through an embryonic-like state : a new paradigm for human cell rejuvenation

    Directory of Open Access Journals (Sweden)

    Jean-Marc Lemaitre

    2014-01-01

    Full Text Available Direct reprogramming of somatic cells into induced pluripotent stem cells (iPSCs provides a unique opportunity to derive patient-specific stem cells with potential application in autologous tissue replacement therapies and without the ethical concerns of Embryonic Stem Cells (hESC. However, this strategy still suffers from several hurdles that need to be overcome before clinical applications. Among them, cellular senescence, which contributes to aging and restricted longevity, has been described as a barrier to the derivation of iPSCs. This suggests that aging might be an important limitation for therapeutic purposes for elderly individuals. Senescence is characterized by an irreversible cell cycle arrest in response to various forms of stress, including activation of oncogenes, shortened telomeres, DNA damage, oxidative stress, and mitochondrial dysfunction. To overcome this barrier, we developed an optimized 6-factor-based reprogramming protocol that is able to cause efficient reversing of cellular senescence and reprogramming into iPSCs. We demonstrated that iPSCs derived from senescent and centenarian fibroblasts have reset telomere size, gene expression profiles, oxidative stress, and mitochondrial metabolism, and are indistinguishable from hESC. Finally, we demonstrate that re-differentiation led to rejuvenated cells with a reset cellular physiology, defining a new paradigm for human cell rejuvenation. We discuss the molecular mechanisms involved in cell reprogramming of senescent cells

  19. A novel paradigm for cell and molecule interaction ontology: from the CMM model to IMGT-ONTOLOGY

    Science.gov (United States)

    2010-01-01

    Background Biology is moving fast toward the virtuous circle of other disciplines: from data to quantitative modeling and back to data. Models are usually developed by mathematicians, physicists, and computer scientists to translate qualitative or semi-quantitative biological knowledge into a quantitative approach. To eliminate semantic confusion between biology and other disciplines, it is necessary to have a list of the most important and frequently used concepts coherently defined. Results We propose a novel paradigm for generating new concepts for an ontology, starting from model rather than developing a database. We apply that approach to generate concepts for cell and molecule interaction starting from an agent based model. This effort provides a solid infrastructure that is useful to overcome the semantic ambiguities that arise between biologists and mathematicians, physicists, and computer scientists, when they interact in a multidisciplinary field. Conclusions This effort represents the first attempt at linking molecule ontology with cell ontology, in IMGT-ONTOLOGY, the well established ontology in immunogenetics and immunoinformatics, and a paradigm for life science biology. With the increasing use of models in biology and medicine, the need to link different levels, from molecules to cells to tissues and organs, is increasingly important. PMID:20167082

  20. The therapeutic effects of MSc1 nanocomplex, synthesized by nanochelating technology, on experimental autoimmune encephalomyelitic C57/BL6 mice

    Directory of Open Access Journals (Sweden)

    Fakharzadeh S

    2014-08-01

    Full Text Available Saideh Fakharzadeh,1 Mohammad Ali Sahraian,2 Maryam Hafizi,1 Somayeh Kalanaky,1 Zahra Masoumi,1 Mehdi Mahdavi,1 Nasser Kamalian,3 Alireza Minagar,4 Mohammad Hassan Nazaran1 1Department of Research and Development, Sodour Ahrar Shargh Company, Tehran, Iran; 2MS Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; 3Department of Pathology, Medical School of Tehran University of Medical Sciences, Tehran, Iran; 4Department of Neurology, LSU Health Sciences Centre, Shreveport, LA, USA Purpose: Currently approved therapies for multiple sclerosis (MS at best only slow down its progression. Therefore, it is necessary to utilize novel technologies in order to synthesize smart multifunctional structures. In the present study, for the first time we evaluated the therapeutic potential of MSc1 nanocomplex, which was designed based on novel nanochelating technology. Materials and methods: MSc1 cell-protection capacity, with and without iron bond, was evaluated against hydrogen peroxide (H2O2-induced oxidative stress in cultured rat pheochromocytoma-12 cells. The ability of MSc1 to maintain iron bond at pH ranges of 1–7 was evaluated. Nanocomplex toxicity was examined by estimating the intraperitoneal median lethal dose (LD50. Experimental autoimmune encephalomyelitic mice were injected with MSc1 14 days after disease induction, when the clinical symptoms appeared. The clinical score, body weight, and disease-induced mortality were monitored until day 54. In the end, after collecting blood samples for assessing hemoglobin and red blood cell count, the brains and livers of the mice were isolated for hematoxylin and eosin staining and analysis of iron content, respectively. Results: The results showed that MSc1 prevented H2O2-induced cell death even after binding with iron, and it preserved its bond with iron constant at pH ranges 1–7. The nanocomplex intraperitoneal LD50 was 1,776.59 mg/kg. MSc1 prompted therapeutic

  1. An MSc Course Module: Wind Turbine Measurement Techniques

    DEFF Research Database (Denmark)

    Hansen, Kurt Schaldemose; Pedersen, Knud Ole Helgesen

    2005-01-01

    The 2-year MSc in Wind power engineering at the Technical University of Denmark comprises modules from core engineering teaching and from other modules specifically designed to the MSc. This Note outlines the content of such a specific module on the subject of wind turbine measurement. The lectures......, practical exercises and work related to measurements from an operating 500 kW turbine are described....

  2. Insulin-like growth factor 1 enhances the migratory capacity of mesenchymal stem cells

    International Nuclear Information System (INIS)

    Li, Yangxin; Yu, XiYong; Lin, ShuGuang; Li, XiaoHong; Zhang, Saidan; Song, Yao-Hua

    2007-01-01

    Mesenchymal stem cells (MSCs) are attractive candidates for cell based therapies. However, the mechanisms responsible for stem cell migration and homing after transplantation remain unknown. It has been shown that insulin-like growth factor-1 (IGF-1) induces proliferation and migration of some cell types, but its effects on stem cells have not been investigated. We isolated and cultured MSC from rat bone marrow, and found that IGF-1 increased the expression levels of the chemokine receptor CXCR4 (receptor for stromal cell-derived factor-1, SDF-1). Moreover, IGF-1 markedly increased the migratory response of MSC to SDF-1. The IGF-1-induced increase in MSC migration in response to SDF-1 was attenuated by PI3 kinase inhibitor (LY294002 and wortmannin) but not by mitogen-activated protein/ERK kinase inhibitor PD98059. Our data indicate that IGF-1 increases MSC migratory responses via CXCR4 chemokine receptor signaling which is PI3/Akt dependent. These findings provide a new paradigm for biological effects of IGF-1 on MSC and have implications for the development of novel stem cell therapeutic strategies

  3. Comparison of MSC-Neurogenin1 administration modality in MCAO rat model

    Directory of Open Access Journals (Sweden)

    Shin Dong Hoon

    2016-12-01

    Full Text Available Intracerebral (IC grafting of mesenchymal stem cells (MSCs is not currently used in humans due to its potential complications. On the other hand, intra-arterial (IA administration can be facilitated for engrafting of intensifed MSCs in the injured human brain. The study is designed to compare the two methods of MSC administration using IA and IC routes through the parameters of behavior, infarct volume, cell distribution, and MSC identification. An ischemic stroke model was generated in Sprague Dawley male rats. This experiment used MSCs/Ngn1 that express Neurogenin1 (Ngn1 to ensure grafted MSC maintenance. MSCs/Ngn1 or normal saline was administrated via the IC or IA route on day 3. All animals were randomly assigned into four groups (five rats in each group: IC-control, IA-control, IC-MSCs/Ngn1, or IA-MSCs/Ngn1. Motor behaviors, infarct volume, and distribution of superparamagnetic iron oxide (SPIO-labeled cells on magnetic resonance imaging (MRI were compared from each group. There were no baseline differencess in motor behaviors or infarct volume between IC-MSCs/Ngn1 and IA-MSCs/Ngn1. Hovever, the IA-MSCs/Ngn1 group showed the greatest recovery on Rotarod testing and adhesive removal tests (p = 0.003 and p = 0.009 vs. IC-MSCs/Ngn1, respectively. The IA-MSCs/Ngn1 group also had more evenly distributed SPIO-labeled cells on MRI. The results suggest that IA administration is likely to be benefcial for humans based on its ability to improve behavioral outcomes and ensure even MSC engrafting.

  4. Adaptive control paradigm for photovoltaic and solid oxide fuel cell in a grid-integrated hybrid renewable energy system

    Science.gov (United States)

    Khan, Laiq

    2017-01-01

    The hybrid power system (HPS) is an emerging power generation scheme due to the plentiful availability of renewable energy sources. Renewable energy sources are characterized as highly intermittent in nature due to meteorological conditions, while the domestic load also behaves in a quite uncertain manner. In this scenario, to maintain the balance between generation and load, the development of an intelligent and adaptive control algorithm has preoccupied power engineers and researchers. This paper proposes a Hermite wavelet embedded NeuroFuzzy indirect adaptive MPPT (maximum power point tracking) control of photovoltaic (PV) systems to extract maximum power and a Hermite wavelet incorporated NeuroFuzzy indirect adaptive control of Solid Oxide Fuel Cells (SOFC) to obtain a swift response in a grid-connected hybrid power system. A comprehensive simulation testbed for a grid-connected hybrid power system (wind turbine, PV cells, SOFC, electrolyzer, battery storage system, supercapacitor (SC), micro-turbine (MT) and domestic load) is developed in Matlab/Simulink. The robustness and superiority of the proposed indirect adaptive control paradigm are evaluated through simulation results in a grid-connected hybrid power system testbed by comparison with a conventional PI (proportional and integral) control system. The simulation results verify the effectiveness of the proposed control paradigm. PMID:28329015

  5. Adaptive control paradigm for photovoltaic and solid oxide fuel cell in a grid-integrated hybrid renewable energy system.

    Science.gov (United States)

    Mumtaz, Sidra; Khan, Laiq

    2017-01-01

    The hybrid power system (HPS) is an emerging power generation scheme due to the plentiful availability of renewable energy sources. Renewable energy sources are characterized as highly intermittent in nature due to meteorological conditions, while the domestic load also behaves in a quite uncertain manner. In this scenario, to maintain the balance between generation and load, the development of an intelligent and adaptive control algorithm has preoccupied power engineers and researchers. This paper proposes a Hermite wavelet embedded NeuroFuzzy indirect adaptive MPPT (maximum power point tracking) control of photovoltaic (PV) systems to extract maximum power and a Hermite wavelet incorporated NeuroFuzzy indirect adaptive control of Solid Oxide Fuel Cells (SOFC) to obtain a swift response in a grid-connected hybrid power system. A comprehensive simulation testbed for a grid-connected hybrid power system (wind turbine, PV cells, SOFC, electrolyzer, battery storage system, supercapacitor (SC), micro-turbine (MT) and domestic load) is developed in Matlab/Simulink. The robustness and superiority of the proposed indirect adaptive control paradigm are evaluated through simulation results in a grid-connected hybrid power system testbed by comparison with a conventional PI (proportional and integral) control system. The simulation results verify the effectiveness of the proposed control paradigm.

  6. Rationale and design of the first randomized, double-blind, placebo-controlled trial of intramyocardial injection of autologous bone-marrow derived Mesenchymal Stromal Cells in chronic ischemic Heart Failure (MSC-HF Trial)

    DEFF Research Database (Denmark)

    Mathiasen, Anders Bruun; Jørgensen, Erik; Qayyum, Abbas Ali

    2012-01-01

    Stem cell therapy is an emerging treatment modality in cardiovascular disease. The best cell type and delivery method in different cardiovascular diseases remain to be determined.......Stem cell therapy is an emerging treatment modality in cardiovascular disease. The best cell type and delivery method in different cardiovascular diseases remain to be determined....

  7. An MSC2 Promoter-lacZ Fusion Gene Reveals Zinc-Responsive Changes in Sites of Transcription Initiation That Occur across the Yeast Genome.

    Directory of Open Access Journals (Sweden)

    Yi-Hsuan Wu

    Full Text Available The Msc2 and Zrg17 proteins of Saccharomyces cerevisiae form a complex to transport zinc into the endoplasmic reticulum. ZRG17 is transcriptionally induced in zinc-limited cells by the Zap1 transcription factor. In this report, we show that MSC2 mRNA also increases (~1.5 fold in zinc-limited cells. The MSC2 gene has two in-frame ATG codons at its 5' end, ATG1 and ATG2; ATG2 is the predicted initiation codon. When the MSC2 promoter was fused at ATG2 to the lacZ gene, we found that unlike the chromosomal gene this reporter showed a 4-fold decrease in lacZ mRNA in zinc-limited cells. Surprisingly, β-galactosidase activity generated by this fusion gene increased ~7 fold during zinc deficiency suggesting the influence of post-transcriptional factors. Transcription of MSC2ATG2-lacZ was found to start upstream of ATG1 in zinc-replete cells. In zinc-limited cells, transcription initiation shifted to sites just upstream of ATG2. From the results of mutational and polysome profile analyses, we propose the following explanation for these effects. In zinc-replete cells, MSC2ATG2-lacZ mRNA with long 5' UTRs fold into secondary structures that inhibit translation. In zinc-limited cells, transcripts with shorter unstructured 5' UTRs are generated that are more efficiently translated. Surprisingly, chromosomal MSC2 did not show start site shifts in response to zinc status and only shorter 5' UTRs were observed. However, the shifts that occur in the MSC2ATG2-lacZ construct led us to identify significant transcription start site changes affecting the expression of ~3% of all genes. Therefore, zinc status can profoundly alter transcription initiation across the yeast genome.

  8. Paradigm Shift

    OpenAIRE

    Besancenot, Damien; Dogguy, Habib

    2011-01-01

    This paper analyses the consequences of young researchers' scientifc choice on the dynamics of sciences. We develop a simple two state mean field game model to analyze the competition between two paradigms based on Kuhn's theory of scientifc revolutions. At the beginning of their career, young researchers choose the paradigm in which they want to work according to social and personal motivations. Despite the possibility of multiple equilibria the model exhibits at least one stable solution in...

  9. Adaptive MscS gating in the osmotic permeability response in E. coli: the question of time.

    Science.gov (United States)

    Boer, Miriam; Anishkin, Andriy; Sukharev, Sergei

    2011-05-17

    Microorganisms adapt to osmotic downshifts by releasing small osmolytes through mechanosensitive (MS) channels. We want to understand how the small mechanosensitive channel's (MscS) activation and inactivation, both driven by membrane tension, optimize survival in varying hypoosmotic shock situations. By measuring light scattering with a stopped-flow device, we estimate bacterial swelling time as 30-50 ms. A partial solute equilibration follows within 150-200 ms, during which optical responses from cells with WT MscS deviate from those lacking MS channels. MscS opening rates estimated in patch clamp show the channels readily respond to tensions below the lytic limit with a time course faster than 20 ms and close promptly upon tension release. To address the role of the tension-insensitive inactivated state in vivo, we applied short, long, and two-step osmotic shock protocols to WT, noninactivating G113A, and fast-inactivating D62N mutants. WT and G113A showed a comparable survival in short 1 min 800 mOsm downshock experiments, but G113A was at a disadvantage under a long 60 min shock. Preshocking cells carrying WT MscS for 15 s to 15 min with a 200 mOsm downshift did not sensitize them to the final 500 mOsm drop in osmolarity of the second step. However, these two-step shocks induced death in D62N more than just a one-step 700 mOsm downshift. We conclude MscS is able to activate and exude osmolytes faster than lytic pressure builds inside the cell under abrupt shock. During prolonged shocks, gradual inactivation prevents continuous channel activity and assists recovery. Slow kinetics of inactivation in WT MscS ensures that mild shocks do not inactivate the entire population, leaving some protection should conditions worsen.

  10. THE EFFECTS OF CULTURE ON KNOWLEDGE MANAGEMENT PRACTICE: A QUALITATIVE CASE STUDY OF MSC STATUS COMPANIES

    Directory of Open Access Journals (Sweden)

    Charmaine Ryan

    2006-01-01

    Full Text Available Knowledge is recognised as being an important asset in organisations these days. Despite this, many organisations are not doing enough to effectively manage this important asset for its competitive advantage. In response to this, knowledge management which is defined as a process that effectively creates, captures, shares and uses organisation-wide knowledge to improve the organisation’s performance was conceived and has since gained widespread acceptance the world over. Despite its widespread acceptance, little is known about the current levels of knowledge management within the Malaysian context, in particular amongst the Multimedia Super Corridor (MSC status companies in Malaysia. Furthermore, the extent to which cultural factors impact upon knowledge management practice in these companies is not known. This study investigated the various cultural factors (collaboration, mutual trust, leadership and incentives/rewards using a multiple case study approach operating within a critical realism research paradigm and found that these factors have impact on the level of knowledge management practice. The study also established that cultural factors do play an important role in facilitating knowledge management practice in these MSC status companies in Malaysia. It was found that collaboration, mutual trust, leadership, kiasu-ism and incentives/rewards have significant impact on the level of knowledge management practice. In view of the findings of this study, it is suggested that the relevant authorities pay adequate attention on these cultural factors to ensure that the knowledge management initiatives undertaken by Malaysian companies are effectively deployed.

  11. Mutations in a Conserved Domain of E. coli MscS to the Most Conserved Superfamily Residue Leads to Kinetic Changes.

    Directory of Open Access Journals (Sweden)

    Hannah R Malcolm

    Full Text Available In Escherichia coli (E. coli the mechanosensitive channel of small conductance, MscS, gates in response to membrane tension created from acute external hypoosmotic shock, thus rescuing the bacterium from cell lysis. E. coli MscS is the most well studied member of the MscS superfamily of channels, whose members are found throughout the bacterial and plant kingdoms. Homology to the pore lining helix and upper vestibule domain of E. coli MscS is required for inclusion into the superfamily. Although highly conserved, in the second half of the pore lining helix (TM3B, E. coli MscS has five residues significantly different from other members of the superfamily. In superfamilies such as this, it remains unclear why variations within such a homologous region occur: is it tolerance of alternate residues, or does it define functional variance within the superfamily? Point mutations (S114I/T, L118F, A120S, L123F, F127E/K/T and patch clamp electrophysiology were used to study the effect of changing these residues in E. coli MscS on sensitivity and gating. The data indicate that variation at these locations do not consistently lead to wildtype channel phenotypes, nor do they define large changes in mechanosensation, but often appear to effect changes in the E. coli MscS channel gating kinetics.

  12. Marketingová strategie podniku Msc.Software

    OpenAIRE

    Mazuch, Jan

    2011-01-01

    Diplomová práce se zabývá sestavením marketingové strategie podniku MSC.Software s.r.o., který prodává simulační software. Práce analyzuje současnou marketingovou strategii podniku a navrhuje její zefektivnění. This master’s thesis deals with making marketing strategy for the MSC.Software Company that sells simulation software. This thesis analyzes the current marketing strategy of the company and proposes it’s more effective usage. D

  13. Unravelling biology and shifting paradigms in cancer with single-cell sequencing.

    Science.gov (United States)

    Baslan, Timour; Hicks, James

    2017-08-24

    The fundamental operative unit of a cancer is the genetically and epigenetically innovative single cell. Whether proliferating or quiescent, in the primary tumour mass or disseminated elsewhere, single cells govern the parameters that dictate all facets of the biology of cancer. Thus, single-cell analyses provide the ultimate level of resolution in our quest for a fundamental understanding of this disease. Historically, this quest has been hampered by technological shortcomings. In this Opinion article, we argue that the rapidly evolving field of single-cell sequencing has unshackled the cancer research community of these shortcomings. From furthering an elemental understanding of intra-tumoural genetic heterogeneity and cancer genome evolution to illuminating the governing principles of disease relapse and metastasis, we posit that single-cell sequencing promises to unravel the biology of all facets of this disease.

  14. Mechanical loading regulates human MSC differentiation in a multi-layer hydrogel for osteochondral tissue engineering.

    Science.gov (United States)

    Steinmetz, Neven J; Aisenbrey, Elizabeth A; Westbrook, Kristofer K; Qi, H Jerry; Bryant, Stephanie J

    2015-07-01

    A bioinspired multi-layer hydrogel was developed for the encapsulation of human mesenchymal stem cells (hMSCs) as a platform for osteochondral tissue engineering. The spatial presentation of biochemical cues, via incorporation of extracellular matrix analogs, and mechanical cues, via both hydrogel crosslink density and externally applied mechanical loads, were characterized in each layer. A simple sequential photopolymerization method was employed to form stable poly(ethylene glycol)-based hydrogels with a soft cartilage-like layer of chondroitin sulfate and low RGD concentrations, a stiff bone-like layer with high RGD concentrations, and an intermediate interfacial layer. Under a compressive load, the variation in hydrogel stiffness within each layer produced high strains in the soft cartilage-like layer, low strains in the stiff bone-like layer, and moderate strains in the interfacial layer. When hMSC-laden hydrogels were cultured statically in osteochondral differentiation media, the local biochemical and matrix stiffness cues were not sufficient to spatially guide hMSC differentiation after 21 days. However dynamic mechanical stimulation led to differentially high expression of collagens with collagen II in the cartilage-like layer, collagen X in the interfacial layer and collagen I in the bone-like layer and mineral deposits localized to the bone layer. Overall, these findings point to external mechanical stimulation as a potent regulator of hMSC differentiation toward osteochondral cellular phenotypes. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  15. A novel paradigm links mitochondrial dysfunction with muscle stem cell impairment in sepsis.

    Science.gov (United States)

    Chatre, Laurent; Verdonk, Franck; Rocheteau, Pierre; Crochemore, Clément; Chrétien, Fabrice; Ricchetti, Miria

    2017-10-01

    Sepsis is an acute systemic inflammatory response of the body to microbial infection and a life threatening condition associated with multiple organ failure. Survivors may display long-term disability with muscle weakness that remains poorly understood. Recent data suggest that long-term myopathy in sepsis survivors is due to failure of skeletal muscle stem cells (satellite cells) to regenerate the muscle. Satellite cells impairment in the acute phase of sepsis is linked to unusual mitochondrial dysfunctions, characterized by a dramatic reduction of the mitochondrial mass and hyperactivity of residual organelles. Survivors maintain the impairment of satellite cells, including alterations of the mitochondrial DNA (mtDNA), in the long-term. This condition can be rescued by treatment with mesenchymal stem cells (MSCs) that restore mtDNA alterations and mitochondrial function in satellite cells, and in fine their regenerative potential. Injection of MSCs in turn increases the force of isolated muscle fibers and of the whole animal, and improves the survival rate. These effects occur in the context of reduced inflammation markers that also raised during sepsis. Targeting muscle stem cells mitochondria, in a context of reduced inflammation, may represent a valuable strategy to reduce morbidity and long-term impairment of the muscle upon sepsis. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Genetic polymorphisms and non-small-cell lung cancer: future paradigms

    Energy Technology Data Exchange (ETDEWEB)

    Mello, Ramon Andrade Bezerra de [Serviço de Oncologia Médica, Instituto Português de Oncologia Francisco Gentil, Porto (Portugal); Departamento de Ciências Biomédicas e Medicina, Universidade do Algarve, Faro (Portugal)

    2014-07-01

    This article addresses some current issues about genetic polymorphisms studied in the non-small-cell lung cancer translational field. Furthermore, it discusses about new potential biomarkers regarding lung cancer risk and prognosis.

  17. How immunoglobulin G antibodies kill target cells: revisiting an old paradigm.

    Science.gov (United States)

    Biburger, Markus; Lux, Anja; Nimmerjahn, Falk

    2014-01-01

    The capacity of immunoglobulin G (IgG) antibodies to eliminate virtually any target cell has resulted in the widespread introduction of cytotoxic antibodies into the clinic in settings of cancer therapy, autoimmunity, and transplantation, for example. More recently, it has become apparent that also the protection from viral infection via IgG antibodies may require cytotoxic effector functions, suggesting that antibody-dependent cellular cytotoxicity (ADCC) directed against malignant or virally infected cells is one of the most essential effector mechanisms triggered by IgG antibodies to protect the host. A detailed understanding of the underlying molecular and cellular pathways is critical, therefore, to make full use of this antibody effector function. Several studies over the last years have provided novel insights into the effector pathways and innate immune effector cells responsible for ADCC reactions. One of the most notable outcomes of many of these reports is that cells of the mononuclear phagocytic system rather than natural killer cells are critical for removal of IgG opsonized target cells in vivo. © 2014 Elsevier Inc. All rights reserved.

  18. Surgery on spinal epidural metastases (SEM) in renal cell carcinoma: a plea for a new paradigm.

    Science.gov (United States)

    Bakker, Nicolaas A; Coppes, Maarten H; Vergeer, Rob A; Kuijlen, Jos M A; Groen, Rob J M

    2014-09-01

    Prediction models for outcome of decompressive surgical resection of spinal epidural metastases (SEM) have in common that they have been developed for all types of SEM, irrespective of the type of primary tumor. It is our experience in clinical practice, however, that these models often fail to accurately predict outcome in the individual patient. To investigate whether decision making could be optimized by applying tumor-specific prediction models. For the proof of concept, we analyzed patients with SEM from renal cell carcinoma that we have operated on. Retrospective chart analysis 2006 to 2012. Twenty-one consecutive patients with symptomatic SEM of renal cell carcinoma. Predictive factors for survival. Next to established predictive factors for survival, we analyzed the predictive value of the Motzer criteria in these patients. The Motzer criteria comprise a specific and validated risk model for survival in patients with renal cell carcinoma. After multivariable analysis, only Motzer intermediate (hazard ratio [HR] 17.4, 95% confidence interval [CI] 1.82-166, p=.01) and high risk (HR 39.3, 95% CI 3.10-499, p=.005) turned out to be significantly associated with survival in patients with renal cell carcinoma that we have operated on. In this study, we have demonstrated that decision making could have been optimized by implementing the Motzer criteria next to established prediction models. We, therefore, suggest that in future, in patients with SEM from renal cell carcinoma, the Motzer criteria are also taken into account. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. MSc degree in color technology for the automotive sector

    Science.gov (United States)

    Martinez-Verdu, F.; Perales, E.; Chorro, E.; Viqueira, V.; Gilabert, E.

    2014-07-01

    Nowadays, the measurement and management of color quality of the gonio-apparent materials is complex, but highly demanded in many industrial sectors, as automotive, cosmetics, plastics for consumer electronics, printing inks, architectural coatings, etc. It is necessary to control complex instrumentation and to do visual assessments of texture and color differences to get, for instance, a visual harmony in car bodies; and a profound knowledge of physics and chemistry of special-effect pigments for their optical formulation to obtain attractive visual effects in coatings, plastics, etc, combining among them and with solid pigments. From University of Alicante, for the academic year 2013-14, we are organizing the first MSc degree in Color Technology for the Automotive Sector, with a design of contents embracing CIE colorimetry and visual perception, included the AUDI2000 color difference formula, instrumentation and color management software, fundamentals of coatings and plastics in the automotive sector, and, optical formulation of pigments. The MSc syllabus, with 60 ECTS, is designed to be taught in two semesters: from September to February with on classroom theoretical and practical activities, and, from March to June at virtual level, with internships of training in some companies. Therefore, the MSc Thesis would be the performance report during the internship in companies or research institutions. Some multinational companies, both as car makers and coatings and plastics providers, from European and non-European countries have already shown their support and interest in welcoming students for specific training, even some job offers when the first MSc edition finishes.

  20. Fit for purpose? Evaluation of an MSc. in Medical Physics.

    LENUS (Irish Health Repository)

    van der Putten, W J

    2014-05-01

    The National University of Ireland in Galway established a Master in Science (MSc.) program in medical physics in 2002. The course was designed to be 90 ECTS(1) credits and of one calendar year duration. From the outset the MSc. was designed to be part of an overall medical physics training program. MSc. programs are now widely used as part of the training and education of medical physicists. There is however paucity of data on the effectiveness of such courses and the purpose of the study reported here is to provide information on one particular MSc. course in medical physics. This is relevant to medical physicists who are involved in the development and running of medical physics training programs. The study used as methodology the Kirkpatrick levels of professional training. It was conducted through an online survey, both from students who graduated from the course and from students who were in the process of completing the course. The survey proved to be an effective way to determine attributes of modules such as learning outcomes, knowledge imparted, quality of teaching materials and others. The survey proved to be remarkably able to demonstrate interventions in the individual course modules. Although the course was shown to be effective in the imparting of the knowledge required to become a qualified medical physicist several areas for improvement were identified. These are mainly in the areas of increased practical experience and in course delivery.

  1. MSc Agriculture students working with ex-campus stakeholders

    DEFF Research Database (Denmark)

    Langer, Vibeke; Lund, Mogens; Bendevis, Mira Arpe

    2014-01-01

    In the MSc program in Agriculture at University of Copenhagen we experience that both domestic and international students increasingly enter the programme without a contextual background of “agriculture” and with solid, but fragmented disciplinary and applied knowledge acquired in other courses...

  2. Analysis of rotating flexible blades using MSC/NASTRAN

    Science.gov (United States)

    Ernst, Michael A.

    1988-01-01

    An overview is given of the use of MSC/NASTRAN in the analysis of rotating flexible blades. The geometrically nonlinear analysis using NASTRAN Solution Sequence 64 is discussed along with the determination of frequencies and mode shapes using Solution Sequence 63. Items unique to rotating blade analysis, such as setting angle, centrifugal softening effects, and hub flexibility, are emphasized.

  3. M.Sc. in Civil and Structural Engineering

    DEFF Research Database (Denmark)

    This catalogue contains a list of project ideas proposed by the scientific staff at the Department of Civil Engineering, Aalborg University, and a number of companies. Most of the project ideas in this catalogue may form the basis for long and short candidate projects as well as regular 3rd...... semester projects at the M.Sc. programme in Civil and Structural Engineering....

  4. M.Sc. in Civil and Structural Engineering

    DEFF Research Database (Denmark)

    Clausen, Johan

    The report contain a list of project ideas proposed by the scientific staff at the Department of Civil Engineering, Aalborg University, and a number of companies. Most of the project ideas in this catalogue may form the basis for long and short candidate projects as well as regular 3rd semester...... projects at the M.Sc. programme in Civil and Structural Engineering....

  5. M.Sc. in Civil and Structural Engineering

    DEFF Research Database (Denmark)

    The catalogue contain a list of project ideas proposed by the scientific staff at the Department of Civil Engineering, Aalborg University, and a number of companies. Most of the project ideas in this catalogue may form the basis for long and short candidate projects as well as regular 3rd semester...... projects at the M.Sc. programme in Civil and Structural Engineering....

  6. Fit for purpose? Evaluation of an MSc. in medical physics.

    Science.gov (United States)

    van der Putten, W J

    2014-05-01

    The National University of Ireland in Galway established a Master in Science (MSc.) program in medical physics in 2002. The course was designed to be 90 ECTS(1) credits and of one calendar year duration. From the outset the MSc. was designed to be part of an overall medical physics training program. MSc. programs are now widely used as part of the training and education of medical physicists. There is however paucity of data on the effectiveness of such courses and the purpose of the study reported here is to provide information on one particular MSc. course in medical physics. This is relevant to medical physicists who are involved in the development and running of medical physics training programs. The study used as methodology the Kirkpatrick levels of professional training. It was conducted through an online survey, both from students who graduated from the course and from students who were in the process of completing the course. The survey proved to be an effective way to determine attributes of modules such as learning outcomes, knowledge imparted, quality of teaching materials and others. The survey proved to be remarkably able to demonstrate interventions in the individual course modules. Although the course was shown to be effective in the imparting of the knowledge required to become a qualified medical physicist several areas for improvement were identified. These are mainly in the areas of increased practical experience and in course delivery. Copyright © 2013 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

  7. Transport across the cell-membrane dictates nanoparticle fate and toxicity: a new paradigm in nanotoxicology

    Science.gov (United States)

    Guarnieri, Daniela; Sabella, Stefania; Muscetti, Ornella; Belli, Valentina; Malvindi, Maria Ada; Fusco, Sabato; de Luca, Elisa; Pompa, Pier Paolo; Netti, Paolo A.

    2014-08-01

    The toxicity of metallic nanoparticles (MNPs) has been fully ascertained, but the mechanisms underlying their cytotoxicity remain still largely unclear. Here we demonstrate that the cytotoxicity of MNPs is strictly reliant on the pathway of cellular internalization. In particular, if otherwise toxic gold, silver, and iron oxide NPs are forced through the cell membrane bypassing any form of active mechanism (e.g., endocytosis), no significant cytotoxic effect is registered. Pneumatically driven NPs across the cell membrane show a different distribution within the cytosol compared to NPs entering the cell by active endocytosis. Specifically, they exhibit free random Brownian motions within the cytosol and do not accumulate in lysosomes. Results suggest that intracellular accumulation of metallic nanoparticles into endo-lysosomal compartments is the leading cause of nanotoxicity, due to consequent nanoparticle degradation and in situ release of metal ions.The toxicity of metallic nanoparticles (MNPs) has been fully ascertained, but the mechanisms underlying their cytotoxicity remain still largely unclear. Here we demonstrate that the cytotoxicity of MNPs is strictly reliant on the pathway of cellular internalization. In particular, if otherwise toxic gold, silver, and iron oxide NPs are forced through the cell membrane bypassing any form of active mechanism (e.g., endocytosis), no significant cytotoxic effect is registered. Pneumatically driven NPs across the cell membrane show a different distribution within the cytosol compared to NPs entering the cell by active endocytosis. Specifically, they exhibit free random Brownian motions within the cytosol and do not accumulate in lysosomes. Results suggest that intracellular accumulation of metallic nanoparticles into endo-lysosomal compartments is the leading cause of nanotoxicity, due to consequent nanoparticle degradation and in situ release of metal ions. Electronic supplementary information (ESI) available. See DOI

  8. Limb derived cells as a paradigm for engineering self-assembling skeletal tissues.

    Science.gov (United States)

    Fernando, Warnakulasuriya A; Papantoniou, Ioannis; Mendes, Luis F; Hall, Gabriella Nilsson; Bosmans, Kathleen; Tam, Wai L; Teixeira, Liliana M; Moos, Malcolm; Geris, Liesbet; Luyten, Frank P

    2017-06-11

    Mimicking developmental events has been proposed as a strategy to engineer tissue constructs for regenerative medicine. However, this approach has not yet been investigated for skeletal tissues. Here, it is demonstrated that ectopic implantation of day-14.5 mouse embryonic long bone anlagen, dissociated into single cells and randomly incorporated in a bioengineered construct, gives rise to epiphyseal growth plate-like structures, bone and marrow, which share many morphological and molecular similarities to epiphyseal units that form after transplanting intact long bone anlage, demonstrating substantial robustness and autonomy of complex tissue self-assembly and the overall organogenesis process. In vitro studies confirm the self-aggregation and patterning capacity of anlage cells and demonstrate that the model can be used to evaluate the effects of large and small molecules on biological behaviour. These results reveal the preservation of self-organizing and self-patterning capacity of anlage cells even when disconnected from their developmental niche and subjected to system perturbations such as cellular dissociation. These inherent features make long bone anlage cells attractive as a model system for tissue engineering technologies aimed at creating constructs that have the potential to self-assemble and self-pattern complex architectural structures. Copyright © 2017 John Wiley & Sons, Ltd.

  9. "String theory" of c-kit(pos) cardiac cells: a new paradigm regarding the nature of these cells that may reconcile apparently discrepant results.

    Science.gov (United States)

    Keith, Matthew C L; Bolli, Roberto

    2015-03-27

    Although numerous preclinical investigations have consistently demonstrated salubrious effects of c-kit(pos) cardiac cells administered after myocardial infarction, the mechanism of action remains highly controversial. We and others have found little or no evidence that these cells differentiate into mature functional cardiomyocytes, suggesting paracrine effects. In this review, we propose a new paradigm predicated on a comprehensive analysis of the literature, including studies of cardiac development; we have (facetiously) dubbed this conceptual construct "string theory" of c-kit(pos) cardiac cells because it reconciles multifarious and sometimes apparently discrepant results. There is strong evidence that, during development, the c-kit receptor is expressed in different pools of cardiac progenitors (some capable of robust cardiomyogenesis and others with little or no contribution to myocytes). Accordingly, c-kit positivity, in itself, does not define the embryonic origins, lineage capabilities, or differentiation capacities of specific cardiac progenitors. C-kit(pos) cells derived from the first heart field exhibit cardiomyogenic potential during development, but these cells are likely depleted shortly before or after birth. The residual c-kit(pos) cells found in the adult heart are probably of proepicardial origin, possess a mesenchymal phenotype (resembling bone marrow mesenchymal stem/stromal cells), and are capable of contributing significantly only to nonmyocytic lineages (fibroblasts, smooth muscle cells, and endothelial cells). If these 2 populations (first heart field and proepicardium) express different levels of c-kit, the cardiomyogenic potential of first heart field progenitors might be reconciled with recent results of c-kit(pos) cell lineage tracing studies. The concept that c-kit expression in the adult heart identifies epicardium-derived, noncardiomyogenic precursors with a mesenchymal phenotype helps to explain the beneficial effects of c

  10. Muse Cells: Nontumorigenic Pluripotent Stem Cells Present in Adult Tissues—A Paradigm Shift in Tissue Regeneration and Evolution

    Directory of Open Access Journals (Sweden)

    Ariel A. Simerman

    2016-01-01

    Full Text Available Muse cells are a novel population of nontumorigenic pluripotent stem cells, highly resistant to cellular stress. These cells are present in every connective tissue and intrinsically express pluripotent stem markers such as Nanog, Oct3/4, Sox2, and TRA1-60. Muse cells are able to differentiate into cells from all three embryonic germ layers both spontaneously and under media-specific induction. Unlike ESCs and iPSCs, Muse cells exhibit low telomerase activity and asymmetric division and do not undergo tumorigenesis or teratoma formation when transplanted into a host organism. Muse cells have a high capacity for homing into damaged tissue and spontaneous differentiation into cells of compatible tissue, leading to tissue repair and functional restoration. The ability of Muse cells to restore tissue function may demonstrate the role of Muse cells in a highly conserved cellular mechanism related to cell survival and regeneration, in response to cellular stress and acute injury. From an evolutionary standpoint, genes pertaining to the regenerative capacity of an organism have been lost in higher mammals from more primitive species. Therefore, Muse cells may offer insight into the molecular and evolutionary bases of autonomous tissue regeneration and elucidate the molecular and cellular mechanisms that prevent mammals from regenerating limbs and organs, as planarians, newts, zebrafish, and salamanders do.

  11. Mesenchymal cells for skeletal tissue engineering.

    Science.gov (United States)

    Panetta, N J; Gupta, D M; Quarto, N; Longaker, M T

    2009-03-01

    Today, surgical intervention remains the mainstay of treatment to intervene upon a multitude of skeletal deficits and defects attributable to congenital malformations, oncologic resection, pathologic degenerative bone destruction, and post-traumatic loss. Despite this significant demand, the tools with which surgeons remain equipped are plagued with a surfeit of inadequacies, often resulting in less than ideal patient outcomes. The failings of current techniques largely arise secondary to their inability to produce a regenerate which closely resembles lost tissue. As such, focus has shifted to the potential of mesenchymal stem cell (MSC)-based skeletal tissue engineering. The successful development of such techniques would represent a paradigm shift from current approaches, carrying with it the potential to regenerate tissues which mimic the form and function of endogenous bone. Lessons learned from investigations probing the endogenous regenerative capacity of skeletal tissues have provided direction to early studies investigating the osteogenic potential of MSC. Additionally, increasing attention is being turned to the role of targeted molecular manipulations in augmenting MSC osteogenesis, as well as the development of an ideal scaffold ''vehicle'' with which to deliver progenitor cells. The following discussion presents the authors' current working knowledge regarding these critical aspects of MSC application in cell-based skeletal tissue engineering strategies, as well as provides insight towards what future steps must be taken to make their clinical translation a reality.

  12. Membrane paradigm

    International Nuclear Information System (INIS)

    Price, R.H.; Thorne, K.S.

    1986-01-01

    The membrane paradigm is a modified frozen star approach to modeling black holes, with particles and fields assuming a complex, static, boundary-layer type structure (membrane) near the event horizon. The membrane has no effects on the present or future evolution of particles and fields above itself. The mathematical representation is a combination of a formalism containing terms for the shear and bulk viscosity, surface pressure, momentum, temperature, entropy, etc., of the horizon and the 3+1 formalism. The latter model considers a family of three-dimensional spacelike hypersurfaces in one-dimensional time. The membrane model considers a magnetic field threading the hole and undergoing torque from the hole rotation. The field is cleaned by the horizon and distributed over the horizon so that ohmic dissipation is minimized. The membrane paradigm is invalid inside the horizon, but is useful for theoretically probing the properties of slowly evolving black holes

  13. MiR-9-5p promotes MSC migration by activating β-catenin signaling pathway.

    Science.gov (United States)

    Li, Xianyang; He, Lihong; Yue, Qing; Lu, Junhou; Kang, Naixin; Xu, Xiaojing; Wang, Huihui; Zhang, Huanxiang

    2017-07-01

    Mesenchymal stem cells (MSCs) have the potential to treat various tissue damages, but the very limited number of cells that migrate to the damaged region strongly restricts their therapeutic applications. Full understanding of mechanisms regulating MSC migration will help to improve their migration ability and therapeutic effects. Increasing evidence shows that microRNAs play important roles in the regulation of MSC migration. In the present study, we reported that miR-9-5p was upregulated in hepatocyte growth factor -treated MSCs and in MSCs with high migration ability. Overexpression of miR-9-5p promoted MSC migration, whereas inhibition of endogenous miR-9-5p decreased MSC migration. To elucidate the underlying mechanism, we screened the target genes of miR-9-5p and report for the first time that CK1α and GSK3β, two inhibitors of β-catenin signaling pathway, were direct targets of miR-9-5p in MSCs and that overexpression of miR-9-5p upregulated β-catenin signaling pathway. In line with these data, inhibition of β-catenin signaling pathway by FH535 decreased the miR-9-5p-promoted migration of MSCs, while activation of β-catenin signaling pathway by LiCl rescued the impaired migration of MSCs triggered by miR-9-5p inhibitor. Furthermore, the formation and distribution of focal adhesions as well as the reorganization of F-actin were affected by the expression of miR-9-5p. Collectively, these results demonstrate that miR-9-5p promotes MSC migration by upregulating β-catenin signaling pathway, shedding light on the optimization of MSCs for cell replacement therapy through manipulating the expression level of miR-9-5p. Copyright © 2017 the American Physiological Society.

  14. Strategy Escalation: An emerging paradigm for safe clinical development of T cell gene therapies

    Directory of Open Access Journals (Sweden)

    Junghans Richard

    2010-06-01

    Full Text Available Abstract Gene therapy techniques are being applied to modify T cells with chimeric antigen receptors (CARs for therapeutic ends. The versatility of this platform has spawned multiple options for their application with new permutations in strategies continually being invented, a testimony to the creative energies of many investigators. The field is rapidly expanding with immense potential for impact against diverse cancers. But this rapid expansion, like the Big Bang, comes with a somewhat chaotic evolution of its therapeutic universe that can also be dangerous, as seen by recently publicized deaths. Time-honored methods for new drug testing embodied in Dose Escalation that were suitable for traditional inert agents are now inadequate for these novel "living drugs". In the following, I propose an approach to escalating risk for patient exposures with these new immuno-gene therapy agents, termed Strategy Escalation, that accounts for the molecular and biological features of the modified cells and the methods of their administration. This proposal is offered not as a prescriptive but as a discussion framework that investigators may wish to consider in configuring their intended clinical applications.

  15. Germline development in amniotes: A paradigm shift in primordial germ cell specification

    Science.gov (United States)

    2016-01-01

    In the field of germline development in amniote vertebrates, primordial germ cell (PGC) specification in birds and reptiles remains controversial. Avians are believed to adopt a predetermination or maternal specification mode of PGC formation, contrary to an inductive mode employed by mammals and, supposedly, reptiles. Here, we revisit and review some key aspects of PGC development that channelled the current subdivision, and challenge the position of birds and reptiles as well as the ‘binary’ evolutionary model of PGC development in vertebrates. We propose an alternative view on PGC specification where germ plasm plays a role in laying the foundation for the formation of PGC precursors (pPGC), but not necessarily of PGCs. Moreover, inductive mechanisms may be necessary for the transition from pPGCs to PGCs. Within this framework, the implementation of data from birds and reptiles could provide new insights on the evolution of PGC specification in amniotes. PMID:27273724

  16. Using PAFEC as a preprocessor for MSC/NASTRAN

    International Nuclear Information System (INIS)

    Gray, W.H.; Baudry, T.V.

    1983-01-01

    Programs for Automatic Finite Element Calculations (PAFEC) is a general-purpose, three-dimensional, linear and nonlinear finite element program. PAFEC's features include free-format input using engineering keywords, powerful mesh-generating facilities, sophisticated database management procedures, and extensive data validation checks. Presented here is a description of a software interface that permits PAFEC to be used as a preprocessor for MSC/NASTRAN. This user-friendly software, called PAFMSC, frees the stress analyst from the laborious and error-prone procedure of creating and debugging a rigid-format MSC/NASTRAN bulk data deck. By interactively creating and debugging a finite element model with PAFEC, thus taking full advantage of the free-format, engineering-keyword-oriented data structure of PAFEC, the stress analyst can drastically reduce the amount of time spent during model generation. The PAFMSC software will automatically convert a PAFEC data structure into an MSC/NASTRAN bulk data deck. The capabilities and limitations of the PAFMSC software are fully discussed

  17. Using PAFEC as a preprocessor for MSC/NASTRAN

    International Nuclear Information System (INIS)

    Gray, W.H.; Baudry, T.V.

    1983-01-01

    Programs for Automatic Finite Element Calculations (PAFEC) is a general-purpose, three-dimensional, linear and nonlinear finite element program. PAFEC's features include free-format input using engineering keywords, powerful mesh-generating facilities, sophisticated database management procedures, and extensive data validation checks. Presented here is a description of a software interface that permits PAFEC to be used as a preprocessor for MSC/NASTRAN. This user-friendly software, called PAFMSC, frees the stress analyst from the laborious and error-prone procedure of creating and debugging a rigid-format MSC/NASTRAN bulk data deck. By interactively creating and debugging a finite element model with PAFEC, thus taking full advantage of the free-format, engineering-keyword-oriented data structure of PAFEC, the stress analyst can drastically reduce the amount of time spent during model generation. The PAFMSC software will automatically convert a PAFEC data structure into an MSC/NASTRAN bulk data deck. The capabilities and limitations of the PAFMSC software are fully discussed in the following report

  18. Simulation of Failure in Gearbox Using MSC.Adams

    Directory of Open Access Journals (Sweden)

    Jan Furch

    2017-01-01

    Full Text Available Vehicle’s gearbox is regarded as one of the most crucial elements in a vehicle but it sustains a variety of faults such as a broken tooth, misalignment, imbalance, looseness, and even a broken case. Using accelerometers, which are mounted on the case to measure a vibration signal, we can detect faults and monitor the condition but the signals are often complicated and difficult to interpret. Moreover, it is costly and almost impossible to change the structure of a gearbox in order to survey, for instance, the dependence of a vibration signal on the structure, or types of a fault. In this paper a dynamic model of gearbox was developed with tooth breakage to study the capability of simulation using MSC.Adams software. In this simulation we focus on the gearbox used in a common military vehicle. The simulation was based on a nonlinear contact force to predict what happens to the gearbox in case the tooth breaks. The contact mechanics model of the meshing teeth is studied thoroughly by selecting contact simulation parameters such as stiffness, force exponent, damping and friction coefficients. To simulate the real working environment of the gearbox, simulated bearings were also built in the MSC.Adams. The paper shows that it is possible to simulate vibration signals by the gearbox model created in 3D CAD software and analyze the results in the multi‑body dynamics software MSC.Adams.

  19. Fibrous hyaluronic acid hydrogels that direct MSC chondrogenesis through mechanical and adhesive cues.

    Science.gov (United States)

    Kim, Iris L; Khetan, Sudhir; Baker, Brendon M; Chen, Christopher S; Burdick, Jason A

    2013-07-01

    Electrospinning has recently gained much interest due to its ability to form scaffolds that mimic the nanofibrous nature of the extracellular matrix, such as the size and depth-dependent alignment of collagen fibers within hyaline cartilage. While much progress has been made in developing bulk, isotropic hydrogels for tissue engineering and understanding how the microenvironment of such scaffolds affects cell response, these effects have not been extensively studied in a nanofibrous system. Here, we show that the mechanics (through intrafiber crosslink density) and adhesivity (through RGD density) of electrospun hyaluronic acid (HA) fibers significantly affect human mesenchymal stem cell (hMSC) interactions and gene expression. Specifically, hMSC spreading, proliferation, and focal adhesion formation were dependent on RGD density, but not on the range of fiber mechanics investigated. Moreover, traction-mediated fiber displacements generally increased with more adhesive fibers. The expression of chondrogenic markers, unlike trends in cell spreading and cytoskeletal organization, was influenced by both fiber mechanics and adhesivity, in which softer fibers and lower RGD densities generally enhanced chondrogenesis. This work not only reveals concurrent effects of mechanics and adhesivity in a fibrous context, but also highlights fibrous HA hydrogels as a promising scaffold for future cartilage repair strategies. Copyright © 2013 Elsevier Ltd. All rights reserved.

  20. ErbB receptors and cell polarity: New pathways and paradigms for understanding cell migration and invasion

    International Nuclear Information System (INIS)

    Feigin, Michael E.; Muthuswamy, Senthil K.

    2009-01-01

    The ErbB family of receptor tyrosine kinases is involved in initiation and progression of a number of human cancers, and receptor activation or overexpression correlates with poor patient survival. Research over the past two decades has elucidated the molecular mechanisms underlying ErbB-induced tumorigenesis, which has resulted in the development of effective targeted therapies. ErbB-induced signal transduction cascades regulate a wide variety of cell processes, including cell proliferation, apoptosis, cell polarity, migration and invasion. Within tumors, disruption of these core processes, through cooperative oncogenic lesions, results in aggressive, metastatic disease. This review will focus on the ErbB signaling networks that regulate migration and invasion and identify a potential role for cell polarity pathways during cancer progression

  1. Gamma irradiation and heat treatment for sterilization of Mushroom Spent Compost (MSC)

    International Nuclear Information System (INIS)

    Rosnani Abdul Rashid; Hassan Hamdani Mutaat; Foziah Ali; Zainab Harun; Hoe, P.C.K.; Mohd Meswan Maskom; Khairuddin Abdul Rahim

    2016-01-01

    Mushroom spent compost (MSC) refers to substrate residue from mushroom cultivation. MSC can be used as a material to improve soil properties for farming. MSC is also suitable as a carrier or substrate to hold beneficial microorganisms in bio fertilizer products. The carrier for bio fertilizer products must be sterilized completely before inoculating with bacteria inoculum. In this study, the effects of gamma irradiation and heat on sterilization of MSC were evaluated by microbial enumeration technique. The MSC was packed into polyethylene bags. The packed MSC were irradiated at different doses of 0 (control), 10, 20, 30, 40, 50 kGy, and heat sterilized at different autoclaving time of 0 (control), 15, 30, 45 and 60 minutes, separately. The irradiated and autoclaved samples were enumerated for viable colonies. The results showed that MSC was completely sterilized by gamma irradiation at the dose of 30 kGy whilst sterilization by heat required 30 minute autoclaving time. (author)

  2. Physiology and pathophysiology of selectins, integrins, and IgSF cell adhesion molecules focusing on inflammation. A paradigm model on infectious endocarditis.

    Science.gov (United States)

    Golias, Christos; Batistatou, Anna; Bablekos, Georgios; Charalabopoulos, Alexandros; Peschos, Dimitrios; Mitsopoulos, Panagiotis; Charalabopoulos, Konstantinos

    2011-06-01

    The development of adhesion bonds, either among cells or among cells and components of the extracellular matrix, is a crucial process. These interactions are mediated by some molecules collectively known as adhesion molecules (CAMs). CAMs are ubiquitously expressed proteins playing a central role in controlling cell migration, proliferation, survival, and apoptosis. Besides their key function in physiological maintenance of tissue integrity, CAMs play an eminent role in various pathological processes such as cardiovascular disorders, atherogenesis, atherosclerotic plaque progression and regulation of the inflammatory response. CAMs such as selectins, integrins, and immunoglobulin superfamily take part in interactions between leukocyte and vascular endothelium (leukocyte rolling, arrest, firm adhesion, migration). Experimental data and pathologic observations support the assumption that pathogenic microorganisms attach to vascular endothelial cells or sites of vascular injury initiating intravascular infections. In this review a paradigm focusing on cell adhesion molecules pathophysiology and infective endocarditis development is given.

  3. Receptor control in mesenchymal stem cell engineering

    Science.gov (United States)

    Dalby, Matthew J.; García, Andrés J.; Salmeron-Sanchez, Manuel

    2018-03-01

    Materials science offers a powerful tool to control mesenchymal stem cell (MSC) growth and differentiation into functional phenotypes. A complex interplay between the extracellular matrix and growth factors guides MSC phenotypes in vivo. In this Review, we discuss materials-based bioengineering approaches to direct MSC fate in vitro and in vivo, mimicking cell-matrix-growth factor crosstalk. We first scrutinize MSC-matrix interactions and how the properties of a material can be tailored to support MSC growth and differentiation in vitro, with an emphasis on MSC self-renewal mechanisms. We then highlight important growth factor signalling pathways and investigate various materials-based strategies for growth factor presentation and delivery. Integrin-growth factor crosstalk in the context of MSC engineering is introduced, and bioinspired material designs with the potential to control the MSC niche phenotype are considered. Finally, we summarize important milestones on the road to MSC engineering for regenerative medicine.

  4. Effects of high glucose on mesenchymal stem cell proliferation and differentiation

    DEFF Research Database (Denmark)

    Li, Yu-Ming; Schilling, Tatjana; Benisch, Peggy

    2007-01-01

    was not influenced by HG in both cell types. MSC treatment with HG favored osteogenic differentiation. MSC are resistant to HG toxicity, depending on the stemness of MSC. Proliferation and osteogenic differentiation are stimulated by HG. Effects of HG on the transient amplifying compartment of MSC may differ from...

  5. Theoretical and Practical Issues That Are Relevant When Scaling Up hMSC Microcarrier Production Processes.

    Science.gov (United States)

    Jossen, Valentin; Schirmer, Cedric; Mostafa Sindi, Dolman; Eibl, Regine; Kraume, Matthias; Pörtner, Ralf; Eibl, Dieter

    2016-01-01

    The potential of human mesenchymal stem cells (hMSCs) for allogeneic cell therapies has created a large amount of interest. However, this presupposes the availability of efficient scale-up procedures. Promising results have been reported for stirred bioreactors that operate with microcarriers. Recent publications focusing on microcarrier-based stirred bioreactors have demonstrated the successful use of Computational Fluid Dynamics (CFD) and suspension criteria (N S1u , N S1) for rapidly scaling up hMSC expansions from mL- to pilot scale. Nevertheless, one obstacle may be the formation of large microcarrier-cell-aggregates, which may result in mass transfer limitations and inhomogeneous distributions of stem cells in the culture broth. The dependence of microcarrier-cell-aggregate formation on impeller speed and shear stress levels was investigated for human adipose derived stromal/stem cells (hASCs) at the spinner scale by recording the Sauter mean diameter (d 32) versus time. Cultivation at the suspension criteria provided d 32 values between 0.2 and 0.7 mm, the highest cell densities (1.25 × 10(6) cells mL(-1) hASCs), and the highest expansion factors (117.0 ± 4.7 on day 7), while maintaining the expression of specific surface markers. Furthermore, suitability of the suspension criterion N S1u was investigated for scaling up microcarrier-based processes in wave-mixed bioreactors for the first time.

  6. Therapeutic effects of hMAPC and hMSC transplantation after stroke in mice.

    Directory of Open Access Journals (Sweden)

    Silvia Mora-Lee

    Full Text Available Stroke represents an attractive target for stem cell therapy. Although different types of cells have been employed in animal models, a direct comparison between cell sources has not been performed. The aim of our study was to assess the effect of human multipotent adult progenitor cells (hMAPCs and human mesenchymal stem cells (hMSCs on endogenous neurogenesis, angiogenesis and inflammation following stroke. BALB/Ca-RAG 2(-/- γC(-/- mice subjected to FeCl(3 thrombosis mediated stroke were intracranially injected with 2 × 10(5 hMAPCs or hMSCs 2 days after stroke and followed for up to 28 days. We could not detect long-term engraftment of either cell population. However, in comparison with PBS-treated animals, hMSC and hMAPC grafted animals demonstrated significantly decreased loss of brain tissue. This was associated with increased angiogenesis, diminished inflammation and a glial-scar inhibitory effect. Moreover, enhanced proliferation of cells in the subventricular zone (SVZ and survival of newly generated neuroblasts was observed. Interestingly, these neuroprotective effects were more pronounced in the group of animals treated with hMAPCs in comparison with hMSCs. Our results establish cell therapy with hMAPCs and hMSCs as a promising strategy for the treatment of stroke.

  7. Theoretical and Practical Issues That Are Relevant When Scaling Up hMSC Microcarrier Production Processes

    Directory of Open Access Journals (Sweden)

    Valentin Jossen

    2016-01-01

    Full Text Available The potential of human mesenchymal stem cells (hMSCs for allogeneic cell therapies has created a large amount of interest. However, this presupposes the availability of efficient scale-up procedures. Promising results have been reported for stirred bioreactors that operate with microcarriers. Recent publications focusing on microcarrier-based stirred bioreactors have demonstrated the successful use of Computational Fluid Dynamics (CFD and suspension criteria (NS1u, NS1 for rapidly scaling up hMSC expansions from mL- to pilot scale. Nevertheless, one obstacle may be the formation of large microcarrier-cell-aggregates, which may result in mass transfer limitations and inhomogeneous distributions of stem cells in the culture broth. The dependence of microcarrier-cell-aggregate formation on impeller speed and shear stress levels was investigated for human adipose derived stromal/stem cells (hASCs at the spinner scale by recording the Sauter mean diameter (d32 versus time. Cultivation at the suspension criteria provided d32 values between 0.2 and 0.7 mm, the highest cell densities (1.25 × 106 cells mL−1 hASCs, and the highest expansion factors (117.0 ± 4.7 on day 7, while maintaining the expression of specific surface markers. Furthermore, suitability of the suspension criterion NS1u was investigated for scaling up microcarrier-based processes in wave-mixed bioreactors for the first time.

  8. Theoretical and Practical Issues That Are Relevant When Scaling Up hMSC Microcarrier Production Processes

    Science.gov (United States)

    Jossen, Valentin; Schirmer, Cedric; Mostafa Sindi, Dolman; Eibl, Regine; Kraume, Matthias; Pörtner, Ralf; Eibl, Dieter

    2016-01-01

    The potential of human mesenchymal stem cells (hMSCs) for allogeneic cell therapies has created a large amount of interest. However, this presupposes the availability of efficient scale-up procedures. Promising results have been reported for stirred bioreactors that operate with microcarriers. Recent publications focusing on microcarrier-based stirred bioreactors have demonstrated the successful use of Computational Fluid Dynamics (CFD) and suspension criteria (N S1u, N S1) for rapidly scaling up hMSC expansions from mL- to pilot scale. Nevertheless, one obstacle may be the formation of large microcarrier-cell-aggregates, which may result in mass transfer limitations and inhomogeneous distributions of stem cells in the culture broth. The dependence of microcarrier-cell-aggregate formation on impeller speed and shear stress levels was investigated for human adipose derived stromal/stem cells (hASCs) at the spinner scale by recording the Sauter mean diameter (d 32) versus time. Cultivation at the suspension criteria provided d 32 values between 0.2 and 0.7 mm, the highest cell densities (1.25 × 106 cells mL−1 hASCs), and the highest expansion factors (117.0 ± 4.7 on day 7), while maintaining the expression of specific surface markers. Furthermore, suitability of the suspension criterion N S1u was investigated for scaling up microcarrier-based processes in wave-mixed bioreactors for the first time. PMID:26981131

  9. A new paradigm in ulcerative colitis: regulatory T cells are key factor which induces/exacerbates UC through an immune imbalance.

    Science.gov (United States)

    Hanai, Hiroyuki; Iida, Takayuki; Ikeya, Kentaro; Abe, Jinrou; Maruyama, Yasuhiko; Shimura, Teruyuki; Sugimoto, Ken; Watanabe, Fumitoshi

    2013-06-01

    Leukocytapheresis (LCAP) appears to remove or inactivate inflammatory cells and to reset immunological responses, resulting to cure responders of ulcerative colitis (UC). The changes of T cell subsets were investigated in UC patients treated with LCAP. Levels of T cell subsets in peripheral blood before and after LCAP were analysed by flow cytometric analysis. Of 20 UC patients, 13 (65%) achieved remission and 2 (10%) showed the improvement of UC symptoms. Ratios of some T cell subtypes such as regulatory T (Treg) cells and memory T cells to CD4(+) T cells changed significantly only in responders. Especially, ratio of resting Treg/CD4(+) T cells was significantly increased after the first LCAP session, and then one of activated Treg/CD4(+) T cells was increased after 2 week. This may lead to the development of a new UC paradigm in which an imbalance in Treg cell subsets triggers the onset and/or exacerbation of UC. Copyright © 2012 Elsevier Ltd. All rights reserved.

  10. The cytoplasmic cage domain of the mechanosensitive channel MscS is a sensor of macromolecular crowding.

    Science.gov (United States)

    Rowe, Ian; Anishkin, Andriy; Kamaraju, Kishore; Yoshimura, Kenjiro; Sukharev, Sergei

    2014-05-01

    Cells actively regulate the macromolecular excluded volume of the cytoplasm to maintain the reciprocal fraction of free aqueous solution that is optimal for intracellular processes. However, the mechanisms whereby cells sense this critical parameter remain unclear. The mechanosensitive channel of small conductance (MscS channel), which is the major regulator of turgor in bacteria, mediates efflux of small osmolytes in response to increased membrane tension. At moderate sustained tensions produced by a decrease in external osmolarity, MscS undergoes slow adaptive inactivation; however, it inactivates abruptly in the presence of cytoplasmic crowding agents. To understand the mechanism underlying this rapid inactivation, we combined extrapolated and equilibrium molecular dynamics simulations with electrophysiological analyses of MscS mutants to explore possible transitions of MscS and generated models of the resting and inactivated states. Our models suggest that the coupling of the gate formed by TM3 helices to the peripheral TM1-TM2 pairs depends on the axial position of the core TM3 barrel relative to the TM1-TM2 shaft and the state of the associated hollow cytoplasmic domain ("cage"). They also indicate that the tension-driven inactivation transition separates the gate from the peripheral helices and promotes kinks in TM3s at G113 and that this conformation is stabilized by association of the TM3b segment with the β domain of the cage. We found that mutations destabilizing the TM3b-β interactions preclude inactivation and make the channel insensitive to crowding agents and voltage; mutations that strengthen this association result in a stable closed state and silent inactivation. Steered simulations showed that pressure exerted on the cage bottom in the inactivated state reduces the volume of the cage in the cytoplasm and at the same time increases the footprint of the transmembrane domain in the membrane, implying coupled sensitivity to both membrane tension

  11. Nonlinear random response prediction using MSC/NASTRAN

    Science.gov (United States)

    Robinson, J. H.; Chiang, C. K.; Rizzi, S. A.

    1993-01-01

    An equivalent linearization technique was incorporated into MSC/NASTRAN to predict the nonlinear random response of structures by means of Direct Matrix Abstract Programming (DMAP) modifications and inclusion of the nonlinear differential stiffness module inside the iteration loop. An iterative process was used to determine the rms displacements. Numerical results obtained for validation on simple plates and beams are in good agreement with existing solutions in both the linear and linearized regions. The versatility of the implementation will enable the analyst to determine the nonlinear random responses for complex structures under combined loads. The thermo-acoustic response of a hexagonal thermal protection system panel is used to highlight some of the features of the program.

  12. Nonlinear random response prediction using MSC/NASTRAN

    Science.gov (United States)

    Robinson, J. H.; Chiang, C. K.; Rizzi, S. A.

    1993-10-01

    An equivalent linearization technique was incorporated into MSC/NASTRAN to predict the nonlinear random response of structures by means of Direct Matrix Abstract Programming (DMAP) modifications and inclusion of the nonlinear differential stiffness module inside the iteration loop. An iterative process was used to determine the rms displacements. Numerical results obtained for validation on simple plates and beams are in good agreement with existing solutions in both the linear and linearized regions. The versatility of the implementation will enable the analyst to determine the nonlinear random responses for complex structures under combined loads. The thermo-acoustic response of a hexagonal thermal protection system panel is used to highlight some of the features of the program.

  13. Seismic analysis of plutonium glovebox by MSC/NASTRAN

    International Nuclear Information System (INIS)

    Hirata, Masaru; Ishikawa, Kazuya; Korosawa, Makoto; Fukushima, Susumu; Hoshina, Hirofumi.

    1993-01-01

    Seismic analysis of the structural strength of gloveboxes is important for plutonium confinement evaluation. However, the analytical methods must be developed for evaluating the mutual displacement between the window frame and acrylic resin window panel with regard to plutonium confinement during an earthquake. Therefore, seismic analysis for a standard glovebox in Plutonium Fuel Research Facility at Oarai Research Establishment of JAERI has been conducted by FEM (Finite Element Method) computer code MSC/NASTRAN (MacNeal-Schwendler Corporation NASA Structural Analysis). Modelling of glovebox window frame has been investigated from the results of natural frequency analysis and static analysis. After the acquisition of a suitable model, displacement around the window frame and glovebox structural strength have been evaluated in detail by use of floor response spectrum analysis and time-history (transient response) analysis. (author)

  14. Behavioral Evaluation of hMSC-GFP+ Transplantation in an Hemiparkinson Experimental Model in Wistar Rat

    Directory of Open Access Journals (Sweden)

    Jéssica Paola Alcázar Arzuza

    2017-05-01

    Full Text Available The effect of hMSCs-GFP+ transplantation was evaluated in an experimental model of Parkinson's disease (PD in 27 Wistar rats, or in three experimental groups: control (CON  n=7, injured (LES n=10 and transplanted (LES+T n=10. In order to evaluate the influence of the transplantation on the motor behavior, one month after the injury, rotation behavior induced by apomorphine, neurological test, transversal bar and SNpc cells positive to TH were developed. Using the Anova test, there was a decrease in the number of turns in transplanted animals (p=0.005 as well as in the neurological test (p=0.0004 and in the transverse bar that lead to this group in an intermediate position regarding LES and CON groups. There is a possible recovery of the transplantation-mediated nigroestriatal pathway of hMSC-GFP +.

  15. Didaktiske paradigmer og refleksion

    DEFF Research Database (Denmark)

    Christensen, Torben Spanget

    2014-01-01

    this article. A possible utilitarian didactical paradigm, already indicated by Krogh as a historical paradigm prominent in our time, is also discussed. It is suggested that reflection could be seen as a normative response to the utilitarian paradigm, and not as a paradigm in its own right. It is concluded...... that reflection must be understood as an overarching cultural phenomenon and a very important qualification of all Nielsen’s paradigms, and also a possible utilitarian paradigm, because it has the potential to add dynamic elements to the more or less static didactic paradigms. Thus the semiotic analysis may...

  16. CNN a paradigm for complexity

    CERN Document Server

    Chua, Leon O

    1998-01-01

    Revolutionary and original, this treatise presents a new paradigm of EMERGENCE and COMPLEXITY, with applications drawn from numerous disciplines, including artificial life, biology, chemistry, computation, physics, image processing, information science, etc.CNN is an acronym for Cellular Neural Networks when used in the context of brain science, or Cellular Nonlinear Networks, when used in the context of emergence and complexity. A CNN is modeled by cells and interactions: cells are defined as dynamical systems and interactions are defined via coupling laws. The CNN paradigm is a universal Tur

  17. Cyclic Tensile Strain Enhances Osteogenesis and Angiogenesis in Mesenchymal Stem Cells from Osteoporotic Donors

    Science.gov (United States)

    Charoenpanich, Adisri; Wall, Michelle E.; Tucker, Charles J.; Andrews, Danica M.K.; Lalush, David S.; Dirschl, Douglas R.

    2014-01-01

    We have shown that the uniaxial cyclic tensile strain of magnitude 10% promotes and enhances osteogenesis of human mesenchymal stem cells (hMSC) and human adipose-derived stem cells (hASC) from normal, nonosteoporotic donors. In the present study, MSC from osteoporotic donors were analyzed for changes in mRNA expression in response to 10% uniaxial tensile strain to identify potential mechanisms underlying the use of this mechanical loading paradigm for prevention and treatment of osteoporosis. Human MSC isolated from three female, postmenopausal osteoporotic donors were analyzed for their responses to mechanical loading using microarray analysis of over 47,000 gene probes. Human MSC were seeded in three-dimensional collagen type I constructs to mimic the organic extracellular matrix of bone and 10% uniaxial cyclic tensile strain was applied to promote osteogenesis. Seventy-nine genes were shown to be regulated within hMSC from osteoporotic donors in response to 10% cyclic tensile strain. Upregulation of six genes were further confirmed with real-time RT-PCR: jun D proto-oncogene (JUND) and plasminogen activator, urokinase receptor (PLAUR), two genes identified as potential key molecules from network analysis; phosphoinositide-3-kinase, catalytic, delta polypeptide (PIK3CD) and wingless-type MMTV integration site family, member 5B (WNT5B), two genes with known importance in bone biology; and, PDZ and LIM domain 4 (PDLIM4) and vascular endothelial growth factor A (VEGFA), two genes that we have previously shown are significantly regulated in hASC in response to this mechanical stimulus. Function analysis indicated that 10% cyclic tensile strain induced expression of genes associated with cell movement, cell proliferation, and tissue development, including development in musculoskeletal and cardiovascular systems. Our results demonstrate that hMSC from aged, osteoporotic donors are capable of enhanced osteogenic differentiation in response to 10% cyclic tensile strain

  18. Immunodepletion and Hypoxia Preconditioning of Mouse Compact Bone Cells as a Novel Protocol to Isolate Highly Immunosuppressive Mesenchymal Stem Cells.

    Science.gov (United States)

    Sivanathan, Kisha Nandini; Gronthos, Stan; Grey, Shane T; Rojas-Canales, Darling; Coates, Patrick T

    2017-04-01

    Compact bones (CB) are major reservoirs of mouse mesenchymal stem cells (mMSC). Here, we established a protocol to isolate MSC from CB and tested their immunosuppressive potential. Collagenase type II digestion of BM-flushed CB from C57B/6 mice was performed to liberate mMSC precursors from bone surfaces to establish nondepleted mMSC. CB cells were also immunodepleted based on the expression of CD45 (leukocytes) and TER119 (erythroid cells) to eliminate hematopoietic cells. CD45 - TER119 - CB cells were subsequently used to generate depleted mMSC. CB nondepleted and depleted mMSC progenitors were cultured under hypoxic conditions to establish primary mMSC cultures. CB depleted mMSC compared to nondepleted mMSC showed greater cell numbers at subculturing and had increased functional ability to differentiate into adipocytes and osteoblasts. CB depleted mMSC had high purity and expressed key mMSC markers (>85% Sca-1, CD29, CD90) with no mature hematopoietic contaminating cells (cells at early passages (P1 or P2), along with high percentages of contaminating CD11b + (35.6%) and CD45 + (39.2%) cells that persisted in culture long term. Depleted and nondepleted mMSC nevertheless exhibited similar potency to suppress total (CD3 + ), CD4 + and CD8 + T cell proliferation, in a dendritic cell allostimulatory one-way mixed lymphocyte reaction. CB depleted mMSC, pretreated with proinflammatory cytokines IFN-γ, TNF-α, and IL-17A, showed superior suppression of CD8 + T cell, but not CD4 + T cell proliferation, relative to untreated-mMSC. In conclusion, CB depleted mMSC established under hypoxic conditions and treated with selective cytokines represent a novel source of potent immunosuppressive MSC. As these cells have enhanced immune modulatory function, they may represent a superior product for use in clinical allotransplantation.

  19. Induced Pluripotent Stem Cell Derived Mesenchymal Stem Cells for Attenuating Age-Related Bone Loss

    Science.gov (United States)

    2012-07-01

    Mesenchymal stem cell (MSC) differentiation towards the bone forming osteoblastic lineage decreases as a function of age and may contribute to age-related...problem of age-related reduced availability of MSC we propose to examine the bone anabolic potential of induced pluripotent stem cell (iPS) derived MSC

  20. Education of MSc and PhD Students in Fluid Power and Mechatronics at DTU

    DEFF Research Database (Denmark)

    Conrad, Finn

    1996-01-01

    The paper deals with education of MSc and PhD students in engineering areas fluid power and mechatronics at the Technical Univ of Denmark, DTU, Lyngby. The new education structure and programs for MSc and PhD students adapted to the change and development of technologies. Focus is on two of twenty...

  1. Depressing Iron Mineral by Metallic-Starch Complex (MSC in Reverse Flotation and Its Mechanism

    Directory of Open Access Journals (Sweden)

    Tao Yue

    2018-02-01

    Full Text Available A series of metallic-starch complex (MSC solutions, synthesized by mixing relevant metallic ionic solutions with the caustic starch solution, were used as the flotation depressants to investigate their depressing effects on hematite ore. The MSC is a nano-sized colloidal complex which is configured by hydrophilic metallic hydroxide as the colloidal nucleus on which starch and hydroxyl complex are adsorbed, resulting in a larger molecule than starch itself. The flotation tests showed that the depressing abilities of various MSC (Fe3+, Zn2+, Pb2+ and Mg2+ on the iron minerals were higher than the caustic starch, and the order of depression ability was: Zn2+-starch > Pb2+-starch > Fe3+-starch > Mg2+-starch > caustic starch. Based on the adsorption analysis, the high depressing ability of the MSC arose from increasing the adsorption density of starch on iron minerals and slightly reducing the absorption of the collector dodecylamine. Adsorption behaviour also indicated that the adsorption of the MSC on mineral surfaces was thicker than the caustic starch, and among various MSC the adsorption of Fe3+-starch exhibited the thickest adsorption layer while that of Mg2+-starch the thinnest. Zeta potential indicated that with a weaker electronegativity than the caustic starch, MSC adsorbed onto iron minerals more easily, and the strong electrostatic adsorption with the aid of the hydrogen bonding and chemisorption agreed well with the high depressing ability of the MSC.

  2. The Marine Stewardship Council (MSC) and the Making of a Market for ‘Sustainable Fish’

    DEFF Research Database (Denmark)

    Ponte, Stefano

    2012-01-01

    , countries or regions. This paper assesses whether these assumptions hold through the analysis of how the Marine Stewardship Council (MSC) label for capture fisheries has managed ‘supply’, ‘demand’ and ‘civic’ concerns in the market for sustainability certifications. The MSC has created and now dominates...

  3. Chemotaxis in densely populated tissue determines germinal center anatomy and cell motility: a new paradigm for the development of complex tissues.

    Directory of Open Access Journals (Sweden)

    Jared B Hawkins

    Full Text Available Germinal centers (GCs are complex dynamic structures that form within lymph nodes as an essential process in the humoral immune response. They represent a paradigm for studying the regulation of cell movement in the development of complex anatomical structures. We have developed a simulation of a modified cyclic re-entry model of GC dynamics which successfully employs chemotaxis to recapitulate the anatomy of the primary follicle and the development of a mature GC, including correctly structured mantle, dark and light zones. We then show that correct single cell movement dynamics (including persistent random walk and inter-zonal crossing arise from this simulation as purely emergent properties. The major insight of our study is that chemotaxis can only achieve this when constrained by the known biological properties that cells are incompressible, exist in a densely packed environment, and must therefore compete for space. It is this interplay of chemotaxis and competition for limited space that generates all the complex and biologically accurate behaviors described here. Thus, from a single simple mechanism that is well documented in the biological literature, we can explain both higher level structure and single cell movement behaviors. To our knowledge this is the first GC model that is able to recapitulate both correctly detailed anatomy and single cell movement. This mechanism may have wide application for modeling other biological systems where cells undergo complex patterns of movement to produce defined anatomical structures with sharp tissue boundaries.

  4. Ovariectomized Rats with Established Osteopenia have Diminished Mesenchymal Stem Cells in the Bone Marrow and Impaired Homing, Osteoinduction and Bone Regeneration at the Fracture Site.

    Science.gov (United States)

    Tewari, Deepshikha; Khan, Mohd Parvez; Sagar, Nitin; China, Shyamsundar P; Singh, Atul K; Kheruka, Subhash C; Barai, Sukanta; Tewari, Mahesh C; Nagar, Geet K; Vishwakarma, Achchhe L; Ogechukwu, Omeje E; Bellare, Jayesh R; Gambhir, Sanjay; Chattopadhyay, Naibedya

    2015-04-01

    We investigated deleterious changes that take place in mesenchymal stem cells (MSC) and its fracture healing competence in ovariectomy (Ovx)-induced osteopenia. MSC from bone marrow (BM) of ovary intact (control) and Ovx rats was isolated. (99m)Tc-HMPAO (Technitium hexamethylpropylene amine oxime) labeled MSC was systemically transplanted to rats and fracture tropism assessed by SPECT/CT. PKH26 labeled MSC (PKH26-MSC) was bound in scaffold and applied to fracture site (drill-hole in femur metaphysis). Osteoinduction was quantified by calcein binding and microcomputed tomography. Estrogen receptor (ER) antagonist, fulvestrant was used to determine ER dependence of osteo-induction by MSC. BM-MSC number was strikingly reduced and doubling time increased in Ovx rats compared to control. SPECT/CT showed reduced localization of (99m)Tc-HMPAO labeled MSC to the fracture site, 3 h post-transplantation in Ovx rats as compared with controls. Post-transplantation, Ovx MSC labeled with PKH26 (Ovx PKH26-MSC) localized less to fracture site than control PKH26-MSC. Transplantation of either control or Ovx MSC enhanced calcein binding and bone volume at the callus of control rats over placebo group however Ovx MSC had lower efficacy than control MSC. Fulvestrant blocked osteoinduction by control MSC. When scaffold bound MSC was applied to fracture, osteoinduction by Ovx PKH26-MSC was less than control PKH26-MSC. In Ovx rats, control MSC/E2 treatment but not Ovx MSC showed osteoinduction. Regenerated bone was irregularly deposited in Ovx MSC group. In conclusion, Ovx is associated with diminished BM-MSC number and its growth, and Ovx MSC displays impaired engraftment to fracture and osteoinduction besides disordered bone regeneration.

  5. Chondrogenic potential of mesenchymal stromal cells derived from equine bone marrow and umbilical cord blood

    DEFF Research Database (Denmark)

    Berg, Lise Charlotte; Koch, Thomas Gadegaard; Heerkens, T.

    2009-01-01

    including bone marrow and umbilical cord blood. The objective of this study was to provide an in vitro comparison of the chondrogenic potential in MSC derived from adult bone marrow (BM-MSC) and umbilical cord blood (CB-MSC). Results: MSC from both sources produced tissue with cartilage-like morphology...... CB- and BM-MSC pellets. Protein concentration of cartilage-derived retinoic acid sensitive protein was higher in culture medium from CB- than BM-MSC pellets. Conclusion: CB-MSC and BM-MSC were both capable of producting hyaline-like cartilage in vitro. Howeverm, in this study the MSC from umbilical...... cord blood appeared to have more chondrogenic potential than the BM-MSC based on the cells tested and parameters measured....

  6. Mesenchymal Stem Cells in Sepsis and Associated Organ Dysfunction: A Promising Future or Blind Alley?

    Directory of Open Access Journals (Sweden)

    Jan Horák

    2017-01-01

    Full Text Available Sepsis, newly defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection, is the most common cause of death in ICUs and one of the principal causes of death worldwide. Although substantial progress has been made in the understanding of fundamental mechanisms of sepsis, translation of these advances into clinically effective therapies has been disappointing. Given the extreme complexity of sepsis pathogenesis, the paradigm “one disease, one drug” is obviously flawed and combinations of multiple targets that involve early immunomodulation and cellular protection are needed. In this context, the immune-reprogramming properties of cell-based therapy using mesenchymal stem cells (MSC represent an emerging therapeutic strategy in sepsis and associated organ dysfunction. This article provides an update of the current knowledge regarding MSC in preclinical models of sepsis and sepsis-induced acute kidney injury. Recommendations for further translational research in this field are discussed.

  7. Pulling MscL open via N-terminal and TM1 helices: A computational study towards engineering an MscL nanovalve.

    Directory of Open Access Journals (Sweden)

    Adam D Martinac

    Full Text Available There are great opportunities in the manipulation of bacterial mechanosensitive (MS ion channels for specific and targeted drug delivery purposes. Recent research has shown that these ion channels have the potential to be converted into nanovalves through clever use of magnetic nanoparticles and magnetic fields. Using a combination of molecular dynamics (MD simulations and the finite element (FE modelling, this study investigates the theoretical feasibility of opening the MscL channel (MS channel of large conductance of E. coli by applying mechanical force directly to its N-terminus. This region has already been reported to function as a major mechanosensor in this channel. The stress-strain behaviour of each MscL helix was obtained using all atom MD simulations. Using the same method, we simulated two models, the wild-type (WT MscL and the G22N mutant MscL, both embedded in a POPE lipid bilayer. In addition to indicating the main interacting residues at the hydrophobic pore, their pairwise interaction energies were monitored during the channel gating. We implemented these inputs into our FE model of MscL using curve-fitting codes and continuum mechanics equations. In the FE model, the channel could be fully opened via pulling directly on the N-terminus and bottom of TM1 by mutating dominant van der Waals interactions in the channel pore; otherwise the stress generated on the channel protein can irreversibly unravel the N-secondary structure. This is a significant finding suggesting that applying force in this manner is sufficient to open an MscL nanovalve delivering various drugs used, for example, in cancer chemotherapy. More importantly, the FE model indicates that to fully operate an MscL nanovalve by pulling directly on the N-terminus and bottom of TM1, gain-of-function (GOF mutants (e.g., G22N MscL would have to be employed rather than the WT MscL channel.

  8. Silicone Substrate with Collagen and Carbon Nanotubes Exposed to Pulsed Current for MSC Osteodifferentiation

    Directory of Open Access Journals (Sweden)

    Daniyal Jamal

    2017-01-01

    Full Text Available Autologous human adipose tissue-derived mesenchymal stem cells (MSCs have the potential for clinical translation through their induction into osteoblasts for regeneration. Bone healing can be driven by biophysical stimulation using electricity for activating quiescent adult stem cells. It is hypothesized that application of electric current will enhance their osteogenic differentiation, and addition of conductive carbon nanotubes (CNTs to the cell substrate will provide increased efficiency in current transmission. Cultured MSCs were seeded and grown onto fabricated silicone-based composites containing collagen and CNT fibers. Chemical inducers, namely, glycerol phosphate, dexamethasone, and vitamin C, were then added to the medium, and pulsatile submilliampere electrical currents (about half mA for 5 cycles at 4 mHz, twice a week were applied for two weeks. Calcium deposition indicative of MSC differentiation and osteoblastic activity was quantified through Alizarin Red S and spectroscopy. It was found that pulsed current significantly increased osteodifferentiation on silicone-collagen films without CNTs. Under no external current, the presence of 10% (m/m CNTs led to a significant and almost triple upregulation of calcium deposition. Both CNTs and current parameters did not appear to be synergistic. These conditions of enhanced osteoblastic activities may further be explored ultimately towards future therapeutic use of MSCs.

  9. Paradigms of polyamory.

    Science.gov (United States)

    Zambrano, M

    1999-01-01

    SUMMARY The paradigm theory of Thomas Kuhn is used as a framework to discuss alternative ways of intimacy. The author discusses the implications of structuring actual lesbian relationships by a paradigm of monogamy among Latin-American women. The author proposes that creating alternative paradigms of multiple relationships would be useful for many lesbians as models for alternative life patterns.

  10. The Paradigms of Programming

    Indian Academy of Sciences (India)

    ciently and reliably without methodological support. I believe that the current state of the art of computer programming reflects inadequacies in our stock of paradigms, in our knowledge of existing paradigms, in the way we teach programming paradigms, and in the way our programming languages support, or fail to support ...

  11. New energy paradigm?

    International Nuclear Information System (INIS)

    Goldoni, Giovanni

    2007-01-01

    The rise of oil prices, the difficulties in markets liberalization, and the poor results of competition have convinced many that a new energy paradigm is necessary. Taking the original definition of scientific paradigm, it doesn't seem that a practical solution could be found outside the present paradigm of energy policy, made of privatisation, liberalisation and competition [it

  12. Cell cycle and tissue of origin contribute to the migratory behaviour of human fetal and adult mesenchymal stromal cells

    NARCIS (Netherlands)

    Maijenburg, Marijke W.; Noort, Willy A.; Kleijer, Marion; Kompier, Charlotte J. A.; Weijer, Kees; van Buul, Jaap D.; van der Schoot, C. Ellen; Voermans, Carlijn

    2010-01-01

    P>Mesenchymal stromal cells (MSC) are potential cells for cellular therapies, in which the recruitment and migration of MSC towards injured tissue is crucial. Our data show that culture-expanded MSC from fetal lung and bone marrow, adult bone marrow and adipose tissue contained a small percentage of

  13. CASK/MSC/WP PREPARATION SYSTEM DESCRIPTION DOCUMENT

    Energy Technology Data Exchange (ETDEWEB)

    S. Drummond

    2005-04-12

    The purpose of this system description document (SDD) is to establish requirements that drive the design of the Cask/MSC/WP preparation system and their bases to allow the design effort to proceed to license application. This SDD is a living document that will be revised at strategic points as the design matures over time. This SDD identifies the requirements and describes the system design, as they exist at this time, with emphasis on those attributes of the design provided to meet the requirements. This SDD has been developed to be an engineering tool for design control. Accordingly, the primary audience and users are design engineers. This type of SDD both leads and trails the design process. It leads the design process with regard to the flow down of upper tier requirements onto the system. Knowledge of these requirements is essential in performing the design process. This SDD trails the design with regard to the description of the system. The description provided in the SDD is a reflection of the results of the design process to date. This SDD addresses the ''Project Requirements Document'' (PRD) (Canori and Leitner 2003 [DIRS 166275]) requirements. Additional PRD requirements may be cited, as applicable, to drive the design of specific aspects of the system, with justifications provided in the basis. Functional and operational requirements applicable to this system are obtained from the ''Project Functional and Operational Requirements'' (F&OR) (Curry 2004 [DIRS 170557]) document. Other requirements to support the design process have been taken from higher-level requirements documents such as the ''Project Design Criteria Document'' (PDC) (BSC 2004 [DIRS 171599]) and the preclosure safety analyses.

  14. Changing paradigms in cranio-facial regeneration: current and new strategies for the activation of endogenous stem cells

    Directory of Open Access Journals (Sweden)

    Luigi eMele

    2016-02-01

    Full Text Available Craniofacial area represent a unique district of human body characterized by a very high complexity of tissues, innervation and vascularization, and being deputed to many fundamental function such as eating, speech, expression of emotions, delivery of sensations such as taste, sight and earing. For this reasons, tissue loss in this area following trauma or for example oncologic resection, have a tremendous impact on patients’ quality of life. In the last 20 years regenerative medicine has emerged as one of the most promising approach to solve problem related to trauma, tissue loss, organ failure etc. One of the most powerful tools to be used for tissue regeneration is represented by stem cells, which have been successfully implanted in different tissue/organs with exciting results. Nevertheless both autologous and allogeneic stem cell transplantation raise many practical and ethical concerns that make this approach very difficult to apply in clinical practice. For this reason different cell free approaches have been developed aiming to the mobilization, recruitment and activation of endogenous stem cells into the injury site avoiding exogenous cells implant but instead stimulating patients’ own stem cells to repair the lesion. To this aim many strategies have been used including functionalized bioscaffold, controlled release of stem cell chemoattractants, growth factors, BMPs, Platelet–Rich-Plasma and other new strategies such as ultrasound wave and laser are just being proposed. Here we review all the current and new strategies used for activation and mobilization of endogenous stem cells in the regeneration of craniofacial tissue.

  15. Mesenchymal Stem Cells

    DEFF Research Database (Denmark)

    Horwood, Nicole J.; Dazzi, Francesco; Zaher, Walid

    2012-01-01

    and differentiation of hematopoietic stem cells (HSC) and hematopoiesis. These cells have been described as important immunoregulators due to their ability to suppress T cells proliferation. MSC can also directly contribute to tissue repair by migrating to sites of injury and providing a source of cells......Mesenchymal stem cells (MSC) are stem cell populations present among the bone marrow stroma and a number of other tissues that are capable of multi-lineage differentiation into mesoderm-type cells such as osteoblasts, adipocytes and chondrocytes. MSC provide supportive stroma for growth...... for differentiation and/or providing bystander support for resident stromal cells. This chapter discusses the cellular and molecular properties of MSC, the mechanisms by which they can modulate immune responses and the clinical applications of MSC in disorders such as graft-versus-host disease and aplastic anaemia...

  16. Mesenchymal Stem Cell-Like Cells Derived from Mouse Induced Pluripotent Stem Cells Ameliorate Diabetic Polyneuropathy in Mice

    OpenAIRE

    Himeno, Tatsuhito; Kamiya, Hideki; Naruse, Keiko; Cheng, Zhao; Ito, Sachiko; Kondo, Masaki; Okawa, Tetsuji; Fujiya, Atsushi; Kato, Jiro; Suzuki, Hirohiko; Kito, Tetsutaro; Hamada, Yoji; Oiso, Yutaka; Isobe, Kenichi; Nakamura, Jiro

    2013-01-01

    Background. Although pathological involvements of diabetic polyneuropathy (DPN) have been reported, no dependable treatment of DPN has been achieved. Recent studies have shown that mesenchymal stem cells (MSCs) ameliorate DPN. Here we demonstrate a differentiation of induced pluripotent stem cells (iPSCs) into MSC-like cells and investigate the therapeutic potential of the MSC-like cell transplantation on DPN. Research Design and Methods. For induction into MSC-like cells, GFP-expressing iPSC...

  17. MSC transplantation: a promising therapeutic strategy to manage the onset and progression of diabetic nephropathy

    Directory of Open Access Journals (Sweden)

    Marcelo E Ezquer

    2012-01-01

    Full Text Available Currently, one of the main threats to public health is diabetes mellitus. Its most detrimental complication is diabetic nephropathy (DN, a clinical syndrome associated with kidney damage and an increased risk of cardiovascular disease. Irrespective of the type of diabetes, DN follows a well-known temporal course. The earliest detectable signs are microalbuminuria and histopathological changes including extracellular matrix deposition, glomerular basement membrane thickening, glomerular and mesangial expansion. Later on macroalbuminuria appears, followed by a progressive decline in glomerular filtration rate and the loss of glomerular podocytes, tubulointerstitial fibrosis, glomerulosclerosis and arteriolar hyalinosis. Tight glycemic and hypertension controls remain the key factors for preventing or arresting the progression of DN. Nevertheless, despite considerable educational effort to control the disease, a significant number of patients not only develop DN, but also progress to chronic kidney disease. Therefore, the availability of a strategy aimed to prevent, delay or revert DN would be highly desirable. In this article, we review the pathophysiological features of DN and the therapeutic mechanisms of multipotent mesenchymal stromal cells, also referred to as mesenchymal stem cells (MSCs. The perfect match between them, together with encouraging pre-clinical data available, allow us to support the notion that MSC transplantation is a promising therapeutic strategy to manage DN onset and progression, not only because of the safety of this procedure, but mainly because of the renoprotective potential of MSCs.

  18. Curriculum (Study Programme) for the M.Sc., Medialogy, at Aalborg University in Copenhagen

    DEFF Research Database (Denmark)

    Serafin, Stefania; Nordahl, Rolf; Lavatino, Salvatore

    2004-01-01

    Defining and describing the education, M.Sc., Medialogy. The curriculum (Study Programme) describes semesters, themes, projectunits, courses and contents of the eduation. offered at Aalborg University in Copenhagen....

  19. Optimum structural design using MSC/NASTRAN and sequential quadratic programming

    Science.gov (United States)

    Mahmoud, K. G.; Engl, H. W.; Holzleitner, L.

    1994-08-01

    A methodology is described for structural optimization using the commercial finite element package MSC/NASTRAN for structural analysis, a quasi-analytical method for design sensitivity analysis, and sequential quadratic programming with an active set strategy for optimization. The optimization and sensitivity analysis modules are efficiently coupled with MSC/NASTRAN using DMAP (direct matrix abstraction program) statements. To demonstrate the feasibility of the proposed methodology, the design optimization of a unit injector rocker arm is presented as an example.

  20. Mesenchymal stem cells promote colorectal cancer progression through AMPK/mTOR-mediated NF-?B activation

    OpenAIRE

    Wu, Xiao-Bing; Liu, Yang; Wang, Gui-Hua; Xu, Xiao; Cai, Yang; Wang, Hong-Yi; Li, Yan-Qi; Meng, Hong-Fang; Dai, Fu; Jin, Ji-De

    2016-01-01

    Mesenchymal stem cells (MSCs) exert a tumor-promoting effect in a variety of human cancers. This study was designed to identify the molecular mechanisms related to the tumor-promoting effect of MSCs in colorectal cancer. In vitro analysis of colorectal cancer cell lines cultured in MSC conditioned media (MSC-CM) showed that MSC-CM significantly promoted the progression of the cancer cells by enhancing cell proliferation, migration and colony formation. The tumorigenic effect of MSC-CM was att...

  1. Cancer exosomes trigger mesenchymal stem cell differentiation into pro-angiogenic and pro-invasive myofibroblasts

    OpenAIRE

    Chowdhury, Ridwana; Webber, Jason P.; Gurney, Mark; Mason, Malcolm David; Tabi, Zsuzsanna; Clayton, Aled

    2015-01-01

    Stromal fibroblasts become altered in response to solid cancers, to exhibit myofibroblastic characteristics, with disease promoting influence. Infiltrating mesenchymal stem cells (MSC) may contribute towards these changes, but the factors secreted by cancer cells that impact MSC differentiation are poorly understood.\\ud \\ud We investigated the role of nano-metre sized vesicles (exosomes), secreted by prostate cancer cells, on the differentiation of bone-marrow MSC (BM-MSC), and the subsequent...

  2. Treatment Paradigms for Retinal and Macular Diseases Using 3-D Retina Cultures Derived From Human Reporter Pluripotent Stem Cell Lines.

    Science.gov (United States)

    Kaewkhaw, Rossukon; Swaroop, Manju; Homma, Kohei; Nakamura, Jutaro; Brooks, Matthew; Kaya, Koray Dogan; Chaitankar, Vijender; Michael, Sam; Tawa, Gregory; Zou, Jizhong; Rao, Mahendra; Zheng, Wei; Cogliati, Tiziana; Swaroop, Anand

    2016-04-01

    We discuss the use of pluripotent stem cell lines carrying fluorescent reporters driven by retinal promoters to derive three-dimensional (3-D) retina in culture and how this system can be exploited for elucidating human retinal biology, creating disease models in a dish, and designing targeted drug screens for retinal and macular degeneration. Furthermore, we realize that stem cell investigations are labor-intensive and require extensive resources. To expedite scientific discovery by sharing of resources and to avoid duplication of efforts, we propose the formation of a Retinal Stem Cell Consortium. In the field of vision, such collaborative approaches have been enormously successful in elucidating genetic susceptibility associated with age-related macular degeneration.

  3. Paradigm Shifts in Ophthalmic Diagnostics.

    Science.gov (United States)

    Sebag, J; Sadun, Alfredo A; Pierce, Eric A

    2016-08-01

    Future advances in ophthalmology will see a paradigm shift in diagnostics from a focus on dysfunction and disease to better measures of psychophysical function and health. Practical methods to define genotypes will be increasingly important and non-invasive nanotechnologies are needed to detect molecular changes that predate histopathology. This is not a review nor meant to be comprehensive. Specific topics have been selected to illustrate the principles of important paradigm shifts that will influence the future of ophthalmic diagnostics. It is our impression that future evaluation of vision will go beyond visual acuity to assess ocular health in terms of psychophysical function. The definition of disease will incorporate genotype into what has historically been a phenotype-centric discipline. Non-invasive nanotechnologies will enable a paradigm shift from disease detection on a cellular level to a sub-cellular molecular level. Vision can be evaluated beyond visual acuity by measuring contrast sensitivity, color vision, and macular function, as these provide better insights into the impact of aging and disease. Distortions can be quantified and the psychophysical basis of vision can be better evaluated than in the past by designing tests that assess particular macular cell function(s). Advances in our understanding of the genetic basis of eye diseases will enable better characterization of ocular health and disease. Non-invasive nanotechnologies can assess molecular changes in the lens, vitreous, and macula that predate visible pathology. Oxygen metabolism and circulatory physiology are measurable indices of ocular health that can detect variations of physiology and early disease. This overview of paradigm shifts in ophthalmology suggests that the future will see significant improvements in ophthalmic diagnostics. The selected topics illustrate the principles of these paradigm shifts and should serve as a guide to further research and development. Indeed

  4. The Next Paradigm

    Directory of Open Access Journals (Sweden)

    Bernardo Kastrup

    2018-04-01

    Full Text Available In order to perceive the world, we need more than just raw sensory input: a subliminal paradigm of thought is required to interpret raw sensory data and, thereby, create the objects and events we perceive around ourselves. As such, the world we see reflects our own unexamined, culture-bound assumptions and expectations, which explains why every generation in history has believed that it more or less understood the world. Today, we perceive a world of objects and events outside and independent of mind, which merely reflects our current paradigm of thought. Anomalies that contradict this paradigm have been accumulated by physicists over the past couple of decades, which will eventually force our culture to move to a new paradigm. Under this new paradigm, a form of universal mind will be viewed as nature’s sole fundamental entity. In this paper, I offer a sketch of what the new paradigm may look like.

  5. Of Paradigms and Power

    DEFF Research Database (Denmark)

    Carstensen, Martin B.; Matthijs, Matthias

    ? Despite the profound impact of Peter Hall’s approach to policy paradigms and social learning, there is a burgeoning consensus that transposing a rudimentary ‘Kuhnian’ understanding of paradigms into the context of public policy making leads to a notion of punctuated equilibrium style shifts as the only...... in the study of policy paradigms. To demonstrate the general applicability of our framework, the paper examines the evolution of British macroeconomic policy making since 1990. We show that various Prime Ministers and their Chancellors were able to reinterpret and redefine the dominant neoliberal understanding......How and why do ruling policy paradigms persist, even in the face of crises or bouts of accumulating evidence that they are not delivering the goods? And how come policy paradigms often undergo significant internal ideational changes instead of it necessarily amounting to a full-blown paradigm shift...

  6. Other paradigms: growth rate constants and tumor burden determined using computed tomography data correlate strongly with the overall survival of patients with renal cell carcinoma.

    Science.gov (United States)

    Stein, Wilfred D; Huang, Hui; Menefee, Michael; Edgerly, Maureen; Kotz, Herb; Dwyer, Andrew; Yang, James; Bates, Susan E

    2009-01-01

    In solid tumors, where curative therapies still elude oncologists, novel paradigms are needed to assess the efficacy of new therapies and those already approved. We used radiologic measurements obtained in patients with metastatic renal cell carcinoma enrolled in a phase II study of the epothilone B analog, ixabepilone (Ixempra), to address this issue. Using a novel 2-phase mathematical equation, we used the radiologic measurements to estimate the concomitant rates of tumor regression and growth (regression and growth rate constants). Eighty-one patients were enrolled on the ixabepilone trial at the time of this analysis. Growth rate constants were determined using computed tomography measurements obtained exclusively while a patient was enrolled on study. The growth rate constants of renal cell carcinomas treated with ixabepilone were significantly reduced compared with those of tumors in patients who received placebo in a previous trial. Furthermore, a correlation with overall survival was found for both the growth rate constant and the initial tumor burden; and this correlation was even stronger when both the growth rate constant and the initial tumor burden were combined. The readily amenable mathematical model described herein has potential applications to many tumor types that can be assessed with imaging modalities. Because the growth rate constant seems to be a surrogate for survival, assessment could aid in the evaluation of relative efficacies of different therapies and perhaps in assessing the potential individual benefit of an experimental therapy.

  7. Induced Pluripotent Stem Cell Technology: A Paradigm Shift in Medical Science for Drug Screening and Disease Modeling.

    Science.gov (United States)

    Nair, Meera; Sandhu, Sardul Singh; Sharma, Anil Kumar

    2017-01-01

    Induced Pluripotent Stem Cell (IPSC) Technology is the most advanced research as it offers an attractive alternative for establishing patient-specific IPSCs to recapitulate phenotypes of not only monogenic diseases (viz. Thalassaemia, Sickle cell anemia, Haemophilia, Tay-Sachs disease), but also late-onset polygenic diseases (viz. Parkinson's disease, Alzheimer's disease, schizophrenia). Over the hindsight, numerous studies of the past and current scientists have led to the production, maturation and understanding of induced pluripotent stem cell technology and its use in basic and clinical research. A systematic search of peer-reviewed scientific literature and clinical trials in public databases were carried out to summarize the evidence on the use of IPSC. Current review sheds light upon the use of patient-derived iPSC models in drug toxicity, screening and discovery which have been derived after referring to more than 200 articles in literature. Furthermore, their use as disease models was also studied signifying the versatility of iPSC lines. Through this review, we describe the advent of iPSC technology, where we comprehensively cover the generation of iPSCs and their characterization along with their prospective applications using IPSC banks in disease modeling and drug screening. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  8. In situ tissue regeneration: chemoattractants for endogenous stem cell recruitment.

    Science.gov (United States)

    Vanden Berg-Foels, Wendy S

    2014-02-01

    Tissue engineering uses cells, signaling molecules, and/or biomaterials to regenerate injured or diseased tissues. Ex vivo expanded mesenchymal stem cells (MSC) have long been a cornerstone of regeneration therapies; however, drawbacks that include altered signaling responses and reduced homing capacity have prompted investigation of regeneration based on endogenous MSC recruitment. Recent successful proof-of-concept studies have further motivated endogenous MSC recruitment-based approaches. Stem cell migration is required for morphogenesis and organogenesis during development and for tissue maintenance and injury repair in adults. A biomimetic approach to in situ tissue regeneration by endogenous MSC requires the orchestration of three main stages: MSC recruitment, MSC differentiation, and neotissue maturation. The first stage must result in recruitment of a sufficient number of MSC, capable of effecting regeneration, to the injured or diseased tissue. One of the challenges for engineering endogenous MSC recruitment is the selection of effective chemoattractant(s). The objective of this review is to synthesize and evaluate evidence of recruitment efficacy by reported chemoattractants, including growth factors, chemokines, and other more recently appreciated MSC chemoattractants. The influence of MSC tissue sources, cell culture methods, and the in vitro and in vivo environments is discussed. This growing body of knowledge will serve as a basis for the rational design of regenerative therapies based on endogenous MSC recruitment. Successful endogenous MSC recruitment is the first step of successful tissue regeneration.

  9. Hepatoma SK Hep-1 cells exhibit characteristics of oncogenic mesenchymal stem cells with highly metastatic capacity.

    Directory of Open Access Journals (Sweden)

    Jong Ryeol Eun

    Full Text Available SK Hep-1 cells (SK cells derived from a patient with liver adenocarcinoma have been considered a human hepatoma cell line with mesenchymal origin characteristics, however, SK cells do not express liver genes and exhibit liver function, thus, we hypothesized whether mesenchymal cells might contribute to human liver primary cancers. Here, we characterized SK cells and its tumourigenicity.We found that classical mesenchymal stem cell (MSC markers were presented on SK cells, but endothelial marker CD31, hematopoietic markers CD34 and CD45 were negative. SK cells are capable of differentiate into adipocytes and osteoblasts as adipose-derived MSC (Ad-MSC and bone marrow-derived MSC (BM-MSC do. Importantly, a single SK cell exhibited a substantial tumourigenicity and metastatic capacity in immunodefficient mice. Metastasis not only occurred in circulating organs such as lung, liver, and kidneys, but also in muscle, outer abdomen, and skin. SK cells presented greater in vitro invasive capacity than those of Ad-MSC and BM-MSC. The xenograft cells from subcutaneous and metastatic tumors exhibited a similar tumourigenicity and metastatic capacity, and showed the same relatively homogenous population with MSC characteristics when compared to parental SK cells. SK cells could unlimitedly expand in vitro without losing MSC characteristics, its tumuorigenicity and metastatic capacity, indicating that SK cells are oncogenic MSC with enhanced self-renewal capacity. We believe that this is the first report that human MSC appear to be transformed into cancer stem cells (CSC, and that their derivatives also function as CSCs.Our findings demonstrate that SK cells represent a transformation mechanism of normal MSC into an enhanced self-renewal CSC with metastasis capacity, SK cells and their xenografts represent a same relative homogeneity of CSC with substantial metastatic capacity. Thus, it represents a novel mechanism of tumor initiation, development and

  10. Mesenchymal Stem Cells

    DEFF Research Database (Denmark)

    Horwood, Nicole J.; Dazzi, Francesco; Zaher, Walid

    2012-01-01

    Mesenchymal stem cells (MSC) are stem cell populations present among the bone marrow stroma and a number of other tissues that are capable of multi-lineage differentiation into mesoderm-type cells such as osteoblasts, adipocytes and chondrocytes. MSC provide supportive stroma for growth...... and differentiation of hematopoietic stem cells (HSC) and hematopoiesis. These cells have been described as important immunoregulators due to their ability to suppress T cells proliferation. MSC can also directly contribute to tissue repair by migrating to sites of injury and providing a source of cells...

  11. Mechanosensitive channels of Escherichia coli: the MscL gene, protein, and activities

    Science.gov (United States)

    Sukharev, S. I.; Blount, P.; Martinac, B.; Kung, C.

    1997-01-01

    Although mechanosensory responses are ubiquitous and diverse, the molecular bases of mechanosensation in most cases remain mysterious MscL, a mechanosensitive channel of large conductance of Escherichia coli and its bacterial homologues are the first and currently only channel molecules shown to directly sense mechanical stretch of the membrane. In response to the tension conveyed via the lipid bilayer, MscL increases its open probability by several orders of magnitude. In the present review we describe the identification, cloning, and first sets of biophysical and structural data on this simplest mechanosensory molecule. We discovered a 2.5-ns mechanosensitive conductance in giant E. coli spheroplasts. Using chromatographies to enrich the target and patch clamp to assay the channel activity in liposome-reconstituted fractions, we identified the MscL protein and cloned the mscL gene. MscL comprises 136 amino acid residues (15 kDa), with two highly hydrophobic regions, and resides in the inner membrane of the bacterium. PhoA-fusion experiments indicate that the protein spans the membrane twice with both termini in the cytoplasm. Spectroscopic techniques show that it is highly helical. Expression of MscL tandems and covalent cross-linking suggest that the active channel complex is a homo-hexamer. We have identified several residues, which when deleted or substituted, affect channel kinetics or mechanosensitivity. Although unique when discovered, highly conserved MscL homologues in both gram-negative and gram-positive bacteria have been found, suggesting their ubiquitous importance among bacteria.

  12. M-Learning: A New Paradigm of Learning Mathematics in Malaysia

    OpenAIRE

    Saipunidzam Mahamad; Mohammad Noor Ibrahim; Shakirah Mohd Taib

    2010-01-01

    M-Learning is a new learning paradigm of the new social structure with mobile and wireless technologies.Smart school is one of the four flagship applications for Multimedia Super Corridor (MSC) under Malaysian government initiative to improve education standard in the country. With the advances of mobile devices technologies, mobile learning could help the government in realizing the initiative. This paper discusses the prospect of implementing mobile learning for primary school students. It ...

  13. Post-thaw non-cultured and post-thaw cultured equine cord blood mesenchymal stromal cells equally suppress lymphocyte proliferation in vitro.

    Directory of Open Access Journals (Sweden)

    Lynn B Williams

    Full Text Available Multipotent mesenchymal stromal cells (MSC are receiving increased attention for their non-progenitor immunomodulatory potential. Cryopreservation is commonly used for long-term storage of MSC. Post-thaw MSC proliferation is associated with a lag-phase in vitro. How this lag-phase affect MSC immunomodulatory properties is unknown. We hypothesized that in vitro there is no difference in lymphocyte suppression potential between quick-thawed cryopreserved equine cord blood (CB MSC immediately included in mixed lymphocyte reaction (MLR and same MSC allowed post-thaw culture time prior to inclusion in MLR. Cryopreserved CB-MSC from five unrelated foals were compared using two-way MLR. For each of the five unrelated MSC cultures, paired MLR assays of MSC allowed five days of post-thaw culture and MSC included in MLR assay immediately post-thawing were evaluated. We report no difference in the suppression of lymphocyte proliferation by CB-MSC that had undergone post-thaw culture and MSC not cultured post-thaw (p<0.0001. Also, there was no inter-donor variability between the lymphocyte suppressive properties of MSC harvested from the five different donors (p = 0.13. These findings suggest that cryopreserved CB-MSC may have clinical utility immediately upon thawing. One implication hereof is the possibility of using cryopreserved CB-MSC at third party locations without the need for cell culture equipment or competencies.

  14. The Generative Paradigm.

    Science.gov (United States)

    Loynes, Chris

    2002-01-01

    The "algorithmic" model of outdoor experiential learning is based in military tradition and characterized by questionable scientific rationale, production line metaphor, and the notion of learning as marketable commodity. Alternatives are the moral paradigm; the ecological paradigm "friluftsliv"; and the emerging…

  15. Dynamic paradigm of turbulence

    International Nuclear Information System (INIS)

    Mukhamedov, Alfred M.

    2006-01-01

    In this paper a dynamic paradigm of turbulence is proposed. The basic idea consists in the novel definition of chaotic structure given with the help of Pfaff system of PDE associated with the turbulent dynamics. A methodological analysis of the new and the former paradigm is produced

  16. Establishment and characterization of fetal and maternal mesenchymal stem/stromal cell lines from the human term placenta.

    Science.gov (United States)

    Qin, Sharon Q; Kusuma, Gina D; Al-Sowayan, Batla; Pace, Rishika A; Isenmann, Sandra; Pertile, Mark D; Gronthos, Stan; Abumaree, Mohamed H; Brennecke, Shaun P; Kalionis, Bill

    2016-03-01

    Human placental mesenchymal stem/stromal cells (MSC) are an attractive source of MSC with great therapeutic potential. However, primary MSC are difficult to study in vitro due to their limited lifespan and patient-to-patient variation. Fetal and maternal MSC were prepared from cells of the chorionic and basal plates of the placenta, respectively. Fetal and maternal MSC were transduced with the human telomerase reverse transcriptase (hTERT). Conventional stem cell assays assessed the MSC characteristics of the cell lines. Functional assays for cell proliferation, cell migration and ability to form colonies in soft agar were used to assess the whether transduced cells retained properties of primary MSC. Fetal chorionic and maternal MSC were successfully transduced with hTERT to create the cell lines CMSC29 and DMSC23 respectively. The lifespans of CMSC29 and DMSC23 were extended in cell culture. Both cell lines retained important MSC characteristics including cell surface marker expression and multipotent differentiation potential. Neither of the cell lines was tumourigenic in vitro. Gene expression differences were observed between CMSC29 and DMSC23 cells and their corresponding parent, primary MSC. Both cell lines show similar migration potential to their corresponding primary, parent MSC. The data show that transduced MSC retained important functional properties of the primary MSC. There were gene expression and functional differences between cell lines CMSC29 and DMSC23 that reflect their different tissue microenvironments of the parent, primary MSC. CMSC29 and DMSC23 cell lines could be useful tools for optimisation and functional studies of MSC. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Chimeras Reveal a Single Lipid-Interface Residue that Controls MscL Channel Kinetics as well as Mechanosensitivity

    Directory of Open Access Journals (Sweden)

    Li-Min Yang

    2013-02-01

    Full Text Available MscL, the highly conserved bacterial mechanosensitive channel of large conductance, serves as an osmotic “emergency release valve,” is among the best-studied mechanosensors, and is a paradigm of how a channel senses and responds to membrane tension. Although all homologs tested thus far encode channel activity, many show functional differences. We tested Escherichia coli and Staphylococcus aureus chimeras and found that the periplasmic region of the protein, particularly E. coli I49 and the equivalent S. aureus F47 at the periplasmic lipid-aqueous interface of the first transmembrane domain, drastically influences both the open dwell time and the threshold of channel opening. One mutant shows a severe hysteresis, confirming the importance of this residue in determining the energy barriers for channel gating. We propose that this site acts similarly to a spring for a clasp knife, adjusting the resistance for obtaining and stabilizing an open or closed channel structure.

  18. Mesenchymal stromal cells: misconceptions and evolving concepts.

    Science.gov (United States)

    Phinney, Donald G; Sensebé, Luc

    2013-02-01

    Nearly half a century has passed since the publication of the first articles describing plastic-adherent cells from bone marrow, referred to initially as colony-forming unit fibroblasts, then marrow stromal cells, mesenchymal stem cells and most recently multipotent mesenchymal stromal cells (MSCs). As expected, our understanding of the nature and biologic functions of MSCs has undergone major paradigm shifts over this time. Despite significant advances made in deciphering their complex biology and therapeutic potential in both experimental animal models and human clinical trials, numerous misconceptions regarding the nature and function of MSCs have persisted in the field. Continued propagation of these misconceptions in some cases may significantly impede the advancement of MSC-based therapies in clinical medicine. We have identified six prevalent misconceptions about MSCs that we believe affect the field, and we attempt to rectify them based on current available data. Copyright © 2013 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  19. Blocking Tumor-Educated MSC Paracrine Activity Halts Osteosarcoma Progression

    NARCIS (Netherlands)

    Baglio, S. Rubina; Lagerweij, Tonny; Pérez-Lanzón, Maria; Ho, Xuan Dung; Léveillé, Nicolas; Melo, Sonia A.; Cleton-Jansen, Anne-Marie; Jordanova, Ekaterina S.; Roncuzzi, Laura; Greco, Michelina; van Eijndhoven, Monique A. J.; Grisendi, Giulia; Dominici, Massimo; Bonafede, Roberta; Lougheed, Sinead M.; de Gruijl, Tanja D.; Zini, Nicoletta; Cervo, Silvia; Steffan, Agostino; Canzonieri, Vincenzo; Martson, Aare; Maasalu, Katre; Köks, Sulev; Wurdinger, Tom; Baldini, Nicola; Pegtel, D. Michiel

    2017-01-01

    Purpose: Human osteosarcoma is a genetically heterogeneous bone malignancy with poor prognosis despite the employment of aggressive chemotherapy regimens. Because druggable driver mutations have not been established, dissecting the interactions between osteosarcoma cells and supporting stroma may

  20. Efficacy of stem cells on periodontal regeneration: Systematic review of pre-clinical studies.

    Science.gov (United States)

    Tassi, S A; Sergio, N Z; Misawa, M Y O; Villar, C C

    2017-10-01

    This systematic review aims to evaluate mesenchymal stem cells (MSC) periodontal regenerative potential in animal models. MEDLINE, EMBASE and LILACS databases were searched for quantitative pre-clinical controlled animal model studies that evaluated the effect of local administration of MSC on periodontal regeneration. The systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guidelines. Twenty-two studies met the inclusion criteria. Periodontal defects were surgically created in all studies. In seven studies, periodontal inflammation was experimentally induced following surgical defect creation. Differences in defect morphology were identified among the studies. Autogenous, alogenous and xenogenous MSC were used to promote periodontal regeneration. These included bone marrow-derived MSC, periodontal ligament (PDL)-derived MSC, dental pulp-derived MSC, gingival margin-derived MSC, foreskin-derived induced pluripotent stem cells, adipose tissue-derived MSC, cementum-derived MSC, periapical follicular MSC and alveolar periosteal cells. Meta-analysis was not possible due to heterogeneities in study designs. In most of the studies, local MSC implantation was not associated with adverse effects. The use of bone marrow-derived MSC for periodontal regeneration yielded conflicting results. In contrast, PDL-MSC consistently promoted increased PDL and cementum regeneration. Finally, the adjunct use of MSC improved the regenerative outcomes of periodontal defects treated with membranes or bone substitutes. Despite the quality level of the existing evidence, the current data indicate that the use of MSC may provide beneficial effects on periodontal regeneration. The various degrees of success of MSC in periodontal regeneration are likely to be related to the use of heterogeneous cells. Thus, future studies need to identify phenotypic profiles of highly regenerative MSC populations. © 2017 John Wiley

  1. Paradigms for machine learning

    Science.gov (United States)

    Schlimmer, Jeffrey C.; Langley, Pat

    1991-01-01

    Five paradigms are described for machine learning: connectionist (neural network) methods, genetic algorithms and classifier systems, empirical methods for inducing rules and decision trees, analytic learning methods, and case-based approaches. Some dimensions are considered along with these paradigms vary in their approach to learning, and the basic methods are reviewed that are used within each framework, together with open research issues. It is argued that the similarities among the paradigms are more important than their differences, and that future work should attempt to bridge the existing boundaries. Finally, some recent developments in the field of machine learning are discussed, and their impact on both research and applications is examined.

  2. ANALYSIS WITH MSC ADAMS OF A 5-FINGER AND 3-PHALANX /FINGER UNDER-ACTUATEDMECHANICAL HAND

    Directory of Open Access Journals (Sweden)

    Gheorghe POPESCU

    2013-05-01

    Full Text Available This paper studies the analysis with MSC ADAMS of a 5-fingered and 3-phalanx/finger underactuatedmechanical hand, designed by the author to work on industrial robots. Moreover, in order to increasegrasping safety in the automated handling process, the author has fitted each finger with a locking sequence inthe final phase of grasping. Thus, the mechanism of mechanical hand is considered to be a mechanical systemand is treated like a set of rigid bodies connected by mechanical linkages and elastic elements. To model andsimulate this mechanism with MSC ADAMS programme, the author covered the following stages: constructionof the model, testing-simulation, validation, finishing, parameterization, and optimization

  3. Návrh komunikačního mixu podniku MSC.Software

    OpenAIRE

    Mazuch, Jan

    2009-01-01

    Bakalářská práce se zabývá sestavením komunikačního mixu podniku MSC.Software s.r.o., zabývající se prodejem simulačních softwarů. Práce analyzuje komunikační mix podniku a navrhuje jeho zefektivnění. This bachelor thesis deals with making communication mix for the MSC.Software Company that sells simulation software. This thesis analyzes the communication mix of the company and proposes it’s more effective usage. C

  4. Further Developments on Optimum Structural Design Using MSC/Nastran and Sequential Quadratic Programming

    DEFF Research Database (Denmark)

    Holzleitner, Ludwig

    1996-01-01

    , here the shape of two dimensional parts with different thickness areas will be optimized. As in the previos paper, a methodology for structural optimization using the commercial finite element package MSC/NASTRAN for structural analysis is described. Three different methods for design sensitivity......This work is closely connected to the paper: K.G. MAHMOUD, H.W. ENGL and HOLZLEITNER: "OPTIMUM STRUCTURAL DESIGN USING MSC/NASTRAN AND SEQUENTIAL QUADRATIC PROGRAMMING", Computers & Structures, Vol. 52, No. 3, pp. 437-447, (1994). In contrast to that paper, where thickness optimization is described...

  5. Safety and immune regulatory properties of canine induced pluripotent stem cell-derived mesenchymal stem cells.

    Science.gov (United States)

    Chow, Lyndah; Johnson, Valerie; Regan, Dan; Wheat, William; Webb, Saiphone; Koch, Peter; Dow, Steven

    2017-12-01

    Mesenchymal stem cells (MSCs) exhibit broad immune modulatory activity in vivo and can suppress T cell proliferation and dendritic cell activation in vitro. Currently, most MSC for clinical usage are derived from younger donors, due to ease of procurement and to the superior immune modulatory activity. However, the use of MSC from multiple unrelated donors makes it difficult to standardize study results and compare outcomes between different clinical trials. One solution is the use of MSC derived from induced pluripotent stem cells (iPSC); as iPSC-derived MSC have nearly unlimited proliferative potential and exhibit in vitro phenotypic stability. Given the value of dogs as a spontaneous disease model for pre-clinical evaluation of stem cell therapeutics, we investigated the functional properties of canine iPSC-derived MSC (iMSC), including immune modulatory properties and potential for teratoma formation. We found that canine iMSC downregulated expression of pluripotency genes and appeared morphologically similar to conventional MSC. Importantly, iMSC retained a stable phenotype after multiple passages, did not form teratomas in immune deficient mice, and did not induce tumor formation in dogs following systemic injection. We concluded therefore that iMSC were phenotypically stable, immunologically potent, safe with respect to tumor formation, and represented an important new source of cells for therapeutic modulation of inflammatory disorders. Copyright © 2017. Published by Elsevier B.V.

  6. Safety and immune regulatory properties of canine induced pluripotent stem cell-derived mesenchymal stem cells

    Directory of Open Access Journals (Sweden)

    Lyndah Chow

    2017-12-01

    Full Text Available Mesenchymal stem cells (MSCs exhibit broad immune modulatory activity in vivo and can suppress T cell proliferation and dendritic cell activation in vitro. Currently, most MSC for clinical usage are derived from younger donors, due to ease of procurement and to the superior immune modulatory activity. However, the use of MSC from multiple unrelated donors makes it difficult to standardize study results and compare outcomes between different clinical trials. One solution is the use of MSC derived from induced pluripotent stem cells (iPSC; as iPSC-derived MSC have nearly unlimited proliferative potential and exhibit in vitro phenotypic stability. Given the value of dogs as a spontaneous disease model for pre-clinical evaluation of stem cell therapeutics, we investigated the functional properties of canine iPSC-derived MSC (iMSC, including immune modulatory properties and potential for teratoma formation. We found that canine iMSC downregulated expression of pluripotency genes and appeared morphologically similar to conventional MSC. Importantly, iMSC retained a stable phenotype after multiple passages, did not form teratomas in immune deficient mice, and did not induce tumor formation in dogs following systemic injection. We concluded therefore that iMSC were phenotypically stable, immunologically potent, safe with respect to tumor formation, and represented an important new source of cells for therapeutic modulation of inflammatory disorders.

  7. Expansion and Harvesting of hMSC-TERT

    DEFF Research Database (Denmark)

    Weber, Christian; Pohl, Sebastian; Pörtner, Ralf

    2007-01-01

    The expansion of human mesenchymal stem cells as suspension culture by means of spinner flasks and microcarriers, compared to the cultivation in tissue culture flasks, offers the advantage of reducing the requirements of large incubator capacities as well as reducing the handling effort during cu...

  8. Human mesenchymal stem cells

    DEFF Research Database (Denmark)

    Abdallah, Basem; Kassem, Moustapha

    2008-01-01

    Mesenchymal stem cells (MSC) are a group of clonogenic cells present among the bone marrow stroma and capable of multilineage differentiation into mesoderm-type cells such as osteoblasts, adipocytes and chondrocytes. Due to their ease of isolation and their differentiation potential, MSC are being...... introduced into clinical medicine in variety of applications and through different ways of administration. Here, we discuss approaches for isolation, characterization and directing differentiation of human mesenchymal stem cells (hMSC). An update of the current clinical use of the cells is also provided....

  9. Streptomycin potency is dependent on MscL channel expression

    OpenAIRE

    Iscla, Irene; Wray, Robin; Wei, Shuguang; Posner, Bruce; Blount, Paul

    2014-01-01

    The antibiotic streptomycin is widely used in the treatment of microbial infections. The primary mechanism of action is inhibition of translation by binding to the ribosome, but how it enters the bacterial cell is unclear. Early in the study of this antibiotic, a mysterious streptomycin-induced K+-efflux preceding any decrease in viability was observed; it was speculated that this changed the electrochemical gradient such that streptomycin better accessed the cytoplasm. Here we use a high thr...

  10. Mesenchymal Stem Cells: Application for Immunomodulation and Tissue Repair

    DEFF Research Database (Denmark)

    Horwood, Nicole J.; Dazzi, Francesco; Zaher, Walid

    2012-01-01

    Mesenchymal stem cells (MSC) are stem cell populations present among the bone marrow stroma and a number of other tissues that are capable of multi-lineage differentiation into mesoderm-type cells such as osteoblasts, adipocytes and chondrocytes. MSC provide supportive stroma for growth and diffe......Mesenchymal stem cells (MSC) are stem cell populations present among the bone marrow stroma and a number of other tissues that are capable of multi-lineage differentiation into mesoderm-type cells such as osteoblasts, adipocytes and chondrocytes. MSC provide supportive stroma for growth...

  11. Dynamics of self-directed learning in M.Sc. nursing students: A qualitative research.

    Science.gov (United States)

    Shirazi, Fatemeh; Sharif, Farkhondeh; Molazem, Zahra; Alborzi, Mahboobeh

    2017-01-01

    Working in the complex and ever changing healthcare settings forces the nurses and nursing students to be equipped with lifelong learning skills. One of the lifelong learning skills is self-directed learning. This study aimed to explore the M.Sc. nursing students' self-directed learning activities. A qualitative design using conventional content analysis approach was used in this study. Semi-structured interviews were conducted with twelve Iranian M.Sc. nursing students who were selected using purposive sampling. Data analysis indicated that the M.Sc. nursing students performed different activities in their self-directed learning. These activities were categorized into four main themes and ten subthemes. The main themes were "sensory perceptions", "knowledge construction", "problem-centered orientation", and "interaction with others". According to the findings, the M.Sc. nursing students performed different intellectual and experiential self-directed activities for promoting their learning. Besides, the students' perseverance and inquisitiveness played an important role in their self-directed learning in the challenging clinical environments.

  12. A student project as part of an MSc curriculum : Delfi-C³

    NARCIS (Netherlands)

    Vaartjes, A.A.; Hamann, R.J.

    2008-01-01

    The Delfi-C3 is a university satellite of the Delft University of Technology. The project started in November 2004 and had a dual mission: (no bullets in abstract!)To offer at least 25 students as part of their Master of Science (MSc) study the opportunity to gain hands on experience on a real space

  13. Aiming for Outstanding: Action Research from Students of the MSc in the Teaching of Psychology

    Science.gov (United States)

    Lintern, Fiona; Davies, Jamie; McGinty, Andrew; Fisher, Jeannine

    2014-01-01

    The first cohort of a new MSc programme is due to complete the course in August 2014. During the three-year online course students conduct several pieces of action research in their classrooms. There is little research specifically related to classroom practice in the pre-tertiary psychology classroom. The following describes the rationale and…

  14. Comparing estimates of EMEP MSC-Wand UFORE models in air pollutant reduction by urban trees

    Czech Academy of Sciences Publication Activity Database

    Guidolotti, G.; Salvatio, M.; Calfapietra, Carlo

    2016-01-01

    Roč. 23, č. 19 (2016), s. 19541-19550 ISSN 0944-1344 Institutional support: RVO:67179843 Keywords : i-Tree * UFORE, EMEP/MSC-Wmodel * urban forest * atmospheric pollutants * O3 * NO2 * PM10 Subject RIV: EF - Botanics Impact factor: 2.741, year: 2016

  15. Post-MSc technological design (PDEng) traineeships by Dutch universities of technology catalyse industrial innovation

    NARCIS (Netherlands)

    Swinkels, P.L.J.

    2015-01-01

    The two-year post-MSc technological design traineeships organized by the Dutch Universities of Technology, and leading to the Professional Doctorate in Engineering (PDEng) degree, are still going strong after 28 years of existence. In 1986 the Dutch government and the Dutch industry - both aiming to

  16. Competencies of BSc and MSc programmes in electrical engineering and student portfolios

    NARCIS (Netherlands)

    Mouthaan, A.J.; Brink, R.W.; Vos, Henk

    2002-01-01

    General goals of a BSc and MSc in electrical engineering are formulated, leading to a 'mission' statement clarifying the rationale behind the programmes in relation to the needs of society. These goals are made operational in terms of competencies that engineers educated through our programmes are

  17. PDX1- and NGN3-mediated in vitro reprogramming of human bone marrow-derived mesenchymal stromal cells into pancreatic endocrine lineages

    DEFF Research Database (Denmark)

    Limbert, Catarina; Päth, Günter; Ebert, Regina

    2011-01-01

    Reprogramming of multipotent adult bone marrow (BM)-derived mesenchymal stromal/stem cells (MSC) (BM-MSC) represents one of several strategies for cell-based therapy of diabetes. However, reprogramming primary BM-MSC into pancreatic endocrine lineages has not yet been consistently demonstrated....

  18. European MSc Programs in Nuclear Sciences - To meet the Need of Stakeholders

    International Nuclear Information System (INIS)

    Salbu, Brit; Skipperud, Lindis; Priest, Nick; Garelick, Hemda; Tamponnet, Christian; Mitchell, Peter

    2009-01-01

    A stakeholder needs assessment, carried out under the EU-EURAC and EU-ENEN II projects, clearly showed that, at the European level, there are a significant and constant need for post-graduates with skills in radiochemistry, radioecology, radiation dosimetry and environmental modelling and a smaller, but still important, demand for radiobiologists and bio-modellers. Most of these needs are from government organizations. If only the nuclear industry is considered, then the largest demand is for radiochemists and radiation protection dosimetrists. Given this spectrum of need and existing capacity in the areas of radiobiology it was concluded that the needs identified would be most efficiently met by three new degree programs: European MSc Radiation Protection European MSc Analytical Radiochemistry European MSc Radioecology. All three master programs would be developed using the framework provided by the Bologna Convention and the lecturing could be shared among specialist Scientists within a network of collaborating universities. Therefore, educational plans have been developed for the above MSc degrees. These plans envisage each degree comprising three modules that are common to all the degrees (3x10 ECTS credits), three specialist modules (3x10 ECTS credits) and a research project (1x60 ECTS credits). The courses should be aimed, not only to fill the identified European postgraduate education gap in radiological sciences, but also to provide a modular structure that is easily accessed by stakeholders for CPD training. It is anticipated that the European Masters will meet the academic training requirements of qualified 'experts', as defined by the European Commission and the IAEA. At the Norwegian University of Life Sciences (UMB) a pilot MSc in Radioecology has successfully been initiated in collaboration with UK and France.

  19. European MSc Programs in Nuclear Sciences-To meet the need of stakeholders

    International Nuclear Information System (INIS)

    Skipperud, L.; Salbu, B.; Priest, N.; Garelick, H.; Tamponnet, C.; Abbott, A.; Mitchell, P.

    2011-01-01

    A stakeholder needs assessment, carried out under the EU-EURAC and EU-ENEN-II projects, clearly showed that, at the European level, there are a significant and constant need for post-graduates with skills in radiochemistry, radioecology, radiation dosimetry and environmental modelling and a smaller, but still important, demand for radiobiologists and bio-modellers. Most of these needs are from government organizations. If only the nuclear industry is considered, then the largest demand is for radio chemists and radiation protection dosimetry experts. Given this spectrum of need and existing capacity in the areas of radiobiology it was concluded that the needs identified would be most efficiently met by three new degree programs: ·European MSc Radiation Protection, ·European MSc Analytical Radiochemistry, ·European MSc Radioecology. All three master programs would be developed using the framework provided by the Bologna Convention and the lecturing could be shared among specialist Scientists within a network of collaborating universities. Therefore, educational plans have been developed for the above MSc degrees. These plans envisage each degree comprising three modules that are common to all the degrees (3 x 10 ECTS credits), three specialist modules (3 x 10 ECTS credits) and a research project (1 x 60 ECTS credits). The courses should be aimed, not only to fill the identified European post-graduate education gap in radiological sciences, but also to provide a modular structure that is easily accessed by stakeholders for CPD training. It is anticipated that the European Masters will meet the academic training requirements of qualified experts', as defined by the European Commission and the IAEA. At the Norwegian University of Life Sciences (UMB) a pilot MSc in Radioecology has successfully been initiated in collaboration with UK and France.

  20. Winnicott's paradigm outlined

    Directory of Open Access Journals (Sweden)

    Zeljko Loparic

    Full Text Available The main objective of this paper is to present a unified view of Winnicott’s contribution to psychoanalysis. Part I (Sections 1-4 starts off by recalling that, according to some important commentators, Winnicott introduced a change in paradigms in psychoanalysis. In order to show that this change can be viewed as an overall “switch in paradigms”, in the sense given by T. S. Kuhn, this paper presents an account of the Kuhn’s view of science and offers a reconstruction of Freud’s Oedipal, Triangular or “Toddler-in-the-Mother’s-Bed” Paradigm. Part II (Sections 5-13 shows that as early as the 1920’s Winnicott encountered insurmountable anomalies in the Oedipal paradigm and, for that reason, started what can be called revolutionary research for a new framework of psychoanalysis. This research led Winnicott, especially during the last period of his life, to produce an alternative dual or “Baby-on-the-Mother’s-Lap” Paradigm. This new paradigm is described in some detail, especially the paradigmatic dual mother-baby relation and Winnicott’s dominant theory of maturation. Final remarks are made regarding Winnicott’s heritage and the future of psychoanalysis.

  1. Inactivated Mesenchymal Stem Cells Maintain Immunomodulatory Capacity

    NARCIS (Netherlands)

    Luk, Franka; de Witte, Samantha F. H.; Korevaar, Sander S.; Roemeling, Marieke; Franquesa, Marcella; Strini, Tanja; van den Engel, Sandra; Gargesha, Madhusudhana; Roy, Debashish; Dor, Frank J. M. F.; Horwitz, Edwin M.; de Bruin, Ron W. F.; Betjes, Michiel G. H.; Baan, Carla C.; Hoogduijn, Martin J.

    2016-01-01

    Mesenchymal stem cells (MSC) are studied as a cell therapeutic agent for treatment of various immune diseases. However, therapy with living culture-expanded cells comes with safety concerns. Furthermore, development of effective MSC immunotherapy is hampered by lack of knowledge of the mechanisms of

  2. Spot14/Spot14R expression may be involved in MSC adipogenic differentiation in patients with adolescent idiopathic scoliosis

    Science.gov (United States)

    WANG, QIFEI; YANG, JUNLIN; LIN, XIANG; HUANG, ZIFANG; XIE, CHAOFAN; FAN, HENGWEI

    2016-01-01

    The aim of the present study was to evaluate the different expression levels of thyroid hormone responsive (THRSP; Spot14)/S14 related, Mig12 (S14R) during bone marrow mesenchymal stem cell (BM-MSC) adipogenesis in adolescent idiopathic scoliosis (AIS) patients. MSCs were retrospectively isolated from AIS patients and controls, and adipogenic differentiation was induced. Total RNA was extracted for Affymetrix 3′-IVT expression profiling microarrays and compared with the results from healthy controls. The results were confirmed by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) validation and the protein expression levels of Spot14 and its paralogous gene S14R by western blotting and immunohistochemistry. A total of 300 significantly altered mRNAs were detected (111 upregulated and 189 downregulated) and confirmed by RT-qPCR. The mRNA expression levels of seven genes, including Spot14, were altered by >2-fold in AIS patients. Spot14/S14R was selected for further investigation. The results of the western blotting demonstrated that mRNA and protein expression levels of Spot14/S14R were significantly higher in AIS patients than the controls (P<0.05). Immunohistochemistry demonstrated Spot14 was expressed in 85% (17/20 cases) in adipose tissue samples from AIS patients and 23.1% (3/13 cases) of adipose tissue samples from controls. The positive ratio of Spot14 in adipose tissue samples from AIS was significantly higher than the controls (P<0.001). The results of the present study indicated that Spot14/S14R were differently expressed in MSC adipogenesis in AIS patients, and they may be important in the abnormal adipogenic differentiation in AIS. PMID:27082501

  3. Three paradigms of horror

    Directory of Open Access Journals (Sweden)

    Dejan Ognjanović

    2016-07-01

    Full Text Available Starting with the definition of horror as a literary genre the core story of which is based on a meeting with threatening Otherness whose influx into consensual reality and it’s tacit normality creates unrest and awakens fear in the protagonists and the audience, this paper defines the three key paradigms of the horror genre, based on the causes of fear, or rather the “monstrous” Otherness in them. Paradigm 1 concerns the “fear of one’s own self”: the root of the fear is inside, in the individual psyche, in the split, deceived, or in some other way unreliable self which is, consciously or unconsciously, harmful to others, and ultimately to itself. Paradigm 2 deals with the “Fear of others”: the root of fear is outside and is concerned with other people and other creatures which have an urge to occupy a certain human microcosm. Paradigm 3 is concerned with the “Fear of the numinous”: the root of the fear is mostly situated on the outside; however its shape is amorphous, ambivalent and unknowable. The “monster” is faceless; it touches on primary forces of the divine/demonic, and as such is situated on the very border between inside/outside. All three paradigms, with their main approaches and constitutive elements, are modulated through two basic possible treatments: the conservative and the progressive (liberal, which affords a total of six basic variations of horror. Starting from definitions given by John Carpenter, Robin Wood and his own, the author analyzes representative examples from horror literature and film for each paradigm and its variation, with a special accent on the image of Otherness and its connection to the norm, its intrusion into the status quo, anthropocentrism and the presence or absence of a happy ending. The paper demonstrates the richness of connotative potential within the horror genre and provides a basis for its taxonomy.

  4. Three paradigms of horror

    OpenAIRE

    Dejan Ognjanović

    2016-01-01

    Starting with the definition of horror as a literary genre the core story of which is based on a meeting with threatening Otherness whose influx into consensual reality and it’s tacit normality creates unrest and awakens fear in the protagonists and the audience, this paper defines the three key paradigms of the horror genre, based on the causes of fear, or rather the “monstrous” Otherness in them. Paradigm 1 concerns the “fear of one’s own self”: the root of the fear is inside, in the indivi...

  5. Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion

    NARCIS (Netherlands)

    E. Eggenhofer (Elke); V. Benseler (Volker); H.K. Kroemer (Heyo); F. Popp (Felix); E.K. Geissler (Edward); H.J. Schlitt (Hans); C.C. Baan (Carla); M.H. Dahlke (Marc); M.J. Hoogduijn (Martin)

    2012-01-01

    textabstractMesenchymal stem cells (MSC) are under investigation as a therapy for a variety of disorders. Although animal models show long term regenerative and immunomodulatory effects of MSC, the fate of MSC after infusion remains to be elucidated. In the present study the localization and

  6. Learning-associated regulation of polysialylated neural cell adhesion molecule expression in the rat prefrontal cortex is region-, cell type- and paradigm-specific.

    Science.gov (United States)

    Ter Horst, Judith P F; Loscher, Jennifer S; Pickering, Mark; Regan, Ciaran M; Murphy, Keith J

    2008-08-01

    The prefrontal cortex (PFC) is an interconnected set of cortical areas that function in the synthesis of a diverse range of information and production of complex behaviour. It is now clear that these frontal structures, through bidirectional excitatory communication with the hippocampal formation, also play a substantial role in long-term memory consolidation. In the hippocampus, morphological synaptic plasticity, supported by regulation of neural cell adhesion molecule (NCAM) polysialylation status, is crucial to information storage. The recent description of polysialylated neurons in the various fields of the medial PFC suggests these structures to possess a similar capacity for synaptic plasticity. Here, using double-labelling immunohistochemistry with glutamic acid decarboxylase 67, we report that the nature of NCAM polysialic acid-positive neurons in the PFC is region-specific, with a high proportion (30-50%) of a gamma-aminobutyric acid (GABA)ergic phenotype in the more ventral infralimbic, orbitofrontal and insular cortices compared with just 10% in the dorsal structures of the cingulate, prelimbic and frontal cortices. Moreover, spatial learning was accompanied by activations in polysialylation expression in ventral PFC structures, while avoidance conditioning involved downregulation of this plasticity marker that was restricted to the dorsomedial PFC--the cingulate and prelimbic cortices. Thus, in contrast to other structures integrated functionally with the hippocampus, memory-associated plasticity mobilized in the PFC is region-, cell type- and task-specific.

  7. Inflammatory conditions dictate the effect of mesenchymal stem or stromal cells on B cell function

    NARCIS (Netherlands)

    F. Luk (Franka); Carreras-Planella, L. (Laura); S.S. Korevaar (Sander); S.F. De Witte (Samantha Fh); F.E. Borràs (Francesc); M.G.H. Betjes (Michiel); C.C. Baan (Carla); M.J. Hoogduijn (Martin); M. Franquesa (Marcella)

    2017-01-01

    textabstractThe immunomodulatory capacity of mesenchymal stem or stromal cells (MSC) makes them a promising tool for treatment of immune disease and organ transplantation. The effects of MSC on B cells are characterized by an abrogation of plasmablast formation and induction of regulatory B cells

  8. About hypotheses and paradigms: exploring the Discreetness-Chance Paradigm.

    Science.gov (United States)

    Kaellis, Eugene

    2006-01-01

    Hypotheses generally conform to paradigms which, over time, change, usually tardily, after they have become increasingly difficult to sustain under the impact of non-conforming evidence and alternative hypotheses, but more important, when they no longer are comfortably ensconced in the surrounding social-economic-political-cultural milieu. It is asserted that this milieu is the most important factor in shaping scientific theorizing. Some examples are cited: the rejection of the evidence that the world orbits around the sun (suspected by Pythagoras) in favor of centuries-long firm adherence to the Ptolemaic geocentric system; the early acceptance of Natural Selection in spite of its tautological essence and only conjectural supporting evidence, because it justified contemporaneous social-political ideologies as typified by, e.g., Spencer and Malthus. Economic, social, and cultural factors are cited as providing the ground, i.e., ideational substrate, for what is cited as the Discreetness-Chance Paradigm (DCP), that has increasingly dominated physics, biology, and medicine for over a century and which invokes small, discrete packets of energy/matter (quanta, genes, microorganisms, aberrant cells) functioning within an environment of statistical, not determined, causality. There is speculation on a possible paradigmatic shift from the DCP, which has fostered the proliferation, parallel with ("splitting") taxonomy, of alleged individual disease entities, their diagnoses, and, when available, their specific remedies, something particularly prominent in, e.g., psychiatry's Diagnostic and Statistical Manual, a codified compendium of alleged mental and behavioral disorders, but evident in any textbook of diagnosis and treatment of physical ailments. This presumed paradigm shift may be reflected in Western medicine, presently increasingly empirical and atomized, towards a growing acceptance of a more generalized, subject-oriented, approach to health and disease, a non

  9. Competing Paradigms of Development.

    Science.gov (United States)

    Weaver, James H.; And Others

    1989-01-01

    Points out the differences between a capitalist approach to development and a radical or political approach. Discusses the two paradigms and their variations. Provides guidelines for a classroom activity using this information, arguing that the use of this activity will bring about a greater awareness of development issues. (KO)

  10. Paradigms in object recognition

    International Nuclear Information System (INIS)

    Mutihac, R.; Mutihac, R.C.

    1999-09-01

    A broad range of approaches has been proposed and applied for the complex and rather difficult task of object recognition that involves the determination of object characteristics and object classification into one of many a priori object types. Our paper revises briefly the three main different paradigms in pattern recognition, namely Bayesian statistics, neural networks, and expert systems. (author)

  11. Programming Language Paradigms

    Directory of Open Access Journals (Sweden)

    Bartoníček Jan

    2014-01-01

    Full Text Available This paper's goal is to briefly explain the basic theory behind programming languages and their history while taking a close look at different programming paradigms that are used today as well as describing their differences, benefits, and drawbacks

  12. The Paradigms of Programming

    Indian Academy of Sciences (India)

    support, the paradigms of their user communities. The state of the art of computer ... structure. John Cocke's experience and mine illustrate the likelihood that continued advance in programming will require the ... MYCIN, allowing an expert user to improve MYCIN'S performance. The TEIRESIAS program elaborates the ...

  13. Paradigms of School Change

    Science.gov (United States)

    Wrigley, Terry

    2011-01-01

    This short paper points to some paradigm issues in the field of school development (leadership, effectiveness, improvement) and their relationship to social justice. It contextualises the dominant School Effectiveness and School Improvement models within neo-liberal marketisation, paying attention to their transformation through a "marriage of…

  14. Advanced finite element simulation with MSC Marc application of user subroutines

    CERN Document Server

    Javanbakht, Zia

    2017-01-01

    This book offers an in-depth insight into the general-purpose finite element program MSC Marc, which is distributed by MSC Software Corporation. It is a specialized program for nonlinear problems (implicit solver) which is common in academia and industry. The primary goal of this book is to provide a comprehensive introduction to a special feature of this software: the user can write user-subroutines in the programming language Fortran, which is the language of all classical finite element packages. This subroutine feature allows the user to replace certain modules of the core code and to implement new features such as constitutive laws or new elements. Thus, the functionality of commercial codes (‘black box’) can easily be extended by linking user written code to the main core of the program. This feature allows to take advantage of a commercial software package with the flexibility of a ‘semi-open’ code. .

  15. President Richard Nixon visits MSC to award Apollo 13 Mission Operations team

    Science.gov (United States)

    1970-01-01

    President Richard M. Nixon introduces Sigurd A. Sjoberg (far right), Director of Flight Operations at Manned Spacecraft Center (MSC), and the four Apollo 13 Flight Directors during the Presidnet's post-mission visit to MSC. The Flight Directors are (l.-r.) Glynn S. Lunney, Eugene A. Kranz, Gerald D. Griffin and Milton L. Windler. Dr. Thomas O. Paine, NASA Administrator, is seated at left. President Nixon was on the site to present the Presidential Medal of Freedom -- the nation's highest civilian honor -- to the Apollo 13 Mission Operations Team (35600); A wide-angle, overall view of the large crowd that was on hand to see President Richard M. Nixon present the Presidnetial Medal of Freedom to the Apollo 13 Mission Operations Team. A temporary speaker's platform was erected beside bldg 1 for the occasion (35601).

  16. The finite element analysis program MSC Marc/Mentat a first introduction

    CERN Document Server

    Öchsner, Andreas

    2016-01-01

    Based on simple examples, this book offers a short introduction to the general-purpose finite element program MSC Marc, a specialized program for non-linear problems (implicit solver) distributed by the MSC Software Corporation, which is commonly used in academia and industry. Today the documentation of all finite element programs includes a variety of step-by-step examples of differing complexity, and in addition, all software companies offer professional workshops on different topics. As such, rather than competing with these, the book focuses on providing simple examples, often single-element problems, which can easily be related to the theory that is discussed in finite element lectures. This makes it an ideal companion book to classical introductory courses on the finite element method.

  17. [Protective effects of human bone marrow mesenchymal stem cells on hematopoietic organs of irradiated mice].

    Science.gov (United States)

    Chen, Ling-Zhen; Yin, Song-Mei; Zhang, Xiao-Ling; Chen, Jia-Yu; Wei, Bo-Xiong; Zhan, Yu; Yu, Wei; Wu, Jin-Ming; Qu, Jia; Guo, Zi-Kuan

    2012-12-01

    The objective of this study was to explore the protective effects of human bone marrow mesenchymal stem cells (MSC) on hematopoietic organs of irradiated mice. Human bone marrow MSC were isolated, ex vivo expanded, and identified by cell biological tests. Female BALB/c mice were irradiated with (60)Co γ-ray at a single dose of 6 Gy, and received different doses of human MSC and MSC lysates or saline via tail veins. The survival of mice was record daily, and the femurs and spleens were harvested on day 9 and 16 for pathologic examination. The histological changes were observed and the cellularity was scored. The results showed that the estimated survival time of MSC- and MSC lysate-treated mice was comparable to that of controls. The hematopoiesis in the bone marrow of mice that received high-dose (5×10(6)) of MSC or MSC lysates was partially restored on day 9 and the capacity of hemopoietic tissue and cellularity scorings were significantly elevated as compared with that of controls (P nudes were also obviously observed in the spleens of mice that received high-dose of MSC or MSC lysates on d 9 after irradiation. The histological structures of the spleen and bone marrow of the mice that received high-doses (5×10(6)) of MSC or MSC lysates were restored to normal, the cell proliferation displayed extraordinarily active. Further, the cellularity scores of the bone marrow were not significantly different between the high-dose MSC and MSC lysate-treated mice. It is concluded that the bone marrow MSC can promote the hematopoietic recovery of the irradiated mice, which probably is associated with the bioactive materials inherently existed in bone marrow cells.

  18. Estudio del deslizamiento del robot bípedo Pasibot mediante el programa MSC Adams

    OpenAIRE

    Pérez González, Guillermo

    2013-01-01

    El objetivo de este Proyecto Fin de Carrera es investigar mediante el programa MSC ADAMS el deslizamiento del pie de apoyo del robot PASIBOT desarrollado en la Universidad Carlos III de Madrid. Los resultados presentados en este trabajo servirán al equipo MAQLAB, del área de Ingeniería Mecánica de la universidad, para compararlos con los datos que obtienen de las simulaciones del programa que han implementado en MATLAB. Ingeniería Industrial

  19. MSc Dissertation

    DEFF Research Database (Denmark)

    Roued-Cunliffe, Henriette

    2008-01-01

    Heritage Portals are in this dissertation defined as deep portals which can give access to external resource contents. This dissertation has developed such a portal which accesses the Swedish SMR, FMIS and the ARK system developed by L – P : Archaeology through web services. The development...... of the web Service for the ARK system was done as a part of this project combined with the creating of a WFS web-mapping service serving the spatial part of the dataset collected as a part of the Sintana project. The textual part of this dataset has been incorporated into an ARK system in the same way...... that the Portus project dataset was. Both these projects are available through the ARK web service. The portal accessed the FMIS and ARK web service and re-maps the XML output to Midas standard formatted XML and combined them. This allows the portal to do a cross-search of the two datasets and return the data...

  20. Paradigm Parallel Pedagogy: The Significance of Parallel Paradigms.

    Science.gov (United States)

    Bucci, Terri Teal

    2002-01-01

    Discusses paradigm pedagogy as incorporating the ontological, epistemological, and methodological structures of research paradigms into teaching and the classroom. States that this multifaceted approach relates the characteristics of the research paradigms of positivism, interpretivism, and critical theory to teacher pedagogy, initiating…

  1. Reduced cellularity of bone marrow in multiple sclerosis with decreased MSC expansion potential and premature ageing in vitro.

    Science.gov (United States)

    Redondo, Juliana; Sarkar, Pamela; Kemp, Kevin; Virgo, Paul F; Pawade, Joya; Norton, Aimie; Emery, David C; Guttridge, Martin G; Marks, David I; Wilkins, Alastair; Scolding, Neil J; Rice, Claire M

    2017-05-01

    Autologous bone-marrow-derived cells are currently employed in clinical studies of cell-based therapy in multiple sclerosis (MS) although the bone marrow microenvironment and marrow-derived cells isolated from patients with MS have not been extensively characterised. To examine the bone marrow microenvironment and assess the proliferative potential of multipotent mesenchymal stromal cells (MSCs) in progressive MS. Comparative phenotypic analysis of bone marrow and marrow-derived MSCs isolated from patients with progressive MS and control subjects was undertaken. In MS marrow, there was an interstitial infiltrate of inflammatory cells with lymphoid (predominantly T-cell) nodules although total cellularity was reduced. Controlling for age, MSCs isolated from patients with MS had reduced in vitro expansion potential as determined by population doubling time, colony-forming unit assay, and expression of β-galactosidase. MS MSCs expressed reduced levels of Stro-1 and displayed accelerated shortening of telomere terminal restriction fragments (TRF) in vitro. Our results are consistent with reduced proliferative capacity and ex vivo premature ageing of bone-marrow-derived cells, particularly MSCs, in MS. They have significant implication for MSC-based therapies for MS and suggest that accelerated cellular ageing and senescence may contribute to the pathophysiology of progressive MS. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Funding for this study was provided by the Medical Research Council, UK (grant no. MR/K004166/1). The ACTiMuS study is sup-ported by the Silverman Family Foundation, Multiple Sclerosis Trust, Rosetree’s Trust, Catholic Bishops of England and Wales and Friends of Frenchay and SIAMMS-II by the Sir Halley Stewart Trust. C.M.R., P.S., and K.K. received support from the Burden Neurological Institute.

  2. MSC/NASTRAN Stress Analysis of Complete Models Subjected to Random and Quasi-Static Loads

    Science.gov (United States)

    Hampton, Roy W.

    2000-01-01

    Space payloads, such as those which fly on the Space Shuttle in Spacelab, are designed to withstand dynamic loads which consist of combined acoustic random loads and quasi-static acceleration loads. Methods for computing the payload stresses due to these loads are well known and appear in texts and NASA documents, but typically involve approximations such as the Miles' equation, as well as possible adjustments based on "modal participation factors." Alternatively, an existing capability in MSC/NASTRAN may be used to output exact root mean square [rms] stresses due to the random loads for any specified elements in the Finite Element Model. However, it is time consuming to use this methodology to obtain the rms stresses for the complete structural model and then combine them with the quasi-static loading induced stresses. Special processing was developed as described here to perform the stress analysis of all elements in the model using existing MSC/NASTRAN and MSC/PATRAN and UNIX utilities. Fail-safe and buckling analyses applications are also described.

  3. Nanomechanical properties of MscL α helices: A steered molecular dynamics study.

    Science.gov (United States)

    Bavi, N; Bavi, O; Vossoughi, M; Naghdabadi, R; Hill, A P; Martinac, B; Jamali, Y

    2017-05-04

    Gating of mechanosensitive (MS) channels is driven by a hierarchical cascade of movements and deformations of transmembrane helices in response to bilayer tension. Determining the intrinsic mechanical properties of the individual transmembrane helices is therefore central to understanding the intricacies of the gating mechanism of MS channels. We used a constant-force steered molecular dynamics (SMD) approach to perform unidirectional pulling tests on all the helices of MscL in M. tuberculosis and E. coli homologs. Using this method, we could overcome the issues encountered with the commonly used constant-velocity SMD simulations, such as low mechanical stability of the helix during stretching and high dependency of the elastic properties on the pulling rate. We estimated Young's moduli of the α-helices of MscL to vary between 0.2 and 12.5 GPa with TM2 helix being the stiffest. We also studied the effect of water on the properties of the pore-lining TM1 helix. In the absence of water, this helix exhibited a much stiffer response. By monitoring the number of hydrogen bonds, it appears that water acts like a 'lubricant' (softener) during TM1 helix elongation. These data shed light on another physical aspect underlying hydrophobic gating of MS channels, in particular MscL.

  4. Novel application of stem cell-derived factors for periodontal regeneration

    Energy Technology Data Exchange (ETDEWEB)

    Inukai, Takeharu, E-mail: t-inukai@med.nagoya-u.ac.jp [Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine (Japan); Katagiri, Wataru, E-mail: w-kat@med.nagoya-u.ac.jp [Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine (Japan); Yoshimi, Ryoko, E-mail: lianzi@med.nagoya-u.ac.jp [Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine (Japan); Osugi, Masashi, E-mail: masashi@med.nagoya-u.ac.jp [Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine (Japan); Kawai, Takamasa, E-mail: takamasa@med.nagoya-u.ac.jp [Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine (Japan); Hibi, Hideharu, E-mail: hibihi@med.nagoya-u.ac.jp [Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine (Japan); Ueda, Minoru, E-mail: mueda@med.nagoya-u.ac.jp [Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine (Japan)

    2013-01-11

    Highlights: Black-Right-Pointing-Pointer Mesenchymal stem cells (MSCs) secrete a variety of cytokines. Black-Right-Pointing-Pointer Cytokines were detected in conditioned medium from cultured MSCs (MSC-CM). Black-Right-Pointing-Pointer MSC-CM enhanced activation of dog MSCs and periodontal ligament cells. Black-Right-Pointing-Pointer MSC-CM significantly promoted alveolar bone and cementum regeneration. Black-Right-Pointing-Pointer Multiple cytokines contained in MSC-CM promote periodontal regeneration. -- Abstract: The effect of conditioned medium from cultured mesenchymal stem cells (MSC-CM) on periodontal regeneration was evaluated. In vitro, MSC-CM stimulated migration and proliferation of dog MSCs (dMSCs) and dog periodontal ligament cells (dPDLCs). Cytokines such as insulin-like growth factor, vascular endothelial growth factor, transforming growth factor-{beta}1, and hepatocyte growth factor were detected in MSC-CM. In vivo, one-wall critical-size, intrabony periodontal defects were surgically created in the mandible of dogs. Dogs with these defects were divided into three groups that received MSC-CM, PBS, or no implants. Absorbable atelo-collagen sponges (TERUPLUG Registered-Sign ) were used as a scaffold material. Based on radiographic and histological observation 4 weeks after transplantation, the defect sites in the MSC-CM group displayed significantly greater alveolar bone and cementum regeneration than the other groups. These findings suggest that MSC-CM enhanced periodontal regeneration due to multiple cytokines contained in MSC-CM.

  5. Comparative Ability of Mesenchymal Stromal Cells from Different Tissues to Limit Neutrophil Recruitment to Inflamed Endothelium.

    Directory of Open Access Journals (Sweden)

    Hafsa Munir

    Full Text Available Mesenchymal stromal cells (MSC are tissue-resident stromal cells capable of modulating immune responses, including leukocyte recruitment by endothelial cells (EC. However, the comparative potency of MSC from different sources in suppressing recruitment, and the necessity for close contact with endothelium remain uncertain, although these factors have implications for use of MSC in therapy. We thus compared the effects of MSC isolated from bone marrow, Wharton's jelly, and trabecular bone on neutrophil recruitment to cytokine-stimulated EC, using co-culture models with different degrees of proximity between MSC and EC. All types of MSC suppressed neutrophil adhesion to inflamed endothelium but not neutrophil transmigration, whether directly incorporated into endothelial monolayers or separated from them by thin micropore filters. Further increase in the separation of the two cell types tended to reduce efficacy, although this diminution was least for the bone marrow MSC. Immuno-protective effects of MSC were also diminished with repeated passage; with BMMSC, but not WJMSC, completing losing their suppressive effect by passage 7. Conditioned media from all co-cultures suppressed neutrophil recruitment, and IL-6 was identified as a common bioactive mediator. These results suggest endogenous MSC have a homeostatic role in limiting inflammatory leukocyte infiltration in a range of tissues. Since released soluble mediators might have effects locally or remotely, infusion of MSC into blood or direct injection into target organs might be efficacious, but in either case, cross-talk between EC and MSC appears necessary.

  6. Novel application of stem cell-derived factors for periodontal regeneration

    International Nuclear Information System (INIS)

    Inukai, Takeharu; Katagiri, Wataru; Yoshimi, Ryoko; Osugi, Masashi; Kawai, Takamasa; Hibi, Hideharu; Ueda, Minoru

    2013-01-01

    Highlights: ► Mesenchymal stem cells (MSCs) secrete a variety of cytokines. ► Cytokines were detected in conditioned medium from cultured MSCs (MSC-CM). ► MSC-CM enhanced activation of dog MSCs and periodontal ligament cells. ► MSC-CM significantly promoted alveolar bone and cementum regeneration. ► Multiple cytokines contained in MSC-CM promote periodontal regeneration. -- Abstract: The effect of conditioned medium from cultured mesenchymal stem cells (MSC-CM) on periodontal regeneration was evaluated. In vitro, MSC-CM stimulated migration and proliferation of dog MSCs (dMSCs) and dog periodontal ligament cells (dPDLCs). Cytokines such as insulin-like growth factor, vascular endothelial growth factor, transforming growth factor-β1, and hepatocyte growth factor were detected in MSC-CM. In vivo, one-wall critical-size, intrabony periodontal defects were surgically created in the mandible of dogs. Dogs with these defects were divided into three groups that received MSC-CM, PBS, or no implants. Absorbable atelo-collagen sponges (TERUPLUG®) were used as a scaffold material. Based on radiographic and histological observation 4 weeks after transplantation, the defect sites in the MSC-CM group displayed significantly greater alveolar bone and cementum regeneration than the other groups. These findings suggest that MSC-CM enhanced periodontal regeneration due to multiple cytokines contained in MSC-CM.

  7. Towards a New Paradigm

    DEFF Research Database (Denmark)

    Marsh, Rob; Larsen, Vibeke Grupe; Hacker, Jake

    2010-01-01

    for developing a new paradigm for zero-energy architecture. There has been a radical transformation in building energy consumption over the last 30 years, with an absolute reduction in heat consumption and a rapid growth in electricity consumption, reflecting wider technological and social transformations...... in the future. With this background, a new paradigm for zero-energy architecture is developed that re-flects the architectural design process. In this way, the architectural focus early in the de-sign process on functional disposition, spatial quality and built form can act as the driving force in the movement......This paper argues that the understanding of architecture again needs to be widened if the architectural profession is to play an active role in combating climate change. The paper therefore examines past, present and future challenges for building energy consumption in Denmark as the basis...

  8. Aging of bone marrow mesenchymal stromal/stem cells: Implications on autologous regenerative medicine.

    Science.gov (United States)

    Charif, N; Li, Y Y; Targa, L; Zhang, L; Ye, J S; Li, Y P; Stoltz, J F; Han, H Z; de Isla, N

    2017-01-01

    With their proliferation, differentiation into specific cell types, and secretion properties, mesenchymal stromal/stem cells (MSC) are very interesting tools to be used in regenerative medicine. Bone marrow (BM) was the first MSC source characterized. In the frame of autologous MSC therapy, it is important to detect donor's parameters affecting MSC potency. Age of the donors appears as one parameter that could greatly affect MSC properties. Moreover, in vitro cell expansion is needed to obtain the number of cells necessary for clinical developments. It will lead to in vitro cell aging that could modify cell properties. This review recapitulates several studies evaluating the effect of in vitro and in vivo MSC aging on cell properties.

  9. The resilience of paradigm mixes

    DEFF Research Database (Denmark)

    Daugbjerg, Carsten; Farsund, Arild Aurvåg; Langhelle, Oluf

    2017-01-01

    This paper argues that a policy regime based on a paradigm mix may be resilient when challenged by changing power balances and new agendas. Controversies between the actors can be contained within the paradigm mix as it enables them to legitimize different ideational positions. Rather than engaging...... context changed. The paradigm mix proved sufficiently flexible to accommodate food security concerns and at the same time continue to take steps toward further liberalization. Indeed, the main players have not challenged the paradigm mix....

  10. Parameters in three-dimensional osteospheroids of telomerized human mesenchymal (stromal) stem cells grown on osteoconductive scaffolds that predict in vivo bone-forming potential

    DEFF Research Database (Denmark)

    Burns, Jorge S; Hansen, Pernille Lund; Larsen, Kenneth H

    2010-01-01

    Osteoblastic differentiation of human mesenchymal stem cells (hMSC) in monolayer culture is artefactual, lacking an organized bone-like matrix. We present a highly reproducible microwell protocol generating three-dimensional ex vivo multicellular aggregates of telomerized hMSC (hMSC-telomerase re...

  11. CHANGE OF ENERGY PARADIGM

    Directory of Open Access Journals (Sweden)

    Ionut PURICA

    2013-05-01

    Full Text Available We are at the beginning of a change of paradigm in the energy systems of the whole World. Both new resources being found and exploited and the new technologies for energy conversion, transport and distribution, along with the associated artificial intelligence systems, are starting to create new futures, with different living values, for the greatest machine created by men: the energy system. Some relevant elements are presented in the paper along with the position and the perspectives of Romania.

  12. Impact of bacteria and bacterial components on osteogenic and adipogenic differentiation of adipose-derived mesenchymal stem cells

    International Nuclear Information System (INIS)

    Fiedler, Tomas; Salamon, Achim; Adam, Stefanie; Herzmann, Nicole; Taubenheim, Jan; Peters, Kirsten

    2013-01-01

    Adult mesenchymal stem cells (MSC) are present in several tissues, e.g. bone marrow, heart muscle, brain and subcutaneous adipose tissue. In invasive infections MSC get in contact with bacteria and bacterial components. Not much is known about how bacterial pathogens interact with MSC and how contact to bacteria influences MSC viability and differentiation potential. In this study we investigated the impact of three different wound infection relevant bacteria, Escherichia coli, Staphylococcus aureus, and Streptococcus pyogenes, and the cell wall components lipopolysaccharide (LPS; Gram-negative bacteria) and lipoteichoic acid (LTA; Gram-positive bacteria) on viability, proliferation, and osteogenic as well as adipogenic differentiation of human adipose tissue-derived mesenchymal stem cells (adMSC). We show that all three tested species were able to attach to and internalize into adMSC. The heat-inactivated Gram-negative E. coli as well as LPS were able to induce proliferation and osteogenic differentiation but reduce adipogenic differentiation of adMSC. Conspicuously, the heat-inactivated Gram-positive species showed the same effects on proliferation and adipogenic differentiation, while its cell wall component LTA exhibited no significant impact on adMSC. Therefore, our data demonstrate that osteogenic and adipogenic differentiation of adMSC is influenced in an oppositional fashion by bacterial antigens and that MSC-governed regeneration is not necessarily reduced under infectious conditions. - Highlights: • Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli bind to and internalize into adMSC. • Heat-inactivated cells of these bacterial species trigger proliferation of adMSC. • Heat-inactivated E. coli and LPS induce osteogenic differentiation of adMSC. • Heat-inactivated E. coli and LPS reduce adipogenic differentiation of adMSC. • LTA does not influence adipogenic or osteogenic differentiation of adMSC

  13. Impact of bacteria and bacterial components on osteogenic and adipogenic differentiation of adipose-derived mesenchymal stem cells

    Energy Technology Data Exchange (ETDEWEB)

    Fiedler, Tomas, E-mail: tomas.fiedler@med.uni-rostock.de [Institute for Medical Microbiology, Virology, and Hygiene, Rostock University Medical Center, Schillingallee 70, D-18057 Rostock (Germany); Salamon, Achim; Adam, Stefanie; Herzmann, Nicole [Department of Cell Biology, Rostock University Medical Center, Schillingallee 69, D-18057 Rostock (Germany); Taubenheim, Jan [Institute for Medical Microbiology, Virology, and Hygiene, Rostock University Medical Center, Schillingallee 70, D-18057 Rostock (Germany); Department of Cell Biology, Rostock University Medical Center, Schillingallee 69, D-18057 Rostock (Germany); Peters, Kirsten [Department of Cell Biology, Rostock University Medical Center, Schillingallee 69, D-18057 Rostock (Germany)

    2013-11-01

    Adult mesenchymal stem cells (MSC) are present in several tissues, e.g. bone marrow, heart muscle, brain and subcutaneous adipose tissue. In invasive infections MSC get in contact with bacteria and bacterial components. Not much is known about how bacterial pathogens interact with MSC and how contact to bacteria influences MSC viability and differentiation potential. In this study we investigated the impact of three different wound infection relevant bacteria, Escherichia coli, Staphylococcus aureus, and Streptococcus pyogenes, and the cell wall components lipopolysaccharide (LPS; Gram-negative bacteria) and lipoteichoic acid (LTA; Gram-positive bacteria) on viability, proliferation, and osteogenic as well as adipogenic differentiation of human adipose tissue-derived mesenchymal stem cells (adMSC). We show that all three tested species were able to attach to and internalize into adMSC. The heat-inactivated Gram-negative E. coli as well as LPS were able to induce proliferation and osteogenic differentiation but reduce adipogenic differentiation of adMSC. Conspicuously, the heat-inactivated Gram-positive species showed the same effects on proliferation and adipogenic differentiation, while its cell wall component LTA exhibited no significant impact on adMSC. Therefore, our data demonstrate that osteogenic and adipogenic differentiation of adMSC is influenced in an oppositional fashion by bacterial antigens and that MSC-governed regeneration is not necessarily reduced under infectious conditions. - Highlights: • Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli bind to and internalize into adMSC. • Heat-inactivated cells of these bacterial species trigger proliferation of adMSC. • Heat-inactivated E. coli and LPS induce osteogenic differentiation of adMSC. • Heat-inactivated E. coli and LPS reduce adipogenic differentiation of adMSC. • LTA does not influence adipogenic or osteogenic differentiation of adMSC.

  14. Human Adipose Tissue-Derived Mesenchymal Stem Cells Abrogate Plasmablast Formation and Induce Regulatory B Cells Independently of T Helper Cells

    NARCIS (Netherlands)

    Franquesa, M.; Mensah, F. K.; Huizinga, R.; Strini, T.; Boon, L.; Lombardo, E.; DelaRosa, O.; Laman, J. D.; Grinyo, J. M.; Weimar, W.; Betjes, M. G. H.; Baan, C. C.; Hoogduijn, M. J.

    Mesenchymal or stromal stem cells (MSC) interact with cells of the immune system in multiple ways. Modulation of the immune system by MSC is believed to be a therapeutic option for autoimmune disease and transplant rejection. In recent years, B cells have moved into the focus of the attention as

  15. Activation of non-canonical Wnt/JNK pathway by Wnt3a is associated with differentiation fate determination of human bone marrow stromal (mesenchymal) stem cells

    DEFF Research Database (Denmark)

    Qiu, Weimin; Chen, Li; Kassem, Moustapha

    2011-01-01

    patterns induced by Wnt3a treatment in two hMSC lines: hMSC-LRP5(T253) and hMSC-LRP5(T244) cells carrying known mutations of Wnt co-receptor LRP5 (T253I or T244M) that either enhances or represses canonical Wnt signaling, respectively. Wnt3a treatment of hMSC activated not only canonical Wnt signaling...

  16. Mesenchymal Stem Cell-Like Cells Derived from Mouse Induced Pluripotent Stem Cells Ameliorate Diabetic Polyneuropathy in Mice

    Directory of Open Access Journals (Sweden)

    Tatsuhito Himeno

    2013-01-01

    Full Text Available Background. Although pathological involvements of diabetic polyneuropathy (DPN have been reported, no dependable treatment of DPN has been achieved. Recent studies have shown that mesenchymal stem cells (MSCs ameliorate DPN. Here we demonstrate a differentiation of induced pluripotent stem cells (iPSCs into MSC-like cells and investigate the therapeutic potential of the MSC-like cell transplantation on DPN. Research Design and Methods. For induction into MSC-like cells, GFP-expressing iPSCs were cultured with retinoic acid, followed by adherent culture for 4 months. The MSC-like cells, characterized with flow cytometry and RT-PCR analyses, were transplanted into muscles of streptozotocin-diabetic mice. Three weeks after the transplantation, neurophysiological functions were evaluated. Results. The MSC-like cells expressed MSC markers and angiogenic/neurotrophic factors. The transplanted cells resided in hindlimb muscles and peripheral nerves, and some transplanted cells expressed S100β in the nerves. Impairments of current perception thresholds, nerve conduction velocities, and plantar skin blood flow in the diabetic mice were ameliorated in limbs with the transplanted cells. The capillary number-to-muscle fiber ratios were increased in transplanted hindlimbs of diabetic mice. Conclusions. These results suggest that MSC-like cell transplantation might have therapeutic effects on DPN through secreting angiogenic/neurotrophic factors and differentiation to Schwann cell-like cells.

  17. Mesenchymal stem cell-like cells derived from mouse induced pluripotent stem cells ameliorate diabetic polyneuropathy in mice.

    Science.gov (United States)

    Himeno, Tatsuhito; Kamiya, Hideki; Naruse, Keiko; Cheng, Zhao; Ito, Sachiko; Kondo, Masaki; Okawa, Tetsuji; Fujiya, Atsushi; Kato, Jiro; Suzuki, Hirohiko; Kito, Tetsutaro; Hamada, Yoji; Oiso, Yutaka; Isobe, Kenichi; Nakamura, Jiro

    2013-01-01

    Although pathological involvements of diabetic polyneuropathy (DPN) have been reported, no dependable treatment of DPN has been achieved. Recent studies have shown that mesenchymal stem cells (MSCs) ameliorate DPN. Here we demonstrate a differentiation of induced pluripotent stem cells (iPSCs) into MSC-like cells and investigate the therapeutic potential of the MSC-like cell transplantation on DPN. For induction into MSC-like cells, GFP-expressing iPSCs were cultured with retinoic acid, followed by adherent culture for 4 months. The MSC-like cells, characterized with flow cytometry and RT-PCR analyses, were transplanted into muscles of streptozotocin-diabetic mice. Three weeks after the transplantation, neurophysiological functions were evaluated. The MSC-like cells expressed MSC markers and angiogenic/neurotrophic factors. The transplanted cells resided in hindlimb muscles and peripheral nerves, and some transplanted cells expressed S100 β in the nerves. Impairments of current perception thresholds, nerve conduction velocities, and plantar skin blood flow in the diabetic mice were ameliorated in limbs with the transplanted cells. The capillary number-to-muscle fiber ratios were increased in transplanted hindlimbs of diabetic mice. These results suggest that MSC-like cell transplantation might have therapeutic effects on DPN through secreting angiogenic/neurotrophic factors and differentiation to Schwann cell-like cells.

  18. p53 regulates the proliferation, differentiation and spontaneous transformation of mesenchymal stem cells

    Energy Technology Data Exchange (ETDEWEB)

    Armesilla-Diaz, Alejandro, E-mail: aarmesilla@cib.csic.es [Department of Cellular and Molecular Physiopathology, Centro de Investigaciones Biologicas, CSIC, Ramiro de Maeztu, 9, 28040 Madrid (Spain); Elvira, Gema; Silva, Augusto [Department of Cellular and Molecular Physiopathology, Centro de Investigaciones Biologicas, CSIC, Ramiro de Maeztu, 9, 28040 Madrid (Spain)

    2009-12-10

    Mesenchymal stem cells (MSC) have been extensively studied and gained wide popularity due to their therapeutic potential. Spontaneous transformation of MSC, from both human and murine origin, has been reported in many studies. MSC transformation depends on the culture conditions, the origin of the cells and the time on culture; however, the precise biological characteristics involved in this process have not been fully defined yet. In this study, we investigated the role of p53 in the biology and transformation of murine bone marrow (BM)-derived MSC. We demonstrate that the MSC derived from p53KO mice showed an augmented proliferation rate, a shorter doubling time and also morphologic and phenotypic changes, as compared to MSC derived from wild-type animals. Furthermore, the MSC devoid of p53 had an increased number of cells able to generate colonies. In addition, not only proliferation but also MSC differentiation is controlled by p53 since its absence modifies the speed of the process. Moreover, genomic instability, changes in the expression of c-myc and anchorage independent growth were also observed in p53KO MSC. In addition, the absence of p53 implicates the spontaneous transformation of MSC in long-term cultures. Our results reveal that p53 plays a central role in the biology of MSC.

  19. Secretomes from bone marrow-derived mesenchymal stromal cells enhance periodontal tissue regeneration.

    Science.gov (United States)

    Kawai, Takamasa; Katagiri, Wataru; Osugi, Masashi; Sugimura, Yukiko; Hibi, Hideharu; Ueda, Minoru

    2015-04-01

    Periodontal tissue regeneration with the use of mesenchymal stromal cells (MSCs) has been regarded as a future cell-based therapy. However, low survival rates and the potential tumorigenicity of implanted MSCs could undermine the efficacy of cell-based therapy. The use of conditioned media from MSCs (MSC-CM) may be a feasible approach to overcome these limitations. The aim of this study was to confirm the effect of MSC-CM on periodontal regeneration. MSC-CM were collected during their cultivation. The concentrations of the growth factors in MSC-CM were measured with the use of enzyme-linked immunoassay. Rat MSCs (rMSCs) and human umbilical vein endothelial cells cultured in MSC-CM were assessed on wound-healing and angiogenesis. The expressions of osteogenetic- and angiogenic-related genes of rMSCs cultured in MSC-CM were quantified by means of real-time reverse transcriptase-polymerase chain reaction analysis. In vivo, periodontal defects were prepared in the rat models and the collagen sponges with MSC-CM were implanted. MSC-CM includes insulin-like growth factor-1, vascular endothelial growth factor, transforming growth factor-β1 and hepatocyte growth factor. In vitro, wound-healing and angiogenesis increased significantly in MSC-CM. The levels of expression of osteogenetic- and angiogenic-related genes were significantly upregulated in rMSCs cultured with MSC-CM. In vivo, in the MSC-CM group, 2 weeks after implantation, immunohistochemical analysis showed several CD31-, CD105-or FLK-1-positive cells occurring frequently. At 4 weeks after implantation, regenerated periodontal tissue was observed in MSC-CM groups. The use of MSC-CM may be an alternative therapy for periodontal tissue regeneration because several cytokines included in MSC-CM will contribute to many processes of complicated periodontal tissue regeneration. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  20. Adult Stromal (Skeletal, Mesenchymal) Stem Cells: Advances Towards Clinical Applications

    DEFF Research Database (Denmark)

    Kermani, Abbas Jafari; Harkness, Linda; Zaher, Walid

    2014-01-01

    Mesenchymal Stem Cells (MSC) are non-hematopoietic adult stromal cells that reside in a perivascular niche in close association with pericytes and endothelial cells and possess self-renewal and multi-lineage differentiation capacity. The origin, unique properties, and therapeutic benefits of MSC ...

  1. Mesenchymal stromal cells induce epithelial-to-mesenchymal transition in human colorectal cancer cells through the expression of surface-bound TGF-?

    OpenAIRE

    Mele, Valentina; Muraro, Manuele G; Calabrese, Diego; Pfaff, Dennis; Amatruda, Nunzia; Amicarella, Francesca; Kvinlaug, Brynn; Bocelli-Tyndall, Chiara; Martin, Ivan; Resink, Therese J; Heberer, Michael; Oertli, Daniel; Terracciano, Luigi; Spagnoli, Giulio C; Iezzi, Giandomenica

    2014-01-01

    Mesenchymal stem/stromal cells (MSC) are multipotent precursors endowed with the ability to home to primary and metastatic tumor sites, where they can integrate into the tumor-associated stroma. However, molecular mechanisms and outcome of their interaction with cancer cells have not been fully clarified. In this study, we investigated the effects mediated by bone marrow-derived MSC on human colorectal cancer (CRC) cells in vitro and in vivo. We found that MSC triggered epithelial-to-mesenchy...

  2. Stem cell therapy for inflammatory bowel disease

    NARCIS (Netherlands)

    Duijvestein, Marjolijn

    2012-01-01

    Hematopoietic stem cell transplantation (HSCT) and mesenchymal stromal (MSC) cell therapy are currently under investigation as novel therapies for inflammatory bowel diseases (IBD). Hematopoietic stem cells are thought to repopulate the immune system and reset the immunological response to luminal

  3. Survival of human mesenchymal stromal cells from bone marrow and adipose tissue after xenogenic transplantation in immunocompetent mice

    DEFF Research Database (Denmark)

    Niemeyer, P; Vohrer, J; Schmal, H

    2008-01-01

    INTRODUCTION: Mesenchymal stromal cells (MSC) represent an attractive cell population for tissue engineering purposes. As MSC are described as immunoprivileged, non-autologous applications seem possible. A basic requirement is the survival of MSC after transplantation in the host. The purpose...... of the current paper was to evaluate the survival of undifferentiated and osteogenically induced human MSC from different origins after transplantation in immunocompetent mice. METHODS: Human MSC were isolated from bone marrow (BMSC) and adipose tissue (ASC). After cultivation on mineralized collagen, MSC were...... osteogenic-induced MSC (group B) could be detected in only three of 24 cases. Quantification of lymphocytes and macrophages revealed significantly higher cell numbers in group B compared with group A (Pcell...

  4. Challenging the Innovation Paradigm

    CERN Document Server

    Sveiby, Karl Erik; Segercrantz, Beata

    2012-01-01

    Innovation is almost always seen as a "good thing". Challenging the Innovation Paradigm is a critical analysis of the innovation frenzy and contemporary innovation research. The one-sided focus on desirable effects of innovation misses many opportunities to reduce the undesirable consequences. Authors in this book show how systemic effects outside the innovating firms reduce the net benefits of innovation for individual employees, customers, as well as for society as a whole - also the innovators' own organizations. This book analyzes the dominant discourses that construct and recons

  5. Paradigms and pragmatic constructivism

    DEFF Research Database (Denmark)

    Nørreklit, Hanne; Nørreklit, Lennart; Mitchell, Falconer

    2010-01-01

    Purpose - The purpose of this paper is to provide a response to a comment written by Richard Laughlin on a previous paper by the authors, which appeared in Accounting, Auditing & Accountability Journal, Volume 23 Number 6. Design/methodology/approach - The paper addresses three issues central...... to the analysis of the comment on their past paper. Findings - In addressing each of the issues in turn the authors clarify their analysis. Originality/value - The paper provides an argument for the development of a paradigm for accounting practice derived from the use of pragmatic constructivism....

  6. SUSTAINABLE DEVELOPMENT PARADIGM - SYNOPSIS

    Directory of Open Access Journals (Sweden)

    Constantinescu Andreea

    2014-07-01

    Full Text Available Even if sustainable development is a concept that gained quite recently its scientific prestige, through contribution of researchers its content has upgraded to a high degree of conceptual luggage and, through contribution from governance representatives, has gained an impressive good-practice background. Allowing the use of different methodological premises and conceptual tools, sustainable development paradigm is equipped with all the elements that would allow the opening of new horizons of knowledge. Based on the facility which can operate the concept of sustainable development, the European Union aims to develop both a more competitive economy based on environmental protection as well as a new governance of economic policy. This on one hand demonstrates the sustainable development ability to irradiate creativity towards the establishment of interdisciplinary bridges and on the other hand explains the growing interest of researchers interested in the problem of analyzing in detail this fruitful concept. Launched first as a theoretical framework to serve justify actions responsible for weighting economic growth, the concept of Sustainable Development has quickly become a topic of ethical debate circumscribed to the area of perfectibility of human nature to the necessity registry. In this regard, the philosophical content of this paradigm could not remain outside researchers concerns, who want to provide both policy makers and the general public a wide range of evidence to demonstrate the viability of this paradigm. Academia waits until maximization of the contribution of governance to achieve sustainable economic development, which consists in conjunction of this upward path with the momentum given by public policy sync, perfectly adapted for globalization era and all crises to come. However, because this concept based its structure and composition on three pillars, equally important economy, society and environment any attempt to strengthen

  7. Competitiveness: new economic paradigm?

    Directory of Open Access Journals (Sweden)

    Marlene Peñaloza

    2005-10-01

    Full Text Available Nowadays competitiveness is made up of “the new” paradigm that allows to prevail in the global World. Thus, it is inevitable to ask, was it required to be competitive to be successful in the international trade arena? Recognizing the discussion about it and its theoretical-conceptual density, the present paper studies this old notion whose meaning, in essence, is always the same one. This applies even though new realities in the present world-wide atmosphere confer to it a distinguishing character and new and old players are forced to organize actions and bring efforts together to obtain the competitive supremacy.

  8. Extracellular membrane vesicles from umbilical cord blood-derived MSC protect against ischemic acute kidney injury, a feature that is lost after inflammatory conditioning

    Directory of Open Access Journals (Sweden)

    Lotta Kilpinen

    2013-12-01

    Full Text Available Background: Mesenchymal stromal cells (MSC are shown to have a great therapeutic potential in many immunological disorders. Currently the therapeutic effect of MSCs is considered to be mediated via paracrine interactions with immune cells. Umbilical cord blood is an attractive but still less studied source of MSCs. We investigated the production of extracellular membrane vesicles (MVs from human umbilical cord blood derived MSCs (hUCBMSC in the presence (MVstim or absence (MVctrl of inflammatory stimulus. Methods: hUCBMSCs were cultured in serum free media with or without IFN-γ and MVs were collected from conditioned media by ultracentrifugation. The protein content of MVs were analyzed by mass spectrometry. Hypoxia induced acute kidney injury rat model was used to analyze the in vivo therapeutic potential of MVs and T-cell proliferation and induction of regulatory T cells were analyzed by co-culture assays. Results: Both MVstim and MVctrl showed similar T-cell modulation activity in vitro, but only MVctrls were able to protect rat kidneys from reperfusion injury in vivo. To clarify this difference in functionality we made a comparative mass spectrometric analysis of the MV protein contents. The IFN-γ stimulation induced dramatic changes in the protein content of the MVs. Complement factors (C3, C4A, C5 and lipid binding proteins (i.e apolipoproteins were only found in the MVctrls, whereas the MVstim contained tetraspanins (CD9, CD63, CD81 and more complete proteasome complex accompanied with MHCI. We further discovered that differently produced MV pools contained specific Rab proteins suggesting that same cells, depending on external signals, produce vesicles originating from different intracellular locations. Conclusions: We demonstrate by both in vitro and in vivo models accompanied with a detailed analysis of molecular characteristics that inflammatory conditioning of MSCs influence on the protein content and functional properties of MVs

  9. Fully-Coupled Fluid/Structure Vibration Analysis Using MSC/NASTRAN

    Science.gov (United States)

    Fernholz, Christian M.; Robinson, Jay H.

    1996-01-01

    MSC/NASTRAN's performance in the solution of fully-coupled fluid/structure problems is evaluated. NASTRAN is used to perform normal modes (SOL 103) and forced-response analyses (SOL 108, 111) on cylindrical and cubic fluid/structure models. Bulk data file cards unique to the specification of a fluid element are discussed and analytic partially-coupled solutions are derived for each type of problem. These solutions are used to evaluate NASTRAN's solutions for accuracy. Appendices to this work include NASTRAN data presented in fringe plot form, FORTRAN source code listings written in support of this work, and NASTRAN data file usage requirements for each analysis.

  10. APPLICATION OF MSC ADAMS – NX NASTRAN/FEMAP INTERFACE IN STRENGTH CALCULATIONS OF TRUCK FRAMES

    Directory of Open Access Journals (Sweden)

    Adam PRZEMYK

    2016-06-01

    Full Text Available In this paper, the finite element method (FEM is used to calculate the strength of truck frames by integrating the MSC Adams software, for dynamics analysis of mechanical systems, and the NX Nastran/Femap software. At the same time, a method for reducing degrees of freedom is been developed based on the Craig–Bampton method. The interface is applied in order to calculate the strength of the frame in the selected truck, which runs on the test track. The selected model of truck can be treated as the virtual prototype that is useful in the design process.

  11. DYNAMIC ANALYSIS OF A CRIMPING DEVICE WITH MULTIPLE CAMS USING MSC ADAMS II

    Directory of Open Access Journals (Sweden)

    Gheorghe Popescu

    2012-05-01

    Full Text Available Through the present paper, the author presents the results of the dynamic analysis with MSC ADAMS of the mechanism with a crimping device with 12 tightening cams, designed and used in the technological process of assembly of the indigenous electrical detonators. In this sense, the mechanism with multiple cams is considered a mechanical system and is treated as an assembly of rigid bodies connected by mechanical connections and elastic elements. For shaping and simulation of the mechanism with multiple cams using ADAMS program, the author got through the following stages: construction of the pattern, its testing and simulation, validation, finishing, parametrization, optimization of the pattern.

  12. A Modal Analysis of the Violin Using MSC/NASTRAN and PATRAN

    OpenAIRE

    Knott, George Anthony

    1987-01-01

    The MSC/NASTRAN finite element computer program and a Cray XMP computer were used to study the modal characteristics of a violin with the Stradivari shape . The violin geometry was modeled using an arcs of circles scheme with PATRAN, a finite element graphics pre/postprocessor program. The violin was modeled in-vacu and with free boundry conditions. Belly, back, sound post, bassbar, neck, bridge, tail-piece, strings, rib linings, end and corner blocks are the components of the model. Mode sha...

  13. Cytomegalovirus Infection Impairs Immunosuppressive and Antimicrobial Effector Functions of Human Multipotent Mesenchymal Stromal Cells

    Directory of Open Access Journals (Sweden)

    Roland Meisel

    2014-01-01

    Full Text Available Human mesenchymal stromal cells (MSC possess immunosuppressive and antimicrobial effects that are partly mediated by the tryptophan-catabolizing enzyme indoleamine-2,3-dioxygenase (IDO. Therefore MSC represent a promising novel cellular immunosuppressant which has the potential to control steroid-refractory acute graft versus host disease (GvHD. In addition, MSC are capable of reducing the risk of infection in patients after haematopoietic stem cell transplantation (HST. Recent data indicate that signals from the microenvironment including those from microbes may modulate MSC effector functions. As Cytomegalovirus (CMV represents a prominent pathogen in immunocompromised hosts, especially in patients following HST, we investigated the impact of CMV infection on MSC-mediated effects on the immune system. We demonstrate that CMV-infected MSC lose their cytokine-induced immunosuppressive capacity and are no longer able to restrict microbial growth. IDO expression is substantially impaired following CMV infection of MSC and this interaction critically depends on intact virus and the number of MSC as well as the viral load. Since overt CMV infection may undermine the clinical efficacy of MSC in the treatment of GvHD in transplant patients, we recommend that patients scheduled for MSC therapy should undergo thorough evaluation for an active CMV infection and receive CMV-directed antiviral therapy prior to the administration of MSC.

  14. Breaking the hydrophobicity of the MscL pore: insights into a charge-induced gating mechanism.

    Directory of Open Access Journals (Sweden)

    Balasubramanian Chandramouli

    Full Text Available The mechanosensitive channel of large conductance (MscL is a protein that responds to membrane tension by opening a transient pore during osmotic downshock. Due to its large pore size and functional reconstitution into lipid membranes, MscL has been proposed as a promising artificial nanovalve suitable for biotechnological applications. For example, site-specific mutations and tailored chemical modifications have shown how MscL channel gating can be triggered in the absence of tension by introducing charged residues at the hydrophobic pore level. Recently, engineered MscL proteins responsive to stimuli like pH or light have been reported. Inspired by experiments, we present a thorough computational study aiming at describing, with atomistic detail, the artificial gating mechanism and the molecular transport properties of a light-actuated bacterial MscL channel, in which a charge-induced gating mechanism has been enabled through the selective cleavage of photo-sensitive alkylating agents. Properties such as structural transitions, pore dimension, ion flux and selectivity have been carefully analyzed. Besides, the effects of charge on alternative sites of the channel with respect to those already reported have been addressed. Overall, our results provide useful molecular insights into the structural events accompanying the engineered MscL channel gating and the interplay of electrostatic effects, channel opening and permeation properties. In addition, we describe how the experimentally observed ionic current in a single-subunit charged MscL mutant is obtained through a hydrophobicity breaking mechanism involving an asymmetric inter-subunit motion.

  15. The WIMP Paradigm: Current Status

    International Nuclear Information System (INIS)

    Feng, Jonathan

    2011-01-01

    The WIMP paradigm is the glue that joins together much of the high energy and cosmic frontiers. It postulates that most of the matter in the Universe is made of weakly-interacting massive particles, with implications for a broad range of experiments and observations. I will review the WIMP paradigm's underlying motivations, its current status in view of rapid experimental progress on several fronts, and recent theoretical variations on the WIMP paradigm theme.

  16. Combining Acceleration and Displacement Dependent Modal Frequency Responses Using an MSC/NASTRAN DMAP Alter

    Science.gov (United States)

    Barnett, Alan R.; Widrick, Timothy W.; Ludwiczak, Damian R.

    1996-01-01

    Solving for dynamic responses of free-free launch vehicle/spacecraft systems acted upon by buffeting winds is commonly performed throughout the aerospace industry. Due to the unpredictable nature of this wind loading event, these problems are typically solved using frequency response random analysis techniques. To generate dynamic responses for spacecraft with statically-indeterminate interfaces, spacecraft contractors prefer to develop models which have response transformation matrices developed for mode acceleration data recovery. This method transforms spacecraft boundary accelerations and displacements into internal responses. Unfortunately, standard MSC/NASTRAN modal frequency response solution sequences cannot be used to combine acceleration- and displacement-dependent responses required for spacecraft mode acceleration data recovery. External user-written computer codes can be used with MSC/NASTRAN output to perform such combinations, but these methods can be labor and computer resource intensive. Taking advantage of the analytical and computer resource efficiencies inherent within MS C/NASTRAN, a DMAP Alter has been developed to combine acceleration- and displacement-dependent modal frequency responses for performing spacecraft mode acceleration data recovery. The Alter has been used successfully to efficiently solve a common aerospace buffeting wind analysis.

  17. MSC/NASTRAN ''expert'' techniques developed and applied to the TFTR poloidal field coils

    International Nuclear Information System (INIS)

    O'Toole, J.A.

    1986-01-01

    The TFTR poloidal field (PF) coils are being analyzed by PPPL and Grumman using MSC/NASTRAN as a part of an overall effort to establish the absolute limiting conditions of operation for TFTR. Each of the PF coils will be analyzed in depth, using a detailed set of finite element models. Several of the models developed are quite large because each copper turn, as well as its surrounding insulation, was modeled using solid elements. Several of the finite element models proved large enough to tax the capabilities of the National Magnetic Fusion Energy Computer Center (NMFECC), specifically disk storage space. To allow the use of substructuring techniques with their associated data bases for the larger models, it became necessary to employ certain infrequently used MSC/NASTRAN ''expert'' techniques. The techniques developed used multiple data bases and data base sets to divide each problem into a series of computer runs. For each run, only the data required was kept on active disk space, the remainder being placed in inactive ''FILEM'' storage, thus, minimizing active disk space required at any time and permitting problem solution using the NMFECC. A representative problem using the TFTR OH-1 coil global model provides an example of the techniques developed. The special considerations necessary to obtain proper results are discussed

  18. Transient Analysis of Thermal Protection System for X-33 Aircraft using MSC/NASTRAN

    Science.gov (United States)

    Miura, Hirokazu; Chargin, M. K.; Bowles, J.; Tam, T.; Chu, D.; Chainyk, M.; Green, Michael J. (Technical Monitor)

    1997-01-01

    X-33 is an advanced technology demonstrator vehicle for the Reusable Launch Vehicle (RLV) program. The thermal protection system (TPS) for the X-33 is composed of complex layers of materials to protect internal components, while withstanding severe external temperatures induced by aerodynamic heating during high speed flight. It also serves as the vehicle aeroshell in some regions using a stand-off design. MSC/NASTRAN thermal analysis capability was used to predict transient temperature distribution (within the TPS) throughout a mission, from launch through the cool-off period after landing. In this paper, a typical analysis model, representing a point on the vehicle where the liquid oxygen tank is closest to the outer mold line, is described. The maximum temperature difference between the outer mold line and the internal surface of the liquid oxygen tank can exceed 1500 F. One dimensional thermal models are used to select the materials and determine the thickness of each layer for minimum weight while insuring that all materials remain within the allowable temperature range. The purpose of working with three dimensional (3D) comprehensive models using MSC/NASTRAN is to assess the 3D radiation effects and the thermal conduction heat shorts of the support fixtures.

  19. A DMAP Program for the Selection of Accelerometer Locations in MSC/NASTRAN

    Science.gov (United States)

    Peck, Jeff; Torres, Isaias

    2004-01-01

    A new program for selecting sensor locations has been written in the DMAP (Direct Matrix Abstraction Program) language of MSC/NASTRAN. The program implements the method of Effective Independence for selecting sensor locations, and is executed within a single NASTRAN analysis as a "rigid format alter" to the normal modes solution sequence (SOL 103). The user of the program is able to choose among various analysis options using Case Control and Bulk Data entries. Algorithms tailored for the placement of both uni-axial and tri- axial accelerometers are available, as well as several options for including the model s mass distribution into the calculations. Target modes for the Effective Independence analysis are selected from the MSC/NASTRAN ASET modes calculated by the "SOL 103" solution sequence. The initial candidate sensor set is also under user control, and is selected from the ASET degrees of freedom. Analysis results are printed to the MSCINASTRAN output file (*.f06), and may include the current candidate sensors set, and their associated Effective Independence distribution, at user specified iteration intervals. At the conclusion of the analysis, the model is reduced to the final sensor set, and frequencies and orthogonality checks are printed. Example results are given for a pre-test analysis of NASA s five-segment solid rocket booster modal test.

  20. Reduced reactivation from dormancy but maintained lineage choice of human mesenchymal stem cells with donor age.

    Directory of Open Access Journals (Sweden)

    Verena Dexheimer

    Full Text Available UNLABELLED: Mesenchymal stem cells (MSC are promising for cell-based regeneration therapies but up to date it is still controversial whether their function is maintained throughout ageing. Aim of this study was to address whether frequency, activation in vitro, replicative function, and in vitro lineage choice of MSC is maintained throughout ageing to answer the question whether MSC-based regeneration strategies should be restricted to younger individuals. MSC from bone marrow aspirates of 28 donors (5-80 years were characterized regarding colony-forming unit-fibroblast (CFU-F numbers, single cell cloning efficiency (SSCE, osteogenic, adipogenic and chondrogenic differentiation capacity in vitro. Alkaline phosphatase (ALP activity, mineralization, Oil Red O content, proteoglycan- and collagen type II deposition were quantified. While CFU-F frequency was maintained, SSCE and early proliferation rate decreased significantly with advanced donor age. MSC with higher proliferation rate before start of induction showed stronger osteogenic, adipogenic and chondrogenic differentiation. MSC with high osteogenic capacity underwent better chondrogenesis and showed a trend to better adipogenesis. Lineage choice was, however, unaltered with age. CONCLUSION: Ageing influenced activation from dormancy and replicative function of MSC in a way that it may be more demanding to mobilize MSC to fast cell growth at advanced age. Since fast proliferation came along with high multilineage capacity, the proliferation status of expanded MSC rather than donor age may provide an argument to restrict MSC-based therapies to certain individuals.

  1. Stem cell technology for bone regeneration: current status and potential applications

    Directory of Open Access Journals (Sweden)

    Asatrian G

    2015-02-01

    Full Text Available Greg Asatrian,1 Dalton Pham,1,2 Winters R Hardy,3 Aaron W James,1–3 Bruno Peault3,4 1Dental and Craniofacial Research Institute and Section of Orthodontics, School of Dentistry, 2Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, 3UCLA/Orthopaedic Hospital Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, Los Angeles, CA, USA; 4Medical Research Council Centre for Regenerative Medicine, Edinburgh, Scotland, UK Abstract: Continued improvements in the understanding and application of mesenchymal stem cells (MSC have revolutionized tissue engineering. This is particularly true within the field of skeletal regenerative medicine. However, much remains unknown regarding the native origins of MSC, the relative advantages of different MSC populations for bone regeneration, and even the biologic safety of such unpurified, grossly characterized cells. This review will first summarize the initial discovery of MSC, as well as the current and future applications of MSC in bone tissue engineering. Next, the relative advantages and disadvantages of MSC isolated from distinct tissue origins are debated, including the MSC from adipose, bone marrow, and dental pulp, among others. The perivascular origin of MSC is next discussed. Finally, we briefly comment on pluripotent stem cell populations and their possible application in bone tissue engineering. While continually expanding, the field of MSC-based bone tissue engineering and regeneration shows potential to become a clinical reality in the not-so-distant future.Keywords: mesenchymal stem cell, pericyte, bone tissue engineering, MSC, ASC, DMSC

  2. The regrammation of paradigms:

    DEFF Research Database (Denmark)

    Heltoft, Lars

    2017-01-01

    ABSTRACT This article surveys the development of voice and tense auxiliaries in Scandinavian with a focus on Danish. Voice is the first category (documented indirectly by Gothic) to show periphrastic forms in paradigmatic cooperation with inflectional forms; and these periphrastic forms are modeled...... on predicative constructions. Modern Danish has introduced verbal constructions at the expense of all predicative morphology, and the Old Scandinavian auxiliary verbs hafa/hava ‘have’ and vera/wæra ‘be’, verða/wartha ‘become’ have undergone semantic changes, including specialisation and markedness shift...... (tense, mood and voice) as part of otherwise inflectional paradigms, and, constructional auxiliaries (copula verbs) with predicate scope. Modern Danish inflectional auxiliaries express perfect tense and active voice with transitive verbs (have ‘have’), perfect tense, active voice and telicity...

  3. PARADIGM OF ACCOUNTING CHANGE

    Directory of Open Access Journals (Sweden)

    Constanta Iacob

    2016-12-01

    Full Text Available The words and phrases swop with each other and the apparent stability of a word’s meaning sometimes change in time. This explains why the generic term of accounting is used when referring to the qualities attributed to accounting,but also when it comes to organizing financial accounting function within the entity, and when referring concretely to keeping a double record with its specific means, methods and tools specific, respectively seen as a technical accounting.Speaking about the qualities of accounting, but also about the organizational form it takes, we note that there is a manifold meaning of the word accounting, which is why the purpose of this article is to demonstrate that the paradigm shift aimed at a new set of rules and if the rules changes, then we can change the very purpose of accounting.

  4. Paradigms for parasite conservation.

    Science.gov (United States)

    Dougherty, Eric R; Carlson, Colin J; Bueno, Veronica M; Burgio, Kevin R; Cizauskas, Carrie A; Clements, Christopher F; Seidel, Dana P; Harris, Nyeema C

    2016-08-01

    Parasitic species, which depend directly on host species for their survival, represent a major regulatory force in ecosystems and a significant component of Earth's biodiversity. Yet the negative impacts of parasites observed at the host level have motivated a conservation paradigm of eradication, moving us farther from attainment of taxonomically unbiased conservation goals. Despite a growing body of literature highlighting the importance of parasite-inclusive conservation, most parasite species remain understudied, underfunded, and underappreciated. We argue the protection of parasitic biodiversity requires a paradigm shift in the perception and valuation of their role as consumer species, similar to that of apex predators in the mid-20th century. Beyond recognizing parasites as vital trophic regulators, existing tools available to conservation practitioners should explicitly account for the unique threats facing dependent species. We built upon concepts from epidemiology and economics (e.g., host-density threshold and cost-benefit analysis) to devise novel metrics of margin of error and minimum investment for parasite conservation. We define margin of error as the risk of accidental host extinction from misestimating equilibrium population sizes and predicted oscillations, while minimum investment represents the cost associated with conserving the additional hosts required to maintain viable parasite populations. This framework will aid in the identification of readily conserved parasites that present minimal health risks. To establish parasite conservation, we propose an extension of population viability analysis for host-parasite assemblages to assess extinction risk. In the direst cases, ex situ breeding programs for parasites should be evaluated to maximize success without undermining host protection. Though parasitic species pose a considerable conservation challenge, adaptations to conservation tools will help protect parasite biodiversity in the face of

  5. Stem cells to regenerate the newborn brain

    NARCIS (Netherlands)

    van Velthoven, C.T.J.

    2011-01-01

    Perinatal hypoxia-ischemia (HI) is a frequent cause of perinatal morbidity and mortality with limited therapeutic options. In this thesis we investigate whether mesenchymal stem cells (MSC) regenerate the neonatal brain after HI injury. We show that transplantation of MSC after neonatal brain injury

  6. Mesenchymal stem cell-conditioned medium prevents radiation-induced liver injury by inhibiting inflammation and protecting sinusoidal endothelial cells

    International Nuclear Information System (INIS)

    Chen Yixing; Zeng Zhaochong; Sun Jing; Huang Yan; Zhang Zhenyu; Zeng Haiying

    2015-01-01

    Current management of radiation-induced liver injury is limited. Sinusoidal endothelial cell (SEC) apoptosis and inflammation are considered to be initiating events in hepatic damage. We hypothesized that mesenchymal stem cells (MSCs) possess anti-apoptotic and anti-inflammatory actions during hepatic irradiation, acting via paracrine mechanisms. This study aims to examine whether MSC-derived bioactive components are protective against radiation-induced liver injury in rats. MSC-conditioned medium (MSC-CM) was generated from rat bone marrow–derived MSCs. The effect of MSC-CM on the viability of irradiated SECs was examined by flow cytometric analysis. Activation of the Akt and ERK pathways was analyzed by western blot. MSC-CM was also delivered to Sprague–Dawley rats immediately before receiving liver irradiation, followed by testing for pathological features, changes in serum hyaluronic acid, ALT, and inflammatory cytokine levels, and liver cell apoptosis. MSC-CM enhanced the viability of irradiated SECs in vitro and induced Akt and ERK phosphorylation in these cells. Infusion of MSC-CM immediately before liver irradiation provided a significant anti-apoptotic effect on SECs and improved the histopathological features of injury in the irradiated liver. MSC-CM also reduced the secretion and expression of inflammatory cytokines and increased the expression of anti-inflammatory cytokines. MSC-derived bioactive components could be a novel therapeutic approach for treating radiation-induced liver injury. (author)

  7. [Exosomes Derived from Mesenchymal Stem Cells--the Future Ideal Vector of Biological Therapy].

    Science.gov (United States)

    Zhang, Juan; Shi, Jing-Shu; Li, Jian

    2015-08-01

    MSC-exosomes are homogeneous menbrane vesicles with diameter 40-100 nm, derived from mesenchymal stem cells at physiological or pathology conditions. MSC-exosomes contain a great quantity and a wide variety of bioactive substances, such as proteins and miRNA. MSC-exosomes transfer bioactive substances to recipient cells to affect their functions through membrane fusion or endocytosis, which like the storage pools of signal vehicles for cell-to-cell comunication in vivo. MSC-exosomes can mimic the beneficial effect of MSC treatment, such as the promotion of tissue repair or the immune regulation. The biological property and functions of MSC-exosomes are reviwed in this article.

  8. Analysis of migration rate and chemotaxis of human adipose-derived mesenchymal stem cells in response to LPS and LTA in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Herzmann, Nicole; Salamon, Achim [Department of Cell Biology, University Medicine Rostock, Schillingallee 69, D-18057 Rostock (Germany); Fiedler, Tomas [Institute for Medical Microbiology, Virology and Hygiene, University Medicine Rostock, Schillingallee 70, D-18057 Rostock (Germany); Peters, Kirsten, E-mail: kirsten.peters@med.uni-rostock.de [Department of Cell Biology, University Medicine Rostock, Schillingallee 69, D-18057 Rostock (Germany)

    2016-03-15

    Mesenchymal stem cells (MSC) are able to stimulate the regeneration of injured tissue. Since bacterial infections are common complications in wound healing, bacterial pathogens and their components come into direct contact with MSC. The interaction with bacterial structures influences the proliferation, differentiation and migratory activity of the MSC, which might be of relevance during regeneration. Studies on MSC migration in response to bacterial components have shown different results depending on the cell type. Here, we analyzed the migration rate and chemotaxis of human adipose-derived MSC (adMSC) in response to the basic cell-wall components lipopolysaccharide (LPS) of Gram-negative bacteria and lipoteichoic acid (LTA) of Gram-positive bacteria in vitro. To this end, we used transwell and scratch assays, as well as a specific chemotaxis assay combined with live-cell imaging. We found no significant influence of LPS or LTA on the migration rate of adMSC in transwell or scratch assays. Furthermore, in the µ-slide chemotaxis assay, the stimulation with LPS did not exert any chemotactic effect on adMSC. - Highlights: • LPS increased the release of IL-6 and IL-8 in adMSC significantly. • The migration rate of adMSC was not influenced by LPS or LTA. • LPS or LTA did not exert a chemotactic effect on adMSC.

  9. Analysis of migration rate and chemotaxis of human adipose-derived mesenchymal stem cells in response to LPS and LTA in vitro

    International Nuclear Information System (INIS)

    Herzmann, Nicole; Salamon, Achim; Fiedler, Tomas; Peters, Kirsten

    2016-01-01

    Mesenchymal stem cells (MSC) are able to stimulate the regeneration of injured tissue. Since bacterial infections are common complications in wound healing, bacterial pathogens and their components come into direct contact with MSC. The interaction with bacterial structures influences the proliferation, differentiation and migratory activity of the MSC, which might be of relevance during regeneration. Studies on MSC migration in response to bacterial components have shown different results depending on the cell type. Here, we analyzed the migration rate and chemotaxis of human adipose-derived MSC (adMSC) in response to the basic cell-wall components lipopolysaccharide (LPS) of Gram-negative bacteria and lipoteichoic acid (LTA) of Gram-positive bacteria in vitro. To this end, we used transwell and scratch assays, as well as a specific chemotaxis assay combined with live-cell imaging. We found no significant influence of LPS or LTA on the migration rate of adMSC in transwell or scratch assays. Furthermore, in the µ-slide chemotaxis assay, the stimulation with LPS did not exert any chemotactic effect on adMSC. - Highlights: • LPS increased the release of IL-6 and IL-8 in adMSC significantly. • The migration rate of adMSC was not influenced by LPS or LTA. • LPS or LTA did not exert a chemotactic effect on adMSC.

  10. A Contact-Based Method for Differentiation of Human Mesenchymal Stem Cells into an Endothelial Cell-Phenotype.

    Science.gov (United States)

    Joddar, Binata; Kumar, Shweta Anil; Kumar, Alok

    2017-09-23

    Adult stem cells such as mesenchymal stem cells (MSC) are known to possess the ability to augment neovascularization processes and are thus widely popular as an autologous source of progenitor cells. However there is a huge gap in our current knowledge of mechanisms involved in differentiating MSC into endothelial cells (EC), essential for lining engineered blood vessels. To fill up this gap, we attempted to differentiate human MSC into EC, by culturing the former onto chemically fixed layers of EC or its ECM, respectively. We expected direct contact of MSC when cultured atop fixed EC or its ECM, would coax the former to differentiate into EC. Results showed that human MSC cultured atop chemically fixed EC or its ECM using EC-medium showed enhanced expression of CD31, a marker for EC, compared to other cases. Further in all human MSC cultured using EC-medium, typically characteristic cobble stone shaped morphologies were noted in comparison to cells cultured using MSC medium, implying that the differentiated cells were sensitive to soluble VEGF supplementation present in the EC-medium. Results will enhance and affect therapies utilizing autologous MSC as a cell source for generating vascular cells to be used in a variety of tissue engineering applications.

  11. Maintenance of differentiation potential of human bone marrow mesenchymal stem cells immortalized by human telomerase reverse transcriptase gene despite of extensive proliferation

    International Nuclear Information System (INIS)

    Abdallah, Basem M.; Haack-Sorensen, Mandana; Burns, Jorge S.; Elsnab, Birgitte; Jakob, Franz; Hokland, Peter; Kassem, Moustapha

    2005-01-01

    Human bone marrow mesenchymal stem cells (hMSC) represent a population of stem cells that are capable of differentiation into multiple lineages. However, these cells exhibit senescence-associated growth arrest and phenotypic changes during long-term in vitro culture. We have recently demonstrated that overexpression of human telomerase reverse transcriptase (hTERT) in hMSC reconstitutes telomerase activity and extends life span of the cells [Nat. Biotechnol. 20 (2002) 592]. In the present study, we have performed extensive characterization of three independent cell lines derived from the parental hMSC-TERT cell line based on different plating densities during expansion in culture: 1:2 (hMSC-TERT2), 1:4 (hMSC-TERT4), and 1:20 (hMSC-TERT20). The 3 cell lines exhibited differences in morphology and growth rates but they all maintained the characteristics of self-renewing stem cells and the ability to differentiate into multiple mesoderm-type cell lineages: osteoblasts, adipocytes, chondrocytes, and endothelial-like cells over a 3-year period in culture. Also, surface marker studies using flow cytometry showed a pattern similar to that known from normal hMSC. Thus, telomerization of hMSC by hTERT overexpression maintains the stem cell phenotype of hMSC and it may be a useful tool for obtaining enough number of cells with a stable phenotype for mechanistic studies of cell differentiation and for tissue engineering protocols

  12. Crohn's disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn's disease.

    Science.gov (United States)

    Brand, S

    2009-08-01

    Traditionally, Crohn's disease has been associated with a Th1 cytokine profile, while Th2 cytokines are modulators of ulcerative colitis. This concept has been challenged by the description of tolerising regulatory T cells (Treg) and by proinflammatory Th17 cells, a novel T cell population characterised by the master transcription factor RORgammat, the surface markers IL23R and CCR6, and by production of the proinflammatory cytokines IL17A, IL17F, IL21, IL22 and IL26, and the chemokine CCL20. Th17 cells differentiate under the influence of IL1beta, IL6, IL21 and IL23. Recent studies indicate that TGFbeta is essential not only for the development of murine Th17 cells but also for differentiation of human Th17 cells. TGFbeta reciprocally regulates the differentiation of inflammatory Th17 cells and suppressive Treg subsets, with the concomitant presence of proinflammatory cytokines favouring Th17 cell differentiation. Several studies demonstrated an important role of Th17 cells in intestinal inflammation, particularly in Crohn's disease. Genome-wide association studies indicate that IL23R and five additional genes involved in Th17 differentiation (IL12B, JAK2, STAT3, CCR6 and TNFSF15) are associated with susceptibility to Crohn's disease and partly also to ulcerative colitis. Taken together, both Th1 and Th17 cells are important mediators of inflammation in Crohn's disease, although activities previously ascribed to IL12 may be mediated by IL23. Anti-IL12/IL23p40 antibody therapy, which targets both Th1 and Th17 cells, is effective in Crohn's disease. However, the complex relationship between Th1 and Th17 cells has not been completely analysed. This will be of great importance to delineate the specific contributions of these cells to Crohn's disease and other autoimmune diseases.

  13. Optimization of human mesenchymal stem cell manufacturing: the effects of animal/xeno-free media.

    Science.gov (United States)

    Oikonomopoulos, Angelos; van Deen, Welmoed K; Manansala, Aida-Rae; Lacey, Precious N; Tomakili, Tamera A; Ziman, Alyssa; Hommes, Daniel W

    2015-11-13

    Due to their immunosuppressive properties, mesenchymal stem cells (MSC) have been evaluated for the treatment of immunological diseases. However, the animal-derived growth supplements utilized for MSC manufacturing may lead to clinical complications. Characterization of alternative media formulations is imperative for MSC therapeutic application. Human BMMSC and AdMSC were expanded in media supplemented with either human platelet lysates (HPL), serum-free media/xeno-free FDA-approved culture medium (SFM/XF), or fetal bovine serum (FBS) and the effects on their properties were investigated. The immunophenotype of resting and IFN-γ primed BMMSC and AdMSC remained unaltered in all media. Both HPL and SFM/XF increased the proliferation of BMMSC and AdMSC. Expansion of BMMSC and AdMSC in HPL increased their differentiation, compared to SFM/XF and FBS. Resting BMMSC and AdMSC, expanded in FBS or SFM/XF, demonstrated potent immunosuppressive properties in both non-primed and IFN-γ primed conditions, whereas HPL-expanded MSC exhibited diminished immunosuppressive properties. Finally, IFN-γ primed BMMSC and AdMSC expanded in SFM/XF and HPL expressed attenuated levels of IDO-1 compared to FBS. Herein, we provide strong evidence supporting the use of the FDA-approved SFM/XF medium, in contrast to the HPL medium, for the expansion of MSC towards therapeutic applications.

  14. The influence of specific binding of collagen-silk chimeras to silk biomaterials on hMSC behavior.

    Science.gov (United States)

    An, Bo; DesRochers, Teresa M; Qin, Guokui; Xia, Xiaoxia; Thiagarajan, Geetha; Brodsky, Barbara; Kaplan, David L

    2013-01-01

    Collagen-like proteins in the bacteria Streptococcus pyogenes adopt a triple-helix structure with a thermal stability similar to that of animal collagens, can be expressed in high yield in Escherichia coli and can be easily modified through molecular biology techniques. However, potential applications for such recombinant collagens are limited by their lack of higher order structure to achieve the physical properties needed for most biomaterials. To overcome this problem, the S. pyogenes collagen domain was fused to a repetitive Bombyx mori silk consensus sequence, as a strategy to direct specific non-covalent binding onto solid silk materials whose superior stability, mechanical and material properties have been previously established. This approach resulted in the successful binding of these new collagen-silk chimeric proteins to silk films and porous scaffolds, and the binding affinity could be controlled by varying the number of repeats in the silk sequence. To explore the potential of collagen-silk chimera for regulating biological activity, integrin (Int) and fibronectin (Fn) binding sequences from mammalian collagens were introduced into the bacterial collagen domain. The attachment of bioactive collagen-silk chimeras to solid silk biomaterials promoted hMSC spreading and proliferation substantially in comparison to the controls. The ability to combine the biomaterial features of silk with the biological activities of collagen allowed more rapid cell interactions with silk-based biomaterials, improved regulation of stem cell growth and differentiation, as well as the formation of artificial extracellular matrices useful for tissue engineering applications. Copyright © 2012 Elsevier Ltd. All rights reserved.

  15. Enhanced neuro-therapeutic potential of Wharton's Jelly-derived mesenchymal stem cells in comparison with bone marrow mesenchymal stem cells culture.

    Science.gov (United States)

    Drela, Katarzyna; Lech, Wioletta; Figiel-Dabrowska, Anna; Zychowicz, Marzena; Mikula, Michał; Sarnowska, Anna; Domanska-Janik, Krystyna

    2016-04-01

    Substantial inconsistencies in mesenchymal stem (stromal) cell (MSC) therapy reported in early translational and clinical studies may indicate need for selection of the proper cell population for any particular therapeutic purpose. In the present study we have examined stromal stem cells derived either from umbilical cord Wharton's Jelly (WJ-MSC) or bone marrow (BM-MSC) of adult, healthy donors. The cells characterized in accordance with the International Society for Cellular Therapy (ISCT) indications as well as other phenotypic and functional parameters have been compared under strictly controlled culture conditions. WJ-MSC, in comparison with BM-MSC, exhibited a higher proliferation rate, a greater expansion capability being additionally stimulated under low-oxygen atmosphere, enhanced neurotrophic factors gene expression and spontaneous tendency toward a neural lineage differentiation commitment confirmed by protein and gene marker induction. Our data suggest that WJ-MSC may represent an example of immature-type "pre-MSC," where a substantial cellular component is embryonic-like, pluripotent derivatives with the default neural-like differentiation. These cells may contribute in different extents to nearly all classical MSC populations adversely correlated with the age of cell donors. Our data suggest that neuro-epithelial markers, like nestin, stage specific embryonic antigens-4 or α-smooth muscle actin expressions, may serve as useful indicators of MSC culture neuro-regeneration-associated potency. Copyright © 2016 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  16. Low Oxygen Tension Maintains Multipotency, Whereas Normoxia Increases Differentiation of Mouse Bone Marrow Stromal Cells

    OpenAIRE

    Berniakovich, Ina; Giorgio, Marco

    2013-01-01

    Optimization of mesenchymal stem cells (MSC) culture conditions is of great importance for their more successful application in regenerative medicine. O2 regulates various aspects of cellular biology and, in vivo, MSC are exposed to different O2 concentrations spanning from very low tension in the bone marrow niche, to higher amounts in wounds. In our present work, we isolated mouse bone marrow stromal cells (BMSC) and showed that they contained a population meeting requirements for MSC defin...

  17. The Consumption Paradigm in Marketing

    OpenAIRE

    Eka Ardianto

    2003-01-01

    This article elaborates consumption paradigm in marketing. In background, this paper reviews different perspectives of consumption: economic perspective and marketing perspective. In ontology, this work describes various issues regarding consumption view. In epistemology, this article demonstrates how marketers especially researches explore the consumption phenomena. In methodology, the article describes experiential marketing –one of applied consumption paradigm in marketing, which could be ...

  18. Theological paradigms and conservative Afrikaners

    African Journals Online (AJOL)

    search traditions were referred to as scientific paradigms by Kuhn (1970:182w). He described the term 'paradigm' as a 'disciplinary ... Not only are certain approaches in the scientific community being accused of foun- dationaiism with its exclusivism, but ..... The structure of scientific revolutions. 2nd ed. Chicago: Univer.

  19. Long-lasting inhibitory effects of fetal liver mesenchymal stem cells on T-lymphocyte proliferation.

    Directory of Open Access Journals (Sweden)

    Massimo Giuliani

    Full Text Available Human bone marrow mesenchymal stem cells (BM-MSC are multipotent progenitor cells that have transient immunomodulatory properties on Natural Killer (NK cells, Dendritic Cells (DC, and T cells. This study compared the use of MSC isolated from bone marrow and fetal liver (FL-MSC to determine which displayed the most efficient immunosuppressive effects on T cell activation. Although both types of MSC exhibit similar phenotype profile, FL-MSC displays a much more extended in vitro life-span and immunomodulatory properties. When co-cultured with CD3/CD28-stimulated T cells, both BM-MSC and FL-MSC affected T cell proliferation by inhibiting their entry into the cell cycle, by inducing the down-regulation of phospho-retinoblastoma (pRb, cyclins A and D1, as well as up-regulating p27(kip1 expression. The T cell inhibition by MSC was not due to the soluble HLA-G5 isoform, but to the surface expression of HLA-G1, as shown by the need of cell-cell contact and by the use of neutralizing anti-HLA-G antibodies. To note, in a HLA-G-mediated fashion, MSC facilitated the expansion of a CD4(low/CD8(low T subset that had decreased secretion of IFN-γ, and an induced secretion of the immunomodulatory cytokine IL-10. Because of their longer lasting in vitro immunosuppressive properties, mainly mediated by HLA-G, and their more efficient induction of IL-10 production and T cell apoptosis, fetal liver MSC could be considered a new tool for MSC therapy to prevent allograft rejection.

  20. PEP-1-CAT-Transduced Mesenchymal Stem Cells Acquire an Enhanced Viability and Promote Ischemia-Induced Angiogenesis

    Science.gov (United States)

    Zhang, Lei; Dong, Xiao-Wei; Wang, Jia-Ning; Tang, Jun-Ming; Yang, Jian-Ye; Guo, Ling-Yun; Zheng, Fei; Kong, Xia; Huang, Yong-Zhang; Chen, Shi-You

    2012-01-01

    Objective Poor survival of mesenchymal stem cells (MSC) compromised the efficacy of stem cell therapy for ischemic diseases. The aim of this study is to investigate the role of PEP-1-CAT transduction in MSC survival and its effect on ischemia-induced angiogenesis. Methods MSC apoptosis was evaluated by DAPI staining and quantified by Annexin V and PI double staining and Flow Cytometry. Malondialdehyde (MDA) content, lactate dehydrogenase (LDH) release, and Superoxide Dismutase (SOD) activities were simultaneously measured. MSC mitochondrial membrane potential was analyzed with JC-1 staining. MSC survival in rat muscles with gender-mismatched transplantation of the MSC after lower limb ischemia was assessed by detecting SRY expression. MSC apoptosis in ischemic area was determined by TUNEL assay. The effect of PEP-1-CAT-transduced MSC on angiogenesis in vivo was determined in the lower limb ischemia model. Results PEP-1-CAT transduction decreased MSC apoptosis rate while down-regulating MDA content and blocking LDH release as compared to the treatment with H2O2 or CAT. However, SOD activity was up-regulated in PEP-1-CAT-transduced cells. Consistent with its effect on MSC apoptosis, PEP-1-CAT restored H2O2-attenuated mitochondrial membrane potential. Mechanistically, PEP-1-CAT blocked H2O2-induced down-regulation of PI3K/Akt activity, an essential signaling pathway regulating MSC apoptosis. In vivo, the viability of MSC implanted into ischemic area in lower limb ischemia rat model was increased by four-fold when transduced with PEP-1-CAT. Importantly, PEP-1-CAT-transduced MSC significantly enhanced ischemia-induced angiogenesis by up-regulating VEGF expression. Conclusions PEP-1-CAT-transduction was able to increase MSC viability by regulating PI3K/Akt activity, which stimulated ischemia-induced angiogenesis. PMID:23285080

  1. β1 Integrins Mediate Attachment of Mesenchymal Stem Cells to Cartilage Lesions

    NARCIS (Netherlands)

    D. Zwolanek (Daniela); M. Flicker (Magdalena); E. Kirstätter (Elisabeth); F. Zaucke (Frank); G.J.V.M. van Osch (Gerjo); R.G. Erben (Reinhold)

    2015-01-01

    textabstractMesenchymal stem cells (MSC) may have great potential for cell-based therapies of osteoarthritis. However, after injection in the joint, only few cells adhere to defective articular cartilage and contribute to cartilage regeneration. Little is known about the molecular mechanisms of MSC

  2. Tre paradigmer i medieforskningen

    Directory of Open Access Journals (Sweden)

    Joshua Meyrowitz

    1997-09-01

    Full Text Available I en tid med stadig flere typer medier og hvor medieforskning dækker snart sagt alle mulige forskningsområder, giver Joshua Meyrowitz´ artikel et aktuelt bud på tre overordnede paradigmer for forståelsen af medierne. Hvad er folks - særligt medieforskernes - opfattelse af medi- erne? Forfatteren opererer analytisk med tre mediemetaforer: Medierne som kanaler, som sprog og som miljøer. Det er konkurrende opfattelser af medier, som forskerne ofte ikke formulerer eller erkender eksplicit. Den manglende klarhed omkring ens mediemetaforiske grundlag fører til uoverensstemmelser og misforståelser. Når grænserne for hver opfat- telse derimod trækkes op, påpeger Meyrowitz, skabes samtidig ønskerne for at forstå og bruge andre opfattelser. Den nødvendige mediemetafo- riske brobygning for forståelse af vor tid, kan først da opstå. Artiklen er oversat af Gunhild Wernblad.

  3. A new method for analyzing fluid-structure interaction using MSC/NASTRAN

    International Nuclear Information System (INIS)

    MacNeal, R.H.; Citerley, R.; Chargin, M.

    1979-01-01

    A popular method for analyzing compressible fluids in flexible containers is to represent the fluid by a three-dimensional finite element model in which the pressure is the unknown nodal point variable, and to represent the structure by another finite element model in which displacement components are the unknown nodal point variables. This method has the computational drawback that the matrix terms coupling the fluid to the structure are unsymmetric. This paper shows that symmetric fluid-structure coupling can be achieved if either the fluid or the structure is represented by its uncoupled vibrational modes, and if additional auxiliary variables are defined. The resulting system equations can be solved efficiently for the coupled vibration modes and for the coupled dynamic response by a general purpose finite element program, such as MSC/NASTRAN. (orig.)

  4. The modeling experience of fuel element units operation under MSC.MARC and MENTAT 2008R1

    International Nuclear Information System (INIS)

    Kulakov, G.; Kashirin, B.; Kosaurov, A.; Konovalov, Y.; Kuznetsov, A.; Medvedev, A.; Novikov, V.; Vatulin, A.

    2009-01-01

    MSC Software is leading developer of CAE-software in the world, so behaviour of fuel elements modeling with MSC.MARC use is of great practical importance. Behaviour of fuel elements usually is modeled in the elastic-viscous-plastic statement with account on fuel swelling during irradiation. For container type fuel elements contact interaction between fuel pellets and cladding or other parts of fuel element in top and bottom plugs must be in account. Results of simulated behaviour of various type fuel elements - container type fuel elements for PWR and RBMK reactors, dispersion type fuel elements for research reactors are presented. (authors)

  5. Inflammatory effects of autologous, genetically modified autologous, allogeneic, and xenogeneic mesenchymal stem cells after intra-articular injection in horses.

    Science.gov (United States)

    Pigott, J H; Ishihara, A; Wellman, M L; Russell, D S; Bertone, A L

    2013-01-01

    To compare the clinical and inflammatory joint responses to intra-articular injection of bone marrow-derived mesenchymal stem cells (MSC) including autologous, genetically modified autologous, allogeneic, or xenogeneic cells in horses. Six five-year-old Thoroughbred mares had one fetlock joint injected with Gey's balanced salt solution as the vehicle control. Each fetlock joint of each horse was subsequently injected with 15 million MSC from the described MSC groups, and were assessed for 28 days for clinical and inflammatory parameters representing synovitis, joint swelling, and pain. There were not any significant differences between autologous and genetically modified autologous MSC for synovial fluid total nucleated cell count, total protein, interleukin (IL)-6, IL-10, fetlock circumference, oedema score, pain-free range-of-motion, and soluble gene products that were detected for at least two days. Allogeneic and xenogeneic MSC produced a greater increase in peak of inflammation at 24 hours than either autologous MSC group. Genetically engineered MSC can act as vehicles to deliver gene products to the joint; further investigation into the therapeutic potential of this cell therapy is warranted. Intra-articular MSC injection resulted in a moderate acute inflammatory joint response that was greater for allogeneic and xenogeneic MSC than autologous MSC. Clinical management of this response may minimize this effect.

  6. Toward an ideal animal model to trace donor cell fates after stem cell therapy: production of stably labeled multipotent mesenchymal stem cells from bone marrow of transgenic pigs harboring enhanced green fluorescence protein gene.

    Science.gov (United States)

    Hsiao, F S H; Lian, W S; Lin, S P; Lin, C J; Lin, Y S; Cheng, E C H; Liu, C W; Cheng, C C; Cheng, P H; Ding, S T; Lee, K H; Kuo, T F; Cheng, C F; Cheng, W T K; Wu, S C

    2011-11-01

    The discovery of postnatal mesenchymal stem cells (MSC) with their general multipotentiality has fueled much interest in the development of cell-based therapies. Proper identification of transplanted MSC is crucial for evaluating donor cell distribution, differentiation, and migration. Lack of an efficient marker of transplanted MSC has precluded our understanding of MSC-related regenerative studies, especially in large animal models such as pigs. In the present study, we produced transgenic pigs harboring an enhanced green fluorescent protein (EGFP) gene. The pigs provide a reliable and reproducible source for obtaining stable EGFP-labeled MSC, which is very useful for donor cell tracking after transplantation. The undifferentiated EGFP-tagged MSC expressed a greater quantity of EGFP while maintaining MSC multipotentiality. These cells exhibited homogeneous surface epitopes and possessed classic trilineage differentiation potential into osteogenic, adipogenic, and chondrogenic lineages, with robust EGFP expression maintained in all differentiated progeny. Injection of donor MSC can dramatically increase the thickness of infarcted myocardium and improve cardiac function in mice. Moreover, the MSC, with their strong EGFP expression, can be easily distinguished from the background autofluorescence in myocardial infarcts. We demonstrated an efficient, effective, and easy way to identify MSC after long-term culture and transplantation. With the transgenic model, we were able to obtain stem or progenitor cells in earlier passages compared with the transfection of traceable markers into established MSC. Because the integration site of the transgene was the same for all cells, we lessened the potential for positional effects and the heterogeneity of the stem cells. The EGFP-transgenic pigs may serve as useful biomedical and agricultural models of somatic stem cell biology.

  7. Baseline and dynamic expression of activating NK cell receptors in the control of chronic viral infections: the paradigm of HIV-1 and HCV.

    Directory of Open Access Journals (Sweden)

    Francesco eMarras

    2014-07-01

    Full Text Available Natural Killer cell function is regulated by a balance between activating and inhibitory receptors expressed on their surface. .A relevant effort has focused so far on the study of KIR carriage/expression setting the basis for NK cell education and self-tolerance. Focus on the evolution and regulation of activating NK receptors has lagged behind so far. Our understanding of activating receptor expression and regulation has recently been improved by evidences derived from in vitro and in vivo studies.. Virus infection – either acute or chronic – has been shown to determine preferential expansion of NK cells with specific phenotypes and activating receptors and with recall-like functional activity.. Studies on patients with viral infection (HIV, HCV and specific diverging clinical courses confirm that interindividual differences may exist in baseline expression of Natural Cytotoxicity receptors (NKp46, NKp30.. In addition, the findings that patients with divergent clinical courses have different kinetics of activating receptor density expression upon NK cell activation in vitro provides an additional dynamic dimension to the informations on basal receptor density expression., Different expression and inducibility of activating receptors on NK cells contribute to the high diversity of NK cell populations and may help our understanding of inherent interindividual differences in innate responses, underlying divergent disease courses

  8. Mechano-growth factor induces migration of rat mesenchymal stem cells by altering its mechanical properties and activating ERK pathway

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Jiamin; Wu, Kewen; Lin, Feng; Luo, Qing; Yang, Li; Shi, Yisong [Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing 400044 (China); Song, Guanbin, E-mail: song@cqu.edu.cn [Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing 400044 (China); Sung, Kuo-Li Paul [Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing 400044 (China); Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093-0412 (United States)

    2013-11-08

    Highlights: •MGF induced the migration of rat MSC in a concentration-dependent manner. •MGF enhanced the mechanical properties of rMSC in inducing its migration. •MGF activated the ERK 1/2 signaling pathway of rMSC in inducing its migration. •rMSC mechanics may synergy with ERK 1/2 pathway in MGF-induced rMSC migration. -- Abstract: Mechano-growth factor (MGF) generated by cells in response to mechanical stimulation has been identified as a mechano effector molecule, playing a key role in regulating mesenchymal stem cell (MSC) function, including proliferation and migration. However, the mechanism(s) underlying how MGF-induced MSC migration occurs is still unclear. In the present study, MGF motivated migration of rat MSCs (rMSCs) in a concentration-dependent manner and optimal concentration of MGF at 50 ng/mL (defined as MGF treatment in this paper) was demonstrated. Notably, enhancement of mechanical properties that is pertinent to cell migration, such as cell traction force and cell stiffness were found to respond to MGF treatment. Furthermore, MGF increased phosphorylation of extracellular signal-regulated kinase (ERK), ERK inhibitor (i.e., PD98059) suppressed ERK phosphorylation, and abolished MGF-induced rMSC migration were found, demonstrating that ERK is involved molecule for MGF-induced rMSC migration. These in vitro evidences of MGF-induced rMSC migration and its direct link to altering rMSC mechanics and activating the ERK pathway, uncover the underlying biomechanical and biological mechanisms of MGF-induced rMSC migration, which may help find MGF-based application of MSC in clinical therapeutics.

  9. Mechano-growth factor induces migration of rat mesenchymal stem cells by altering its mechanical properties and activating ERK pathway

    International Nuclear Information System (INIS)

    Wu, Jiamin; Wu, Kewen; Lin, Feng; Luo, Qing; Yang, Li; Shi, Yisong; Song, Guanbin; Sung, Kuo-Li Paul

    2013-01-01

    Highlights: •MGF induced the migration of rat MSC in a concentration-dependent manner. •MGF enhanced the mechanical properties of rMSC in inducing its migration. •MGF activated the ERK 1/2 signaling pathway of rMSC in inducing its migration. •rMSC mechanics may synergy with ERK 1/2 pathway in MGF-induced rMSC migration. -- Abstract: Mechano-growth factor (MGF) generated by cells in response to mechanical stimulation has been identified as a mechano effector molecule, playing a key role in regulating mesenchymal stem cell (MSC) function, including proliferation and migration. However, the mechanism(s) underlying how MGF-induced MSC migration occurs is still unclear. In the present study, MGF motivated migration of rat MSCs (rMSCs) in a concentration-dependent manner and optimal concentration of MGF at 50 ng/mL (defined as MGF treatment in this paper) was demonstrated. Notably, enhancement of mechanical properties that is pertinent to cell migration, such as cell traction force and cell stiffness were found to respond to MGF treatment. Furthermore, MGF increased phosphorylation of extracellular signal-regulated kinase (ERK), ERK inhibitor (i.e., PD98059) suppressed ERK phosphorylation, and abolished MGF-induced rMSC migration were found, demonstrating that ERK is involved molecule for MGF-induced rMSC migration. These in vitro evidences of MGF-induced rMSC migration and its direct link to altering rMSC mechanics and activating the ERK pathway, uncover the underlying biomechanical and biological mechanisms of MGF-induced rMSC migration, which may help find MGF-based application of MSC in clinical therapeutics

  10. Antimicrobial peptides secreted by equine mesenchymal stromal cells inhibit the growth of bacteria commonly found in skin wounds.

    Science.gov (United States)

    Harman, Rebecca M; Yang, Steven; He, Megan K; Van de Walle, Gerlinde R

    2017-07-04

    The prevalence of chronic skin wounds in humans is high, and treatment is often complicated by the presence of pathogenic bacteria. Therefore, safe and innovative treatments to reduce the bacterial load in cutaneous wounds are needed. Mesenchymal stromal cells (MSC) are known to provide paracrine signals that act on resident skin cells to promote wound healing, but their potential antibacterial activities are not well described. The present study was designed to examine the antibacterial properties of MSC from horses, as this animal model offers a readily translatable model for MSC therapies in humans. Specifically, we aimed to (i) evaluate the in vitro effects of equine MSC on the growth of representative gram-negative and gram-positive bacterial species commonly found in skin wounds and (ii) define the mechanisms by which MSC inhibit bacterial growth. MSC were isolated from the peripheral blood of healthy horses. Gram-negative E. coli and gram-positive S. aureus were cultured in the presence of MSC and MSC conditioned medium (CM), containing all factors secreted by MSC. Bacterial growth was measured by plating bacteria and counting viable colonies or by reading the absorbance of bacterial cultures. Bacterial membrane damage was detected by incorporation of N-phenyl-1-naphthylamine (NPN). Antimicrobial peptide (AMP) gene and protein expression by equine MSC were determined by RT-PCR and Western blot analysis, respectively. Blocking of AMP activity of MSC CM was achieved using AMP-specific antibodies. We found that equine MSC and MSC CM inhibit the growth of E. coli and S. aureus, and that MSC CM depolarizes the cell membranes of these bacteria. In addition, we found that equine MSC CM contains AMPs, and blocking these AMPs with antibodies reduces the effects of MSC CM on bacteria. Our results demonstrate that equine MSC inhibit bacterial growth and secrete factors that compromise the membrane integrity of bacteria commonly found in skin wounds. We also identified

  11. Towards reduction of Paradigm coordination models

    NARCIS (Netherlands)

    S. Andova; L.P.J. Groenewegen; E.P. de Vink (Erik Peter); L. Aceto (Luca); M.R. Mousavi

    2011-01-01

    htmlabstractThe coordination modelling language Paradigm addresses collaboration between components in terms of dynamic constraints. Within a Paradigm model, component dynamics are consistently specified at a detailed and a global level of abstraction. To enable automated verification of Paradigm

  12. Articular cartilage-derived cells hold a strong osteogenic differentiation potential in comparison to mesenchymal stem cells in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Salamon, Achim, E-mail: achim.salamon@med.uni-rostock.de [Department of Cell Biology, Rostock University Medical Center, Schillingallee 69, D-18057 Rostock (Germany); Jonitz-Heincke, Anika, E-mail: anika.jonitz@med.uni-rostock.de [Biomechanics and Implant Technology Research Laboratory, Department of Orthopedics, Rostock University Medical Center, Doberaner Straße 142, D-18057 Rostock (Germany); Adam, Stefanie, E-mail: stefanie.adam@med.uni-rostock.de [Department of Cell Biology, Rostock University Medical Center, Schillingallee 69, D-18057 Rostock (Germany); Rychly, Joachim, E-mail: joachim.rychly@med.uni-rostock.de [Department of Cell Biology, Rostock University Medical Center, Schillingallee 69, D-18057 Rostock (Germany); Müller-Hilke, Brigitte, E-mail: brigitte.mueller-hilke@med.uni-rostock.de [Institute of Immunology, Rostock University Medical Center, Schillingallee 68, D-18057 Rostock (Germany); Bader, Rainer, E-mail: rainer.bader@med.uni-rostock.de [Biomechanics and Implant Technology Research Laboratory, Department of Orthopedics, Rostock University Medical Center, Doberaner Straße 142, D-18057 Rostock (Germany); Lochner, Katrin, E-mail: katrin.lochner@med.uni-rostock.de [Biomechanics and Implant Technology Research Laboratory, Department of Orthopedics, Rostock University Medical Center, Doberaner Straße 142, D-18057 Rostock (Germany); Peters, Kirsten, E-mail: kirsten.peters@med.uni-rostock.de [Department of Cell Biology, Rostock University Medical Center, Schillingallee 69, D-18057 Rostock (Germany)

    2013-11-01

    Cartilaginous matrix-degenerative diseases like osteoarthritis (OA) are characterized by gradual cartilage erosion, and also by increased presence of cells with mesenchymal stem cell (MSC) character within the affected tissues. Moreover, primary chondrocytes long since are known to de-differentiate in vitro and to be chondrogenically re-differentiable. Since both findings appear to conflict with each other, we quantitatively assessed the mesenchymal differentiation potential of OA patient cartilage-derived cells (CDC) towards the osteogenic and adipogenic lineage in vitro and compared it to that of MSC isolated from adipose tissue (adMSC) of healthy donors. We analyzed expression of MSC markers CD29, CD44, CD105, and CD166, and, following osteogenic and adipogenic induction in vitro, quantified their expression of osteogenic and adipogenic differentiation markers. Furthermore, CDC phenotype and proliferation were monitored. We found that CDC exhibit an MSC CD marker expression pattern similar to adMSC and a similar increase in proliferation rate during osteogenic differentiation. In contrast, the marked reduction of proliferation observed during adipogenic differentiation of adMSC was absent in CDC. Quantification of differentiation markers revealed a strong osteogenic differentiation potential for CDC, however almost no capacity for adipogenic differentiation. Since in the pathogenesis of OA, cartilage degeneration coincides with high bone turnover rates, the high osteogenic differentiation potential of OA patient-derived CDC may affect clinical therapeutic regimens aiming at autologous cartilage regeneration in these patients. - Highlights: • We analyze the mesenchymal differentiation capacity of cartilage-derived cells (CDC). • CDC express mesenchymal stem cell (MSC) markers CD29, CD44, CD105, and CD166. • CDC and MSC proliferation is reduced in adipogenesis and increased in osteogenesis. • Adipogenic differentiation is virtually absent in CDC, but

  13. Articular cartilage-derived cells hold a strong osteogenic differentiation potential in comparison to mesenchymal stem cells in vitro

    International Nuclear Information System (INIS)

    Salamon, Achim; Jonitz-Heincke, Anika; Adam, Stefanie; Rychly, Joachim; Müller-Hilke, Brigitte; Bader, Rainer; Lochner, Katrin; Peters, Kirsten

    2013-01-01

    Cartilaginous matrix-degenerative diseases like osteoarthritis (OA) are characterized by gradual cartilage erosion, and also by increased presence of cells with mesenchymal stem cell (MSC) character within the affected tissues. Moreover, primary chondrocytes long since are known to de-differentiate in vitro and to be chondrogenically re-differentiable. Since both findings appear to conflict with each other, we quantitatively assessed the mesenchymal differentiation potential of OA patient cartilage-derived cells (CDC) towards the osteogenic and adipogenic lineage in vitro and compared it to that of MSC isolated from adipose tissue (adMSC) of healthy donors. We analyzed expression of MSC markers CD29, CD44, CD105, and CD166, and, following osteogenic and adipogenic induction in vitro, quantified their expression of osteogenic and adipogenic differentiation markers. Furthermore, CDC phenotype and proliferation were monitored. We found that CDC exhibit an MSC CD marker expression pattern similar to adMSC and a similar increase in proliferation rate during osteogenic differentiation. In contrast, the marked reduction of proliferation observed during adipogenic differentiation of adMSC was absent in CDC. Quantification of differentiation markers revealed a strong osteogenic differentiation potential for CDC, however almost no capacity for adipogenic differentiation. Since in the pathogenesis of OA, cartilage degeneration coincides with high bone turnover rates, the high osteogenic differentiation potential of OA patient-derived CDC may affect clinical therapeutic regimens aiming at autologous cartilage regeneration in these patients. - Highlights: • We analyze the mesenchymal differentiation capacity of cartilage-derived cells (CDC). • CDC express mesenchymal stem cell (MSC) markers CD29, CD44, CD105, and CD166. • CDC and MSC proliferation is reduced in adipogenesis and increased in osteogenesis. • Adipogenic differentiation is virtually absent in CDC, but

  14. The Impact of IBM Cell Technology on the Programming Paradigm in the Context of Computer Systems for Climate and Weather Models

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Shujia; Duffy, Daniel; Clune, Thomas; Suarez, Max; Williams, Samuel; Halem, Milton

    2009-01-10

    The call for ever-increasing model resolutions and physical processes in climate and weather models demands a continual increase in computing power. The IBM Cell processor's order-of-magnitude peak performance increase over conventional processors makes it very attractive to fulfill this requirement. However, the Cell's characteristics, 256KB local memory per SPE and the new low-level communication mechanism, make it very challenging to port an application. As a trial, we selected the solar radiation component of the NASA GEOS-5 climate model, which: (1) is representative of column physics components (half the total computational time), (2) has an extremely high computational intensity: the ratio of computational load to main memory transfers, and (3) exhibits embarrassingly parallel column computations. In this paper, we converted the baseline code (single-precision Fortran) to C and ported it to an IBM BladeCenter QS20. For performance, we manually SIMDize four independent columns and include several unrolling optimizations. Our results show that when compared with the baseline implementation running on one core of Intel's Xeon Woodcrest, Dempsey, and Itanium2, the Cell is approximately 8.8x, 11.6x, and 12.8x faster, respectively. Our preliminary analysis shows that the Cell can also accelerate the dynamics component (~;;25percent total computational time). We believe these dramatic performance improvements make the Cell processor very competitive as an accelerator.

  15. 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.

  16. Mesenchymal stem cells promote colorectal cancer progression through AMPK/mTOR-mediated NF-κB activation.

    Science.gov (United States)

    Wu, Xiao-Bing; Liu, Yang; Wang, Gui-Hua; Xu, Xiao; Cai, Yang; Wang, Hong-Yi; Li, Yan-Qi; Meng, Hong-Fang; Dai, Fu; Jin, Ji-De

    2016-02-19

    Mesenchymal stem cells (MSCs) exert a tumor-promoting effect in a variety of human cancers. This study was designed to identify the molecular mechanisms related to the tumor-promoting effect of MSCs in colorectal cancer. In vitro analysis of colorectal cancer cell lines cultured in MSC conditioned media (MSC-CM) showed that MSC-CM significantly promoted the progression of the cancer cells by enhancing cell proliferation, migration and colony formation. The tumorigenic effect of MSC-CM was attributed to altered expression of cell cycle regulatory proteins and inhibition of apoptosis. Furthermore, MSC-CM induced high level expression of a number of pluripotency factors in the cancer cells. ELISAs revealed MSC-CM contained higher levels of IL-6 and IL-8, which are associated with the progression of cancer. Moreover, MSC-CM downregulated AMPK mRNA and protein phosphorylation, but upregulated mTOR mRNA and protein phosphorylation. The NF-κB pathway was activated after addition of MSC-CM. An in vivo model in Balb/C mice confirmed the ability of MSC-CM to promote the invasion and proliferation of colorectal cancer cells. This study indicates that MSCs promote the progression of colorectal cancer via AMPK/mTOR-mediated NF-κB activation.

  17. Banking of Adipose- and Cord Tissue-Derived Stem Cells: Technical and Regulatory Issues.

    Science.gov (United States)

    Harris, David T

    2016-01-01

    Stem cells are found in all multicellular organisms and are defined as cells that can differentiate into specialized mature cells as well as divide to produce more stem cells. Mesenchymal stem cells (MSC) were among the first stem cell types to be utilized for regenerative medicine. Although initially isolated from bone marrow, based on ease and costs of procurement, MSC derived from adipose tissue (AT-MSC) and umbilical cord tissue (CT-MSC) are now preferred stem cell sources for these applications. Both adipose tissues and cord tissue present unique problems for biobanking however, in that these are whole tissues, not cellular suspensions. Although the tissues could be processed to facilitate the biobanking process, by doing so additional regulatory issues arise that must be addressed. This review will discuss the technical issues associated with biobanking of these tissues, as well as regulatory concerns when banking of utilizing MSC derived from these sources in the clinic.

  18. Human mesenchymal stem cells protect neutrophils from serum-deprived cell death.

    Science.gov (United States)

    Maqbool, Maryam; Vidyadaran, Sharmili; George, Elizabeth; Ramasamy, Rajesh

    2011-12-01

    We have previously shown that human MSC (mesenchymal stem cells) inhibit the proliferation of most of the immune cells. However, there are innate immune cells such as neutrophils and other PMN (polymorphonuclear) cells that do not require an extensive proliferation prior to their effector function. In this study, the effect of MSC on neutrophils in the presence of complete and serum-deprived culture media was investigated. In the presence of MSC, the viability of neutrophils increase as measured in 24 h of incubation at various supplementation of serum concentration. We have utilized Annexin V and PI (propidium iodide) staining to confirm whether the enhancement of neutrophil's viability is due to a reduction in PCD (programmed cell death). MSC significantly rescue neutrophils from apoptosis at 1, 5 and 10% of FBS (fetal bovine serum) supplementation. The fractions of viable and dead cells were increased and decreased respectively in the presence of MSC. Our results indicate MSC rescue neutrophils from nutrient- or serum-deprived cell death. However, whether this effect is exerted through a specific signalling pathway or confining neutrophils in resting state by MSC requires further investigation.

  19. Mesenchymal stem cells-conditioned medium protects PC12 cells against 2,5-hexanedione-induced apoptosis via inhibiting mitochondria-dependent caspase 3 pathway.

    Science.gov (United States)

    Li, Shuang-Yue; Qi, Yuan; Hu, Shu-Hai; Piao, Feng-Yuan; Guan, Huai; Wang, Zhe-Min; Chen, Ruo-Lin; Liu, Shuang

    2017-02-01

    Studies suggested that the conditioned medium of mesenchymal stem cells (MSC-CM) inhibited the increased apoptosis in various cells. However, there are no reports underlying the protection of MSC-CM against 2,5-hexanedione (HD)-induced apoptosis in neural cells. In the present study, the viability was observed in PC12 cells that received HD alone or with MSC-CM by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Apoptosis was estimated by Hoechst 33342 staining and flow cytometry. Mitochondrial transmembrane potential was examined by rhodamine 123. Moreover, we investigated the expression of Bax and Bcl-2, cytochrome c translocation, and caspase 3 activity by real-time polymerase chain reaction, Western blot, and immunochemistry. Nerve growth factor (NGF) was examined in MSCs and MSC-CM. Our results showed that MSC-CM promoted cell survival and reduced apoptosis in HD-exposed PC12 cells. Moreover, MSC-CM significantly reversed disturbance of Bax and Bcl-2, ameliorated disruption of mitochondrial transmembrane potential, and reduced release of cytochrome c and activity of caspase 3 in HD-exposed PC12 cells. In the meantime, NGF was detected in MSCs and MSC-CM. These findings demonstrate that MSC-CM protects against HD-induced apoptosis in PC12 cells via inhibiting mitochondrial pathway. Our results indicate that NGF in MSC-CM may be involved in the protection of MSC-CM against HD-induced apoptosis. Our study clarifies the protection of MSC-CM on HD neurotoxicity and its underlying mechanism.

  20. Acceleration of wound healing with stem cell-derived growth factors.

    Science.gov (United States)

    Tamari, Masayuki; Nishino, Yudai; Yamamoto, Noriyuki; Ueda, Minoru

    2013-01-01

    Recently, it has been revealed that bone marrow-derived mesenchymal stem cells (MSCs) accelerate the healing of skin wounds. Although the proliferative capacity of MSCs decreases with age, MSCs secrete many growth factors. The present study examined the effect of mesenchymal stem cell-conditioned medium (MSC-CM) on wound healing. The wound-healing process was observed macroscopically and histologically using an excisional wound-splinting mouse model, and the expression level of hyaluronic acid related to the wound healing process was observed to evaluate the wound-healing effects of MSC, MSC-CM, and control (phosphate-buffered saline). The MSC and MSC-CM treatments accelerated wound healing versus the control group. At 7 days after administration, epithelialization was accelerated, thick connective tissue had formed in the skin defect area, and the wound area was reduced in the MSC and MSC-CM groups versus the control group. At 14 days, infiltration of inflammatory cells was decreased versus 7 days, and the wounds were closed in the MSC and MSC-CM groups, while a portion of epithelium was observed in the control group. At 7 and 14 days, the MSC and MSC-CM groups expressed significantly higher levels of hyaluronic acid versus the control group (P wound healing versus the control group to a similar degree. Accordingly, it is suggested that the MSC-CM contains growth factor derived from stem cells, is able to accelerate wound healing as well as stem cell transplantation, and may become a new therapeutic method for wound healing in the future.

  1. Mesenchymal stromal cell derived endothelial progenitor treatment in patients with refractory angina

    DEFF Research Database (Denmark)

    Friis, Tina; Haack-Sørensen, Mandana; Mathiasen, Anders B

    2011-01-01

    Abstract Aims. We evaluated the feasibility, safety and efficacy of intra-myocardial injection of autologous mesenchymal stromal cells derived endothelial progenitor cell (MSC) in patients with stable coronary artery disease (CAD) and refractory angina in this first in man trial. Methods......-myocardial injection of MSC. After six months follow-up myocardial perfusion was unaltered, but the patients increased exercise capacity (p ... patients with stable CAD with autologous culture expanded MSC. Moreover, MSC treated patients had significant improvement in left ventricular function and exercise capacity, in addition to an improvement in clinical symptoms and SAQ evaluations....

  2. The Consumption Paradigm in Marketing

    Directory of Open Access Journals (Sweden)

    Eka Ardianto

    2003-08-01

    Full Text Available This article elaborates consumption paradigm in marketing. In background, this paper reviews different perspectives of consumption: economic perspective and marketing perspective. In ontology, this work describes various issues regarding consumption view. In epistemology, this article demonstrates how marketers especially researches explore the consumption phenomena. In methodology, the article describes experiential marketing –one of applied consumption paradigm in marketing, which could be an alternative choice of marketing practices.

  3. Longitudinal Cell Tracking and Simultaneous Monitoring of Tissue Regeneration after Cell Treatment of Natural Tendon Disease by Low-Field Magnetic Resonance Imaging

    Directory of Open Access Journals (Sweden)

    Dagmar Berner

    2016-01-01

    Full Text Available Treatment of tendon disease with multipotent mesenchymal stromal cells (MSC is a promising option to improve tissue regeneration. To elucidate the mechanisms by which MSC support regeneration, longitudinal tracking of MSC labelled with superparamagnetic iron oxide (SPIO by magnetic resonance imaging (MRI could provide important insight. Nine equine patients suffering from tendon disease were treated with SPIO-labelled or nonlabelled allogeneic umbilical cord-derived MSC by local injection. Labelling of MSC was confirmed by microscopy and MRI. All animals were subjected to clinical, ultrasonographical, and low-field MRI examinations before and directly after MSC application as well as 2, 4, and 8 weeks after MSC application. Hypointense artefacts with characteristically low signal intensity were identified at the site of injection of SPIO-MSC in T1- and T2∗-weighted gradient echo MRI sequences. They were visible in all 7 cases treated with SPIO-MSC directly after injection, but not in the control cases treated with nonlabelled MSC. Furthermore, hypointense artefacts remained traceable within the damaged tendon tissue during the whole follow-up period in 5 out of 7 cases. Tendon healing could be monitored at the same time. Clinical and ultrasonographical findings as well as T2-weighted MRI series indicated a gradual improvement of tendon function and structure.

  4. Shifting the paradigm

    DEFF Research Database (Denmark)

    Kiss, Katalin; Brozik, Anna; Kucsma, Nora

    2012-01-01

    reticulocytes during the final steps of erythroid maturation. Consistent with its presence in exosomes, endogenous ABCB6 is localized to the endo/lysosomal compartment, and is absent from the mitochondria of cells. Knock-down studies demonstrate that ABCB6 function is not required for de novo heme biosynthesis...... in differentiating K562 cells, excluding this ABC transporter as a key regulator of porphyrin synthesis. We confirm the mitochondrial localization of ABCB7, ABCB8 and ABCB10, suggesting that only three ABC transporters should be classified as mitochondrial proteins. Taken together, our results challenge the current...

  5. Improving the performance of P3HT-fullerene solar cells with side-chain-functionalized poly(thiophene) additives: a new paradigm for polymer design.

    Science.gov (United States)

    Lobez, Jose M; Andrew, Trisha L; Bulović, Vladimir; Swager, Timothy M

    2012-04-24

    The motivation of this study is to determine if small amounts of designer additives placed at the polymer-fullerene interface in bulk heterojunction (BHJ) solar cells can influence their performance. A series of AB-alternating side-chain-functionalized poly(thiophene) analogues, P1-6, are designed to selectively localize at the interface between regioregular poly(3-hexylthiophene) (rr-P3HT) and PC(n)BM (n = 61, 71). The side chains of every other repeat unit in P1-6 contain various terminal aromatic moieties. BHJ solar cells containing ternary mixtures of rr-P3HT, PC(n)BM, and varying weight ratios of additives P1-6 are fabricated and studied. At low loadings, the presence of P1-6 consistently increases the short circuit current and decreases the series resistance of the corresponding devices, leading to an increase in power conversion efficiency (PCE) compared to reference P3HT/PC(61)BM cells. Higher additive loadings (>5 wt %) lead to detrimental nanoscale phase separation within the active layer blend and produce solar cells with high series resistances and low overall PCEs. Small-perturbation transient open circuit voltage decay measurements reveal that, at 0.25 wt % incorporation, additives P1-6 increase charge carrier lifetimes in P3HT/PC(61)BM solar cells. Pentafluorophenoxy-containing polymer P6 is the most effective side-chain-functionalized additive and yields a 28% increase in PCE when incorporated into a 75 nm thick rr-P3HT/PC(61)BM BHJ at a 0.25 wt % loading. Moreover, devices with 220 nm thick BHJs containing 0.25 wt % P6 display PCE values of up to 5.3% (30% PCE increase over a control device lacking P6). We propose that additives P1-6 selectively localize at the interface between rr-P3HT and PC(n)BM phases and that aromatic moieties at side-chain termini introduce a dipole at the polymer-fullerene interface, which decreases the rate of bimolecular recombination and, therefore, improves charge collection across the active layer.

  6. Study of hMSC proliferation and differentiation on Mg and Mg–Sr containing biphasic β-tricalcium phosphate and amorphous calcium phosphate ceramics

    Energy Technology Data Exchange (ETDEWEB)

    Singh, Satish S., E-mail: sss42@pitt.edu [Department of Chemical & Petroleum Engineering, University of Pittsburgh, Pittsburgh, PA 15261 (United States); Roy, Abhijit, E-mail: abr20@pitt.edu [Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15261 (United States); Lee, Boeun [Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15261 (United States); Kumta, Prashant N., E-mail: pkumta@pitt.edu [Department of Chemical & Petroleum Engineering, University of Pittsburgh, Pittsburgh, PA 15261 (United States); Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15261 (United States); Center for Craniofacial Regeneration, University of Pittsburgh, Pittsburgh, PA 15261 (United States); Department of Mechanical Engineering and Materials Science, University of Pittsburgh, PA 15261 (United States)

    2016-07-01

    Biphasic mixtures of either Mg{sup 2+} or combined Mg{sup 2+} and Sr{sup 2+} cation substituted β-tricalcium phosphate (β-TCP) and amorphous calcium phosphate (ACP) were prepared using a low temperature chemical phosphatizing and hydrolysis reaction approach. Scaffolds prepared using the cation substituted calcium phosphates were capable of supporting similar levels of human mesenchymal stem cell proliferation in comparison to commercially available β-TCP. The concentrations of Mg{sup 2+}, Sr{sup 2+}, and PO{sub 4}{sup 3−} released from these scaffolds were also within the ranges desired from previous reports to support both hMSC proliferation and osteogenic differentiation. Interestingly, hMSCs cultured directly on scaffolds prepared with only Mg{sup 2+} substituted β-TCP were capable of supporting statistically significantly increased alkaline phosphatase activity, osteopontin, and osteoprotegerin expression in comparison to all compositions containing both Mg{sup 2+} and Sr{sup 2+}, and commercially available β-TCP. hMSCs cultured in the presence of scaffold extracts also exhibited similar trends in the expression of osteogenic markers as was observed during direct culture. Therefore, it was concluded that the enhanced differentiation observed was due to the release of bioactive ions rather than the surface microstructure. The role of these ions on transforming growth factor-β and bone morphogenic protein signaling was also evaluated using a PCR array. It was concluded that the release of these ions may support enhanced differentiation through SMAD dependent TGF-β and BMP signaling. - Highlights: • Synthesis of Mg and Mg-Sr containing biphasic beta tricalcium phosphate ceramics • Magnesium substitution influences ALP activity compared to strontium content. • Solution extract plays a more dominant role on hMSC differentiation. • Direct and indirect Mg and Mg-Sr TCP culture show similar OPG and OPN expression.

  7. Tissue distribution and engraftment of human mesenchymal stem cells immortalized by human telomerase reverse transcriptase gene

    DEFF Research Database (Denmark)

    Bentzon, J.F.; Stenderup, K.; Hansen, F.D.

    2005-01-01

    Engraftment of mesenchymal stem cells (MSC) in peripheral tissues for replenishing of local stem cell function has been proposed as a therapeutic approach to degenerative diseases. We have previously reported the development of an immortalized human telomerase reverse transcriptase transduced MSC...

  8. Development of novel monoclonal antibodies that define differentiation stages of human stromal (mesenchymal) stem cells

    DEFF Research Database (Denmark)

    Andersen, Ditte Caroline; Kortesidis, Angela; Zannettino, Andrew C W

    2011-01-01

    Human mesenchymal stem cells (hMSC) are currently being introduced for cell therapy, yet, antibodies specific for native and differentiated MSCs are required for their identification prior to clinical use. Herein, high quality antibodies against MSC surface proteins were developed by immunizing...

  9. [Effects of catalase on the engraftment of human hematopoietic stem cells in NOD/SCID mice].

    Science.gov (United States)

    Shi, Ming; Hu, Lin-Ping; Zhang, Xiao-Bing; Yuan, Wei-Ping; Cheng, Tao

    2015-02-01

    To investigate the effect of catalase (CAT) on engraftment of human hematopoietic stem cells (HSC) by co-transplanting umbilical cord-derived mesenchymal stem cells (UC-MSC) with over-expressed CAT and human HSC into NOD/SCID mice. The UC-MSC cultured in vitro were transfected by the retrovirus containing green fluorescent protein (GFP) and GFP-CAT genes respectively. MSC-GFP and MSC-GFP-CAT cell lines were sorted by flow cytometry. Co-culture and co-transplant experiments were performed to detect the effects of CAT on expansion and engraftment of human HSC. The percentage of GFP(+) cells were approximately 97.6% and 96.8% after sorting. The mRNA expression of CAT in MSC-GFP-CAT was 23.9-fold higher than that in UC-MSC. The activity of CAT in UC-MSC, MSC-GFP, MSC-GFP-CAT cells were 19.5, 20.3 and 74.1 Unit respectively. There was no significant differences in the percentage of CD34(+) cells between 3 groups in co-culture experiment. And the percentage of human CD45(+) cells in NOD/SCID mice were (3.22 ± 3.1)%, (4.26 ± 3.56)% and (7.37 ± 4.51)% respectively. MSC-GFP-CAT significantly improves the engraftment of human HSC in NOD/SCID mice, whereas co-culture with the MSC-GFP-CAT can not promote the expansion of HSC in vitro.

  10. Transient analysis mode participation for modal survey target mode selection using MSC/NASTRAN DMAP

    Science.gov (United States)

    Barnett, Alan R.; Ibrahim, Omar M.; Sullivan, Timothy L.; Goodnight, Thomas W.

    1994-01-01

    Many methods have been developed to aid analysts in identifying component modes which contribute significantly to component responses. These modes, typically targeted for dynamic model correlation via a modal survey, are known as target modes. Most methods used to identify target modes are based on component global dynamic behavior. It is sometimes unclear if these methods identify all modes contributing to responses important to the analyst. These responses are usually those in areas of hardware design concerns. One method used to check the completeness of target mode sets and identify modes contributing significantly to important component responses is mode participation. With this method, the participation of component modes in dynamic responses is quantified. Those modes which have high participation are likely modal survey target modes. Mode participation is most beneficial when it is used with responses from analyses simulating actual flight events. For spacecraft, these responses are generated via a structural dynamic coupled loads analysis. Using MSC/NASTRAN DMAP, a method has been developed for calculating mode participation based on transient coupled loads analysis results. The algorithm has been implemented to be compatible with an existing coupled loads methodology and has been used successfully to develop a set of modal survey target modes.

  11. A Finite Element Procedure for Calculating Fluid-Structure Interaction Using MSC/NASTRAN

    Science.gov (United States)

    Chargin, Mladen; Gartmeier, Otto

    1990-01-01

    This report is intended to serve two purposes. The first is to present a survey of the theoretical background of the dynamic interaction between a non-viscid, compressible fluid and an elastic structure is presented. Section one presents a short survey of the application of the finite element method (FEM) to the area of fluid-structure-interaction (FSI). Section two describes the mathematical foundation of the structure and fluid with special emphasis on the fluid. The main steps in establishing the finite element (FE) equations for the fluid structure coupling are discussed in section three. The second purpose is to demonstrate the application of MSC/NASTRAN to the solution of FSI problems. Some specific topics, such as fluid structure analogy, acoustic absorption, and acoustic contribution analysis are described in section four. Section five deals with the organization of the acoustic procedure flowchart. Section six includes the most important information that a user needs for applying the acoustic procedure to practical FSI problems. Beginning with some rules concerning the FE modeling of the coupled system, the NASTRAN USER DECKs for the different steps are described. The goal of section seven is to demonstrate the use of the acoustic procedure with some examples. This demonstration includes an analytic verification of selected FE results. The analytical description considers only some aspects of FSI and is not intended to be mathematically complete. Finally, section 8 presents an application of the acoustic procedure to vehicle interior acoustic analysis with selected results.

  12. Transient analysis mode participation for modal survey target mode selection using MSC/NASTRAN DMAP

    Science.gov (United States)

    Barnett, Alan R.; Ibrahim, Omar M.; Sullivan, Timothy L.; Goodnight, Thomas W.

    1994-03-01

    Many methods have been developed to aid analysts in identifying component modes which contribute significantly to component responses. These modes, typically targeted for dynamic model correlation via a modal survey, are known as target modes. Most methods used to identify target modes are based on component global dynamic behavior. It is sometimes unclear if these methods identify all modes contributing to responses important to the analyst. These responses are usually those in areas of hardware design concerns. One method used to check the completeness of target mode sets and identify modes contributing significantly to important component responses is mode participation. With this method, the participation of component modes in dynamic responses is quantified. Those modes which have high participation are likely modal survey target modes. Mode participation is most beneficial when it is used with responses from analyses simulating actual flight events. For spacecraft, these responses are generated via a structural dynamic coupled loads analysis. Using MSC/NASTRAN DMAP, a method has been developed for calculating mode participation based on transient coupled loads analysis results. The algorithm has been implemented to be compatible with an existing coupled loads methodology and has been used successfully to develop a set of modal survey target modes.

  13. Analysis of SMA Hybrid Composite Structures in MSC.Nastran and ABAQUS

    Science.gov (United States)

    Turner, Travis L.; Patel, Hemant D.

    2005-01-01

    A thermoelastic constitutive model for shape memory alloy (SMA) actuators and SMA hybrid composite (SMAHC) structures was recently implemented in the commercial finite element codes MSC.Nastran and ABAQUS. The model may be easily implemented in any code that has the capability for analysis of laminated composite structures with temperature dependent material properties. The model is also relatively easy to use and requires input of only fundamental engineering properties. A brief description of the model is presented, followed by discussion of implementation and usage in the commercial codes. Results are presented from static and dynamic analysis of SMAHC beams of two types; a beam clamped at each end and a cantilever beam. Nonlinear static (post-buckling) and random response analyses are demonstrated for the first specimen. Static deflection (shape) control is demonstrated for the cantilever beam. Approaches for modeling SMAHC material systems with embedded SMA in ribbon and small round wire product forms are demonstrated and compared. The results from the commercial codes are compared to those from a research code as validation of the commercial implementations; excellent correlation is achieved in all cases.

  14. Umbilical cord-derived mesenchymal stromal cells: predictive obstetric factors for cell proliferation and chondrogenic differentiation.

    Science.gov (United States)

    Avercenc-Léger, Léonore; Guerci, Philippe; Virion, Jean-Marc; Cauchois, Ghislaine; Hupont, Sébastien; Rahouadj, Rachid; Magdalou, Jacques; Stoltz, Jean-François; Bensoussan, Danièle; Huselstein, Céline; Reppel, Loïc

    2017-07-05

    The umbilical cord is becoming a notable alternative to bone marrow (BM) as a source of mesenchymal stromal cells (MSC). Although age-dependent variations in BM-MSC are well described, less data are available for MSC isolated from Wharton's jelly (WJ-MSC). We initiated a study to identify whether obstetric factors influenced MSC properties. We aimed to evaluate the correlation between a large number of obstetric factors collected during pregnancy and until peripartum (related to the mother, the labor and delivery, and the newborn) with WJ-MSC proliferation and chondrogenic differentiation parameters. Correlations were made between 27 obstetric factors and 8 biological indicators including doubling time at passage (P)1 and P2, the percentage of proteoglycans and collagens, and the relative transcriptional expression of Sox-9, aggrecans, and total type 2 collagen (Coll2T). Amongst the obstetric factors considered, birth weight, the number of amenorrhea weeks, placental weight, normal pregnancy, and the absence of preeclampsia were identified as relevant factors for cell expansion, using multivariate linear regression analysis. Since all the above parameters are related to term, we concluded that WJ-MSC from healthy, full-term infants exhibit greater proliferation capacity. As for chondrogenesis, we also observed that obstetric factors influencing proliferation seemed beneficial, with no negative impact on MSC differentiation. Awareness of obstetric factors influencing the proliferation and/or differentiation of WJ-MSC will make it possible to define criteria for collecting optimal umbilical cords with the aim of decreasing the variability of WJ-MSC batches produced for clinical use in cell and tissue engineering.

  15. Hepatogenic and neurogenic differentiation of bone marrow mesenchymal stem cells from abattoir-derived bovine fetuses.

    Science.gov (United States)

    Dueñas, Fernando; Becerra, Víctor; Cortes, Yennifer; Vidal, Sonia; Sáenz, Leonardo; Palomino, Jaime; De Los Reyes, Mónica; Peralta, Oscar A

    2014-07-10

    Mesenchymal stem cells (MSC) are multipotent progenitor cells characterized by their ability to both self-renew and differentiate into tissues of mesodermal origin. The plasticity or transdifferentiation potential of MSC is not limited to mesodermal derivatives, since under appropriate cell culture conditions and stimulation by bioactive factors, MSC have also been differentiated into endodermal (hepatocytes) and neuroectodermal (neurons) cells. The potential of MSC for hepatogenic and neurogenic differentiation has been well documented in different animal models; however, few reports are currently available on large animal models. In the present study we sought to characterize the hepatogenic and neurogenic differentiation and multipotent potential of bovine MSC (bMSC) isolated from bone marrow (BM) of abattoir-derived fetuses. Plastic-adherent bMSC isolated from fetal BM maintained a fibroblast-like morphology under monolayer culture conditions. Flow cytometric analysis demonstrated that bMSC populations were positive for MSC markers CD29 and CD73 and pluripotency markers OCT4 and NANOG; whereas, were negative for hematopoietic markers CD34 and CD45. Levels of mRNA of hepatic genes α-fetoprotein (AFP), albumin (ALB), alpha1 antitrypsin (α1AT), connexin 32 (CNX32), tyrosine aminotransferase (TAT) and cytochrome P450 (CYP3A4) were up-regulated in bMSC during a 28-Day period of hepatogenic differentiation. Functional analyses in differentiated bMSC cultures evidenced an increase (P < 0.05) in albumin and urea production and glycogen storage. bMSC cultured under neurogenic conditions expressed NESTIN and MAP2 proteins at 24 h of culture; whereas, at 144 h also expressed TRKA and PrPC. Levels of MAP2 and TRKA mRNA were up-regulated at the end of the differentiation period. Conversely, bMSC expressed lower levels of NANOG mRNA during both hepatogenic and neurogenic differentiation processes. The expression patterns of linage-specific markers and the production of

  16. Cultural Paradigms in Management Sciences

    Directory of Open Access Journals (Sweden)

    Lukasz Sulkowski

    2013-09-01

    Full Text Available Purpose: The purpose of this paper is to present an idea for understanding cultural processes in the organizational discourse from the perspective of four paradigms in management sciences based on the concept of G. Burrell and G. Morgan.Methodology: The author has elaborated a valuable list of structures of the scientifi c theory based on the respective paradigms and has compared cultural paradigms in management sciences. The methodology involves an analysis of classical and recent world literature. Nowadays there is no consensus on the defi nitions, types or research models of organizational culture.Originality: In the literature on the subject we can fi nd many, sometimes contradictory cultural research studies that require further analysis. Precisely because of the diversity and complexity of cultural issues in management sciences a multi-paradigmatic analysis is necessary. The paper presents a proposal for a pluralistic approach to the theory and methodology of cultural studies in management sciences.

  17. Paradigms for environmentally conscious manufacturing

    Science.gov (United States)

    Edinbarough, Immanuel A.; Wells, Wayne E.

    2004-12-01

    There are several stories involving the industries that pledge themselves for the environmentally conscious manufacturing practices. Paradigms for environmentally conscious manufacturing are associated with one of the aspects of environmental quality, protection, resource management, commitment or sustainability. The engineering rules of thumb that can easily be adopted by aspiring companies need identification. The underlying thread that unifies the efforts of environmentally conscious manufacturing companies, in offering the environmentally safe products to the world, is grouped and presented in the paper as paradigms for successful practices. The various ways in which a start up company, that wants to excel in environmentally conscious manufacturing, can position itself based on the paradigms is also discussed in the paper.

  18. The downregulation of CD4 and MHC-I by primate lentiviruses: a paradigm for the modulation of cell surface receptors.

    Science.gov (United States)

    Piguet, V; Schwartz, O; Le Gall, S; Trono, D

    1999-04-01

    The human and simian immunodeficiency viruses (HIV and SIV) downregulate the cell surface expression of CD4, their primary receptor, and of class I histocompatibility complex (MHC-I), a critical mediator of immune recognition. While the first of these effects seems important to preserve viral infectivity, the second likely promotes immune evasion. Three HIV-1 proteins, Nef, Env and Vpu, contribute to downregulate CD4, Env forms a complex with CD4 in the endoplasmic reticulum, thereby retaining the receptor in this compartment. Nef and Vpu, on the other hand, act as connectors between CD4 and specific intracellular trafficking pathways, targeting the receptor for degradation in the lysosome and the proteasome, respectively. Some of the downstream partners of the viral proteins in these events have been identified, and include the adaptor complex of clathrin-coated pits, the beta subunit of COP-I coatomer, and the ubiquitin pathway-related h-beta TrCP protein. HIV-induced MHC-I downregulation, mostly the effect of Nef, also reflects a redistribution of this receptor, with its accumulation in the Golgi. The modalities of this process, however, are as yet imperfectly understood. New evidence indicates that the mechanisms employed by primate lentiviruses to downmodulate CD4 and MHC-I are also exploited by a number of cellular regulatory processes.

  19. Treatment paradigms for patients with metastatic non small cell lung cancer (NSCLC, squamous lung cancer: first, second and third-line

    Directory of Open Access Journals (Sweden)

    Abdulaziz eAl Farsi

    2014-06-01

    Full Text Available Historically, the treatment algorithm applied to non small cell lung cancer (NSCLC was the same for all histologic subtypes. However, recent advances in our understanding of the molecular profiles of squamous and non-squamous NSCLC have changed this perspective. Histologic subtype and the presence of specific molecular abnormalities have predictive value for response to and toxicity from therapy, as well as overall survival. For patients with squamous NSCLC, a platinum agent plus gemcitabine, or paclitaxel is recommended as first-line therapy. The role of EGFR monoclonal antibodies is uncertain. Maintenance therapy is not widely recommended, although data exist for the use of erlotinib. The standard recommendation for second-line therapy is docetaxel and erlotinib should be considered as second or third-line therapy. There is ongoing research identifying molecular targets in squamous NSCLC and many agents are in early phase clinical trials. Immunotherapeutic approaches targeting programmed death 1 receptor (PD-1 and its ligand (PD-L1 appear promising.

  20. Human stromal (mesenchymal) stem cells

    DEFF Research Database (Denmark)

    Aldahmash, Abdullah; Zaher, Walid; Al-Nbaheen, May

    2012-01-01

    Human stromal (mesenchymal) stem cells (hMSC) represent a group of non-hematopoietic stem cells present in the bone marrow stroma and the stroma of other organs including subcutaneous adipose tissue, placenta, and muscles. They exhibit the characteristics of somatic stem cells of self......-renewal and multi-lineage differentiation into mesoderm-type of cells, e.g., to osteoblasts, adipocytes, chondrocytes and possibly other cell types including hepatocytes and astrocytes. Due to their ease of culture and multipotentiality, hMSC are increasingly employed as a source for cells suitable for a number...

  1. Defining the role of mesenchymal stromal cells on the regulation of matrix metalloproteinases in skeletal muscle cells

    Energy Technology Data Exchange (ETDEWEB)

    Sassoli, Chiara; Nosi, Daniele; Tani, Alessia; Chellini, Flaminia [Dept. of Experimental and Clinical Medicine—Section of Anatomy and Histology, University of Florence, Largo Brambilla, 3, 50134, Florence (Italy); Mazzanti, Benedetta [Dept. of Experimental and Clinical Medicine—Section of Haematology, University of Florence, Largo Brambilla, 3, 50134, Florence (Italy); Quercioli, Franco [CNR-National Institute of Optics (INO), Largo Enrico Fermi 6, 50125 Arcetri-Florence (Italy); Zecchi-Orlandini, Sandra [Dept. of Experimental and Clinical Medicine—Section of Anatomy and Histology, University of Florence, Largo Brambilla, 3, 50134, Florence (Italy); Formigli, Lucia, E-mail: formigli@unifi.it [Dept. of Experimental and Clinical Medicine—Section of Anatomy and Histology, University of Florence, Largo Brambilla, 3, 50134, Florence (Italy)

    2014-05-01

    Recent studies indicate that mesenchymal stromal cell (MSC) transplantation improves healing of injured and diseased skeletal muscle, although the mechanisms of benefit are poorly understood. In the present study, we investigated whether MSCs and/or their trophic factors were able to regulate matrix metalloproteinase (MMP) expression and activity in different cells of the muscle tissue. MSCs in co-culture with C2C12 cells or their conditioned medium (MSC-CM) up-regulated MMP-2 and MMP-9 expression and function in the myoblastic cells; these effects were concomitant with the down-regulation of the tissue inhibitor of metalloproteinases (TIMP)-1 and -2 and with increased cell motility. In the single muscle fiber experiments, MSC-CM administration increased MMP-2/9 expression in Pax-7{sup +} satellite cells and stimulated their mobilization, differentiation and fusion. The anti-fibrotic properties of MSC-CM involved also the regulation of MMPs by skeletal fibroblasts and the inhibition of their differentiation into myofibroblasts. The treatment with SB-3CT, a potent MMP inhibitor, prevented in these cells, the decrease of α-smooth actin and type-I collagen expression induced by MSC-CM, suggesting that MSC-CM could attenuate the fibrogenic response through mechanisms mediated by MMPs. Our results indicate that growth factors and cytokines released by these cells may modulate the fibrotic response and improve the endogenous mechanisms of muscle repair/regeneration. - Highlights: • MSC-CM contains paracrine factors that up-regulate MMP expression and function in different skeletal muscle cells. • MSC-CM promotes myoblast and satellite cell migration, proliferation and differentiation. • MSC-CM negatively interferes with fibroblast-myoblast transition in primary skeletal fibroblasts. • Paracrine factors from MSCs modulate the fibrotic response and improve the endogenous mechanisms of muscle regeneration.

  2. Defining the role of mesenchymal stromal cells on the regulation of matrix metalloproteinases in skeletal muscle cells

    International Nuclear Information System (INIS)

    Sassoli, Chiara; Nosi, Daniele; Tani, Alessia; Chellini, Flaminia; Mazzanti, Benedetta; Quercioli, Franco; Zecchi-Orlandini, Sandra; Formigli, Lucia

    2014-01-01

    Recent studies indicate that mesenchymal stromal cell (MSC) transplantation improves healing of injured and diseased skeletal muscle, although the mechanisms of benefit are poorly understood. In the present study, we investigated whether MSCs and/or their trophic factors were able to regulate matrix metalloproteinase (MMP) expression and activity in different cells of the muscle tissue. MSCs in co-culture with C2C12 cells or their conditioned medium (MSC-CM) up-regulated MMP-2 and MMP-9 expression and function in the myoblastic cells; these effects were concomitant with the down-regulation of the tissue inhibitor of metalloproteinases (TIMP)-1 and -2 and with increased cell motility. In the single muscle fiber experiments, MSC-CM administration increased MMP-2/9 expression in Pax-7 + satellite cells and stimulated their mobilization, differentiation and fusion. The anti-fibrotic properties of MSC-CM involved also the regulation of MMPs by skeletal fibroblasts and the inhibition of their differentiation into myofibroblasts. The treatment with SB-3CT, a potent MMP inhibitor, prevented in these cells, the decrease of α-smooth actin and type-I collagen expression induced by MSC-CM, suggesting that MSC-CM could attenuate the fibrogenic response through mechanisms mediated by MMPs. Our results indicate that growth factors and cytokines released by these cells may modulate the fibrotic response and improve the endogenous mechanisms of muscle repair/regeneration. - Highlights: • MSC-CM contains paracrine factors that up-regulate MMP expression and function in different skeletal muscle cells. • MSC-CM promotes myoblast and satellite cell migration, proliferation and differentiation. • MSC-CM negatively interferes with fibroblast-myoblast transition in primary skeletal fibroblasts. • Paracrine factors from MSCs modulate the fibrotic response and improve the endogenous mechanisms of muscle regeneration

  3. Transmission pricing: paradigms and methodologies

    Energy Technology Data Exchange (ETDEWEB)

    Shirmohammadi, Dariush [Pacific Gas and Electric Co., San Francisco, CA (United States); Vieira Filho, Xisto; Gorenstin, Boris [Centro de Pesquisas de Energia Eletrica (CEPEL), Rio de Janeiro, RJ (Brazil); Pereira, Mario V.P. [Power System Research, Rio de Janeiro, RJ (Brazil)

    1994-12-31

    In this paper we describe the principles of several paradigms and methodologies for pricing transmission services. The paper outlines some of the main characteristics of these paradigms and methodologies such as where they may be used for best results. Due to their popularity, power flow based MW-mile and short run marginal cost pricing methodologies will be covered in some detail. We conclude the paper with examples of the application of these two pricing methodologies for pricing transmission services in Brazil. (author) 25 refs., 2 tabs.

  4. The synthesis paradigm in genetics.

    Science.gov (United States)

    Rice, William R

    2014-02-01

    Experimental genetics with model organisms and mathematically explicit genetic theory are generally considered to be the major paradigms by which progress in genetics is achieved. Here I argue that this view is incomplete and that pivotal advances in genetics--and other fields of biology--are also made by synthesizing disparate threads of extant information rather than generating new information from experiments or formal theory. Because of the explosive expansion of information in numerous "-omics" data banks, and the fragmentation of genetics into numerous subdisciplines, the importance of the synthesis paradigm will likely expand with time.

  5. Mesenchymal Stem Cell Protection of Neurons against Glutamate Excitotoxicity Involves Reduction of NMDA-Triggered Calcium Responses and Surface GluR1, and Is Partly Mediated by TNF

    Directory of Open Access Journals (Sweden)

    Irini Papazian

    2018-02-01

    Full Text Available Mesenchymal stem cells (MSC provide therapeutic effects in experimental CNS disease models and show promise as cell-based therapies for humans, but their modes of action are not well understood. We previously show that MSC protect rodent neurons against glutamate excitotoxicity in vitro, and in vivo in an epilepsy model. Neuroprotection is associated with reduced NMDA glutamate receptor (NMDAR subunit expression and neuronal glutamate-induced calcium (Ca2+ responses, and increased expression of stem cell-associated genes. Here, to investigate whether MSC-secreted factors modulate neuronal AMPA glutamate receptors (AMPAR and gene expression, we performed longitudinal studies of enriched mouse cortical neurons treated with MSC conditioned medium (CM. MSC CM did not alter total levels of GluR1 AMPAR subunit in neurons, but its distribution, reducing cell surface levels compared to non-treated neurons. Proportions of NeuN-positive neurons, and of GFAP- and NG2-positive glia, were equal in untreated and MSC CM-treated cultures over time suggesting that neurons, rather than differentially-expanded glia, account for the immature gene profile previously reported in MSC CM-treated cultures. Lastly, MSC CM contained measurable amounts of tumor necrosis factor (TNF bioactivity and pre-treatment of MSC CM with the TNF inhibitor etanercept reduced its ability to protect neurons. Together these results indicate that MSC-mediated neuroprotection against glutamate excitotoxicity involves reduced NMDAR and GluR1-containing AMPAR function, and TNF-mediated neuroprotection.

  6. Management Trends and Outcomes for Stage I to II Mantle Cell Lymphoma Using the National Cancer Data Base: Ascertaining the Ideal Treatment Paradigm

    Energy Technology Data Exchange (ETDEWEB)

    Gill, Beant S.; Vargo, John A. [Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (United States); Pai, Sarah S. [Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (United States); Balasubramani, Goundappa K. [Department of Epidemiology, Epidemiology Data Center, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania (United States); Beriwal, Sushil, E-mail: beriwals@upmc.edu [Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (United States)

    2015-11-01

    Purpose: Mantle cell lymphoma (MCL) is a rare, albeit aggressive subset of non-Hodgkin lymphoma, resulting in varied treatment approaches. Given the paucity of data defining the optimal management for early-stage MCL, we conducted an analysis using the National Cancer Data Base (NCDB) to identify practice patterns and outcomes. Methods and Materials: The NCDB was queried for patients with stage I to II MCL diagnosed from 1998 to 2012 receiving chemotherapy (CT) or radiation therapy (RT), or both (CT+RT). Univariate and multivariable analyses for factors associated with treatment selection were completed using logistic regression. Propensity scores with inverse probability treatment weighting (IPTW) were calculated based on the conditional probability of receiving CT+RT. The log-rank test and Cox proportional hazards modeling with IPTW adjustment were conducted for the survival analyses. Results: In total, 2539 patients were identified. The key characteristics were as follows: 69% were male, 71% were aged ≥60 years, 28% had extranodal involvement, and 51% had stage I disease. Of the 2539 patients, 70% underwent CT, 11% underwent RT, and 19% underwent CT+RT. The use of CT+RT decreased from 23.1% to 14.1% in 1998 to 2002 and 2010 to 2012 (P<.001). CT+RT usage was lower for patients with the following characteristics: age ≥60 years, female sex, stage II disease, and the presence of B symptoms. With a median follow-up period of 42.8 months, the unadjusted 3-year overall survival estimates for patients receiving CT, RT, or CT+RT were 67.8%, 72.4%, and 79.8%, respectively (P<.001). After correcting for indication bias through IPTW-adjusted modeling, CT+RT reduced the risk of overall mortality compared with monotherapy (hazard ratio 0.65, P=.029). Conclusions: Although uncommon, patients with stage I-II MCL can have favorable outcomes. Despite a continued decline in the usage of consolidative RT, combined modality therapy improves survival in this cohort compared

  7. Cell-based therapy for acute organ injury: preclinical evidence and ongoing clinical trials using mesenchymal stem cells.

    Science.gov (United States)

    Monsel, Antoine; Zhu, Ying-Gang; Gennai, Stephane; Hao, Qi; Liu, Jia; Lee, Jae W

    2014-11-01

    Critically ill patients often suffer from multiple organ failures involving lung, kidney, liver, or brain. Genomic, proteomic, and metabolomic approaches highlight common injury mechanisms leading to acute organ failure. This underlines the need to focus on therapeutic strategies affecting multiple injury pathways. The use of adult stem cells such as mesenchymal stem or stromal cells (MSC) may represent a promising new therapeutic approach as increasing evidence shows that MSC can exert protective effects following injury through the release of promitotic, antiapoptotic, antiinflammatory, and immunomodulatory soluble factors. Furthermore, they can mitigate metabolomic and oxidative stress imbalance. In this work, the authors review the biological capabilities of MSC and the results of clinical trials using MSC as therapy in acute organ injuries. Although preliminary results are encouraging, more studies concerning safety and efficacy of MSC therapy are needed to determine their optimal clinical use. (ANESTHESIOLOGY 2014; 121:1099-121).

  8. [Mesenchymal stromal cells in the treatment of graft-versus-host disease: where do we stand?].

    Science.gov (United States)

    Schüle, Silke; Berger, André

    2015-11-01

    Medicinal products based on mesenchymal stromal cells (MSC) are expected to have a therapeutic benefit in a variety of conditions and, accordingly, are being tested in many clinical studies. The treatment and prevention of graft-versus-host disease (GVHD) is one of the world's most widely studied MSC therapy concepts. So far, one MSC medicinal product has been approved for the treatment of GvHD. This article gives an overview of the particular features related to the production of MSC-based medicinal products, the state of non-clinical research, and the clinical development status of MSCs and the associated challenges, especially in the context of GvHD.

  9. Mesenchymal stem cell secretome and regenerative therapy after cancer.

    Science.gov (United States)

    Zimmerlin, Ludovic; Park, Tea Soon; Zambidis, Elias T; Donnenberg, Vera S; Donnenberg, Albert D

    2013-12-01

    Cancer treatment generally relies on tumor ablative techniques that can lead to major functional or disfiguring defects. These post-therapy impairments require the development of safe regenerative therapy strategies during cancer remission. Many current tissue repair approaches exploit paracrine (immunomodulatory, pro-angiogenic, anti-apoptotic and pro-survival effects) or restoring (functional or structural tissue repair) properties of mesenchymal stem/stromal cells (MSC). Yet, a major concern in the application of regenerative therapies during cancer remission remains the possible triggering of cancer recurrence. Tumor relapse implies the persistence of rare subsets of tumor-initiating cancer cells which can escape anti-cancer therapies and lie dormant in specific niches awaiting reactivation via unknown stimuli. Many of the components required for successful regenerative therapy (revascularization, immunosuppression, cellular homing, tissue growth promotion) are also critical for tumor progression and metastasis. While bi-directional crosstalk between tumorigenic cells (especially aggressive cancer cell lines) and MSC (including tumor stroma-resident populations) has been demonstrated in a variety of cancers, the effects of local or systemic MSC delivery for regenerative purposes on persisting cancer cells during remission remain controversial. Both pro- and anti-tumorigenic effects of MSC have been reported in the literature. Our own data using breast cancer clinical isolates have suggested that dormant-like tumor-initiating cells do not respond to MSC signals, unlike actively dividing cancer cells which benefited from the presence of supportive MSC. The secretome of MSC isolated from various tissues may partially diverge, but it includes a core of cytokines (i.e. CCL2, CCL5, IL-6, TGFβ, VEGF), which have been implicated in tumor growth and/or metastasis. This article reviews published models for studying interactions between MSC and cancer cells with a focus

  10. Acute and chronic effects of treatment with mesenchymal stromal cells on LPS-induced pulmonary inflammation, emphysema and atherosclerosis development

    OpenAIRE

    Khedoe, P. Padmini S. J.; de Kleijn, Stan; van Oeveren-Rietdijk, Annemarie M.; Plomp, Jaap J.; de Boer, Hetty C.; van Pel, Melissa; Rensen, Patrick C. N.; Berb?e, Jimmy F. P.; Hiemstra, Pieter S.

    2017-01-01

    Background COPD is a pulmonary disorder often accompanied by cardiovascular disease (CVD), and current treatment of this comorbidity is suboptimal. Systemic inflammation in COPD triggered by smoke and microbial exposure is suggested to link COPD and CVD. Mesenchymal stromal cells (MSC) possess anti-inflammatory capacities and MSC treatment is considered an attractive treatment option for various chronic inflammatory diseases. Therefore, we investigated the immunomodulatory properties of MSC i...

  11. Mesenchymal stromal cells induce epithelial-to-mesenchymal transition in human colorectal cancer cells through the expression of surface-bound TGF-β.

    Science.gov (United States)

    Mele, Valentina; Muraro, Manuele G; Calabrese, Diego; Pfaff, Dennis; Amatruda, Nunzia; Amicarella, Francesca; Kvinlaug, Brynn; Bocelli-Tyndall, Chiara; Martin, Ivan; Resink, Therese J; Heberer, Michael; Oertli, Daniel; Terracciano, Luigi; Spagnoli, Giulio C; Iezzi, Giandomenica

    2014-06-01

    Mesenchymal stem/stromal cells (MSC) are multipotent precursors endowed with the ability to home to primary and metastatic tumor sites, where they can integrate into the tumor-associated stroma. However, molecular mechanisms and outcome of their interaction with cancer cells have not been fully clarified. In this study, we investigated the effects mediated by bone marrow-derived MSC on human colorectal cancer (CRC) cells in vitro and in vivo. We found that MSC triggered epithelial-to-mesenchymal transition (EMT) in tumor cells in vitro, as indicated by upregulation of EMT-related genes, downregulation of E-cadherin and acquisition of mesenchymal morphology. These effects required cell-to-cell contact and were mediated by surface-bound TGF-β newly expressed on MSC upon coculture with tumor cells. In vivo tumor masses formed by MSC-conditioned CRC cells were larger and characterized by higher vessel density, decreased E-cadherin expression and increased expression of mesenchymal markers. Furthermore, MSC-conditioned tumor cells displayed increased invasiveness in vitro and enhanced capacity to invade peripheral tissues in vivo. Thus, by promoting EMT-related phenomena, MSC appear to favor the acquisition of an aggressive phenotype by CRC cells. © 2013 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC.

  12. Cardiomyocyte protection by GATA-4 gene engineered mesenchymal stem cells is partially mediated by translocation of miR-221 in microvesicles.

    Directory of Open Access Journals (Sweden)

    Bin Yu

    Full Text Available microRNAs (miRs, a novel class of small non-coding RNAs, are involved in cell proliferation, differentiation, development, and death. In this study, we found that miR-221 translocation by microvesicles (MVs plays an important role in cardioprotection mediated by GATA-4 overexpressed mesenchymal stem cells (MSC.Adult rat bone marrow MSC and neonatal rat ventricle cardiomyocytes (CM were harvested as primary cultures. MSC were transduced with GATA-4 (MSC(GATA-4 using the murine stem cell virus (pMSCV retroviral expression system. Empty vector transfection was used as a control (MSC(Null. The expression of miRs was assessed by real-time PCR and localized using in situ hybridization (ISH. MVs collected from MSC cultures were characterized by expression of CD9, CD63, and HSP70, and photographed with electron microscopy. Cardioprotection during hypoxia afforded by conditioned medium (CdM from MSC cultures was evaluated by lactate dehydrogenase (LDH release, MTS uptake by CM, and caspase 3/7 activity. Expression of miR-221/222 was significantly higher in MSC than in CM and miR-221 was upregulated in MSC(GATA-4. MSC overexpression of miR-221 significantly enhanced cardioprotection by reducing the expression of p53 upregulated modulator of apoptosis (PUMA. Moreover, expression of PUMA was significantly decreased in CM co-cultured with MSC. MVs derived from MSC expressed high levels of miR-221, and were internalized quickly by CM as documented in images obtained from a Time-Lapse Imaging System.Our results demonstrate that cardioprotection by MSC(GATA-4 may be regulated in part by a transfer of anti-apoptotic miRs contained within MVs.

  13. Prolonged hypoxic culture and trypsinization increase the pro-angiogenic potential of human adipose tissue-derived stem cells

    DEFF Research Database (Denmark)

    Rasmussen, Jeppe Grøndahl; Frøbert, Ole; Pilgaard, Linda

    2011-01-01

    Transplantation of mesenchymal stromal cells (MSC), including adipose tissue-derived stem cells (ASC), is a promising option in the treatment of vascular disease. Short-term hypoxic culture of MSC augments secretion of anti-apoptotic and angiogenic cytokines. We hypothesized that prolonged hypoxic...

  14. Comprehensive Characterization of Mesenchymal Stem Cells from Human Placenta and Fetal Membrane and Their Response to Osteoactivin Stimulation

    Directory of Open Access Journals (Sweden)

    C. M. Raynaud

    2012-01-01

    Full Text Available Mesenchymal stem cells (MSCs are the most promising seed cells for cell therapy and can be isolated from various sources of human adult tissues such as bone marrow (BM-MSC and adipose tissue. However, cells from these tissues must be obtained through invasive procedures. We, therefore, characterized MSCs isolated from fresh placenta (Pl-MSC and fetal membrane (Mb-MSC through morphological and fluorescent-activated cell sorting (FACS. MSC frequency is higher in membrane than placenta (2.14%  ± 0.65 versus 15.67%  ± 0.29%. Pl/Mb-MSCs in vitro expansion potential was significantly higher than BM-MSCs. We demonstrated that one of the MSC-specific marker is sufficient for MSC isolation and that culture in specific media is the optimal way for selecting very homogenous MSC population. These MSCs could be differentiated into mesodermal cells expressing cell markers and cytologic staining consistent with mature osteoblasts and adipocytes. Transcriptomic analysis and cytokine arrays demonstrated broad similarity between placenta- and membrane-derived MSCs and only discrete differences with BM-MSCs with enrichment of networks involved in bone differentiation. Pl/Mb-MSCs displayed higher osteogenic differentiation potential than BM-MSC when their response to osteoactivin was evaluated. Fetal-tissue-derived mesenchymal cells may, therefore, be considered as a major source of MSCs to reach clinical scale banking in particular for bone regeneration.

  15. Degenerate wave and capacitive coupling increase human MSC invasion and proliferation while reducing cytotoxicity in an in vitro wound healing model.

    Directory of Open Access Journals (Sweden)

    Michelle Griffin

    Full Text Available Non-unions pose complications in fracture management that can be treated using electrical stimulation (ES. Bone marrow mesenchymal stem cells (BMMSCs are essential in fracture healing; however, the effect of different clinical ES waveforms on BMMSCs cellular activities remains unknown. We compared the effects of direct current (DC, capacitive coupling (CC, pulsed electromagnetic field (PEMF and degenerate wave (DW on cellular activities including cytotoxicity, proliferation, cell-kinetics and apoptosis by stimulating human-BMMSCs 3 hours a day, up to 5 days. In addition, migration and invasion were assessed using fluorescence microscopy and by quantifying gene and protein expression. We found that DW had the greatest proliferative and least apoptotic and cytotoxic effects compared to other waveforms. DC, DW and CC stimulations resulted in a higher number of cells in S phase and G(2/M phase as shown by cell cycle analysis. CC and DW caused more cells to invade collagen and showed increased MMP-2 and MT1-MMP expression. DC increased cellular migration in a scratch-wound assay and all ES waveforms enhanced expression of migratory genes with DC having the greatest effect. All ES treated cells showed similar progenitor potential as determined by MSC differentiation assay. All above findings were shown to be statistically significant (p<0.05. We conclude that ES can influence BMMSCs activities, especially DW and CC, which show greater invasion and higher cell proliferation compared to other types of ES. Application of DW or CC to the fracture site may help in the recruitment of BMMSCs to the wound that may enhance rate of bone healing at the fracture site.

  16. Solving modal equations of motion with initial conditions using MSC/NASTRAN DMAP. Part 1: Implementing exact mode superposition

    Science.gov (United States)

    Abdallah, Ayman A.; Barnett, Alan R.; Ibrahim, Omar M.; Manella, Richard T.

    1993-01-01

    Within the MSC/NASTRAN DMAP (Direct Matrix Abstraction Program) module TRD1, solving physical (coupled) or modal (uncoupled) transient equations of motion is performed using the Newmark-Beta or mode superposition algorithms, respectively. For equations of motion with initial conditions, only the Newmark-Beta integration routine has been available in MSC/NASTRAN solution sequences for solving physical systems and in custom DMAP sequences or alters for solving modal systems. In some cases, one difficulty with using the Newmark-Beta method is that the process of selecting suitable integration time steps for obtaining acceptable results is lengthy. In addition, when very small step sizes are required, a large amount of time can be spent integrating the equations of motion. For certain aerospace applications, a significant time savings can be realized when the equations of motion are solved using an exact integration routine instead of the Newmark-Beta numerical algorithm. In order to solve modal equations of motion with initial conditions and take advantage of efficiencies gained when using uncoupled solution algorithms (like that within TRD1), an exact mode superposition method using MSC/NASTRAN DMAP has been developed and successfully implemented as an enhancement to an existing coupled loads methodology at the NASA Lewis Research Center.

  17. Solving modal equations of motion with initial conditions using MSC/NASTRAN DMAP. Part 1: Implementing exact mode superposition

    Science.gov (United States)

    Abdallah, Ayman A.; Barnett, Alan R.; Ibrahim, Omar M.; Manella, Richard T.

    1993-05-01

    Within the MSC/NASTRAN DMAP (Direct Matrix Abstraction Program) module TRD1, solving physical (coupled) or modal (uncoupled) transient equations of motion is performed using the Newmark-Beta or mode superposition algorithms, respectively. For equations of motion with initial conditions, only the Newmark-Beta integration routine has been available in MSC/NASTRAN solution sequences for solving physical systems and in custom DMAP sequences or alters for solving modal systems. In some cases, one difficulty with using the Newmark-Beta method is that the process of selecting suitable integration time steps for obtaining acceptable results is lengthy. In addition, when very small step sizes are required, a large amount of time can be spent integrating the equations of motion. For certain aerospace applications, a significant time savings can be realized when the equations of motion are solved using an exact integration routine instead of the Newmark-Beta numerical algorithm. In order to solve modal equations of motion with initial conditions and take advantage of efficiencies gained when using uncoupled solution algorithms (like that within TRD1), an exact mode superposition method using MSC/NASTRAN DMAP has been developed and successfully implemented as an enhancement to an existing coupled loads methodology at the NASA Lewis Research Center.

  18. System Trade-Off Study and Opto-Thermo Analysis of a Sunshield on the MSC of the KOMPSAT-2

    Directory of Open Access Journals (Sweden)

    Young-Soo Kim

    2003-12-01

    Full Text Available The Multi-Spectral Camera (MSC is the payload of KOMPSAT-2 which is designed for earth imaging in optical and near-infrared region on a sun-synchronous orbit. The telescope in the MSC is a Ritchey-Chretien type with large aperture. The telescope structure should be well stabilized and the optical alignment should be kept steady so that best images can be achieved. However, the MSC is exposed to adverse thermal environment on the orbit which can give impacts on optical performance. Solar incidence can bring non-uniform temperature rise on the telescope tube which entails unfavorable thermal distortion. Three ways of preventing the solar radiation were proposed, which were installing external mechanical shield, internal shield, and maneuvering the spacecraft. After trade-off study, internal sun shield was selected as a practical and optimal solution to minimize the effect of the solar radiation. In addition, detailed designs of the structure and sunshield were produced and analyses have been performed. The results were assessed to verify their impacts to the image quality. It was confirmed that the internal sunshield complies with the requirements and would improve image quality.

  19. Understanding the land management paradigm

    DEFF Research Database (Denmark)

    Enemark, Stig

    2006-01-01

    There is a worldwide need to build understanding of the land management paradigm and for institutional development to establish sustainable national concepts. This includes creation and adoption of a policy on land development, and an approach that combines the land administration...

  20. Programming Language: Concepts and Paradigms

    OpenAIRE

    Ruiz Lizama, Edgar

    2014-01-01

    The article presents the concepts that govern around the programming languages and the paradigms of the programming and the influence in the development of the software. El artículo presenta los conceptos que rigen a los lenguajes de programación y los paradigmas de la programación y como estos influyen en el desarrollo del software.

  1. Artificial life, the new paradigm

    International Nuclear Information System (INIS)

    Martinez Paez, Jose Jesus

    1998-01-01

    A chronological synthesis of the most important facts is presented in the theoretical development and computational simulation that they have taken to the formation of a new paradigm that is known as artificial life; their characteristics and their main investigation lines are analyzed. Finally, a description of its work is made in the National University of Colombia

  2. The Paradigm of Distributed Creativity

    DEFF Research Database (Denmark)

    Glaveanu, Vlad Petre

    This presentation aims to focus on and develop the notion of distributed creativity from a cultural psychological perspective. It will start by outlining the need for a cultural psychological paradigm of creative expression and argue that this perspective is primarily concerned with what can...

  3. The emerging land management paradigm

    DEFF Research Database (Denmark)

    Enemark, Stig

    2006-01-01

    Manchet: This paper was first presented by Professor Enemark at the RICS Christmas Lecture in December last year. It provides a cogent and detailed reference point for the current state of land management in developed countries, charts a course for the future and looks at how education must chang...... to meet the new paradigm....

  4. Multiple Transceptors for Macro- and Micro-Nutrients Control Diverse Cellular Properties Through the PKA Pathway in Yeast: A Paradigm for the Rapidly Expanding World of Eukaryotic Nutrient Transceptors Up to Those in Human Cells

    Directory of Open Access Journals (Sweden)

    Fenella Steyfkens

    2018-03-01

    the development of receptors from nutrient transporters during evolution. The nutrient-sensing transceptor system in yeast for activation of the PKA pathway has served as a paradigm for similar studies on candidate nutrient transceptors in other eukaryotes and we succinctly discuss the many examples of transceptors that have already been documented in other yeast species, filamentous fungi, plants, and animals, including the examples in human cells.

  5. Multiple Transceptors for Macro- and Micro-Nutrients Control Diverse Cellular Properties Through the PKA Pathway in Yeast: A Paradigm for the Rapidly Expanding World of Eukaryotic Nutrient Transceptors Up to Those in Human Cells.

    Science.gov (United States)

    Steyfkens, Fenella; Zhang, Zhiqiang; Van Zeebroeck, Griet; Thevelein, Johan M

    2018-01-01

    of receptors from nutrient transporters during evolution. The nutrient-sensing transceptor system in yeast for activation of the PKA pathway has served as a paradigm for similar studies on candidate nutrient transceptors in other eukaryotes and we succinctly discuss the many examples of transceptors that have already been documented in other yeast species, filamentous fungi, plants, and animals, including the examples in human cells.

  6. Isolation, culture and intraportal transplantation of rat marrow stromal cell

    International Nuclear Information System (INIS)

    Wang Ping; Wang Jianhua; Yan Zhiping; Li Wentao; Lin Genlai; Hu Meiyu; Wang Yanhong

    2004-01-01

    Objective: To observe the tracing and evolution of marrow stromal cell (MSC) after intraportal transplantation into the liver of homogenous rats, and to provide experimental data for MSC differentiation to hepatocyte in vivo. Methods: The MSC was isolated from the leg bone marrow of adult SD rats, and purified by culture-expanded in vitro. Before transplantation, MSC was labeled with DAPI. Then 10 5 MSC were intraportally transplanted into the homogenous rat liver. Rats were killed at 2 hours and 1, 2, 3 and 4 weeks after transplantation. The cryosection samples of liver and lung were observed under fluorescence microscopy. Results: MSC in vitro culture had high ability of proliferation. Except 4 rats were dead because of abdominal bleeding or infection, other recipients were healthy until sacrificed. The implantation cells were detected by identifying the DAPI labeled MSC in the host livers, but not in the host lungs. Conclusion: Intraportal transplanted MSC could immigrate and survive in the host livers at least for 4 weeks. They could immigrate from the small branches of portal veins to hepatic parenchyma

  7. Human bone-marrow-derived mesenchymal stem cells

    DEFF Research Database (Denmark)

    Kassem, Moustapha; Abdallah, Basem M

    2008-01-01

    Mesenchymal stem cells (MSC) are a group of cells present in bone-marrow stroma and the stroma of various organs with the capacity for mesoderm-like cell differentiation into, for example, osteoblasts, adipocytes, and chondrocytes. MSC are being introduced in the clinic for the treatment...... of a variety of clinical conditions. The aim of this review is to provide an update regarding the biology of MSC, their identification and culture, and mechanisms controlling their proliferation and differentiation. We also review the current status of their clinical use. Areas in which research is needed...

  8. Cell origin of human mesenchymal stem cells determines a different healing performance in cardiac regeneration.

    Directory of Open Access Journals (Sweden)

    Ralf Gaebel

    2011-02-01

    Full Text Available The possible different therapeutic efficacy of human mesenchymal stem cells (hMSC derived from umbilical cord blood (CB, adipose tissue (AT or bone marrow (BM for the treatment of myocardial infarction (MI remains unexplored. This study was to assess the regenerative potential of hMSC from different origins and to evaluate the role of CD105 in cardiac regeneration. Male SCID mice underwent LAD-ligation and received the respective cell type (400.000/per animal intramyocardially. Six weeks post infarction, cardiac catheterization showed significant preservation of left ventricular functions in BM and CD105(+-CB treated groups compared to CB and nontreated MI group (MI-C. Cell survival analyzed by quantitative real time PCR for human GAPDH and capillary density measured by immunostaining showed consistent results. Furthermore, cardiac remodeling can be significantly attenuated by BM-hMSC compared to MI-C. Under hypoxic conditions in vitro, remarkably increased extracellular acidification and apoptosis has been detected from CB-hMSC compared to BM and CD105 purified CB-derived hMSC. Our findings suggests that hMSC originating from different sources showed a different healing performance in cardiac regeneration and CD105(+ hMSC exhibited a favorable survival pattern in infarcted hearts, which translates into a more robust preservation of cardiac function.

  9. Potential of iPSC-Derived Mesenchymal Stromal Cells for Treating Periodontal Disease

    Directory of Open Access Journals (Sweden)

    K. Hynes

    2018-01-01

    Full Text Available Mesenchymal stromal cell-like populations have been derived from mouse-induced pluripotent stem cells (miPSC-MSC with the capability for tissue regeneration. In this study, murine iPSC underwent differentiation towards an MSC-like immunophenotype. Stable miPSC-MSC cultures expressed the MSC-associated markers, CD73, CD105, and Sca-1, but lacked expression of the pluripotency marker, SSEA1, and hematopoietic markers, CD34 and CD45. Functionally, miPSC-MSC exhibited the potential for trilineage differentiation into osteoblasts, adipocytes, and chondrocytes and the capacity to suppress the proliferation of mitogen-activated splenocytes. The efficacy of miPSC-MSC was assessed in an acute inflammation model following systemic or local delivery into mice with subcutaneous implants containing heat-inactivated P. gingivalis. Histological analysis revealed less inflammatory cellular infiltrate within the sponges in mice treated with miPSC-MSC cells delivered locally rather than systemically. Assessment of proinflammatory cytokines in mouse spleens found that CXCL1 transcripts and protein were reduced in mice treated with miPSC-MSC. In a periodontitis model, mice subjected to oral inoculation with P. gingivalis revealed less bone tissue destruction and inflammation within the jaws when treated with miPSC-MSC compared to PBS alone. Our results demonstrated that miPSC-MSC derived from iPSC have the capacity to control acute and chronic inflammatory responses associated with the destruction of periodontal tissue. Therefore, miPSC-MSC present a promising novel source of stromal cells which could be used in the treatment of periodontal disease and other inflammatory systemic diseases such as rheumatoid arthritis.

  10. Teaching sustainability science from a systems analysis perspective: MSc course at Utrecht University

    Science.gov (United States)

    Santos, Maria J.; de Boer, Hugo; Dekker, Stefan

    2017-04-01

    Sustainability science has emerged as a key discipline that embraces both disciplinary depth and interdisciplinary breadth. The challenge is to design University courses that convey both properties without sacrificing either of them. Here we present the design of such course at Utrecht University (the Netherlands) for the MSC program 'Sustainable Development' and discuss the perceived learning and student evaluations. Our course (Sustainability Modelling and Indicators (SMI)) follows an introductory course on Sustainability Perspectives. SMI philosophy is that system thinking and system analysis is central to sustainability science. To convey this philosophy, we focus on four themes: the Anthropocene, Food security, Energy security and Agency and decision making. We developed four hands-on assignments with increasing complexity and make use of different software (Stella, Excel, IMAGE and Netlogo). The assignments aimed at: (1) teaching students the system components by using a pre-existing model in Stella, (2) challenge students to build their own coupled system in Excel, (3) assess outputs from the fully-coupled and dynamic model integrated assessment model IMAGE, and (4) understand emergent properties using an agent-based model in Netlogo. Based on detailed student evaluations (n = 95) we found that the mathematics presented a manageable challenge to a part of the students. The student pool identified a priori having higher experience with Excel in comparison with other software. Netlogo was the highest ranked software in the student evaluations and this was linked to its user-interface with moving agents. The Excel assignment received the highest and lowest scores, and students found it challenging, time consuming but also indicated that they learned the most from this assignment. Students graded what we considered 'easy' assignments with the highest grades. These results suggest that a systems analytical approach to sustainability science can be operationalized

  11. Policy paradigms, transnationalism, and domestic politics

    National Research Council Canada - National Science Library

    Skogstad, Grace Darlene

    2011-01-01

    Policy Paradigms, Transnationalism, and Domestic Politics offers a variety of perspectives on the development of policy paradigms -- the ideas that structure thinking about what can and should be done in a policy domain...

  12. Mesenchymal stromal/stem cell-derived extracellular vesicles promote human cartilage regeneration in vitro

    NARCIS (Netherlands)

    Vonk, Lucienne A.; van Dooremalen, Sanne F.J.; Liv, Nalan; Klumperman, Judith; Coffer, Paul J.; Saris, Daniël B.F.; Lorenowicz, Magdalena J.

    2018-01-01

    Osteoarthritis (OA) is a rheumatic disease leading to chronic pain and disability with no effective treatment available. Recently, allogeneic human mesenchymal stromal/stem cells (MSC) entered clinical trials as a novel therapy for OA. Increasing evidence suggests that therapeutic efficacy of MSC

  13. Properties and potential of bone marrow mesenchymal stromal cells from children with hematologic diseases.

    Science.gov (United States)

    Dimitriou, H; Linardakis, E; Martimianaki, G; Stiakaki, E; Perdikogianni, C H; Charbord, P; Kalmanti, M

    2008-01-01

    Mesenchymal stromal cells (MSC) have become the focus of cellular therapeutics but little is known regarding bone marrow (BM) MSC derived from children. As MSC constitute part of BM stroma, we examined their properties in children with hematologic diseases. BM MSC from children with non-malignant hematologic disorders and acute lymphoblastic leukemia (ALL) were isolated and expanded. MSC were immunophenotypically characterized and their functional characteristics were assessed by CFU-F assay and cell doubling time calculation. Their ability for trilineage differentiation was verified by molecular and histochemical methods. Apoptosis was evaluated and clonal analysis was performed. MSC were isolated from BM of all groups. They acquired the mesenchymal-related markers from the first passage, with a simultaneous decrease of hematopoietic markers. A very low percentage of apoptotic cells was detected in all passages. The proliferative and clonogenic capacity did not differ among groups, with the exception of ALL at diagnosis, in which they were defective. Histochemical and molecular analysis of differentiated MSC yielded characteristics for adipocytes, osteoblasts and chondrocytes. Clonal analysis in a number of BM samples revealed a highly heterogeneous population of cells within each clone. MSC from BM of children with hematologic disorders, with the exception of ALL at diagnosis, can be isolated in sufficient number and quality to serve as a potential source for clinical applications.

  14. Local Use-Dependent Sleep; Synthesis of the New Paradigm

    OpenAIRE

    Krueger, James M.; Tononi, Giulio

    2011-01-01

    The logic and potential mechanisms for a new paradigm, the local use-dependent view of sleep as a distributed dynamic process in brain, are presented. This new paradigm is needed because the current dominant top-down imposition of sleep on the brain by sleep regulatory centers is either silent or is of inadequate explanatory value for many well-known sleep phenomena, e.g. sleep inertia. Two mechanistic falsifiable hypotheses linking sleep to cell use and the emergence of sleep/wake states are...

  15. Black hole evaporation: a paradigm

    International Nuclear Information System (INIS)

    Ashtekar, Abhay; Bojowald, Martin

    2005-01-01

    A paradigm describing black hole evaporation in non-perturbative quantum gravity is developed by combining two sets of detailed results: (i) resolution of the Schwarzschild singularity using quantum geometry methods and (ii) time evolution of black holes in the trapping and dynamical horizon frameworks. Quantum geometry effects introduce a major modification in the traditional spacetime diagram of black hole evaporation, providing a possible mechanism for recovery of information that is classically lost in the process of black hole formation. The paradigm is developed directly in the Lorentzian regime and necessary conditions for its viability are discussed. If these conditions are met, much of the tension between expectations based on spacetime geometry and structure of quantum theory would be resolved

  16. Exploring Paradigms of Crime Reduction

    DEFF Research Database (Denmark)

    Soothill, Keith; Christoffersen, Mogens N.; Hussain, Azhar

    2010-01-01

    Using Danish registers for a 1980 birth cohort of 29,944 males with parental information and following up these cases for 25 years, the study considers four paradigms of crime reduction (parental child rearing, structural factors around adolescence, locality and individual resources). Focusing...... have more widespread benefits, but the assumed causal links need to be further explored. The use of population registers, under controlled conditions, provides an important window on criminal careers....

  17. Mandarin functional MRI Language paradigms

    OpenAIRE

    Ci, He; van Graan, Andre; Gonz?lvez, Gloria; Thompson, Pamela; Hill, Andrea; Duncan, John S.

    2016-01-01

    Abstract Objective The objective of this study was to implement convenient, fast, and accurate Mandarin task paradigms for functional MRI, and to locate the Chinese language functional areas in frontal and temporal lobes. Materials and Methods Nineteen healthy Chinese volunteers participated in this study, which utilized a block design with four language tasks: auditory naming (AN), picture naming (PN), verbal fluency?character (VFC), and verbal fluency?letter (VFL). All functional images wer...

  18. Technology Is Culture: Two Paradigms

    OpenAIRE

    Zimmermann, Basile

    2005-01-01

    The author discusses the relationship of technology to culture in the People's Republic of China. Basing his discussion on his experiences in Beijing between 2001 and 2004, the author suggests that the two paradigms of accumulation of decisions and struggle against difference can be used to describe technology in its relation to culture, including–but not limited to–popular electronic music in Beijing.

  19. Sustainability Planning as Paradigm Change

    Directory of Open Access Journals (Sweden)

    Stephen M. Wheeler

    2016-11-01

    Full Text Available The theme of the next issue of Urban Planning will be Paradigm Shifts. To make the link between “sustainability” and “paradigm change,” the following commentary analyzes the former concept as a main example of the latter. Although it is often applied to rather modest planning initiatives, “sustainability” can be seen as requiring shifts in cognitive paradigm that are transformational, radical, and not yet fully appreciated by most of those who use the term. Specifically, this term implies a proactive, results-oriented approach (e.g. initiatives to actually meet GHG reduction targets, a long-term viewpoint (e.g. planning for 50 or 100+ years in the future, and a holistic or ecological mindset able to understand dynamic, evolving systems. This last change is the most difficult and requires thinking across scales of action, across time frames, across issue areas and goals (e.g. the “Three E’s” of environment, economy, and social equity, and across communities. It also means integrating different types of actions into a broader program of social change. Though challenging, these cognitive shifts can lead to radically different outcomes than past urban planning.

  20. Poverty eradication: a new paradigm.

    Science.gov (United States)

    Pethe, V P

    1998-08-01

    This article offers a new paradigm for eradicating poverty in India. It was assumed incorrectly by Mahatma Gandhi that a good society without mass poverty would follow after independence. India copied Western models of development and developed giant factories, big dams, and megacities. Agriculture did not expand the number of jobs for people. The Western paradigm failed in India because of the false assumption of "trickle down" of income to the masses. The targeted programs to the poor did not directly benefit enough of the poor. Mega-industrialization led to reduced employment and higher skill needs. The model failed mainly because it was a proxy and relied on indirect ways of reaching the poor. The models failed to be adapted to conditions in India. The Swadeshi paradigm is a direct model for addressing mass poverty. Poverty is affected by immediate, intermediate, and ultimate determinants. Poverty begets social and economic problems, such as ignorance, ill health, high fertility, unemployment, and crime. In India and developing countries, mass poverty results from under use of human resources; lack of equal opportunities; and an outdated non-egalitarian social structure, an unjust global economic order, human cruelty, and erosion of ethical values. Indians are squandering their precious resources mimicking Western consumerism. Poverty leads to rapid population growth. People become productive assets with universal literacy, compulsory and free education, health services and sanitation, vocational training, and work ethics. India needs people-oriented policies with less emphasis on capital accumulation.

  1. Partial suppression of the respiratory defect of qrs1/her2 glutamyl-tRNA amidotransferase mutants by overexpression of the mitochondrial pentatricopeptide Msc6p.

    Science.gov (United States)

    Moda, Bruno S; Ferreira-Júnior, José Ribamar; Barros, Mario H

    2016-08-01

    Recently, a large body of evidences indicates the existence in the mitochondrial matrix of foci that contain different proteins involved in mitochondrial RNA metabolism. Some of these proteins have a pentatricopeptide repeat motif that constitutes their RNA-binding structures. Here we report that MSC6, a mitochondrial pentatricopeptide protein of unknown function, is a multi copy suppressor of mutations in QRS1/HER2 a component of the trimeric complex that catalyzes the transamidation of glutamyl-tRNAQ to glutaminyl-tRNAQ. This is an essential step in mitochondrial translation because of the lack of a specific mitochondrial aminoacyl glutaminyl-tRNA synthetase. MSC6 over-expression did not abolish translation of an aberrant variant form of Cox2p detected in QRS1/HER2 mutants, arguing against a suppression mechanism that bypasses Qrs1p function. A slight decrement of the mitochondrial translation capacity as well as diminished growth on respiratory carbon sources media for respiratory activity was observed in the msc6 null mutant. Additionally, the msc6 null mutant did not display any impairment in RNA transcription, processing or turnover. We concluded that Msc6p is a mitochondrial matrix protein and further studies are required to indicate the specific function of Msc6p in mitochondrial translation.

  2. Induction of Cardiac Myogenic Lineage Development Differs between Mesenchymal and Satellite Cells and is Accelerated by Bone Morphogenetic Protein-4

    Science.gov (United States)

    Grajales, Liliana; García, Jesús; Geenen, David L.

    2012-01-01

    Our aim was to further elucidate the cardiac lineage development of bone marrow-derived mesenchymal stem cells (MSC) and to identify cells which had the potential for cardiac myogenic differentiation when compared to skeletal muscle satellite (Sk-sat) myogenesis. Unlike Sk-sat, MSC expressed the early cardiac markers Nkx2.5 and GATA4. Their expression was significantly increased by culturing MSC with Bone Morphogenetic Protein 4 (BMP4). Enhanced cardiac myogenic lineage differentiation and loss of stem cell characteristics induced by BMP4 were further confirmed by flow cytometry of cells stained for Nkx2.5 and Sca-1 expression. MSC also expressed skeletal genes (MyoG, ssTnI, Sk-Act) early in culture but their expression was suppressed when BMP4 was added from day 0–6 (p < 0.05). BMP4 treated MSC also exhibited a 6-fold increase in cTnI expression by day 12 in culture. The average MSC action potential time duration at 90% (APD90) was 32.3 ± 4 ms, with some cells exhibiting action potentials closer to Sk-sat APD90 of 13.7 ± 0.9 ms. After treatment with BMP4, MSC significantly increased their APD90 to 54.4 ± 7.6 ms, shifting from the shorter skeletal-like signature, towards a longer action potential duration more characteristic of a cardiomyocyte signature. Our results show that MSC and Sk-sat exhibit similarities in myogenic lineage development early in culture but that BMP4 clearly enhances cardiac myogenic development, suppresses skeletal myogenesis, and leads to loss of “stemness” in MSC. These findings provide novel information regarding the use of BMP4 to accelerate cardiac myogenic development in harvested MSC and further support the use of MSC in cardiac regenerative therapy. PMID:22709559

  3. Prospectively defined murine mesenchymal stem cells inhibit Klebsiella pneumoniae-induced acute lung injury and improve pneumonia survival.

    Science.gov (United States)

    Hackstein, Holger; Lippitsch, Anne; Krug, Philipp; Schevtschenko, Inna; Kranz, Sabine; Hecker, Matthias; Dietert, Kristina; Gruber, Achim D; Bein, Gregor; Brendel, Cornelia; Baal, Nelli

    2015-10-06

    Numerous studies have described the immunosuppressive capacity of mesenchymal stem cells (MSC) but these studies use mixtures of heterogeneous progenitor cells for in vitro expansion. Recently, multipotent MSC have been prospectively identified in murine bone marrow (BM) on the basis of PDFGRa(+) SCA1(+) CD45(-) TER119(-) (PαS) expression but the immunomodulatory capacity of these MSC is unknown. We isolated PαS MSC by high-purity FACS sorting of murine BM and after in vitro expansion we analyzed the in vivo immunomodulatory activity during acute pneumonia. PαS MSC (1 × 10(6)) were applied intratracheally 4 h after acute respiratory Klebsiella pneumoniae induced infection. PαS MSC treatment resulted in significantly reduced alveolitis and protein leakage in comparison to mock-treated controls. PαS MSC-treated mice exhibited significantly reduced alveolar TNF-α and IL-12p70 expression, while IL-10 expression was unaffected. Dissection of respiratory dendritic cell (DC) subsets by multiparameter flow cytometry revealed significantly reduced lung DC infiltration and significantly reduced CD86 costimulatory expression on lung CD103(+) DC in PαS MSC-treated mice. In the post-acute phase of pneumonia, PαS MSC-treated animals exhibited significantly reduced respiratory IL-17(+) CD4(+) T cells and IFN-γ(+) CD4(+) T cells. Moreover, PαS MSC treatment significantly improved overall pneumonia survival and did not increase bacterial load. In this study we demonstrated for the first time the feasibility and in vivo immunomodulatory capacity of prospectively defined MSC in pneumonia.

  4. 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

  5. Environmental parameters influence non-viral transfection of human mesenchymal stem cells for tissue engineering applications

    Science.gov (United States)

    King, William J.; Kouris, Nicholas A.; Choi, Siyoung; Ogle, Brenda M.; Murphy, William L.

    2012-01-01

    Non-viral transfection is a promising technique which could be used to increase the therapeutic potential of stem cells. The purpose of this study was to explore practical culture parameters of relevance in potential human mesenchymal stem cell (hMSC) clinical and tissue engineering applications, including type of polycationic transfection reagent, N/P ratio and dose of polycation/pDNA polyplexes, cell passage number, cell density, and cell proliferation. The non-viral transfection efficiency was significantly influenced by N/P ratio, polyplex dose, cell density, and cell passage number. hMSC culture conditions that inhibited cell division also decreased transfection efficiency, suggesting that strategies to promote hMSC proliferation may be useful to enhance transfection efficiency in future tissue engineering studies. Non-viral transfection treatments influenced hMSC phenotype, including the expression level of the hMSC marker CD105, and the ability of hMSCs to differentiate down the osteogenic and adipogenic lineages. The parameters found here to promote hMSC transfection efficiency, minimize toxicity, and influence hMSC phenotype may be instructive in future non-viral transfection studies and tissue engineering applications. PMID:22277991

  6. Human Umbilical Cord Mesenchymal Stem Cells: Subpopulations and Their Difference in Cell Biology and Effects on Retinal Degeneration in RCS Rats.

    Science.gov (United States)

    Wang, L; Li, P; Tian, Y; Li, Z; Lian, C; Ou, Q; Jin, C; Gao, F; Xu, J-Y; Wang, J; Wang, F; Zhang, J; Zhang, J; Li, W; Tian, H; Lu, L; Xu, G-T

    2017-01-01

    Human umbilical cord mesenchymal stem cells (hUC-MSCs) are potential candidates for treating retinal degeneration (RD). To further study the biology and therapeutic effects of the hUC-MSCs on retinal degeneration. Two hUC-MSC subpopulations, termed hUC-MSC1 and hUC-MSC2, were isolated by single-cell cloning method and their therapeutic functions were compared in RCS rat, a RD model. Although both subsets satisfied the basic requirements for hUC-MSCs, they were significantly different in morphology, proliferation rate, differentiation capacity, phenotype and gene expression. Furthermore, only the smaller, fibroblast-like, faster growing subset hUC-MSC1 displayed stronger colony forming potential as well as adipogenic and osteogenic differentiation capacities. When the two subsets were respectively transplanted into the subretinal spaces of RCS rats, both subsets survived, but only hUC-MSC1 expressed RPE cell markers Bestrophin and RPE65. More importantly, hUC-MSC1 showed stronger rescue effect on the retinal function as indicated by the higher b-wave amplitude on ERG examination, thicker retinal nuclear layer, and decreased apoptotic photoreceptors. When both subsets were treated with interleukin-6, mimicking the inflammatory environment when the cells were transplanted into the eyes with degenerated retina, hUC-MSC1 expressed much higher levels of trophic factors in comparison with hUC-MSC2. The data here, in addition to prove the heterogeneity of hUC-MSCs, confirmed that the stronger therapeutic effects of hUC-MSC1 were attributed to its stronger anti-apoptotic effect, paracrine of trophic factors and potential RPE cell differentiation capacity. Thus, the subset hUC-MSC1, not the other subset or the ungrouped hUC-MSCs should be used for effective treatment of RD. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  7. Human bone marrow-derived and umbilical cord-derived mesenchymal stem cells for alleviating neuropathic pain in a spinal cord injury model.

    Science.gov (United States)

    Yousefifard, Mahmoud; Nasirinezhad, Farinaz; Shardi Manaheji, Homa; Janzadeh, Atousa; Hosseini, Mostafa; Keshavarz, Mansoor

    2016-03-08

    Stem cell therapy can be used for alleviating the neuropathic pain induced by spinal cord injuries (SCIs). However, survival and differentiation of stem cells following their transplantation vary depending on the host and intrinsic factors of the cell. Therefore, the present study aimed to determine the effect of stem cells derived from bone marrow (BM-MSC) and umbilical cord (UC-MSC) on neuropathic pain relief. A compression model was used to induce SCI in a rat model. A week after SCI, about 1 million cells were transplanted into the spinal cord. Behavioral tests, including motor function recovery, mechanical allodynia, cold allodynia, mechanical hyperalgesia, and thermal hyperalgesia, were carried out every week for 8 weeks after SCI induction. A single unit recording and histological evaluation were then performed. We show that BM-MSC and UC-MSC transplantations led to improving functional recovery, allodynia, and hyperalgesia. No difference was seen between the two cell groups regarding motor recovery and alleviating the allodynia and hyperalgesia. These cells survived in the tissue at least 8 weeks and prevented cavity formation due to SCI. However, survival rate of UC-MSC was significantly higher than BM-MSC. Electrophysiological evaluations showed that transplantation of UC-MSC brings about better results than BM-MSCs in wind up of wide dynamic range neurons. The results of the present study show that BM-MSC and UC-MSC transplantations alleviated the symptoms of neuropathic pain and resulted in subsequent motor recovery after SCI. However, survival rate and electrophysiological findings of UC-MSC were significantly better than BM-MSC.

  8. Toxicogenomics: A New Paradigm for Nanotoxicity Evaluation.

    Science.gov (United States)

    Dwivedi, Sourabh; Saquib, Quaiser; Ahmad, Bilal; Ansari, Sabiha M; Azam, Ameer; Musarrat, Javed

    2018-01-01

    The wider applications of nanoparticles (NPs) has evoked a world-wide concern due to their possible risk of toxicity in humans and other organisms. Aggregation and accumulation of NPs into cell leads to their interaction with biological macromolecules including proteins, nucleic acids and cellular organelles, which eventually induce toxicological effects. Application of toxicogenomics to investigate molecular pathway-based toxicological consequences has opened new vistas in nanotoxicology research. Indeed, genomic approaches appeared as a new paradigm in terms of providing information at molecular levels and have been proven to be as a powerful tool for identification and quantification of global shifts in gene expression. Toxicological responses of NPs have been discussed in this chapter with the aim to provide a clear understanding of the molecular mechanism of NPs induced toxicity both in in vivo and in vitro test models.

  9. Patient-specific age: the other side of the coin in advanced mesenchymal stem cell therapy

    Directory of Open Access Journals (Sweden)

    Magdalena Maria Schimke

    2015-12-01

    Full Text Available Multipotential mesenchymal stromal cells (MSC are present as a rare subpopulation within any type of stroma in the body of higher animals. Prominently, MSC have been recognized to reside in perivascular locations, supposedly maintaining blood vessel integrity. During tissue damage and injury, MSC/pericytes become activated, evade from their perivascular niche and are thus assumed to support wound healing and tissue regeneration.In vitro MSC exhibit demonstrated capabilities to differentiate into a wide variety of tissue cell types. Hence, many MSC-based therapeutic approaches have been performed to address bone, cartilage or heart regeneration. Furthermore, prominent studies showed efficacy of ex vivo expanded MSC to countervail graft-versus-host-disease. Therefore, additional fields of application are presently conceived, in which MSC-based therapies potentially unfold beneficial effects, such as amelioration of non-healing conditions after tendon or spinal cord injury, as well as neuropathies. Working along these lines, MSC-based scientific research has been forged ahead to prominently occupy the clinical stage.Aging is to a great deal stochastic by nature bringing forth changes in an individual fashion. Yet, is aging of stem cells or/and their corresponding niche considered a determining factor for outcome and success of clinical therapies?

  10. Experimental and Computational Insight Into Human Mesenchymal Stem Cell Paracrine Signaling and Heterocellular Coupling Effects on Cardiac Contractility and Arrhythmogenicity.

    Science.gov (United States)

    Mayourian, Joshua; Cashman, Timothy J; Ceholski, Delaine K; Johnson, Bryce V; Sachs, David; Kaji, Deepak A; Sahoo, Susmita; Hare, Joshua M; Hajjar, Roger J; Sobie, Eric A; Costa, Kevin D

    2017-08-04

    Myocardial delivery of human mesenchymal stem cells (hMSCs) is an emerging therapy for treating the failing heart. However, the relative effects of hMSC-mediated heterocellular coupling (HC) and paracrine signaling (PS) on human cardiac contractility and arrhythmogenicity remain unresolved. The objective is to better understand hMSC PS and HC effects on human cardiac contractility and arrhythmogenicity by integrating experimental and computational approaches. Extending our previous hMSC-cardiomyocyte HC computational model, we incorporated experimentally calibrated hMSC PS effects on cardiomyocyte L-type calcium channel/sarcoendoplasmic reticulum calcium-ATPase activity and cardiac tissue fibrosis. Excitation-contraction simulations of hMSC PS-only and combined HC+PS effects on human cardiomyocytes were representative of human engineered cardiac tissue (hECT) contractile function measurements under matched experimental treatments. Model simulations and hECTs both demonstrated that hMSC-mediated effects were most pronounced under PS-only conditions, where developed force increased ≈4-fold compared with non-hMSC-supplemented controls during physiological 1-Hz pacing. Simulations predicted contractility of isolated healthy and ischemic adult human cardiomyocytes would be minimally sensitive to hMSC HC, driven primarily by PS. Dominance of hMSC PS was also revealed in simulations of fibrotic cardiac tissue, where hMSC PS protected from potential proarrhythmic effects of HC at various levels of engraftment. Finally, to study the nature of the hMSC paracrine effects on contractility, proteomic analysis of hECT/hMSC conditioned media predicted activation of PI3K/Akt signaling, a recognized target of both soluble and exosomal fractions of the hMSC secretome. Treating hECTs with exosome-enriched, but not exosome-depleted, fractions of the hMSC secretome recapitulated the effects observed with hMSC conditioned media on hECT-developed force and expression of calcium

  11. Modelado y simulación de mecanismos con MSC.ADAMS : aplicación a sistemas de rodamiento

    OpenAIRE

    Tarancón Ollero, Carlos

    2011-01-01

    El presente proyecto trata, como objetivo principal, el modelado y simulación de sistemas de rodamiento empleando el software MSC.Adams. Para la consecución del objetivo principal se ha realizado el análisis cinemático de un rodamiento genérico de anillo exterior fijo y establecimiento de las condiciones que regirán nuestros modelos de rodamiento. También se ha realizado un análisis dinámico de rodamientos de bolas y de rodillos bajo carga radial, presentando las distintas metodologías de cál...

  12. Stress-Strain state of structural elements of LWR fuel rods modeling in the MSC.MARC and ANSYS software

    International Nuclear Information System (INIS)

    Kuznetsov, A.; Kuznetsov, V.; Krupkin, A.; Kashirin, B.; Medvedev, A.; Novikov, V.

    2009-01-01

    The results of stress-strain state in the fuel rod spring fixing lock coils modeling are presented in this paper. The solution of this problem was realized in finite-element software MSC.MARC and ANSIS. The solution was obtained in the three-dimensional setting, taking into account multicontact interaction and all physical and geometric nonlinearities. The finite-element models were verified on analytical parities and experimental data. Results of verification have proved a correctness of the accepted finite-element models

  13. Software Realization on the MSC nanoRISC Hardware Platform, for Communication according to the IEC61850 Standard

    Directory of Open Access Journals (Sweden)

    A. V. Kabović

    2015-06-01

    Full Text Available This paper describes software realization and its implementation for the communication, according to the IEC61850 standard, between the module for monitoring teleprotection devices and the control/monitoring server in a power substation. Teleprotection devices have an important role in the transmission of messages for power line section tripping. The software is implemented on the “MSC nanoRISC-S3C2416 MB2” hardware platform type, which belongs to the COM (computer on module systems.

  14. Isolation and characterization of multipotent mesenchymal stromal cells from the gingiva and the periodontal ligament of the horse

    Directory of Open Access Journals (Sweden)

    Pfarrer Christiane

    2011-08-01

    Full Text Available Abstract Background The equine periodontium provides tooth support and lifelong tooth eruption on a remarkable scale. These functions require continuous tissue remodeling. It is assumed that multipotent mesenchymal stromal cells (MSC reside in the periodontal ligament (PDL and play a crucial role in regulating physiological periodontal tissue regeneration. The aim of this study was to isolate and characterize equine periodontal MSC. Tissue samples were obtained from four healthy horses. Primary cell populations were har-vested and cultured from the gingiva, from three horizontal levels of the PDL (apical, midtooth and subgingival and for comparison purposes from the subcutis (masseteric region. Colony-forming cells were grown on uncoated culture dishes and typical in vitro characteristics of non-human MSC, i.e. self-renewal capacity, population doubling time, expression of stemness markers and trilineage differentiation were analyzed. Results Colony-forming cell populations from all locations showed expression of the stemness markers CD90 and CD105. In vitro self-renewal capacity was demonstrated by colony-forming unit fibroblast (CFU-F assays. CFU-efficiency was highest in cell populations from the apical and from the mid-tooth PDL. Population doubling time was highest in subcutaneous cells. All investigated cell populations possessed trilineage differentiation potential into osteogenic, adipogenic and chondrogenic lineages. Conclusions Due to the demonstrated in vitro characteristics cells were referred to as equine subcutaneous MSC (eSc-MSC, equine gingival MSC (eG-MSC and equine periodontal MSC (eP-MSC. According to different PDL levels, eP-MSC were further specified as eP-MSC from the apical PDL (eP-MSCap, eP-MSC from the mid-tooth PDL (eP-MSCm and eP-MSC from the subgingival PDL (eP-MSCsg. Considering current concepts of cell-based regenerative therapies in horses, eP-MSC might be promising candidates for future clinical applications in

  15. Characterization and Application of a Disposable Rotating Bed Bioreactor for Mesenchymal Stem Cell Expansion

    Directory of Open Access Journals (Sweden)

    Anne Neumann

    2014-11-01

    Full Text Available Recruitment of mesenchymal stromal cells (MSC into the field of tissue engineering is a promising development since these cells can be expanded vivo to clinically relevant numbers and, after expansion, retain their ability to differentiate into various cell lineages. Safety requirements and the necessity to obtain high cell numbers without frequent subcultivation of cells raised the question of the possibility of expanding MSC in one-way (single-use disposable bioreactors. In this study, umbilical cord-derived MSC (UC-MSC were expanded in a disposable Z 2000 H bioreactor under dynamic conditions. Z was characterized regarding residence time and mixing in order to evaluate the optimal bioreactor settings, enabling optimal mass transfer in the absence of shear stress, allowing an reproducible expansion of MSC, while maintaining their stemness properties. Culture of the UC-MSC in disposable Z 2000 H bioreactor resulted in a reproducible 8-fold increase of cell numbers after 5 days. Cells were shown to maintain specific MSC surface marker expression as well as trilineage differentiation potential and lack stress-induced premature senescence.

  16. Antioxidant properties of mesenchymal stem cells against oxidative stress in a murine model of colitis.

    Science.gov (United States)

    da Costa Gonçalves, Fabiany; Grings, Mateus; Nunes, Natália Schneider; Pinto, Fernanda Otesbelgue; Garcez, Tuane Nerissa Alves; Visioli, Fernanda; Leipnitz, Guilhian; Paz, Ana Helena

    2017-04-01

    To investigate the effects of oxidative stress injury in dextran sulfate sodium (DSS)-induced colitis in mice treated with mesenchymal stem cells (MSC). Mice exposed to oral administration of 2% DSS over 7 days presented a high disease activity index and an intense colonic inflammation. Systemic infusion of MSC protected from severe colitis, reducing weight loss and diarrhea while lowering the infiltration of inflammatory cells. Moreover, toxic colitis injury increased oxidative stress. Administration of DSS decreased reduced glutathione (GSH) and superoxide dismutase (SOD) activity, and increased thiobarbituric acid-reactive substances levels in the colon. No alteration was found in catalase (CAT) and glutathione peroxidase (GPx) activity. Otherwise, MSC transplantation was able to prevent the decrease of GSH levels and SOD activity suggestive of an antioxidant property of MSC. The oxidative stress is a pathomechanism underlying the pathophysiology of colitis and MSC play an important role in preventing the impairment of antioxidants defenses in inflamed colon.

  17. Psychiatry beyond the current paradigm.

    LENUS (Irish Health Repository)

    Bracken, Pat

    2012-12-01

    A series of editorials in this Journal have argued that psychiatry is in the midst of a crisis. The various solutions proposed would all involve a strengthening of psychiatry\\'s identity as essentially \\'applied neuroscience\\'. Although not discounting the importance of the brain sciences and psychopharmacology, we argue that psychiatry needs to move beyond the dominance of the current, technological paradigm. This would be more in keeping with the evidence about how positive outcomes are achieved and could also serve to foster more meaningful collaboration with the growing service user movement.

  18. Generation of transgenic mesenchymal stem cells expressing green fluorescent protein as reporter gene using no viral vector in caprine.

    Science.gov (United States)

    Kumar, Manish; Yasotha, T; Singh, R K; Singh, Renu; Kumar, Kuldeep; Ranjan, R; Meshram, Chetan D; Das, B C; Bag, Sadhan

    2013-07-01

    Mesenchymal stromal cells (MSC) are multipotent cells that can be derived from many different organs and tissues. While there are many ways to label and track cells each with strengths and weakness, the green fluorescent protein (GFP) is a reporter gene commonly employed. In the present study, caprine MSC were collected from bone marrow and cells were characterised with MSC specific markers. Passage 10 (P10) MSC cells were transfected using plasmid vector containing GFP as reporter gene with different concentrations of DNA and lipofectamine. Six different concentrations of DNA and lipofectamine as 1 microg DNA: 2 microL lipofectamine, 1 microg DNA: 2.5 microL lipofectamine, 1.2 microg DNA: 2.2 microL lipofectamine, 1.2 microg DNA: 2.5 microL lipofectamine, 1.5 microg DNA: 2.5 microL lipofectamine, 1.5 microg DNA: 3 microL lipofectamine were used. After 24 h and 48 h of transfection, caprine MSC were observed under florescent microscope. Highest transfection rate indicating green flourecscent MSC were found when the cells were transfected with 1.2 microg DNA: 2.2 microL lipofectamine and 1.5 microg DNA: 2.5 microL lipofectamine than other combinations. These cells have been propagated beyond 4th passage maintaining GFP expression. The results indicated that stable GFP positive MSC cells can be generated using the above protocol. These cells are being used for transplantation studies.

  19. Evaluation of gene delivery strategies to efficiently overexpress functional HLA-G on human bone marrow stromal cells

    Directory of Open Access Journals (Sweden)

    Joana S Boura

    2014-01-01

    Full Text Available Mesenchymal stromal cells (MSC constitutively express low levels of human leukocyte antigen-G (HLA-G, which has been shown to contribute to their immunomodulatory and anti-inflammatory properties. Here, we hypothesized that overexpression of HLA-G on bone marrow-derived MSC would improve their immunomodulatory function, thus increasing their therapeutic potential. Therefore, we investigated which gene transfer system is best suited for delivering this molecule while maintaining its immunomodulatory effects. We performed a side-by-side comparison between three nonviral plasmid-based platforms (pmax-HLA-G1; MC-HLA-G1; pEP-HLA-G1 and a viral system (Lv-HLA-G1 using gene transfer parameters that yielded similar levels of HLA-G1-expressing MSC. Natural killer (NK cell–mediated lysis assays and T cell proliferation assays showed that MSC modified with the HLA-G1 expressing viral vector had significantly lower susceptibility to NK-lysis and significantly reduced T cell proliferation when compared to nonmodified cells or MSC modified with plasmid. We also show that, in plasmid-modified MSC, an increase in Toll-like receptor (TLR9 expression is the mechanism responsible for the abrogation of HLA-G1's immunomodulatory effect. Although MSC can be efficiently modified to overexpress HLA-G1 using viral and nonviral strategies, only viral-based delivery of HLA-G1 is suitable for improvement of MSC's immunomodulatory properties.

  20. CD146/MCAM defines functionality of human bone marrow stromal stem cell populations

    DEFF Research Database (Denmark)

    Harkness, Linda; Zaher, Walid; Ditzel, Nicholas

    2016-01-01

    BACKGROUND: Identification of surface markers for prospective isolation of functionally homogenous populations of human skeletal (stromal, mesenchymal) stem cells (hMSCs) is highly relevant for cell therapy protocols. Thus, we examined the possible use of CD146 to subtype a heterogeneous h......MSC population. METHODS: Using flow cytometry and cell sorting, we isolated two distinct hMSC-CD146(+) and hMSC-CD146(-) cell populations from the telomerized human bone marrow-derived stromal cell line (hMSC-TERT). Cells were examined for differences in their size, shape and texture by using high......-content analysis and additionally for their ability to differentiate toward osteogenesis in vitro and form bone in vivo, and their migrational ability in vivo and in vitro was investigated. RESULTS: In vitro, the two cell populations exhibited similar growth rate and differentiation capacity to osteoblasts...

  1. Cartilage repair by mesenchymal stem cells: Clinical trial update and perspectives

    Directory of Open Access Journals (Sweden)

    Wayne Yuk-wai Lee

    2017-04-01

    The translational potential of this article: This review summarises recent MSC-related clinical research that focuses on cartilage repair. We also propose a novel possible translational direction for hyaline cartilage formation and a new paradigm making use of extra-cellular signalling and epigenetic regulation in the application of MSCs for cartilage repair.

  2. Mesenchymal stem cells from rats with chronic kidney disease exhibit premature senescence and loss of regenerative potential.

    Directory of Open Access Journals (Sweden)

    Barbara Mara Klinkhammer

    Full Text Available Mesenchymal stem cell (MSC transplantation has the potential for organ repair. Nevertheless, some factors might lessen the regenerative potential of MSCs, e.g. donor age or systemic disease. It is thus important to carefully assess the patient's suitability for autologous MSC transplantation. Here we investigated the effects of chronic kidney disease (CKD on MSC function. We isolated bone marrow MSCs from remnant kidney rats (RK with CKD (CKD-RK-MSC and found signs of premature senescence: spontaneous adipogenesis, reduced proliferation capacity, active senescence-associated-β-galactosidase, accumulation of actin and a modulated secretion profile. The functionality of CKD-RK-MSCs in vivo was tested in rats with acute anti-Thy1.1-nephritis, where healthy MSCs have been shown to be beneficial. Rats received healthy MSCs, CKD-RK-MSC or medium by injection into the left renal artery. Kidneys receiving healthy MSCs exhibited accelerated healing of glomerular lesions, whereas CKD-RK-MSC or medium exerted no benefit. The negative influence of advanced CKD/uremia on MSCs was confirmed in a second model of CKD, adenine nephropathy (AD. MSCs from rats with adenine nephropathy (CKD-AD-MSC also exhibited cellular modifications and functional deficits in vivo. We conclude that CKD leads to a sustained loss of in vitro and in vivo functionality in MSCs, possibly due to premature cellular senescence. Considering autologous MSC therapy in human renal disease, studies identifying uremia-associated mechanisms that account for altered MSC function are urgently needed.

  3. Intramyocardial Delivery of Mesenchymal Stem Cell-Seeded Hydrogel Preserves Cardiac Function and Attenuates Ventricular Remodeling after Myocardial Infarction

    Science.gov (United States)

    Mathieu, Eva; Lamirault, Guillaume; Toquet, Claire; Lhommet, Pierre; Rederstorff, Emilie; Sourice, Sophie; Biteau, Kevin; Hulin, Philippe; Forest, Virginie; Weiss, Pierre

    2012-01-01

    Background To improve the efficacy of bone marrow-derived mesenchymal stem cell (MSC) therapy targeted to infarcted myocardium, we investigated whether a self-setting silanized hydroxypropyl methylcellulose (Si-HPMC) hydrogel seeded with MSC (MSC+hydrogel) could preserve cardiac function and attenuate left ventricular (LV) remodeling during an 8-week follow-up study in a rat model of myocardial infarction (MI). Methodology/Principal Finding Si-HPMC hydrogel alone, MSC alone or MSC+hydrogel were injected into the myocardium immediately after coronary artery ligation in female Lewis rats. Animals in the MSC+hydrogel group showed an increase in cardiac function up to 28 days after MI and a mid-term prevention of cardiac function alteration at day 56. Histological analyses indicated that the injection of MSC+hydrogel induced a decrease in MI size and an increase in scar thickness and ultimately limited the transmural extent of MI. These findings show that intramyocardial injection of MSC+hydrogel induced short-term recovery of ventricular function and mid-term attenuation of remodeling after MI. Conclusion/Significance These beneficial effects may be related to the specific scaffolding properties of the Si-HPMC hydrogel that may provide the ability to support MSC injection and engraftment within myocardium. PMID:23284842

  4. Detrimental effects of rat mesenchymal stromal cell pre-treatment in a model of acute kidney rejection

    Directory of Open Access Journals (Sweden)

    Martina eSeifert

    2012-07-01

    Full Text Available Mesenchymal stromal cells (MSC have shown immunomodulatory and tissue repair potential including partial tolerance induction by pre-treatment of donor-specific cells in a rat heart transplantation model. Very recently, we could show that autologous MSC attenuated ischemia reperfusion injury in a highly mismatched donor-recipient rat kidney transplant model. Therefore, we investigated donor-specific MSC pre-treatment in this rat kidney transplantation model to study whether graft function could be improved, or if tolerance could be induced.Donor- and recipient-type MSC or PBS as a control were injected i.v. four days before kidney transplantation. Mycophenolate mofetil (MMF immunosuppression (20 mg/kg body weight was applied for 7 days. Kidney grafts and spleens were harvested between days 8-10 and analyzed by quantitative RT-PCR and immunohistology. In addition, creatinine levels in the blood were measured and serum was screened for the presence of donor-specific antibodies.Surprisingly, application of both donor- and recipient-specific MSC resulted in enhanced humoral immune responses verified by intragraft B cell infiltration and complement factor C4d deposits. Moreover, signs of inflammation and rejection were generally enhanced in both MSC-treated groups relative to PBS control group. Additionally, pre-treatment with donor-specific MSC significantly enhanced the level of donor-specific antibody formation when compared with PBS- or recipient-MSC-treated groups. Pre-treatment with both MSC types resulted in a higher degree of kidney cortex tissue damage and elevated creatinine levels at the time point of rejection. Thus, MSC pre-sensitization in this model impairs the allograft outcome.Our data from this pre-clinical kidney transplantation model indicate that pre-operative MSC administration may not be optimal in kidney transplantation and caution must be exerted before moving forward with clinical studies in order to avoid adverse effects.

  5. Biofabrication: a 21st century manufacturing paradigm

    International Nuclear Information System (INIS)

    Mironov, V; Trusk, T; Markwald, R; Kasyanov, V; Little, S; Swaja, R

    2009-01-01

    Biofabrication can be defined as the production of complex living and non-living biological products from raw materials such as living cells, molecules, extracellular matrices, and biomaterials. Cell and developmental biology, biomaterials science, and mechanical engineering are the main disciplines contributing to the emergence of biofabrication technology. The industrial potential of biofabrication technology is far beyond the traditional medically oriented tissue engineering and organ printing and, in the short term, it is essential for developing potentially highly predictive human cell- and tissue-based technologies for drug discovery, drug toxicity, environmental toxicology assays, and complex in vitro models of human development and diseases. In the long term, biofabrication can also contribute to the development of novel biotechnologies for sustainable energy production in the future biofuel industry and dramatically transform traditional animal-based agriculture by inventing 'animal-free' food, leather, and fur products. Thus, the broad spectrum of potential applications and rapidly growing arsenal of biofabrication methods strongly suggests that biofabrication can become a dominant technological platform and new paradigm for 21st century manufacturing. The main objectives of this review are defining biofabrication, outlining the most essential disciplines critical for emergence of this field, analysis of the evolving arsenal of biofabrication technologies and their potential practical applications, as well as a discussion of the common challenges being faced by biofabrication technologies, and the necessary conditions for the development of a global biofabrication research community and commercially successful biofabrication industry. (topical review)

  6. Human Serum is as Efficient as Fetal Bovine Serum in Supporting Proliferation and Differentiation of Human Multipotent Stromal (Mesenchymal) Stem Cells In Vitro and In Vivo

    DEFF Research Database (Denmark)

    Aldahmash, Abdullah; Haack-Sørensen, Mandana; Al-Nbaheen, May

    2011-01-01

    pose a health risk for patients. METHODS: We carried out a side-by-side comparison of the effects of allogenic pooled human serum (HuS) versus FBS on hMSC proliferation and differentiation in vitro and in vivo. As a model for hMSC, we employed telomerase-immortalized hMSC; hMSC-TERT cell line. RESULTS....... FBS. hMSC-TERT or primary bone marrow derived hMSC induced to osteoblastic or adipocytic differentiation in the presence of HuS or FBS showed comparable levels of gene expression and protein production of osteoblastic markers (CBFA1/Runx2, alkaline phosphastase, collagen type I and osteocalcin...... subcutaneously in immune deficient mice. hMSC maintained in HuS vs. FBS formed comparable heterotopic bone. DISCUSSION: Human serum can support proliferation and differentiation of hMSC in vitro and can maintain their bone forming capacity in vivo. The use of human serum in cell cultures of hMSC intended...

  7. Autonomous magnetic labelling of functional mesenchymal stem cells for improved traceability and spatial control in cell therapy applications.

    Science.gov (United States)

    Harrison, Richard; Markides, Hareklea; Morris, Robert H; Richards, Paula; El Haj, Alicia J; Sottile, Virginie

    2017-08-01

    Mesenchymal stem cells (MSCs) represent a valuable resource for regenerative medicine treatments for orthopaedic repair and beyond. Following developments in isolation, expansion and differentiation protocols, efforts to promote clinical translation of emerging cellular strategies now seek to improve cell delivery and targeting. This study shows efficient live MSC labelling using silica-coated magnetic particles (MPs), which enables 3D tracking and guidance of stem cells. A procedure developed for the efficient and unassisted particle uptake was shown to support MSC viability and integrity, while surface marker expression and MSC differentiation capability were also maintained. In vitro, MSCs showed a progressive decrease in labelling over increasing culture time, which appeared to be linked to the dilution effect of cell division, rather than to particle release, and did not lead to detectable secondary particle uptake. Labelled MSC populations demonstrated magnetic responsiveness in vitro through directed migration in culture and, when seeded onto a scaffold, supporting MP-based approaches to cell targeting. The potential of these silica-coated MPs for MRI cell tracking of MSC populations was validated in 2D and in a cartilage repair model following cell delivery. These results highlight silica-coated magnetic particles as a simple, safe and effective resource to enhance MSC targeting for therapeutic applications and improve patient outcomes. © 2016 The Authors Journal of Tissue Engineering and Regenerative Medicine Published by John Wiley & Sons Ltd. © 2016 The Authors Journal of Tissue Engineering and Regenerative Medicine Published by John Wiley & Sons Ltd.

  8. E.P Makokha, BSc, MSc, PhD. Department of Immunology, Faculty of ...

    African Journals Online (AJOL)

    2002-11-01

    Nov 1, 2002 ... Results: Among 107 women sampled, only 59 received full dose of AZT and thus qualified for present analysis. .... counts were performed on whole blood in EDTA using an electronic blood cell counter (Sysmex^M Electronic cell counter, Japan). Aliquots of 50ul of whole blood in EDTA were incubated with ...

  9. Endometrial regenerative cells for treatment of heart failure: a new stem cell enters the clinic.

    Science.gov (United States)

    Bockeria, Leo; Bogin, Vladimir; Bockeria, Olga; Le, Tatyana; Alekyan, Bagrat; Woods, Erik J; Brown, Amalia A; Ichim, Thomas E; Patel, Amit N

    2013-03-05

    Heart failure is one of the key causes of morbidity and mortality world-wide. The recent findings that regeneration is possible in the heart have made stem cell therapeutics the Holy Grail of modern cardiovascular medicine. The success of cardiac regenerative therapies hinges on the combination of an effective allogeneic "off the shelf" cell product with a practical delivery system. In 2007 Medistem discovered the Endometrial Regenerative Cell (ERC), a new mesenchymal-like stem cell. Medistem and subsequently independent groups have demonstrated that ERC are superior to bone marrow mesenchymal stem cells (MSC), the most widely used stem cell source in development. ERC possess robust expansion capability (one donor can generate 20,000 patients doses), key growth factor production and high levels of angiogenic activity. ERC have been published in the peer reviewed literature to be significantly more effect at treating animal models of heart failure (Hida et al. Stem Cells 2008).Current methods of delivering stem cells into the heart suffer several limitations in addition to poor delivery efficiency. Surgical methods are highly invasive, and the classical catheter based techniques are limited by need for sophisticated cardiac mapping systems and risk of myocardial perforation. Medistem together with Dr. Amit Patel Director of Clinical Regenerative Medicine at University of Utah have developed a novel minimally invasive delivery method that has been demonstrated safe and effective for delivery of stem cells (Tuma et al. J Transl Med 2012). Medistem is evaluating the combination of ERC, together with our retrograde delivery procedure in a 60 heart failure patient, double blind, placebo controlled phase II trial. To date 17 patients have been dosed and preliminary analysis by the Data Safety Monitoring Board has allowed for trial continuation.The combined use of a novel "off the shelf" cell together with a minimally invasive 30 minute delivery method provides a

  10. Telomerase promoter reprogramming and interaction with general transcription factors in the human mesenchymal stem cell

    DEFF Research Database (Denmark)

    Serakinci, Nedime; Hoare, Stacey F.; Kassem, Moustapha

    2006-01-01

    The human adult mesenchymal stem cell (hMSC) does not express telomerase and has been shown to be the target for neoplastic transformation after transduction with hTERT. These findings lend support to the stem cell hypothesis of cancer development but by supplying hTERT, the molecular events...... required to upregulate hTERT expression in cancer development are missed. Therefore, the hMSC is ideal for the identification of molecular mechanisms regulating telomerase gene expression in stem cells. This study shows that the repression of hTERT expression in hMSC is chromatin based...

  11. Changing strategy and implementation of a new treatment protocol for cleft palate surgery in "Maria Sklodowska Curie" (MSC) Children's Hospital, Bucharest, Romania.

    Science.gov (United States)

    Spataru, Radu; Mark, Hans

    2014-12-01

    In "Maria Sklodowska Curie" (MSC) Children's Hospital, Bucharest, Romania, cleft palate repair has been performed according to von Langenbeck since 1984. The speech was good in most patients but wide clefts had a high percentage of fistulas, abnormal speech due to short length and limited mobility of the soft palate. In 2009, the protocol was changed to Gothenburg Delayed Hard Palate Closure, (DHPC) technique. The present evaluation was performed to study the implementation of this technique. One hundred and sixty-eight patients with cleft palate were admitted, 89 isolated cleft palate (ICP), 53 unilateral (UCLP) and 26 bilateral (BCLP). In these, 228 surgical interventions were performed. Soft Palate Repair (SPR) and Hard Palate Repair (HPR) were performed with the DHPC procedure. The transfer to this technique was successfully performed in three steps: one team visit to Gothenburg by a surgeon from MSC and two visits by surgeons from Gothenburg to the MSC. Patients with SPR and HPR were operated on without major complications and there were no differences in results between Gothenburg surgeons and MSC surgeons. The interventions with SPR and HPR technique were proven to be easy to teach and learn and successfully performed without major complications. For cleft patients at MSC hospital it has meant earlier surgery, less re-operations and complications. This report shows a successful change of strategy for palatal repair with improved outcome regarding surgery. In future, speech and growth will be followed on a regular basis and will be compared with results from the Gothenburg Cleft Team.

  12. The detour paradigm in animal cognition.

    Science.gov (United States)

    Kabadayi, Can; Bobrowicz, Katarzyna; Osvath, Mathias

    2018-01-01

    In this paper, we review one of the oldest paradigms used in animal cognition: the detour paradigm. The paradigm presents the subject with a situation where a direct route to the goal is blocked and a detour must be made to reach it. Often being an ecologically valid and a versatile tool, the detour paradigm has been used to study diverse cognitive skills like insight, social learning, inhibitory control and route planning. Due to the relative ease of administrating detour tasks, the paradigm has lately been used in large-scale comparative studies in order to investigate the evolution of inhibitory control. Here we review the detour paradigm and some of its cognitive requirements, we identify various ecological and contextual factors that might affect detour performance, we also discuss developmental and neurological underpinnings of detour behaviors, and we suggest some methodological approaches to make species comparisons more robust.

  13. Comparison of exosomes secreted by induced pluripotent stem cell-derived mesenchymal stem cells and synovial membrane-derived mesenchymal stem cells for the treatment of osteoarthritis.

    Science.gov (United States)

    Zhu, Yu; Wang, Yuchen; Zhao, Bizeng; Niu, Xin; Hu, Bin; Li, Qing; Zhang, Juntao; Ding, Jian; Chen, Yunfeng; Wang, Yang

    2017-03-09

    Osteoarthritis (OA) is the most common joint disease worldwide. In the past decade, mesenchymal stem cells (MSCs) have been used widely for the treatment of OA. A potential mechanism of MSC-based therapies has been attributed to the paracrine secretion of trophic factors, in which exosomes may play a major role. In this study, we aimed to compare the effectiveness of exosomes secreted by synovial membrane MSCs (SMMSC-Exos) and exosomes secreted by induced pluripotent stem cell-derived MSCs (iMSC-Exos) on the treatment of OA. Induced pluripotent stem cell-derived MSCs and synovial membrane MSCs were characterized by flow cytometry. iMSC-Exos and SMMSC-Exos were isolated using an ultrafiltration method. Tunable resistive pulse-sensing analysis, transmission electron microscopy, and western blots were used to identify exosomes. iMSC-Exos and SMMSC-Exos were injected intra-articularly in a mouse model of collagenase-induced OA and the efficacy of exosome injections was assessed by macroscopic, histological, and immunohistochemistry analysis. We also evaluated the effects of iMSC-Exos and SMMSC-Exos on proliferation and migration of human chondrocytes by cell-counting and scratch assays, respectively. The majority of iMSC-Exos and SMMSC-Exos were approximately 50-150 nm in diameter and expressed CD9, CD63, and TSG101. The injection of iMSC-Exos and SMMSC-Exos both attenuated OA in the mouse OA model, but iMSC-Exos had a superior therapeutic effect compared with SMMSC-Exos. Similarly, chondrocyte migration and proliferation were stimulated by both iMSC-Exos and SMMSC-Exos, with iMSC-Exos exerting a stronger effect. The present study demonstrated that iMSC-Exos have a greater therapeutic effect on OA than SMMSC-Exos. Because autologous iMSCs are theoretically inexhaustible, iMSC-Exos may represent a novel therapeutic approach for the treatment of OA.

  14. Gene expression profiling of human mesenchymal stem cells derived from bone marrow during expansion and osteoblast differentiation

    Directory of Open Access Journals (Sweden)

    Windhager Reinhard

    2007-03-01

    Full Text Available Abstract Background Human mesenchymal stem cells (MSC with the capacity to differentiate into osteoblasts provide potential for the development of novel treatment strategies, such as improved healing of large bone defects. However, their low frequency in bone marrow necessitate ex vivo expansion for further clinical application. In this study we asked if MSC are developing in an aberrant or unwanted way during ex vivo long-term cultivation and if artificial cultivation conditions exert any influence on their stem cell maintenance. To address this question we first developed human oligonucleotide microarrays with 30.000 elements and then performed large-scale expression profiling of long-term expanded MSC and MSC during differentiation into osteoblasts. Results The results showed that MSC did not alter their osteogenic differentiation capacity, surface marker profile, and the expression profiles of MSC during expansion. Microarray analysis of MSC during osteogenic differentiation identified three candidate genes for further examination and functional analysis: ID4, CRYAB, and SORT1. Additionally, we were able to reconstruct the three developmental phases during osteoblast differentiation: proliferation, matrix maturation, and mineralization, and illustrate the activation of the SMAD signaling pathways by TGF-β2 and BMPs. Conclusion With a variety of assays we could show that MSC represent a cell population which can be expanded for therapeutic applications.

  15. Putative cancer stem cells may be the key target to inhibit cancer cell repopulation between the intervals of chemoradiation in murine mesothelioma.

    Science.gov (United States)

    Wu, Licun; Blum, Walter; Zhu, Chang-Qi; Yun, Zhihong; Pecze, Laszlo; Kohno, Mikihiro; Chan, Mei-Lin; Zhao, Yidan; Felley-Bosco, Emanuela; Schwaller, Beat; de Perrot, Marc

    2018-04-27

    Cancer cell repopulation during chemotherapy or radiotherapy is a major factor limiting the efficacy of treatment. Cancer stem cells (CSC) may play critical roles during this process. We aim to demonstrate the role of mesothelioma stem cells (MSC) in treatment failure and eventually to design specific target therapies against MSC to improve the efficacy of treatment in malignant mesothelioma. Murine mesothelioma AB12 and RN5 cells were used to compare tumorigenicity in mice. The expression of CSC-associated genes was evaluated by quantitative real-time PCR in both cell lines treated with chemo-radiation. Stemness properties of MSC-enriched RN5-EOS-Puro2 cells were characterized with flow cytometry and immunostaining. A MSC-specific gene profile was screened by microarray assay and confirmed thereafter. Gene Ontology analysis of the selected genes was performed by GOMiner. Tumor growth delay of murine mesothelioma AB12 cells was achieved after each cycle of cisplatin treatment, however, tumors grew back rapidly due to cancer cell repopulation between courses of chemotherapy. Strikingly, a 10-times lower number of irradiated cells in both cell lines led to a similar tumor incidence and growth rate as with untreated cells. The expression of CSC-associated genes such as CD24, CD133, CD90 and uPAR was dramatically up-regulated, while others did not change significantly after chemoradiation. Highly enriched MSC after selection with puromycin displayed an increasing GFP-positive population and showed typical properties of stemness. Comparatively, the proportion of MSC significantly increased after RN5-EOS parental cells were treated with either chemotherapy, γ-ray radiation, or a combination of the two, while MSC showed more resistance to the above treatments. A group of identified genes are most likely MSC-specific, and major pathways related to regulation of cell growth or apoptosis are involved. Upregulation of the gene transcripts Tnfsf18, Serpinb9b, Ly6a

  16. Polycaprolactone nanomesh cultured with hMSC evaluated by synchrotron tomography

    DEFF Research Database (Denmark)

    Nygaard, Jens Vinge; Andersen, Morten Østergaard; Cloetens, Peter

    2009-01-01

    Introduction Cell response is closely related to substrate stiffness. Successful induced tissue repair from bioengineered constructs must possess both optimal bioactivity and mechanical strength. This is because cell interaction with the extracellular matrix (ECM) produces two different...... for 2 and 3 weeks shown the formations of extracellular matrix.  Conclusions We have demonstrated that it is possible to control the microstructure of polycaprolactone based scaffolds. Microstructures can evolve into single and double graded structures, but also three dimensional fibrous nano meshes...

  17. Human Endothelial-Like Differentiated Precursor Cells Maintain Their Endothelial Characteristics When Cocultured with Mesenchymal Stem Cell and Seeded onto Human Cancellous Bone

    Directory of Open Access Journals (Sweden)

    Dirk Henrich

    2013-01-01

    Full Text Available Introduction. Cancellous bone is frequently used for filling bone defects in a clinical setting. It provides favourable conditions for regenerative cells such as MSC and early EPC. The combination of MSC and EPC results in superior bone healing in experimental bone healing models. Materials and Methods. We investigated the influence of osteogenic culture conditions on the endothelial properties of early EPC and the osteogenic properties of MSC when cocultured on cancellous bone. Additionally, cell adhesion, metabolic activity, and differentiation were assessed 2, 6, and 10 days after seeding. Results. The number of adhering EPC and MSC decreased over time; however the cells remained metabolically active over the 10-day measurement period. In spite of a decline of lineage specific markers, cells maintained their differentiation to a reduced level. Osteogenic stimulation of EPC caused a decline but not abolishment of endothelial characteristics and did not induce osteogenic gene expression. Osteogenic stimulation of MSC significantly increased their metabolic activity whereas collagen-1α and alkaline phosphatase gene expressions declined. When cocultured with EPC, MSC’s collagen-1α gene expression increased significantly. Conclusion. EPC and MSC can be cocultured in vitro on cancellous bone under osteogenic conditions, and coculturing EPC with MSC stabilizes the latter’s collagen-1α gene expression.

  18. Improved proliferation and differentiation capacity of human mesenchymal stromal cells cultured with basement-membrane extracellular matrix proteins.

    Science.gov (United States)

    Lindner, Ulrich; Kramer, Jan; Behrends, Jochen; Driller, Birgit; Wendler, Nils-Ole; Boehrnsen, Florian; Rohwedel, Jürgen; Schlenke, Peter

    2010-12-01

    In vitro cultured mesenchymal stromal cells (MSC) are characterized by a short proliferative lifespan, an increasing loss of proliferation capacity and progressive reduction of differentiation potential. Laminin-1, laminin-5, collagen IV and fibronectin are important constituents of the basement membrane extracellular matrix (ECM) that are involved in a variety of cellular activities, including cell attachment and motility. The in vitro proliferation capacity of MSC was significantly improved when the cells were incubated in the presence of basement membrane ECM proteins. For example, a mixture of proteins improved proliferation capacity 250-fold in comparison with standard conditions after five passages. Furthermore, in colony-forming unit-fibroblast (CFU-F) assays colony numbers and size were significantly extended. Blocking specific integrin cell-surface receptors, positive effects on the proliferation capacity of MSC were inhibited. Additionally, when MSC were co-cultivated with ECM proteins, cells maintained their multipotential differentiation capacity throughout many culture passages in comparison with cells cultivated on plastic. However, expansion of MSC on laminin-5 suppressed any subsequent chondrogenic differentiation. Our results suggest that expansion of bone marrow-derived MSC in the presence of ECM proteins is a powerful approach for generating large numbers of MSC, showing a prolonged capacity to differentiate into mesodermal cell lineages, with the exception of the lack of chondrogenesis by using laminin-5 coating.

  19. Characterization and Immunomodulatory Effects of Canine Adipose Tissue- and Bone Marrow-Derived Mesenchymal Stromal Cells.

    Directory of Open Access Journals (Sweden)

    Keith A Russell

    Full Text Available Mesenchymal stromal cells (MSC hold promise for both cell replacement and immune modulation strategies owing to their progenitor and non-progenitor functions, respectively. Characterization of MSC from different sources is an important and necessary step before clinical use of these cells is widely adopted. Little is known about the biology and function of canine MSC compared to their mouse or human counterparts. This knowledge-gap impedes development of canine evidence-based MSC technologies.We hypothesized that canine adipose tissue (AT and bone marrow (BM MSC (derived from the same dogs will have similar differentiation and immune modulatory profiles. Our objectives were to evaluate progenitor and non-progenitor functions as well as other characteristics of AT- and BM-MSC including 1 proliferation rate, 2 cell surface marker expression, 3 DNA methylation levels, 4 potential for trilineage differentiation towards osteogenic, adipogenic, and chondrogenic cell fates, and 5 immunomodulatory potency in vitro.1 AT-MSC proliferated at more than double the rate of BM-MSC (population doubling times in days for passage (P 2, AT: 1.69, BM: 3.81; P3, AT: 1.80, BM: 4.06; P4, AT: 2.37, BM: 5.34; P5, AT: 3.20, BM: 7.21. 2 Canine MSC, regardless of source, strongly expressed cell surface markers MHC I, CD29, CD44, and CD90, and were negative for MHC II and CD45. They also showed moderate expression of CD8 and CD73 and mild expression of CD14. Minor differences were found in expression of CD4 and CD34. 3 Global DNA methylation levels were significantly lower in BM-MSC compared to AT-MSC. 4 Little difference was found between AT- and BM-MSC in their potential for adipogenesis and osteogenesis. Chondrogenesis was poor to absent for both sources in spite of adding varying levels of bone-morphogenic protein to our standard transforming growth factor (TGF-β3-based induction medium. 5 Immunomodulatory capacity was equal regardless of cell source when tested in

  20. The Oral Paradigm and Snapchat

    Directory of Open Access Journals (Sweden)

    Oren Soffer

    2016-09-01

    Full Text Available In this short essay, I argue that the ephemeral nature of emerging instant-messaging applications, such as Snapchat, applies an oral paradigm. While online discourse of computer-mediated communication shares many qualities with oral communication, the case of ephemeral applications is unique, as the oral features are already integrated in the application technology design and as orality is often implemented on highly visual products. Snapchat applies technology that fades visual contents as if they were spoken words fading in the air after utterance. Moreover, Snapchat’s promise to delete all messages from its database after they are viewed echoes a key characteristic of primary oral culture: that is, the inability (and in our case, the obligation not to store knowledge. In this, Snapchat demonstrates counter-logic to the contemporary grammar of new media, which is based on information aggregation.

  1. Emerging Paradigms in Machine Learning

    CERN Document Server

    Jain, Lakhmi; Howlett, Robert

    2013-01-01

    This  book presents fundamental topics and algorithms that form the core of machine learning (ML) research, as well as emerging paradigms in intelligent system design. The  multidisciplinary nature of machine learning makes it a very fascinating and popular area for research.  The book is aiming at students, practitioners and researchers and captures the diversity and richness of the field of machine learning and intelligent systems.  Several chapters are devoted to computational learning models such as granular computing, rough sets and fuzzy sets An account of applications of well-known learning methods in biometrics, computational stylistics, multi-agent systems, spam classification including an extremely well-written survey on Bayesian networks shed light on the strengths and weaknesses of the methods. Practical studies yielding insight into challenging problems such as learning from incomplete and imbalanced data, pattern recognition of stochastic episodic events and on-line mining of non-stationary ...

  2. Shield calculations, optimization vs. paradigm

    International Nuclear Information System (INIS)

    Cornejo D, N.; Hernandez S, A.; Martinez G, A.

    2006-01-01

    Many shieldings have been designed under the criteria of 'Maximum dose rates of project'. It has created the paradigm of those 'low dose rates', for the one which not few specialists would consider unacceptable levels of dose rate superior to the units of μSv.h -1 , independently of the exposure times. At the present time numerous shieldings are being designed considering dose restrictions in real times of exposure. After these new shieldings, the dose rates could be notably superior to those after traditional shieldings, without it implies inadequate designs or constructive errors. In the work significant differences in levels of dose rates and thickness of shieldings estimated by both methods for some typical facilities. It was concluded that the use of real times of exposure is more adequate for the optimization of the Radiological Protection, although this method demands bigger care in its application. (Author)

  3. Shielding calculations. Optimization vs. Paradigms

    International Nuclear Information System (INIS)

    Cornejo Diaz, Nestor; Hernandez Saiz, Alejandro; Martinez Gonzalez, Alina

    2005-01-01

    Many radiation shielding barriers in Cuba have been designed according to the criterion of Maxi-mum Projected Dose Rates. This fact has created the paradigm of low dose rates. Because of this, dose rate levels greater than units of Sv.h-1 would be considered unacceptable by many specialists, regardless of the real exposure times. Nowadays many shielding barriers are being designed using dose constraints in real exposure times. Behind the new barriers, dose rates could be notably greater than those behind the traditional ones, and it does not imply inadequate designs or constructive errors. In this work were obtained significant differences in dose rate levels and shield-ing thicknesses calculated by both methods for some typical installations. The work concludes that real exposure time approach is more adequate in order to optimise Radiation Protection, although this method should be carefully applied

  4. Explaining (Missing) Regulator Paradigm Shifts

    DEFF Research Database (Denmark)

    Wigger, Angela; Buch-Hansen, Hubert

    2014-01-01

    The global financial and economic crisis has prompted some scholars to suggest that a fundamental regulatory shift away from neoliberalism will take place – both in general and in the field of EU competition regulation. This paper shows that so far no radical break with the neoliberal type...... of competition regulation is heaving into sight. It sets out to explain this from the vantage point of a critical political economy perspective, which identifies the circumstances under which a crisis can result in a regulatory paradigm shift. Contrasting the current situation with the shift in EC/EU competition...... regulation after the crisis in the 1970s, the paper argues that the preconditions for a fundamental shift in this issue area are not present this time around. Several reasons account for this: the current crisis has been construed by economic and political elites as a crisis within and not of neoliberal...

  5. Lipopolysaccharide induces proliferation and osteogenic differentiation of adipose-derived mesenchymal stromal cells in vitro via TLR4 activation

    Energy Technology Data Exchange (ETDEWEB)

    Herzmann, Nicole; Salamon, Achim [Department of Cell Biology, University Medicine Rostock, Schillingallee 69, D-18057 Rostock (Germany); Fiedler, Tomas [Institute for Medical Microbiology, Virology and Hygiene, University Medicine Rostock, Schillingallee 70, D-18057 Rostock (Germany); Peters, Kirsten, E-mail: kirsten.peters@med.uni-rostock.de [Department of Cell Biology, University Medicine Rostock, Schillingallee 69, D-18057 Rostock (Germany)

    2017-01-01

    Multipotent mesenchymal stromal cells (MSC) are capable of multi-lineage differentiation and support regenerative processes. In bacterial infections, resident MSC can come intocontact with and need to react to bacterial components. Lipopolysaccharide (LPS), a typical structure of Gram-negative bacteria, increases the proliferation and osteogenic differentiation of MSC. LPS is usually recognized by the toll-like receptor (TLR) 4 and induces pro-inflammatory reactions in numerous cell types. In this study, we quantified the protein expression of TLR4 and CD14 on adipose-derived MSC (adMSC) in osteogenic differentiation and investigated the effect of TLR4 activation by LPS on NF-κB activation, proliferation and osteogenic differentiation of adMSC. We found that TLR4 is expressed on adMSC whereas CD14 is not, and that osteogenic differentiation induced an increase of the amount of TLR4 protein whereas LPS stimulation did not. Moreover, we could show that NF-κB activation via TLR4 occurs upon LPS treatment. Furthermore, we were able to show that competitive inhibition of TLR4 completely abolished the stimulatory effect of LPS on the proliferation and osteogenic differentiation of adMSC. In addition, the inhibition of TLR4 leads to the complete absence of osteogenic differentiation of adMSC, even when osteogenically stimulated. Thus, we conclude that LPS induces proliferation and osteogenic differentiation of adMSC in vitro through the activation of TLR4 and that the TLR4 receptor seems to play a role during osteogenic differentiation of adMSC.

  6. Datacubes as a Service Paradigm

    Science.gov (United States)

    Rossi, Angelo Pio; Baumann, Peter

    2016-04-01

    Spatio-temporal data sets often can be represented conveniently through datacubes as a common unifying paradigm. Flexible, scalable services can be offered based on the concept of a datacube query language while hiding the technicalities, thereby allowing user-friendly visual data interaction. One of today's most influential initiatives in Big Geo Data is EarthServer which is paving the way for flexible, scalable datacube services based on innovative NewSQL technology (Fig. 1). Researchers from Europe, the US and recently Australia have teamed up to rigorously materialize the datacube paradigm for Earth Observation, ocean, meteorological, and planetary science. EarthServer has established client and server technology for such spatio-temporal datacubes strictly based on the open datacube standards, OGC WCS and WPCS. The underlying scalable array engine, rasdaman, enables direct interaction, including 3-D visualization, what-if scenarios, common EO data processing, and general analytics on regular and irregular grids. Integration of datacube and metadata retrieval, together with advanced visualization based on NASA WorldWind, are geared towards an effective, user-friendly access and analysis. Conversely, EarthServer is significantly shaping the ISO, OGC, and INSPIRE Big Data standards landscape by being specification editor. Phase 1 of EarthServer has advanced scalable array data¬base technology into 100+ TB services; in phase 2, a federation of Petabyte datacubes is being built in Europe and Australia to perform ad-hoc querying and merging. Phase 1 reviewers have attested rasdaman to "significantly transform the way that scientists in different areas of Earth Science will be able to access and use data in a way that hitherto was not possible". Altogether, these large-scale deployments prove that datacubes are a convenient model for presenting users with a simple, consolidated view on the massive amount of data files gathered - "a cube tells more than a million

  7. Minimal modulation of the host immune response to SIS matrix implants by mesenchymal stem cells from the amniotic fluid.

    Science.gov (United States)

    Lesage, F; Pranpanus, S; Bosisio, F M; Jacobs, M; Ospitalieri, S; Toelen, J; Deprest, J

    2017-12-01

    Surgical restoration of soft tissue defects often requires implantable devices. The clinical outcome of the surgery is determined by the properties inherent to the used matrix. Mesenchymal stem cells (MSC) modulate the immune processes after in vivo transplantation and their addition to matrices is associated with constructive remodeling. Herein we evaluate the potential of MSC derived from the amniotic fluid (AF-MSC), an interesting MSC source for cell therapeutic applications in the perinatal period, for immune modulation when added to a biomaterial. We implant cell free small intestinal submucosa (SIS) or SIS seeded with AF-MSC at a density of 1 × 10 5 /cm 2 subcutaneously at the abdominal wall in immune competent rats. The host immune response is evaluated at 3, 7 and 14 days postoperatively. The matrix-specific or cellular characteristics are not altered after 24 h of in vitro co-culture of SIS with AF-MSC. The host immune response was not different between animals implanted with cell free or AF-MSC-seeded SIS in terms of cellular infiltration, vascularity, macrophage polarization or scaffold replacement. Profiling the mRNA expression level of inflammatory cytokines at the matrix interface shows a significant reduction in the expression of the pro-inflammatory marker Tnf-α and a trend towards lower iNos expression upon AF-MSC-seeding of the SIS matrix. Anti-inflammatory marker expression does not alter upon cell seeding of matrix implants. We conclude that SIS is a suitable substrate for in vitro culture of AF-MSC and fibroblasts. AF-MSC addition to SIS does not significantly modulate the host immune response after subcutaneous implantation in rats.

  8. Aging is associated with decreased maximal life span and accelerated senescence of bone marrow stromal cells

    DEFF Research Database (Denmark)

    Dokkedahl, Karin Stenderup; Justesen, Jeannette; Clausen, Christian

    2003-01-01

    +/- 11 population doublings [PD] vs 41 +/- 10 PD, P beta-galactosidase positive (SA beta......-gal+) cells and mean telomere length in early-passage cells obtained from young and old donors. However, MSC from old donors exhibited accelerated senescence evidenced by increased number of SA beta-gal+ cells per PD as compared with young (4% per PD vs 0.4% per PD, respectively). MSC from young and old...

  9. Human Cardiac Mesenchymal Stromal Cells with CD105+CD34- Phenotype Enhance the Function of Post-Infarction Heart in Mice.

    Directory of Open Access Journals (Sweden)

    Justyna Czapla

    Full Text Available The aim of the present study was to isolate mesenchymal stromal cells (MSC with CD105+CD34- phenotype from human hearts, and to investigate their therapeutic potential in a mouse model of hindlimb ischemia and myocardial infarction (MI. The study aimed also to investigate the feasibility of xenogeneic MSCs implantation.MSC isolated from human hearts were multipotent cells. Separation of MSC with CD105+CD34- phenotype limited the heterogeneity of the originally isolated cell population. MSC secreted a number of anti-inflammatory and proangiogenic cytokines (mainly IL-6, IL-8, and GRO. Human MSC were transplanted into C57Bl/6NCrl mice. Using the mouse model of hindlimb ischemia it was shown that human MSC treated mice demonstrated a higher capillary density 14 days after injury. It was also presented that MSC administrated into the ischemic muscle facilitated fast wound healing (functional recovery by ischemic limb. MSC transplanted into an infarcted myocardium reduced the post-infarction scar, fibrosis, and increased the number of blood vessels both in the border area, and within the post-infarction scar. The improvement of left ventricular ejection fraction was also observed.In two murine models (hindlimb ischemia and MI we did not observe the xenotransplant rejection. Indeed, we have shown that human cardiac mesenchymal stromal cells with CD105+CD34- phenotype exhibit therapeutic potential. It seems that M2 macrophages are essential for healing and repair of the post-infarcted heart.

  10. Linking metacommunity paradigms to spatial coexistence mechanisms.

    Science.gov (United States)

    Shoemaker, Lauren G; Melbourne, Brett A

    2016-09-01

    Four metacommunity paradigms-usually called neutral, species sorting, mass effects, and patch dynamics, respectively-are widely used for empirical and theoretical studies of spatial community dynamics. The paradigm framework highlights key ecological mechanisms operating in metacommunities, such as dispersal limitation, competition-colonization tradeoffs, or species equivalencies. However, differences in coexistence mechanisms between the paradigms and in situations with combined influences of multiple paradigms are not well understood. Here, we create a common model for competitive metacommunities, with unique parameterizations for each metacommunity paradigm and for scenarios with multiple paradigms operating simultaneously. We derive analytical expressions for the strength of Chesson's spatial coexistence mechanisms and quantify these for each paradigm via simulation. For our model, fitness-density covariance, a concentration effect measuring the importance of intraspecific aggregation of individuals, is the dominant coexistence mechanism in all three niche-based metacommunity paradigms. Increased dispersal between patches erodes intraspecific aggregation, leading to lower coexistence strength in the mass effects paradigm compared to species sorting. Our analysis demonstrates the potential importance of aggregation of individuals (fitness-density covariance) over co-variation in abiotic environments and competition between species (the storage effect), as fitness-density covariance can be stronger than the storage effect and is the sole stabilizing mechanism in the patch dynamics paradigm. As expected, stable coexistence does not occur in the neutral paradigm, which requires species to be equal and emphasizes the role of stochasticity. We show that stochasticity also plays an important role in niche-structured metacommunities by altering coexistence strength. We conclude that Chesson's spatial coexistence mechanisms provide a flexible framework for comparing

  11. Enhanced Adipogenicity of Bone Marrow Mesenchymal Stem Cells in Aplastic Anemia

    Directory of Open Access Journals (Sweden)

    Naresh Kumar Tripathy

    2014-01-01

    Full Text Available Fatty bone marrow (BM and defective hematopoiesis are a pathologic hallmark of aplastic anemia (AA. We have investigated adipogenic and osteogenic potential of BM mesenchymal stem cells (BM-MSC in 10 AA patients (08 males and 02 females with median age of 37 years (range: 06 to 79 years and in the same number of age and sex matched controls. It was observed that BM-MSC of AA patients had a morphology, phenotype, and osteogenic differentiation potential similar to control subjects but adipocytes differentiated from AA BM-MSC had a higher density and larger size of lipid droplets and they expressed significantly higher levels of adiponectin and FABP4 genes and proteins as compared to control BM-MSC (P<0.01 for both. Thus our data shows that AA BM-MSC have enhanced adipogenicity, which may have an important implication in the pathogenesis of the disease.

  12. Solving modal equations of motion with initial conditions using MSC/NASTRAN DMAP. Part 2: Coupled versus uncoupled integration

    Science.gov (United States)

    Barnett, Alan R.; Ibrahim, Omar M.; Abdallah, Ayman A.; Sullivan, Timothy L.

    1993-05-01

    By utilizing MSC/NASTRAN DMAP (Direct Matrix Abstraction Program) in an existing NASA Lewis Research Center coupled loads methodology, solving modal equations of motion with initial conditions is possible using either coupled (Newmark-Beta) or uncoupled (exact mode superposition) integration available within module TRD1. Both the coupled and newly developed exact mode superposition methods have been used to perform transient analyses of various space systems. However, experience has shown that in most cases, significant time savings are realized when the equations of motion are integrated using the uncoupled solver instead of the coupled solver. Through the results of a real-world engineering analysis, advantages of using the exact mode superposition methodology are illustrated.

  13. Solving Modal Equations of Motion with Initial Conditions Using MSC/NASTRAN DMAP. Part 2; Coupled Versus Uncoupled Integration

    Science.gov (United States)

    Barnett, Alan R.; Ibrahim, Omar M.; Abdallah, Ayman A.; Sullivan, Timothy L.

    1993-01-01

    By utilizing MSC/NASTRAN DMAP (Direct Matrix Abstraction Program) in an existing NASA Lewis Research Center coupled loads methodology, solving modal equations of motion with initial conditions is possible using either coupled (Newmark-Beta) or uncoupled (exact mode superposition) integration available within module TRD1. Both the coupled and newly developed exact mode superposition methods have been used to perform transient analyses of various space systems. However, experience has shown that in most cases, significant time savings are realized when the equations of motion are integrated using the uncoupled solver instead of the coupled solver. Through the results of a real-world engineering analysis, advantages of using the exact mode superposition methodology are illustrated.

  14. CRANK-PISTON MODEL OF INTERNAL COMBUSTION ENGINE USING CAD/CAM/CAE IN THE MSC ADAMS

    Directory of Open Access Journals (Sweden)

    Michał BIAŁY

    2017-03-01

    Full Text Available The article presents the modeling and simulation of the crank-piston model of internal combustion engine. The object of the research was the engine of the vehicle from the B segment. The individual elements of the gasoline engine were digitizing using the process of reverse engineering. After converting the geometry, assembling was imported to MSC Adams software. The crank-piston system was specified by boundary conditions of piston forces applied on the pistons crowns. This force was obtain from the cylinder pressure recorded during the tests, that were carried out on a chassis dynamometer. The simulation studies allowed t determine the load distribution in a dynamic state for the selected kinematic pairs.

  15. Input Files and Procedures for Analysis of SMA Hybrid Composite Beams in MSC.Nastran and ABAQUS

    Science.gov (United States)

    Turner, Travis L.; Patel, Hemant D.

    2005-01-01

    A thermoelastic constitutive model for shape memory alloys (SMAs) and SMA hybrid composites (SMAHCs) was recently implemented in the commercial codes MSC.Nastran and ABAQUS. The model is implemented and supported within the core of the commercial codes, so no user subroutines or external calculations are necessary. The model and resulting structural analysis has been previously demonstrated and experimentally verified for thermoelastic, vibration and acoustic, and structural shape control applications. The commercial implementations are described in related documents cited in the references, where various results are also shown that validate the commercial implementations relative to a research code. This paper is a companion to those documents in that it provides additional detail on the actual input files and solution procedures and serves as a repository for ASCII text versions of the input files necessary for duplication of the available results.

  16. Education of 'nuclear' students (BSc and MSc curricula) at the Faculty of Nuclear Science and Physical Engineering, Czech Technical University in Prague

    International Nuclear Information System (INIS)

    Matejka, K.; Zeman, J.

    2003-01-01

    The Faculty of Nuclear Science and Physical Engineering, Czech Technical University in Prague has been educating nuclear power engineering experts for nearly half a century. The article describes the current status and prospects of education of new specialists at the faculty for all nuclear power-related areas within the MSc and BSc level curricula. The current transition to 'European type' structured education, enabling students who have graduated from the BSc programme to continue smoothly their MSc programme, is outlined. The major courses of the 'Nuclear Engineering' educational specialisation, focused on nuclear power, environment, and dosimetry, are highlighted, including the number of lessons taught in each study year. (author)

  17. Insufficient stromal support in MDS results from molecular and functional deficits of mesenchymal stromal cells.

    Science.gov (United States)

    Geyh, S; Oz, S; Cadeddu, R-P; Fröbel, J; Brückner, B; Kündgen, A; Fenk, R; Bruns, I; Zilkens, C; Hermsen, D; Gattermann, N; Kobbe, G; Germing, U; Lyko, F; Haas, R; Schroeder, T

    2013-09-01

    Ineffective hematopoiesis is a major characteristic of myelodysplastic syndromes (MDS) causing relevant morbidity and mortality. Mesenchymal stromal cells (MSC) have been shown to physiologically support hematopoiesis, but their contribution to the pathogenesis of MDS remains elusive. We show that MSC from patients across all MDS subtypes (n=106) exhibit significantly reduced growth and proliferative capacities accompanied by premature replicative senescence. Osteogenic differentiation was significantly reduced in MDS-derived MSC, indicated by cytochemical stainings and reduced expressions of Osterix and Osteocalcin. This was associated with specific methylation patterns that clearly separated MDS-MSC from healthy controls and showed a strong enrichment for biological processes associated with cellular phenotypes and transcriptional regulation. Furthermore, in MDS-MSC, we detected altered expression of key molecules involved in the interaction with hematopoietic stem and progenitor cells (HSPC), in particular Osteopontin, Jagged1, Kit-ligand and Angiopoietin as well as several chemokines. Functionally, this translated into a significantly diminished ability of MDS-derived MSC to support CD34+ HSPC in long-term culture-initiating cell assays associated with a reduced cell cycle activity. Taken together, our comprehensive analysis shows that MSC from all MDS subtypes are structurally, epigenetically and functionally altered, which leads to impaired stromal support and seems to contribute to deficient hematopoiesis in MDS.

  18. Endovenous administration of bone-marrow-derived multipotent mesenchymal stromal cells prevents renal failure in diabetic mice.

    Science.gov (United States)

    Ezquer, Fernando; Ezquer, Marcelo; Simon, Valeska; Pardo, Fabian; Yañez, Alejandro; Carpio, Daniel; Conget, Paulette

    2009-11-01

    Twenty-five to 40% of diabetic patients develop diabetic nephropathy, a clinical syndrome that comprises renal failure and increased risk of cardiovascular disease. It represents the major cause of chronic kidney disease and is associated with premature morbimortality of diabetic patients. Multipotent mesenchymal stromal cells (MSC) contribute to the regeneration of several organs, including acutely injured kidney. We sought to evaluate if MSC protect kidney function and structure when endovenously administered to mice with severe diabetes. A month after nonimmunologic diabetes induction by streptozotocin injection, C57BL/6 mice presented hyperglycemia, glycosuria, hypoinsulinemia, massive beta-pancreatic islet destruction, low albuminuria, but not renal histopathologic changes (DM mice). At this stage, one group of animals received the vehicle (untreated) and other group received 2 doses of 0.5 x 10(6) MSC/each (MSC-treated). Untreated DM mice gradually increased urinary albumin excretion and 4 months after diabetes onset, they reached values 15 times higher than normal animals. In contrast, MSC-treated DM mice maintained basal levels of albuminuria. Untreated DM mice had marked glomerular and tubular histopathologic changes (sclerosis, mesangial expansion, tubular dilatation, proteins cylinders, podocytes lost). However, MSC-treated mice showed only slight tubular dilatation. Observed renoprotection was not associated with an improvement in endocrine pancreas function in this animal model, because MSC-treated DM mice remained hyperglycemic and hypoinsulinemic, and maintained few remnant beta-pancreatic islets throughout the study period. To study MSC biodistribution, cells were isolated from isogenic mice that constitutively express GFP (MSC(GFP)) and endovenously administered to DM mice. Although at very low levels, donor cells were found in kidney of DM mice 3 month after transplantation. Presented preclinical results support MSC administration as a cell

  19. Testing the membrane paradigm with holography

    NARCIS (Netherlands)

    de Boer, J.; Heller, M.P.; Pinzani-Fokeeva, N.

    2015-01-01

    One version of the membrane paradigm states that, as far as outside observers are concerned, black holes can be replaced by a dissipative membrane with simple physical properties located at the stretched horizon. We demonstrate that such a membrane paradigm is incomplete in several aspects. We argue

  20. The Technological Paradigm of Psychological Research

    Science.gov (United States)

    Kvale, Steinar

    1973-01-01

    The experiment in physics has often been pictured as an ideal for the less mature social sciences, especially by positivist philosophy of science. The thesis to be presented here is that the physical experiment as a paradigm for psychology is merely a pretext, a smoke-screen for a more fundamental and concealed technological paradigm for the study…

  1. Is This the Paradigm Shift We Need?

    Science.gov (United States)

    Mirvis, Jonathan

    2012-01-01

    Dr. Woocher's essay, states Mirvis, is seminal in the field of Jewish education. It proposes a new paradigm for Jewish education in North America. This proposed paradigm is supported by a comprehensive multi-disciplinary research drawing on literature from education, philosophy, history, sociology, psychology, and economics. The essay reflects a…

  2. Derfor har vi brug for paradigmer

    DEFF Research Database (Denmark)

    Kragh, Kirsten A. Jeppesen; Schøsler, Lene

    2016-01-01

    Based on previous studies on verbs of perception in French and Ita- lian, this study claims that the notion of paradigm is useful for the understanding of grammatical structure. Our case-study concerns the status of Modern French voir in the paradigms of presentation and of progressivity....

  3. The Failure of Progressive Paradigm Reversal

    Science.gov (United States)

    Guthrie, Gerard

    2017-01-01

    The student-centred, progressive paradigm has not had sustained success in changing teacher-centred, formalistic practices in "developing" country classrooms. Does "Gestalt-switch" and paradigm reversal demonstrate that progressive theory has realigned with formalistic reality, or has it remained axiomatic in the research and…

  4. Priming Adipose-Derived Mesenchymal Stem Cells with Hyaluronan Alters Growth Kinetics and Increases Attachment to Articular Cartilage

    Directory of Open Access Journals (Sweden)

    Peter Succar

    2016-01-01

    Full Text Available Background. Biological therapeutics such as adipose-derived mesenchymal stem cell (MSC therapy are gaining acceptance for knee-osteoarthritis (OA treatment. Reports of OA-patients show reductions in cartilage defects and regeneration of hyaline-like-cartilage with MSC-therapy. Suspending MSCs in hyaluronan commonly occurs in animals and humans, usually without supporting data. Objective. To elucidate the effects of different concentrations of hyaluronan on MSC growth kinetics. Methods. Using a range of hyaluronan concentrations, we measured MSC adherence and proliferation on culture plastic surfaces and a novel cartilage-adhesion assay. We employed time-course and dispersion imaging to assess MSC binding to cartilage. Cytokine profiling was also conducted on the MSC-secretome. Results. Hyaluronan had dose-dependent effects on growth kinetics of MSCs at concentrations of entanglement point (1 mg/mL. At higher concentrations, viscosity effects outweighed benefits of additional hyaluronan. The cartilage-adhesion assay highlighted for the first time that hyaluronan-primed MSCs increased cell attachment to cartilage whilst the presence of hyaluronan did not. Our time-course suggested patients undergoing MSC-therapy for OA could benefit from joint-immobilisation for up to 8 hours. Hyaluronan also greatly affected dispersion of MSCs on cartilage. Conclusion. Our results should be considered in future trials with MSC-therapy using hyaluronan as a vehicle, for the treatment of OA.

  5. Mechanisms of Cdc42-mediated rat MSC differentiation on micro/nano-textured topography.

    Science.gov (United States)

    Li, Guangwen; Song, Yanyan; Shi, Mengqi; Du, Yuanhong; Wang, Wei; Zhang, Yumei

    2017-02-01

    Micro/nano-textured titanium surface topography promotes osteoblast differentiation and the Wnt/β-catenin signaling pathway. However, the response of rat bone mesenchymal stem cells (MSCs) to micro/nano-textured topography, and the underlying mechanisms of its effects, are not well understood. We hypothesized that cell division cycle 42 protein (Cdc42), a key member of the Rho GTPases family, may regulate rat MSCs morphology and osteogenic differentiation by micro/nano-textured topography, and that crosstalk between Cdc42 and Wnt/β-catenin is the underlying mechanism. To confirm the hypothesis, we first tested rat MSCs' morphology, cytoskeleton, and osteogenic differentiation on micro/nano-textured topography. We then examined the cells' Wnt pathway and Cdc42 signaling activity. The results show that micro/nano-textured topography enhances MSCs' osteogenic differentiation. In addition, the cells' morphology and cytoskeletal reorganization were dramatically different on smooth surfaces and micropitted/nanotubular topography. Ligands of the canonical Wnt pathway, as well as accumulation of β-catenin in the nucleus, were up-regulated by micro/nano-textured topography. Cdc42 protein expression was markedly increased under these conditions; conversely, Cdc42 silencing significantly depressed the enhancement of MSCs osteogenic differentiation by micro/nano-textured topography. Moreover, Cdc42si attenuated p-GSK3β activation and resulted in β-catenin cytoplasmic degradation on the micro/nano-textured topography. Our results indicate that Cdc42 is a key modulator of rat MSCs morphology and cytoskeletal reorganization, and that crosstalk between Cdc42 and Wnt/β-catenin signaling though GSK3β regulates MSCs osteogenic differentiation by implant topographical cues. Topographical modification at micro- and nanoscale is widely applied to enhance the tissue integration properties of biomaterials. However, the response of bone mesenchymal stem cells (MSCs) to the micro

  6. A New Paradigm for Chemical Engineering?

    DEFF Research Database (Denmark)

    Gani, Rafiqul

    businesses has been observed. There is an increasing trend within the chemical industry to focus on products and the sustainable processes that can make them. Do these changes point to a paradigm shift in chemical engineering as a discipline? Historically, two previous paradigm shifts in chemical engineering...... corresponded to major shifts in chemical engineering as a discipline, which affected not only the education of chemical engineers, but also the development of chemical engineering as a discipline. Has the time come for a new paradigm shift that will prepare the current and future chemical engineering graduates...... to tackle the complex problems facing the chemicals based industries and serve the modern society more efficiently? The lecture will review the current status of chemical engineering as a discipline, the proposals for the third paradigm, the need for such a paradigm shift and related educational issues....

  7. Allogeneic Mesenchymal Stem Cell Treatment Induces Specific Alloantibodies in Horses

    Directory of Open Access Journals (Sweden)

    Sean D. Owens

    2016-01-01

    Full Text Available Background. It is unknown whether horses that receive allogeneic mesenchymal stem cells (MSCs injections develop specific humoral immune response. Our goal was to develop and validate a flow cytometric MSC crossmatch procedure and to determine if horses that received allogeneic MSCs in a clinical setting developed measurable antibodies following MSC administration. Methods. Serum was collected from a total of 19 horses enrolled in 3 different research projects. Horses in the 3 studies all received unmatched allogeneic MSCs. Bone marrow (BM or adipose tissue derived MSCs (ad-MSCs were administered via intravenous, intra-arterial, intratendon, or intraocular routes. Anti-MSCs and anti-bovine serum albumin antibodies were detected via flow cytometry and ELISA, respectively. Results. Overall, anti-MSC antibodies were detected in 37% of the horses. The majority of horses (89% were positive for anti-bovine serum albumin (BSA antibodies prior to and after MSC injection. Finally, there was no correlation between the amount of anti-BSA antibody and the development of anti-MSC antibodies. Conclusion. Anti allo-MSC antibody development was common; however, the significance of these antibodies is unknown. There was no correlation between either the presence or absence of antibodies and the percent antibody binding to MSCs and any adverse reaction to a MSC injection.

  8. Mesenchymal stem cells induce T-cell tolerance and protect the preterm brain after global hypoxia-ischemia.

    Directory of Open Access Journals (Sweden)

    Reint K Jellema

    Full Text Available Hypoxic-ischemic encephalopathy (HIE in preterm infants is a severe disease for which no curative treatment is available. Cerebral inflammation and invasion of activated peripheral immune cells have been shown to play a pivotal role in the etiology of white matter injury, which is the clinical hallmark of HIE in preterm infants. The objective of this study was to assess the neuroprotective and anti-inflammatory effects of intravenously delivered mesenchymal stem cells (MSC in an ovine model of HIE. In this translational animal model, global hypoxia-ischemia (HI was induced in instrumented preterm sheep by transient umbilical cord occlusion, which closely mimics the clinical insult. Intravenous administration of 2 x 10(6 MSC/kg reduced microglial proliferation, diminished loss of oligodendrocytes and reduced demyelination, as determined by histology and Diffusion Tensor Imaging (DTI, in the preterm brain after global HI. These anti-inflammatory and neuroprotective effects of MSC were paralleled by reduced electrographic seizure activity in the ischemic preterm brain. Furthermore, we showed that MSC induced persistent peripheral T-cell tolerance in vivo and reduced invasion of T-cells into the preterm brain following global HI. These findings show in a preclinical animal model that intravenously administered MSC reduced cerebral inflammation, protected against white matter injury and established functional improvement in the preterm brain following global HI. Moreover, we provide evidence that induction of T-cell tolerance by MSC might play an important role in the neuroprotective effects of MSC in HIE. This is the first study to describe a marked neuroprotective effect of MSC in a translational animal model of HIE.

  9. Aging of marrow stromal (skeletal) stem cells and their contribution to age-related bone loss

    DEFF Research Database (Denmark)

    Bellantuono, Ilaria; Aldahmash, Abdullah; Kassem, Moustapha

    2009-01-01

    Marrow stromal cells (MSC) are thought to be stem cells with osteogenic potential and therefore responsible for the repair and maintenance of the skeleton. Age related bone loss is one of the most prevalent diseases in the elder population. It is controversial whether MSC undergo a process of aging...... in vivo, leading to decreased ability to form and maintain bone homeostasis with age. In this review we summarize evidence of MSC involvement in age related bone loss and suggest new emerging targets for intervention....

  10. Mesenchymal Stem Cell-Based Tumor-Targeted Gene Therapy in Gastrointestinal Cancer

    Science.gov (United States)

    Bao, Qi; Zhao, Yue; Niess, Hanno; Conrad, Claudius; Schwarz, Bettina; Jauch, Karl-Walter; Huss, Ralf; Nelson, Peter J.

    2012-01-01

    Mesenchymal stem (or stromal) cells (MSCs) are nonhematopoietic progenitor cells that can be obtained from bone marrow aspirates or adipose tissue, expanded and genetically modified in vitro, and then used for cancer therapeutic strategies in vivo. Here, we review available data regarding the application of MSC-based tumor-targeted therapy in gastrointestinal cancer, provide an overview of the general history of MSC-based gene therapy in cancer research, and discuss potential problems associated with the utility of MSC-based therapy such as biosafety, immunoprivilege, transfection methods, and distribution in the host. PMID:22530882

  11. How to Improve the Survival of Transplanted Mesenchymal Stem Cell in Ischemic Heart?

    Directory of Open Access Journals (Sweden)

    Liangpeng Li

    2016-01-01

    Full Text Available Mesenchymal stem cell (MSC is an intensely studied stem cell type applied for cardiac repair. For decades, the preclinical researches on animal model and clinical trials have suggested that MSC transplantation exerts therapeutic effect on ischemic heart disease. However, there remain major limitations to be overcome, one of which is the very low survival rate after transplantation in heart tissue. Various strategies have been tried to improve the MSC survival, and many of them showed promising results. In this review, we analyzed the studies in recent years to summarize the methods, effects, and mechanisms of the new strategies to address this question.

  12. High content imaging in the screening of biomaterial-induced MSC behavior.

    Science.gov (United States)

    Unadkat, H V; Groen, N; Doorn, J; Fischer, B; Barradas, A M C; Hulsman, M; van de Peppel, J; Moroni, L; van Leeuwen, J P; Reinders, M J T; van Blitterswijk, C A; de Boer, J

    2013-02-01

    Upon contact with a biomaterial, cells and surrounding tissues respond in a manner dictated by the physicochemical and mechanical properties of the material. Traditionally, cellular responses are monitored using invasive analytical methods that report the expression of genes or proteins. These analytical methods involve assessing commonly used markers for a predefined readout, masking the actual situation induced in the cells. Hence, a broader expression profile of the cellular response should be envisioned, which technically limits up scaling to higher throughput systems. However, it is increasingly recognized that morphometric readouts, obtained non-invasively, are related to gene expression patterns. Here, we introduced distinct surface roughness to three PLA surfaces, by exposure to oxygen plasma of different duration times. The response of mesenchymal stromal cells was compared to smooth untreated PLA surfaces without the addition of differentiation agents. Morphological and genome wide expression profiles revealed underlying cellular changes which was hidden for the commonly used gene markers for osteo-, chondro- and adipogenesis. Using 3 morphometric parameters, obtained by high content imaging, we were able to build a classifier and discriminate between oxygen plasma-induced modified sheets and non-modified PLA sheets where evaluating classical candidates missed this effect. This approach shows the feasibility to use noninvasive morphometric data in high-throughput systems to screen biomaterial surfaces indicating the underlying genetic biomaterial-induced changes. Copyright © 2012 Elsevier Ltd. All rights reserved.

  13. Cryopreserved mesenchymal stromal cells display impaired immunosuppressive properties as a result of heat-shock response and impaired interferon-γ licensing.

    Science.gov (United States)

    François, Moïra; Copland, Ian B; Yuan, Shala; Romieu-Mourez, Raphaëlle; Waller, Edmund K; Galipeau, Jacques

    2012-02-01

    Human mesenchymal stromal cells (MSC) can suppress T-cell activation in vitro in an indoleamine 2,3-dioxygenase (IDO)-dependent manner. However, their clinical effects on immune ailments have been inconsistent, with a recent phase III study showing no benefit in acute graft-versus-host disease (GvHD). We here tested the hypothesis that the banked, cryopreserved MSC often used in clinical trials display biologic properties distinct from that of MSC in the log phase of growth typically examined in pre-clinical studies. In freshly thawed cryopreserved MSC derived from normal human volunteers, we observed that MSC up-regulate heat-shock proteins, are refractory to interferon (IFN)-γ-induced up-regulation of IDO, and are compromised in suppressing CD3/CD28-driven T cell proliferation. Immune suppressor activity, IFN-γ responsiveness and induction of IDO were fully restored following 24 h of MSC tissue culture post-thaw. These results highlight a possible cause for the inefficacy of MSC-based immunotherapy reported in clinical trials using cryopreserved MSC thawed immediately prior to infusion.

  14. Exosomes Derived from Mesenchymal Stem Cells Suppress Angiogenesis by Down-Regulating VEGF Expression in Breast Cancer Cells

    Science.gov (United States)

    Lee, Jong-Kuen; Park, Sae-Ra; Jung, Bong-Kwang; Jeon, Yoon-Kyung; Lee, Yeong-Shin; Kim, Min-Kyoung; Kim, Yong-Goo; Jang, Ji-Young; Kim, Chul-Woo

    2013-01-01

    Exosomes are small membrane vesicles released by a variety of cell types. Exosomes contain genetic materials, such as mRNAs and microRNAs (miRNAs), implying that they may play a pivotal role in cell-to-cell communication. Mesenchymal stem cells (MSCs), which potentially differentiate into multiple cell types, can migrate to the tumor sites and have been reported to exert complex effects on tumor progression. To elucidate the role of MSCs within the tumor microenvironment, previous studies have suggested various mechanisms such as immune modulation and secreted factors of MSCs. However, the paracrine effects of MSC-derived exosomes on the tumor microenvironment remain to be explored. The hypothesis of this study was that MSC-derived exosomes might reprogram tumor behavior by transferring their molecular contents. To test this hypothesis, exosomes from MSCs were isolated and characterized. MSC-derived exosomes exhibited different protein and RNA profiles compared with their donor cells and these vesicles could be internalized by breast cancer cells. The results demonstrated that MSC-derived exosomes significantly down-regulated the expression of vascular endothelial growth factor (VEGF) in tumor cells, which lead to inhibition of angiogenesis in vitro and in vivo. Additionally, miR-16, a miRNA known to target VEGF, was enriched in MSC-derived exosomes and it was partially responsible for the anti-angiogenic effect of MSC-derived exosomes. The collective results suggest that MSC-derived exosomes may serve as a significant mediator of cell-to-cell communication within the tumor microenvironment and suppress angiogenesis by transferring anti-angiogenic molecules. PMID:24391924

  15. Black holes: the membrane paradigm

    International Nuclear Information System (INIS)

    Thorne, K.S.; Price, R.H.; Macdonald, D.A.

    1986-01-01

    The physics of black holes is explored in terms of a membrane paradigm which treats the event horizon as a two-dimensional membrane embedded in three-dimensional space. A 3+1 formalism is used to split Schwarzschild space-time and the laws of physics outside a nonrotating hole, which permits treatment of the atmosphere in terms of the physical properties of thin slices. The model is applied to perturbed slowly or rapidly rotating and nonrotating holes, and to quantify the electric and magnetic fields and eddy currents passing through a membrane surface which represents a stretched horizon. Features of tidal gravitational fields in the vicinity of the horizon, quasars and active galalctic nuclei, the alignment of jets perpendicular to accretion disks, and the effects of black holes at the center of ellipsoidal star clusters are investigated. Attention is also given to a black hole in a binary system and the interactions of black holes with matter that is either near or very far from the event horizon. Finally, a statistical mechanics treatment is used to derive a second law of thermodynamics for a perfectly thermal atmosphere of a black hole

  16. A handy new design paradigm

    Directory of Open Access Journals (Sweden)

    B. Bergelin

    2011-02-01

    Full Text Available In light of technological advances, researchers have lost sight of robotic grippers/end effectors design intent. In a semi-structured environment the biomimetic approach is impractical due to the high complexity of the mechanism and control algorithms. Current industrial grippers are robust, but lack the flexibility that allows for in hand manipulation. The authors believe that underactuated grippers provide the best approach to allow for in hand manipulation along with being rugged enough for an industrial setting. Thinking of the robotic gripper and the robotic arm as one system (as opposed to two separate subsystems, one is capable of using the degrees of freedom of the robot in conjunction with that of the gripper to provide the desired motion profile without the complexity of running two subsystems. This paper will outline where recent grippers have failed and will introduce a new design paradigm for grippers along with several underactuated gripper ideas.

    This paper was presented at the IFToMM/ASME International Workshop on Underactuated Grasping (UG2010, 19 August 2010, Montréal, Canada.

  17. Anti-Donor Immune Responses Elicited by Allogeneic Mesenchymal Stem Cells and Their Extracellular Vesicles: Are We Still Learning?

    Directory of Open Access Journals (Sweden)

    Paul Lohan

    2017-11-01

    Full Text Available Mesenchymal stromal cells (MSC have been used to treat a broad range of disease indications such as acute and chronic inflammatory disorders, autoimmune diseases, and transplant rejection due to their potent immunosuppressive/anti-inflammatory properties. The breadth of their usage is due in no small part to the vast quantity of published studies showing their ability to modulate multiple immune cell types of both the innate and adaptive immune response. While patient-derived (autologous MSC may be the safer choice in terms of avoiding unwanted immune responses, factors including donor comorbidities may preclude these cells from use. In these situations, allogeneic MSC derived from genetically unrelated individuals must be used. While allogeneic MSC were initially believed to be immune-privileged, substantial evidence now exists to prove otherwise with multiple studies documenting specific cellular and humoral immune responses against donor antigens following administration of these cells. In this article, we will review recent published studies using non-manipulated, inflammatory molecule-activated (licensed and differentiated allogeneic MSC, as well as MSC extracellular vesicles focusing on the immune responses to these cells and whether or not such responses have an impact on allogeneic MSC-mediated safety and efficacy.

  18. Tridimensional configurations of human mesenchymal stem/stromal cells to enhance cell paracrine potential towards wound healing processes.

    Science.gov (United States)

    Costa, Marta H G; McDevitt, Todd C; Cabral, Joaquim M S; da Silva, Cláudia L; Ferreira, Frederico Castelo

    2017-11-20

    This study proposes to use alginate encapsulation as a strategy to assess the paracrine activity of 3D- and 2D-cultured human bone marrow mesenchymal stem/stromal cells (BM MSC) in the setting of wound repair and regeneration processes. A side-by-side comparison of MSC culture in three different 3D configurations (spheroids, encapsulated spheroids and encapsulated single cells) versus 2D monolayer cell culture is presented. The results reveal enhanced resistance to oxidative stress and paracrine potential of 3D spheroid-organized BM MSC. MSC spheroids (148±2μm diameter) encapsulated in alginate microbeads evidence increased angiogenic and chemotactic potential relatively to encapsulated single cells, as supported by higher secreted levels of angiogenic factors and by functional assays showing the capability of encapsulated MSC to promote formation of tubelike structures and migration of fibroblasts into a wounded area. In addition, a higher expression of the anti-inflammatory factor tumor necrosis factor alpha-induced protein 6 (TSG-6) was demonstrated by RT-PCR for encapsulated and non-encapsulated spheroids. Culture of spheroids within an alginate matrix maintains low aggregation levels below 5% and favors resistance to oxidative stress. These are important factors towards the establishment of more standardized and controlled systems, crucial to explore the paracrine effects of 3D-cultured MSC in therapeutic settings. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Adipogenic Differentiation of Mesenchymal Stem Cells Alters Their Immunomodulatory Properties in a Tissue-Specific Manner.

    Science.gov (United States)

    Munir, Hafsa; Ward, Lewis S C; Sheriff, Lozan; Kemble, Samuel; Nayar, Saba; Barone, Francesca; Nash, Gerard B; McGettrick, Helen M

    2017-06-01

    Chronic inflammation is associated with formation of ectopic fat deposits that might represent damage-induced aberrant mesenchymal stem cell (MSC) differentiation. Such deposits are associated with increased levels of inflammatory infiltrate and poor prognosis. Here we tested the hypothesis that differentiation from MSC to adipocytes in inflamed tissue might contribute to chronicity through loss of immunomodulatory function. We assessed the effects of adipogenic differentiation of MSC isolated from bone marrow or adipose tissue on their capacity to regulate neutrophil recruitment by endothelial cells and compared the differentiated cells to primary adipocytes from adipose tissue. Bone marrow derived MSC were immunosuppressive, inhibiting neutrophil recruitment to TNFα-treated endothelial cells (EC), but MSC-derived adipocytes were no longer able to suppress neutrophil adhesion. Changes in IL-6 and TGFβ1 signalling appeared critical for the loss of the immunosuppressive phenotype. In contrast, native stromal cells, adipocytes derived from them, and mature adipocytes from adipose tissue were all immunoprotective. Thus disruption of normal tissue stroma homeostasis, as occurs in chronic inflammatory diseases, might drive "abnormal" adipogenesis which adversely influences the behavior of MSC and contributes to pathogenic recruitment of leukocytes. Interestingly, stromal cells programmed in native fat tissue retain an immunoprotective phenotype. Stem Cells 2017;35:1636-1646. © 2017 The Authors STEM CELLS published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

  20. Metabolic syndrome alters expression of insulin signaling-related genes in swine mesenchymal stem cells.

    Science.gov (United States)

    Conley, Sabena M; Zhu, Xiang-Yang; Eirin, Alfonso; Tang, Hui; Lerman, Amir; van Wijnen, Andre J; Lerman, Lilach O

    2018-02-20

    Metabolic syndrome (MetS) is associated with insulin resistance (IR) and impaired glucose metabolism in muscle, fat, and other cells, and may induce inflammation and vascular remodeling. Endogenous reparative systems, including adipose tissue-derived mesenchymal stem/stromal cells (MSC), are responsible for repair of damaged tissue. MSC have also been proposed as an exogenous therapeutic intervention in patients with cardiovascular and chronic kidney disease (CKD). The feasibility of using autologous cells depends on their integrity, but whether in MetS IR involves adipose tissue-derived MSC remains unknown. The aim of this study was to examine the expression of mRNA involved in insulin signaling in MSC from subjects with MetS. Domestic pigs consumed a lean or obese diet (n=6 each) for 16weeks. MSC were collected from subcutaneous abdominal fat and analyzed using high-throughput RNA-sequencing for expression of genes involved in insulin signaling. Expression profiles for enriched (fold change>1.4, pinsulin signaling. Enriched mRNAs were implicated in biological pathways including hepatic glucose metabolism, adipocyte differentiation, and transcription regulation, and down-regulated mRNAs in intracellular calcium signaling and cleaving peptides. Functional analysis suggested that overall these alterations could increase IR. MetS alters mRNA expression related to insulin signaling in adipose tissue-derived MSC. These observations mandate caution during administration of autologous MSC in subjects with MetS. Copyright © 2017. Published by Elsevier B.V.

  1. Identification of Pathways in Liver Repair Potentially Targeted by Secretory Proteins from Human Mesenchymal Stem Cells

    Directory of Open Access Journals (Sweden)

    Sandra Winkler

    2016-07-01

    Full Text Available Background: The beneficial impact of mesenchymal stem cells (MSC on both acute and chronic liver diseases has been confirmed, although the molecular mechanisms behind it remain elusive. We aim to identify factors secreted by undifferentiated and hepatocytic differentiated MSC in vitro in order to delineate liver repair pathways potentially targeted by MSC. Methods: Secreted factors were determined by protein arrays and related pathways identified by biomathematical analyses. Results: MSC from adipose tissue and bone marrow expressed a similar pattern of surface markers. After hepatocytic differentiation, CD54 (intercellular adhesion molecule 1, ICAM-1 increased and CD166 (activated leukocyte cell adhesion molecule, ALCAM decreased. MSC secreted different factors before and after differentiation. These comprised cytokines involved in innate immunity and growth factors regulating liver regeneration. Pathway analysis revealed cytokine-cytokine receptor interactions, chemokine signalling pathways, the complement and coagulation cascades as well as the Januskinase-signal transducers and activators of transcription (JAK-STAT and nucleotide-binding oligomerization domain-like receptor (NOD-like receptor signalling pathways as relevant networks. Relationships to transforming growth factor β (TGF-β and hypoxia-inducible factor 1-α (HIF1-α signalling seemed also relevant. Conclusion: MSC secreted proteins, which differed depending on cell source and degree of differentiation. The factors might address inflammatory and growth factor pathways as well as chemo-attraction and innate immunity. Since these are prone to dysregulation in most liver diseases, MSC release hepatotropic factors, potentially supporting liver regeneration.

  2. Performance-enhanced mesenchymal stem cells via intracellular delivery of steroids

    Science.gov (United States)

    Ankrum, James A.; Dastidar, Riddhi G.; Ong, Joon Faii; Levy, Oren; Karp, Jeffrey M.

    2014-04-01

    Inadequate immunomodulatory potency of mesenchymal stem cells (MSC) may limit their therapeutic efficacy. We report glucocorticoid steroids augment MSC expression and activity of indoleamine-2,3-dioxygenase (IDO), a primary mediator of MSC immunomodulatory function. This effect depends on signaling through the glucocorticoid receptor and is mediated through up-regulation of FOXO3. Treatment of MSCs with glucocorticoids, budesonide or dexamethasone, enhanced IDO expression following IFN-γ stimulation in multiple donors and was able to restore IDO expression in over-passaged MSCs. As IDO enhancement was most notable when cells were continuously exposed to budesonide, we engineered MSC with budesonide loaded PLGA microparticles. MSC efficiently internalized budesonide microparticles and exhibited 4-fold enhanced IDO activity compared to budesonide preconditioned and naïve MSC, resulting in a 2-fold improvement in suppression of stimulated peripheral blood mononuclear cells in an IDO-dependent manner. Thus, the augmentation of MSC immune modulation may abrogate challenges associated with inadequate potency and enhance their therapeutic efficacy.

  3. Clinicopathologic findings following intra-articular injection of autologous and allogeneic placentally derived equine mesenchymal stem cells in horses.

    Science.gov (United States)

    Carrade, Danielle D; Owens, Sean D; Galuppo, Larry D; Vidal, Martin A; Ferraro, Gregory L; Librach, Fred; Buerchler, Sabine; Friedman, Michael S; Walker, Naomi J; Borjesson, Dori L

    2011-04-01

    The development of an allogeneic mesenchymal stem cell (MSC) product to treat equine disorders would be useful; however, there are limited in vivo safety data for horses. We hypothesized that the injection of self (autologous) and non-self (related allogeneic or allogeneic) MSC would not elicit significant alterations in physical examination, gait or synovial fluid parameters when injected into the joints of healthy horses. Sixteen healthy horses were used in this study. Group 1 consisted of foals (n = 6), group 2 consisted of their dams (n = 5) and group 3 consisted of half-siblings (n = 5) to group 1 foals. Prior to injection, MSC were phenotyped. Placentally derived MSC were injected into contralateral joints and MSC diluent was injected into a separate joint (control). An examination, including lameness evaluation and synovial fluid analysis, was performed at 0, 24, 48 and 72 h post-injection. MSC were major histocompatibility complex (MHC) I positive, MHC II negative and CD86 negative. Injection of allogeneic MSC did not elicit a systemic response. Local responses such as joint swelling or lameness were minimal and variable. Intra-articular MSC injection elicited marked inflammation within the synovial fluid (as measured by nucleated cell count, neutrophil number and total protein concentration). However, there were no significant differences between the degree and type of inflammation elicited by self and non-self-MSC. The healthy equine joint responds similarly to a single intra-articular injection of autologous and allogeneic MSC. This pre-clinical safety study is an important first step in the development of equine allogeneic stem cell therapies.

  4. Spatial organization of mesenchymal stem cells in vitro--results from a new individual cell-based model with podia.

    Directory of Open Access Journals (Sweden)

    Martin Hoffmann

    Full Text Available Therapeutic application of mesenchymal stem cells (MSC requires their extensive in vitro expansion. MSC in culture typically grow to confluence within a few weeks. They show spindle-shaped fibroblastoid morphology and align to each other in characteristic spatial patterns at high cell density. We present an individual cell-based model (IBM that is able to quantitatively describe the spatio-temporal organization of MSC in culture. Our model substantially improves on previous models by explicitly representing cell podia and their dynamics. It employs podia-generated forces for cell movement and adjusts cell behavior in response to cell density. At the same time, it is simple enough to simulate thousands of cells with reasonable computational effort. Experimental sheep MSC cultures were monitored under standard conditions. Automated image analysis was used to determine the location and orientation of individual cells. Our simulations quantitatively reproduced the observed growth dynamics and cell-cell alignment assuming cell density-dependent proliferation, migration, and morphology. In addition to cell growth on plain substrates our model captured cell alignment on micro-structured surfaces. We propose a specific surface micro-structure that according to our simulations can substantially enlarge cell culture harvest. The 'tool box' of cell migratory behavior newly introduced in this study significantly enhances the bandwidth of IBM. Our approach is capable of accommodating individual cell behavior and collective cell dynamics of a variety of cell types and tissues in computational systems biology.

  5. Rapid deterioration of preexisting renal insufficiency after autologous mesenchymal stem cell therapy

    Directory of Open Access Journals (Sweden)

    Jun-Seop Kim

    2017-06-01

    Full Text Available Administration of autologous mesenchymal stem cells (MSCs has been shown to improve renal function and histological findings in acute kidney injury (AKI models. However, its effects in chronic kidney disease (CKD are unclear, particularly in the clinical setting. Here, we report our experience with a CKD patient who was treated by intravenous infusion of autologous MSCs derived from adipose tissue in an unknown clinic outside of Korea. The renal function of the patient had been stable for several years before MSC administration. One week after the autologous MSC infusion, the preexisting renal insufficiency was rapidly aggravated without any other evidence of AKI. Hemodialysis was started 3 months after MSC administration. Renal biopsy findings at dialysis showed severe interstitial fibrosis and inflammatory cell infiltration, with a few cells expressing CD34 and CD117, 2 surface markers of stem cells. This case highlights the potential nephrotoxicity of autologous MSC therapy in CKD patients.

  6. Human bone marrow-derived and umbilical cord-derived mesenchymal stem cells for alleviating neuropathic pain in a spinal cord injury model

    OpenAIRE

    Yousefifard, Mahmoud; Nasirinezhad, Farinaz; Shardi Manaheji, Homa; Janzadeh, Atousa; Hosseini, Mostafa; Keshavarz, Mansoor

    2016-01-01

    Background Stem cell therapy can be used for alleviating the neuropathic pain induced by spinal cord injuries (SCIs). However, survival and differentiation of stem cells following their transplantation vary depending on the host and intrinsic factors of the cell. Therefore, the present study aimed to determine the effect of stem cells derived from bone marrow (BM-MSC) and umbilical cord (UC-MSC) on neuropathic pain relief. Methods A compression model was used to induce SCI in a rat model. A w...

  7. Use of most significant change (MSC) technique to evaluate health promotion training of maternal community health workers in Cianjur district, Indonesia.

    Science.gov (United States)

    Limato, Ralalicia; Ahmed, Rukhsana; Magdalena, Amelia; Nasir, Sudirman; Kotvojs, Fiona

    2018-02-01

    Maternal health promotion is a defined activity in the community integrated posts (Posyandu) in Indonesia. However, it is often neglected due to limited knowledge and skills of the community health workers (kader). We conducted health promotion training for the kader and village midwives in four villages in Cianjur district. This study describes the use of "most significant change" (MSC) technique to evaluate impact of health promotion to the beneficiaries and community at large. The MSC uses stories as raw data. Through interviews focused on perception of change, stories were collected from four pregnant women, eight kader and three village midwives. A Panel consisting of policy and programme managers and implementers read all the stories. The story by a pregnant woman who routinely attended Posyandu was selected as the story with most significant change. Her story highlighted changes in kader's knowledge and communication of health messages and attitude towards pregnant women. She expressed these changes impacted community awareness about health and to seek help from kader.The MSC technique enabled stakeholders to view raw data and evaluate the impact of health promotion from the beneficiary's perspective. At the same time, recipients of health promotion contributed to the decision process of evaluation through their stories. The different perspectives on the MSC reflected individual's objectives of the health promotion. The application of this technique is limited in maternal health promotion programme in Indonesia, and none have been published in peer reviewed journals. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  8. Evolution of the radiological protection paradigms

    International Nuclear Information System (INIS)

    Sordi, Gian Maria A.A.

    2009-01-01

    We consider as initial radiological protection paradigms those in vigour after the release of the atomic energy for pacific usages in 1955. In that occasion, only one paradigm was introduced, presently named dose limitation system. After arguing about the basis that raised the paradigm, we introduced the guidance, that is, the measurements to be implemented to comply with the paradigm. In that occasion, they were two, i.e., the radiation dose monitoring and the workplace classification. Afterwards, the reasons that caused the radiological protection paradigms changes in force until 1995 are discussed. The initial paradigm was modified introducing the justification and the optimization principles, adding that the radiological protection should be economical and effective. The guidance also increased to four: personal monitoring, workplace classification, reference level and workers classification. Afterwards, we give the main justifications for the present paradigms that besides the formers were added the dose constraints, the potential exposure and the annual risk limits. Due to these modifications, the workers classifications were eliminated from the guidance, but the potential exposure and the search for the dose constraints were added. Eventually, we discuss the tendencies for the next future and the main changes introduced by the ICRP in the Publication 103, 2007. (author)

  9. Ostracism Online: A social media ostracism paradigm.

    Science.gov (United States)

    Wolf, Wouter; Levordashka, Ana; Ruff, Johanna R; Kraaijeveld, Steven; Lueckmann, Jan-Matthis; Williams, Kipling D

    2015-06-01

    We describe Ostracism Online, a novel, social media-based ostracism paradigm designed to (1) keep social interaction experimentally controlled, (2) provide researchers with the flexibility to manipulate the properties of the social situation to fit their research purposes, (3) be suitable for online data collection, (4) be convenient for studying subsequent within-group behavior, and (5) be ecologically valid. After collecting data online, we compared the Ostracism Online paradigm with the Cyberball paradigm (Williams & Jarvis Behavior Research Methods, 38, 174-180, 2006) on need-threat and mood questionnaire scores (van Beest & Williams Journal of Personality and Social Psychology 91, 918-928, 2006). We also examined whether ostracized targets of either paradigm would be more likely to conform to their group members than if they had been included. Using a Bayesian analysis of variance to examine the individual effects of the different paradigms and to compare these effects across paradigms, we found analogous effects on need-threat and mood. Perhaps because we examined conformity to the ostracizers (rather than neutral sources), neither paradigm showed effects of ostracism on conformity. We conclude that Ostracism Online is a cost-effective, easy to use, and ecologically valid research tool for studying the psychological and behavioral effects of ostracism.

  10. Bioprocess integration for human mesenchymal stem cells: From up to downstream processing scale-up to cell proteome characterization.

    Science.gov (United States)

    Cunha, Bárbara; Aguiar, Tiago; Carvalho, Sofia B; Silva, Marta M; Gomes, Ricardo A; Carrondo, Manuel J T; Gomes-Alves, Patrícia; Peixoto, Cristina; Serra, Margarida; Alves, Paula M

    2017-04-20

    To deliver the required cell numbers and doses to therapy, scaling-up production and purification processes (at least to the liter-scale) while maintaining cells' characteristics is compulsory. Therefore, the aim of this work was to prove scalability of an integrated streamlined bioprocess compatible with current good manufacturing practices (cGMP) comprised by cell expansion, harvesting and volume reduction unit operations using human mesenchymal stem cells (hMSC) isolated from bone marrow (BM-MSC) and adipose tissue (AT-MSC). BM-MSC and AT-MSC expansion and harvesting steps were scaled-up from spinner flasks to 2L scale stirred tank single-use bioreactor using synthetic microcarriers and xeno-free medium, ensuring high cellular volumetric productivities (50×10 6 cellL -1 day -1 ), expansion factors (14-16 fold) and cell recovery yields (80%). For the concentration step, flat sheet cassettes (FSC) and hollow fiber cartridges (HF) were compared showing a fairly linear scale-up, with a need to slightly decrease the permeate flux (30-50 LMH, respectively) to maximize cell recovery yield. Nonetheless, FSC allowed to recover 18% more cells after a volume reduction factor of 50. Overall, at the end of the entire bioprocess more than 65% of viable (>95%) hMSC could be recovered without compromising cell's critical quality attributes (CQA) of viability, identity and differentiation potential. Alongside the standard quality assays, a proteomics workflow based on mass spectrometry tools was established to characterize the impact of processing on hMSC's CQA; These analytical tools constitute a powerful tool to be used in process design and development. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Local use-dependent sleep; synthesis of the new paradigm.

    Science.gov (United States)

    Krueger, James M; Tononi, Giulio

    2011-01-01

    The logic and potential mechanisms for a new paradigm, the local use-dependent view of sleep as a distributed dynamic process in brain, are presented. This new paradigm is needed because the current dominant top-down imposition of sleep on the brain by sleep regulatory centers is either silent or is of inadequate explanatory value for many well-known sleep phenomena, e.g. sleep inertia. Two mechanistic falsifiable hypotheses linking sleep to cell use and the emergence of sleep/wake states are presented. These hypotheses are not mutually exclusive and both firmly link sleep to activity-dependent epigenetic brain plasticity and the need to integrate and balance waking activity induced-network connectivity changes. The views presented herein emphasize the inseparability of sleep mechanisms from a connectivity sleep function.

  12. Soliciting strategies for developing cell-based reference materials to advance mesenchymal stromal cell research and clinical translation.

    Science.gov (United States)

    Viswanathan, Sowmya; Keating, Armand; Deans, Robert; Hematti, Peiman; Prockop, Darwin; Stroncek, David F; Stacey, Glyn; Weiss, Dan J; Mason, Christopher; Rao, Mahendra S

    2014-06-01

    The mesenchymal stromal cell (MSC) field continues to rapidly progress with a number of clinical trials initiated and completed, with some reported successes in multiple clinical indications, and a growing number of companies established. The field, nevertheless, faces several challenges. Persistent issues include the definition of a MSC and comparability between MSC preparations. This is because of inherent cell heterogeneity, the absence of markers that are unique to MSCs, and the difficulty in precisely defining them by developmental origin. Differences in the properties of MSCs also depend on the site of tissue harvest, phenotypic and genotypic characteristics of the donor and the isolation, and storage and expansion methods used. These differences may be sufficient to ensure that attributes of the final MSC product could differ in potentially significant ways. Since there are currently no gold standards, we propose using a reference material to establish methods of comparability among MSC preparations. We suggest four possible "ruler scenarios" and a method for global distribution. We further suggest that critical to establishing a reference material is the need to define protocols for comparing cells. The main purpose of this article is to solicit input in establishing a consensus-based comparison. A comparative approach will be critical to all stages of translation to better clarify mechanisms of MSC actions, define an optimal cell manufacturing process, ensure best practice clinical investigations, extend the use of an MSC product for new indications, protect an MSC product from imitators, and develop uniform reimbursement policies. Importantly, a reference material may enable a consensus on a practical definition of MSCs.

  13. The Cognitive Paradigm Ontology: Design and Application

    Science.gov (United States)

    Laird, Angela R.

    2013-01-01

    We present the basic structure of the Cognitive Paradigm Ontology (CogPO) for human behavioral experiments. While the experimental psychology and cognitive neuroscience literature may refer to certain behavioral tasks by name (e.g., the Stroop paradigm or the Sternberg paradigm) or by function (a working memory task, a visual attention task), these paradigms can vary tremendously in the stimuli that are presented to the subject, the response expected from the subject, and the instructions given to the subject. Drawing from the taxonomy developed and used by the BrainMap project (www.brainmap.org) for almost two decades to describe key components of published functional imaging results, we have developed an ontology capable of representing certain characteristics of the cognitive paradigms used in the fMRI and PET literature. The Cognitive Paradigm Ontology is being developed to be compliant with the Basic Formal Ontology (BFO), and to harmonize where possible with larger ontologies such as RadLex, NeuroLex, or the Ontology of Biomedical Investigations (OBI). The key components of CogPO include the representation of experimental conditions focused on the stimuli presented, the instructions given, and the responses requested. The use of alternate and even competitive terminologies can often impede scientific discoveries. Categorization of paradigms according to stimulus, response, and instruction has been shown to allow advanced data retrieval techniques by searching for similarities and contrasts across multiple paradigm levels. The goal of CogPO is to develop, evaluate, and distribute a domain ontology of cognitive paradigms for application and use in the functional neuroimaging community. PMID:21643732

  14. [Putrescine Promotes Human Marrow Mesenchymal Stem Cells to Differentiate along Osteogenic Pathway].

    Science.gov (United States)

    Chen, Jing-Li; Bi, Xiao-Yun; Zhang, Hui; Wang, Fang; Wang, Yan; Guo, Zi-Kuan

    2015-06-01

    To investigate the effects of putrescine on the growth and differentiation of human bone marrow mesenchymal stem cells (MSC) to develop a new inductive medium mixture for their osteogenic differentiation. Human bone marrow MSC were collected from three healthy donors and were used to observe the growth-promoting activity of putrescine with MTT test. Experiments were divided into 3 groups: (1) putrescine group, (2) positive control group (presence of dexamethasone, ascorbate, and glycerol phosphate) and negative group (d-alpha with 5% FCS). The cellular expression level of Runx-2 was detected by PCR assay after the culture was maintained for 1 week. After 2 weeks, the intracellular activity of alkaline phosphatase was revealed by histochemistry staining, the phosphatase activity, and the protein concentration in the cell lysates were also detected. Furthermore, MSC were cultured in the presence of putrescine for 2 weeks and Oil-red O staining was performed to reveal the differentiated adipocytes; the cells induced by the standard agent cocktail were used as the positive control. Putrescine promoted the proliferation of human marrow MSC in a dose-dependent manner. MSC exposed to putrescine at a concentration of 100 µmol/L for 1 week expressed greatly higher level of Runx-2, compared with the negative control. Alkaline phosphatase activity was evidently observed after MSC were maintained in the presence of putrescine for 2 weeks. The phosphatase activity contrasted to the protein content in putrescine-treated MSC was significantly higher than that of the control cells (0.87±0.012 vs 0.52±0.010) (Pputrescine did not differentiate into adipoblasts. Putrescine can promote the proliferation and osteogenic differentiation of MSC, suggesting the potential application of putrescine as a novel inductive agent for in vitro osteogenesis of MSC.

  15. Gas transmission : a paradigm shift

    International Nuclear Information System (INIS)

    Cornelson, D.W.

    1997-01-01

    The evolution of energy markets in North America was discussed. The investment opportunities that are possible in a deregulated energy market, be it in production or in the generation of energy commodities, in the development of midstream infrastructure, or in the provision of energy services, were outlined. Deregulation of crude oil, natural gas and electricity has resulted in significant changes in the structure of energy markets and the way in which customers are served. One of the advantages of competition regarding power generation is that it has turned energy into a commodity which has resulted in greater customer choice and efficiency. As one example of midstream infrastructure development, the Alliance Pipeline project was described. This project was conceived as a means to enhance the value of western Canadian natural gas. The 1,900 mile pipeline will run from British Columbia, through Alberta into Chicago where it will interconnect with the North American gas transmission grid. The pipeline is an efficient means of transporting energy from Western Canada to North American markets, and Alliance, as a lowest cost transporter, will continue to put pressure on the traditional infrastructure to become even more competitive at the margin. As such, Alliance represents a paradigm shift in energy transportation, and serves as an excellent example of the type of investment opportunity that a deregulated market can provide. It was suggested that innovation and competition in a deregulated North American energy market will continue to increase. As electricity is deregulated, the energy market will respond more quickly to changes in supply and demand than it did in the past, in an effort to satisfy the needs of investors and customers. This will provide increased opportunities for restructuring and further competition

  16. Biodistribution and Immunogenicity of Allogeneic Mesenchymal Stem Cells in a Rat Model of Intraarticular Chondrocyte Xenotransplantation

    Directory of Open Access Journals (Sweden)

    Maribel Marquina

    2017-11-01

    Full Text Available Xenogeneic chondrocytes and allogeneic mesenchymal stem cells (MSC are considered a potential source of cells for articular cartilage repair. We here assessed the immune response triggered by xenogeneic chondrocytes when injected intraarticularly, as well as the immunoregulatory effect of allogeneic bone marrow-derived MSC after systemic administration. To this end, a discordant xenotransplantation model was established by injecting three million porcine articular chondrocytes (PAC into the femorotibial joint of Lewis rats and monitoring the immune response. First, the fate of MSC injected using various routes was monitored in an in vivo imaging system. The biodistribution revealed a dependency on the injection route with MSC injected intravenously (i.v. succumbing early after 24 h and MSC injected intraperitoneally (i.p. lasting locally for at least 5 days. Importantly, no migration of MSC to the joint was detected in rats previously injected with PAC. MSC were then administered either i.v. 1 week before PAC injection or i.p. 3 weeks after to assess their immunomodulatory function on humoral and adaptive immune parameters. Anti-PAC IgM and IgG responses were detected in all PAC-injected rats with a peak at week 2 postinjection and reactivity remaining above baseline levels by week 18. IgG2a and IgG2b were the predominant and long-lasting IgG subtypes. By contrast, no anti-MSC antibody response was detected in the cohort injected with MSC only, but infusion of MSC before PAC injection temporarily augmented the anti-PAC antibody response. Consistent with a cellular immune response to PAC in PAC-injected rats, cytokine/chemokine profiling in serum by antibody array revealed a distinct pattern relative to controls characterized by elevation of multiple markers at week 2, as well as increases in proliferation in draining lymph nodes. Notably, systemic administration of allogeneic MSC under the described conditions did not diminish the immune

  17. PARADIGM OF EDUCATION FOR THE INFORMATION SOCIETY

    Directory of Open Access Journals (Sweden)

    Yuriy M. Bogachkov

    2015-10-01

    Full Text Available Considering total crisis in education in Informational Age, we suggest that to overcome the crisis, it is necessary to promote pedagogical science up from "pre-paradigm stage” to the "paradigm stage". For this purpose it is necessary to separate the "educational science" from "education." “Educational paradigm” in such study will be the subject of the science. The key concepts for the "pedagogical paradigm" should be the concepts of "educational practice", "class of problems" and "educational text". We offer some axioms around these concepts.

  18. The Prerequisites for a Degrowth Paradigm Shift

    DEFF Research Database (Denmark)

    Buch-Hansen, Hubert

    2018-01-01

    What would it take for a degrowth paradigm shift to take place? Drawing on contemporary critical political economy scholarship, this article identifies four prerequisites for socio-economic paradigm shifts: deep crisis, an alternative political project, a comprehensive coalition of social forces...... currently facing humanity. On the other hand, the prospects for a degrowth paradigm shift remain bleak: unlike political projects that became hegemonic in the past, degrowth has neither support from a comprehensive coalition of social forces nor any consent to its agenda among the broader population....

  19. Dynamic Consistency in Process Algebra: From Paradigm to ACP

    NARCIS (Netherlands)

    S. Andova; L.P.J. Groenewegen; E.P. de Vink (Erik Peter)

    2011-01-01

    htmlabstractThe coordination modelling language Paradigm addresses collaboration between components in terms of dynamic constraints. Within a Paradigm model, component dynamics are consistently specified at various levels of abstraction. The operational semantics of Paradigm is given. For a

  20. Non-multipotent stroma inhibit the proliferation and differentiation of mesenchymal stromal cells in vitro.

    Science.gov (United States)

    Rosu-Myles, Michael; Fair, Joel; Pearce, Nelson; Mehic, Jelica

    2010-10-01

    The ability to expand and maintain bone marrow (BM)-derived mesenchymal stem cells (MSC) in vitro is an important aspect of their therapeutic potential. Despite this, the exact composition of stromal cell types within these cultures and the potential effects of non-stem cells on the maintenance of MSC are poorly understood. C57BL/6J BM stroma was investigated as a model to determine the relationship between MSC and non-multipotent cells in vitro. Whole BM and single-cell derived cultures were characterized using flow cytometry and cell sorting combined with multipotent differentiation. Proliferation of individual stromal populations was evaluated using BrdU. At a single-cell level, MSC were distinguished from committed progenitors, and cells lacking differentiation ability, by the expression of CD105 (CD105+). A 3-fold reduction in the percentage of CD105+ cells was detected after prolonged culture and correlated with loss of MSC. Depletion of CD105+ cells coincided with a 10-20% increase in the frequency of proliferating CD105(-) cells. Removal of CD105(-) stroma caused increased proliferation in CD105+ cells, which could be diminished by conditioned media from parent cultures. Comparison of the multipotent differentiation potential in purified and non-purified CD105+ cells determined that MSC were detectable for at least 3 weeks longer when cultured in the absence of CD105(-) cells. This work identifies a simple model for characterizing the different cellular components present in BM stromal cultures and demonstrates that stromal cells lacking multipotent differentiating capacity greatly reduce the longevity of MSC.

  1. Enzymatic detachment of therapeutic mesenchymal stromal cells grown on glass carriers in a bioreactor.

    Science.gov (United States)

    Salzig, Denise; Schmiermund, Alexandra; P Grace, Pablo; Elseberg, Christiane; Weber, Christian; Czermak, Peter

    2013-01-01

    Cell therapies require the in vitro expansion of adherent cells such as mesenchymal stromal cells (hMSCs) in bioreactor systems or other culture environments, followed by cell harvest. As hMSCs are strictly adherent cells, cell harvest requires cell detachment. The use of hMSCs for cell therapy requires GMP production in accordance with the guidelines for advanced therapeutic medical products. Therefore, several GMP-conform available proteolytic enzymes were investigated for their ability to promote hMSC detachment. An allogeneic hMSC cell line (hMSC-TERT) that is used in clinical trials in the form of alginate cell capsules was chosen as a model. This study investigated the influence of several factors on the outcome of proteolytic hMSC-TERT detachment. Therefore, hMSC-TERT detachment was analyzed in different cultivation systems (static, dynamic) and in combination with further cell processing including encapsulation. Only two of the commercially available enzymes (AccutaseTM, TrypZeanTM) that fulfill all process requirements (commercial availability, cost, GMP conditions during manufacturing and non-animal origin) are found to be generally suitable for detaching hMSC-TERT. Combining cell detachment with encapsulation demonstrated a high impact of the experimental set up on cell damage. It was preferable to reduce the temperature during detachment and limit the detachment time to a maximum of 20 minutes. Cell detachment in static systems was not comparable with detachment in dynamic systems. Detachment yields in dynamic systems were lower and cell damage was higher for the same experimental conditions. Finally, only TrypZeanTM seemed to be suitable for the detachment of hMSC-TERT from dynamic reactor systems.

  2. The effect of a chitosan-gelatin matrix and dexamethasone on the behavior of rabbit mesenchymal stem cells

    International Nuclear Information System (INIS)

    Medrado, G C B; Machado, C B; Valerio, P; Sanches, M D; Goes, A M

    2006-01-01

    Cartilage tissue has poor capability of self-repair, especially in the case of severe cartilage damage due to trauma or age-related degeneration. Cell-based tissue engineering using scaffolds has provided an option for the repair of defects in adult cartilage tissue. Mesenchymal stem cells (MSC) and chondrocytes are the two major cell sources for cartilage tissue engineering. The present study combined culture conditions of MSC in a chitosan-gelatin matrix in chondrogenic media to evaluate their effects on MSC viability and chondrogenesis for cartilage tissue engineering. MSC were harvested from rabbit bone marrows and cultured in chondrogenic media supplemented, or not, with dexamethasone in a chitosan-gelatin film (C-GF). The association of C-GF and dexamethasone promoted significant increase in cell adhesivity, viability and proliferation when compared to MCS cultured in media without dexamethasone or C-GF. In addition, dexamethasone promoted increase in the collagen concentration of MSC cultures. A reduction of alkaline phosphatase activity after three weeks of culture in chondrogenic media was verified. No influence of the C-GF or of dexamethasone was observed in this matter. Therefore, it is reasonable to suggest that biomaterial-based chitosan-gelatin and chondrogenic media supplemented with dexamethasone may stimulate the proliferation and differentiation of MSC according to the complex environmental conditions. The information presented here should be useful for the development of biomaterials to regulate the chondrogenesis of MSC suitable for cartilage tissue engineering

  3. Mesenchymal stem cell derived secretome and extracellular vesicles for acute lung injury and other inflammatory lung diseases.

    Science.gov (United States)

    Monsel, Antoine; Zhu, Ying-Gang; Gudapati, Varun; Lim, Hyungsun; Lee, Jae W

    2016-07-01

    Acute respiratory distress syndrome is a major cause of respiratory failure in critically ill patients. Despite extensive research into its pathophysiology, mortality remains high. No effective pharmacotherapy exists. Based largely on numerous preclinical studies, administration of mesenchymal stem or stromal cell (MSC) as a therapeutic for acute lung injury holds great promise, and clinical trials are currently underway. However, concern for the use of stem cells, specifically the risk of iatrogenic tumor formation, remains unresolved. Accumulating evidence now suggest that novel cell-free therapies including MSC-derived conditioned medium and extracellular vesicles released from MSCs might constitute compelling alternatives. The current review summarizes the preclinical studies testing MSC conditioned medium and/or MSC extracellular vesicles as treatment for acute lung injury and other inflammatory lung diseases. While certain logistical obstacles limit the clinical applications of MSC conditioned medium such as the volume required for treatment, the therapeutic application of MSC extracellular vesicles remains promising, primarily due to ability of extracellular vesicles to maintain the functional phenotype of the parent cell. However, utilization of MSC extracellular vesicles will require large-scale production and standardization concerning identification, characterization and quantification.

  4. Mesenchymal Stem Cell-Based Tumor-Targeted Gene Therapy in Gastrointestinal Cancer

    OpenAIRE

    Bao, Qi; Zhao, Yue; Niess, Hanno; Conrad, Claudius; Schwarz, Bettina; Jauch, Karl-Walter; Huss, Ralf; Nelson, Peter J.; Bruns, Christiane J.

    2012-01-01

    Mesenchymal stem (or stromal) cells (MSCs) are nonhematopoietic progenitor cells that can be obtained from bone marrow aspirates or adipose tissue, expanded and genetically modified in vitro, and then used for cancer therapeutic strategies in vivo. Here, we review available data regarding the application of MSC-based tumor-targeted therapy in gastrointestinal cancer, provide an overview of the general history of MSC-based gene therapy in cancer research, and discuss potential problems associa...

  5. The Effect of Mesenchymal Stem Cell-Derived Extracellular Vesicles on Hematopoietic Stem Cells Fate

    Directory of Open Access Journals (Sweden)

    Hamze Timari

    2017-12-01

    Full Text Available Hematopoietic stem cells (HSCs are multipotent stem cells, with self-renewal ability as well as ability to generate all blood cells. Mesenchymal stem cells (MSCs are multipotent stem cells, with self-renewal ability, and capable of differentiating into a variety of cell types. MSCs have supporting effects on hematopoiesis; through direct intercellular communications as well as secreting cytokines, chemokines, and extracellular vesicles (EVs. Recent investigations demonstrated that some biological functions and effects of MSCs are mediated by their EVs. MSC-EVs are the cell membrane and endosomal membrane compartments, which are important mediators in the intercellular communications. MSC-EVs contain some of the molecules such as proteins, mRNA, siRNA, and miRNA from their parental cells. MSC-EVs are able to inhibit tumor, repair damaged tissue, and modulate immune system responses. MSC-EVs compared to their parental cells, may have the specific safety advantages such as the lower potential to trigger immune system responses and limited side effects. Recently some studies demonstrated the effect of MSC-EVs on the expansion, differentiation, and clinical applications of HSCs such as improvement of hematopoietic stem cell transplantation (HSCT and inhibition of graft versus host disease (GVHD. HSCT may be the only therapeutic choice for patients who suffer from malignant and non-malignant hematological disorders. However, there are several severe side effects such GVHD that restricts the successfulness of HSCT. In this review, we will discuss the most important effects of MSCs and MSC-EVs on the improvement of HSCT, inhibition and treatment of GVHD, as well as, on the expansion of HSCs.

  6. The safety implications of emerging software paradigms

    Energy Technology Data Exchange (ETDEWEB)

    Suski, G.J.; Persons, W.L.; Johnson, G.L.

    1994-10-01

    This paper addresses some of the emerging software paradigms that may be used in developing safety-critical software applications. Paradigms considered in this paper include knowledge-based systems, neural networks, genetic algorithms, and fuzzy systems. It presents one view of the software verification and validation activities that should be associated with each paradigm. The paper begins with a discussion of the historical evolution of software verification and validation. Next, a comparison is made between the verification and validation processes used for conventional and emerging software systems. Several verification and validation issues for the emerging paradigms are discussed and some specific research topics are identified. This work is relevant for monitoring and control at nuclear power plants.

  7. The safety implications of emerging software paradigms

    International Nuclear Information System (INIS)

    Suski, G.J.; Persons, W.L.; Johnson, G.L.

    1994-10-01

    This paper addresses some of the emerging software paradigms that may be used in developing safety-critical software applications. Paradigms considered in this paper include knowledge-based systems, neural networks, genetic algorithms, and fuzzy systems. It presents one view of the software verification and validation activities that should be associated with each paradigm. The paper begins with a discussion of the historical evolution of software verification and validation. Next, a comparison is made between the verification and validation processes used for conventional and emerging software systems. Several verification and validation issues for the emerging paradigms are discussed and some specific research topics are identified. This work is relevant for monitoring and control at nuclear power plants

  8. Theological paradigms and conservative Afrikaners | Robbertze ...

    African Journals Online (AJOL)

    1988) reject foundationalistic theology and recommend a holistic theological ap proach. In this process contextual theology, which emphasises the distinctiveness of individual nations, is accused of being the 'domination paradigm' and is even ...

  9. Levelling in the German Verb Paradigm

    Science.gov (United States)

    Newman, John

    1974-01-01

    Levelling processes in the history of the German verb paradigm from Old High German to the present are discussed. It is asserted that the theory of transformational generative grammar provides a proper framework for the study of linguistic change. (RM)

  10. The quiet paradigm revolution of social investment

    NARCIS (Netherlands)

    Hemerijck, A.C.

    2015-01-01

    This paper surveys the emergence, diffusion, merits, and critics of social investment as a distinctive welfare policy paradigm. After revisiting its intellectual roots, the article subsequently develops a multidimensional life-course taxonomy of three complementary social investment functions: (i)

  11. Gene expression changes in the injured spinal cord following transplantation of mesenchymal stem cells or olfactory ensheathing cells.

    Directory of Open Access Journals (Sweden)

    Abel Torres-Espín

    Full Text Available Transplantation of bone marrow derived mesenchymal stromal cells (MSC or olfactory ensheathing cells (OEC have demonstrated beneficial effects after spinal cord injury (SCI, providing tissue protection and improving the functional recovery. However, the changes induced by these cells after their transplantation into the injured spinal cord remain largely unknown. We analyzed the changes in the spinal cord transcriptome after a contusion injury and MSC or OEC transplantation. The cells were injected immediately or 7 days after the injury. The mRNA of the spinal cord injured segment was extracted and analyzed by microarray at 2 and 7 days after cell grafting. The gene profiles were analyzed by clustering and functional enrichment analysis based on the Gene Ontology database. We found that both MSC and OEC transplanted acutely after injury induce an early up-regulation of genes related to tissue protection and regeneration. In contrast, cells transplanted at 7 days after injury down-regulate genes related to tissue regeneration. The most important change after MSC or OEC transplant was a marked increase in expression of genes associated with foreign body response and adaptive immune response. These data suggest a regulatory effect of MSC and OEC transplantation after SCI regarding tissue repair processes, but a fast rejection response to the grafted cells. Our results provide an initial step to determine the mechanisms of action and to optimize cell therapy for SCI.

  12. [Biological characteristics of mesenchymal stem cell and hematopoietic stem cell in the co-culture system].

    Science.gov (United States)

    Wei, Wei; Xu, Chao; Ye, Zhi-Yong; Huang, Xiao-Jun; Yuan, Jia-En; Ma, Tian-Bao; Lin, Han-Biao; Chen, Xiu-Qiong

    2016-10-25

    The aim of the present study was to obtain the qualified hematopoietic stem/progenitor cells (HSC/HPC) and human umbilical cord-mesenchymal stem cells (MSC) in vitro in the co-culture system. Cord blood mononuclear cells were separated from umbilical cord blood by Ficoll lymphocyte separation medium, and then CD34 + HSC was collected by MACS immunomagnetic beads. The selected CD34 + HSC/HPC and MSC were transferred into culture flask. IMDM culture medium with 15% AB-type cord plasma supplemented with interleukin-3 (IL-3), IL-6, thrombopoietin (TPO), stem cell factor (SCF) and FMS-like tyrosine kinase 3 ligand (Flt-3L) factors were used as the co-culture system for the amplification of HSC/HPC and MSC. The cellular growth status and proliferation on day 6 and 10 after co-culture were observed by using inverted microscope. The percentage of positive expression of CD34 in HSC/HPC, as well as the percentages of positive expressions of CD105, CD90, CD73, CD45, CD34 and HLA-DR in the 4 th generation MSC, was tested by flow cytometry. Semisolid colony culture was used to test the HSC/HPC colony forming ability. The osteogenic, chondrogenesis and adipogenic ability of the 4 th generation MSC were assessed. The karyotype analysis of MSC was conducted by colchicines. The results demonstrated that the HSC/HPC of co-culture group showed higher ability of amplification, CFU-GM and higher CD34 + percentage compared with the control group. The co-cultured MSC maintained the ability to differentiate into bone cells, fat cells and chondrocytes. And the karyotype stability of MSC remained normal. These results reveal that the appropriate co-culture system for MSC and HSC is developed, and via this co-culture system we could gain both two kinds of these cells. The MSCs under the co-culture system maintain the biological characteristics. The CFU-GM ability, cell counting and the flow cytometry results of HSC/HPC under the co-culture system are conform to the criterion, showing that

  13. Engineering paradigms and anthropogenic global change

    Science.gov (United States)

    Bohle, Martin

    2016-04-01

    This essay discusses 'paradigms' as means to conceive anthropogenic global change. Humankind alters earth-systems because of the number of people, the patterns of consumption of resources, and the alterations of environments. This process of anthropogenic global change is a composite consisting of societal (in the 'noosphere') and natural (in the 'bio-geosphere') features. Engineering intercedes these features; e.g. observing stratospheric ozone depletion has led to understanding it as a collateral artefact of a particular set of engineering choices. Beyond any specific use-case, engineering works have a common function; e.g. civil-engineering intersects economic activity and geosphere. People conceive their actions in the noosphere including giving purpose to their engineering. The 'noosphere' is the ensemble of social, cultural or political concepts ('shared subjective mental insights') of people. Among people's concepts are the paradigms how to shape environments, production systems and consumption patterns given their societal preferences. In that context, engineering is a means to implement a given development path. Four paradigms currently are distinguishable how to make anthropogenic global change happening. Among the 'engineering paradigms' for anthropogenic global change, 'adaptation' is a paradigm for a business-as-usual scenario and steady development paths of societies. Applying this paradigm implies to forecast the change to come, to appropriately design engineering works, and to maintain as far as possible the current production and consumption patterns. An alternative would be to adjust incrementally development paths of societies, namely to 'dovetail' anthropogenic and natural fluxes of matter and energy. To apply that paradigm research has to identify 'natural boundaries', how to modify production and consumption patterns, and how to tackle process in the noosphere to render alterations of common development paths acceptable. A further alternative

  14. New Indivisible Planetary Science Paradigm: Consequence of Questioning Popular Paradigms

    Science.gov (United States)

    Marvin Herndon, J.

    2014-05-01

    Progress in science involves replacing less precise understanding with more precise understanding. In science and in science education one should always question popular ideas; ask "What's wrong with this picture?" Finding limitations, conflicts or circumstances that require special ad hoc consideration sometimes is the key to making important discoveries. For example, from thermodynamic considerations, I found that the 'standard model of solar system formation' leads to insufficiently massive planetary cores. That understanding led me to discover a new indivisible planetary science paradigm. Massive-core planets formed by condensing and raining-out from within giant gaseous protoplanets at high pressures and high temperatures, accumulating heterogeneously on the basis of volatility with liquid core-formation preceding mantle-formation; the interior states of oxidation resemble that of the Abee enstatite chondrite. Core-composition was established during condensation based upon the relative solubilities of elements, including uranium, in liquid iron in equilibrium with an atmosphere of solar composition at high pressures and high temperatures. Uranium settled to the central region and formed planetary nuclear fission reactors, producing heat and planetary magnetic fields. Earth's complete condensation included a ~300 Earth-mass gigantic gas/ice shell that compressed the rocky kernel to about 66% of Earth's present diameter. T-Tauri eruptions, associated with the thermonuclear ignition of the Sun, stripped the gases away from the Earth and the inner planets. The T-Tauri outbursts stripped a portion of Mercury's incompletely condensed protoplanet and transported it to the region between Mars and Jupiter where it fused with in-falling oxidized condensate from the outer regions of the Solar System, forming the parent matter of ordinary chondrite meteorites, the main-Belt asteroids, and veneer for the inner planets, especially Mars. With its massive gas/ice shell

  15. Mesenchymal Stem Cell Conditioned Medium Promotes Proliferation and Migration of Alveolar Epithelial Cells under Septic Conditions In Vitro via the JNK-P38 Signaling Pathway

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    Jie Chen

    2015-11-01

    Full Text Available Background/Aims: Mesenchymal stem cell (MSC based therapies may be useful for treating acute respiratory distress syndrome (ARDS, but the underlying mechanisms are incompletely understood. We investigated the impact of human umbilical cord Wharton's jelly-derived MSC (hUC-MSC secreted factors on alveolar epithelial cells under septic conditions and determined the relevant intracellular signaling pathways. Methods: Human alveolar epithelial cells (AEC and primary human small airway epithelial cells (SAEC were subjected to lipopolysaccharide (LPS with or without the presence of hUC-MSC-conditioned medium (CM. Proliferation and migration of AEC and SAEC were determined via an MTT assay, a wound healing assay and a transwell migration assay (only for AEC. Protein phosphorylation was determined by western blot and the experiments were repeated in presence of small-molecule inhibitors. The hMSC-secretory proteins were identified by LC-MS/MS mass spectrometry. Results: MSC-CM enhanced proliferation and migration. Activation of JNK and P38, but not ERK, was required for the proliferation and migration of AEC and SAEC. Pretreatment of AEC or SAEC with SP600125, an inhibitor of JNK1 or SB200358, an inhibitor of P38, significantly reduced cell proliferation and migration. An array of proteins including TGF-beta receptor type-1, TGF-beta receptor type-2, Ras-related C3 botulinum toxin substrate 1 and Ras-related C3 botulinum toxin substrate 2 which influencing the proliferation and migration of AEC and SAEC were detected in MSC-CM. Conclusion: Our data suggest MSC promote epithelial cell repair through releasing a repertoire of paracrine factors via activation of JNK and P38 MAPK.

  16. Mesenchymal stem cells: biological characteristics and potential clinical applications

    DEFF Research Database (Denmark)

    Kassem, Moustapha

    2004-01-01

    Mesenchymal stem cells (MSC) are clonogenic, non-hematpoietic stem cells present in the bone marrow and are able to differentiate into multiple mesoderm-type cell lineages, for example, osteoblasts, chondrocytes, endothelial-cells and also non-mesoderm-type lineages, for example, neuronal...

  17. Growing Bladder-Cancer Cells In Three-Dimensional Clusters

    Science.gov (United States)

    Spaulding, Glenn F.; Prewett, Tacey L.; Goodwin, Thomas J.

    1995-01-01

    Artificial growth process helps fill gaps in cancer research. Cell cultures more accurate as models for in vivo studies and as sources of seed cells for in vivo studies. Effected in horizontal rotating bioreactor described in companion article, "Simplified Bioreactor for Growing Mammalian Cells" (MSC-22060). Provides aggregates of cells needed to fill many of gaps.

  18. Reversal of Experimental Liver Damage after Transplantation of Stem-Derived Cells Detected by FTIR Spectroscopy

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    Danna Ye

    2017-01-01

    Full Text Available The transplantation of autologous BM-MSCs holds great potential for treating end-stage liver diseases. The aim of this study was to compare the efficiency of transplanted rBM-MSCs and rBM-MSC-derived differentiated stem cells (rBM-MSC-DSCs for suppression of dimethylnitrosamine-injured liver damage in rat model. Synchrotron radiation Fourier-transform infrared (SR-FTIR microspectroscopy was applied to investigate changes in the macromolecular composition. Transplantation of rBM-MSC-DSCs into liver-injured rats restored their serum albumin level and significantly suppressed transaminase activity as well as the morphological manifestations of liver disease. The regenerative effects of rBM-MSC-DSCs were corroborated unequivocally by the phenotypic difference analysis between liver tissues revealed by infrared spectroscopy. Spectroscopic changes in the spectral region from 1190–970 cm−1 (bands with absorbance maxima at 1150 cm−1, 1081 cm−1, and 1026 cm−1 indicated decreased levels of carbohydrates, in rBM-MSC-DSC-transplanted livers, compared with untreated and rBM-MSC--transplanted animals. Principal component analysis (PCA of spectra acquired from liver tissue could readily discriminate rBM-MSC-DSC-transplanted animals from the untreated and rBM-MSC-transplanted animals. We conclude that the transplantation of rBM-MSC-DSCs effectively treats liver disease in rats and SR-FTIR microspectroscopy provides important insights into the fundamental biochemical alterations induced by the stem-derived cell transplantation, including an objective “signature” of the regenerative effects of stem cell therapy upon liver injury.

  19. Molecular characterisation of stromal populations derived from human embryonic stem cells

    DEFF Research Database (Denmark)

    Harkness, L.; Twine, N. A.; Abu Dawud, R.

    2015-01-01

    Human bone marrow-derived stromal (skeletal) stem cells (BM-hMSC) are being employed in an increasing number of clinical trials for tissue regeneration. A limiting factor for their clinical use is the inability to obtain sufficient cell numbers. Human embryonic stem cells (hESC) can provide...... an unlimited source of clinical grade cells for therapy. We have generated MSC-like cells from hESC (called here hESC-stromal) that exhibit surface markers and differentiate to osteoblasts and adipocytes, similar to BM-hMSC. In the present study, we used microarray analysis to compare the molecular phenotype...... of hESC-stromal and immortalised BM-hMSC cells (hMSC-TERT). Of the 7379 genes expressed above baseline, only 9.3% of genes were differentially expressed between undifferentiated hESC-stromal and BM-hMSC. Following ex vivo osteoblast induction, 665 and 695 genes exhibited >. 2-fold change (FC) in h...

  20. The Underlying Social Dynamics of Paradigm Shifts.

    Directory of Open Access Journals (Sweden)

    Carlos Rodriguez-Sickert

    Full Text Available We develop here a multi-agent model of the creation of knowledge (scientific progress or technological evolution within a community of researchers devoted to such endeavors. In the proposed model, agents learn in a physical-technological landscape, and weight is attached to both individual search and social influence. We find that the combination of these two forces together with random experimentation can account for both i marginal change, that is, periods of normal science or refinements on the performance of a given technology (and in which the community stays in the neighborhood of the current paradigm; and ii radical change, which takes the form of scientific paradigm shifts (or discontinuities in the structure of performance of a technology that is observed as a swift migration of the knowledge community towards the new and superior paradigm. The efficiency of the search process is heavily dependent on the weight that agents posit on social influence. The occurrence of a paradigm shift becomes more likely when each member of the community attaches a small but positive weight to the experience of his/her peers. For this parameter region, nevertheless, a conservative force is exerted by the representatives of the current paradigm. However, social influence is not strong enough to seriously hamper individual discovery, and can act so as to empower successful individual pioneers who have conquered the new and superior paradigm.

  1. Project management: a new service delivery paradigm

    Directory of Open Access Journals (Sweden)

    G. van der Walt

    2007-07-01

    Full Text Available In line with international trends in governance, the South African Government’s initial focus on the development of policy frameworks, structures and systems in order to give effect to the values and principles of the Constitution, shifted to the most critical issue, namely service delivery. The Government became increasingly aware that a significant expansion in the scope and quality of service provision was not possible with traditional delivery settings and approaches. There is growing evidence that there is a need for a significant departure from conventional approaches and that a leap into a new service delivery paradigm is necessary. Increasingly this new paradigm highlights the need to further develop the government’s project management skills and applications with a view to achieving improved delivery capability. In this article the focus will be placed on the changing service delivery paradigm – from an “old” traditional model through the transition to a “new” paradigm. This paradigm is shaped by international and national trends and events in government. The contribution and advantages of project management applications for effective governance are highlighted and the article concludes with an explanation of project management organisational arrangements necessary to support the new paradigm.

  2. The Underlying Social Dynamics of Paradigm Shifts.

    Science.gov (United States)

    Rodriguez-Sickert, Carlos; Cosmelli, Diego; Claro, Francisco; Fuentes, Miguel Angel

    2015-01-01

    We develop here a multi-agent model of the creation of knowledge (scientific progress or technological evolution) within a community of researchers devoted to such endeavors. In the proposed model, agents learn in a physical-technological landscape, and weight is attached to both individual search and social influence. We find that the combination of these two forces together with random experimentation can account for both i) marginal change, that is, periods of normal science or refinements on the performance of a given technology (and in which the community stays in the neighborhood of the current paradigm); and ii) radical change, which takes the form of scientific paradigm shifts (or discontinuities in the structure of performance of a technology) that is observed as a swift migration of the knowledge community towards the new and superior paradigm. The efficiency of the search process is heavily dependent on the weight that agents posit on social influence. The occurrence of a paradigm shift becomes more likely when each member of the community attaches a small but positive weight to the experience of his/her peers. For this parameter region, nevertheless, a conservative force is exerted by the representatives of the current paradigm. However, social influence is not strong enough to seriously hamper individual discovery, and can act so as to empower successful individual pioneers who have conquered the new and superior paradigm.

  3. Exosome: A Novel and Safer Therapeutic Refinement of Mesenchymal Stem Cell

    Directory of Open Access Journals (Sweden)

    Ronne Wee Yeh Yeo

    2013-01-01

    Full Text Available Mesenchymal stem cell (MSC has just been approved as the first “off-the-shelf” stem cell pharmaceutical drug with an anticipation of more approvals following completion of numerous rigorous clinical trials. Despite this progress, the rationale for MSC therapeutic efficacy remains tenuous and is increasingly rationalized on a secretion rather than differentiation mechanism. Recent studies identifying exosome as the secreted agent mediating MSC therapeutic efficacy could potentially reduce a cell-based drug to a safer biologic-based alternative. Here we review the development of MSC exosome as a potential first-in-class therapeutic, and the unique challenges in the manufacture and regulatory oversight of this new class of therapeutics.

  4. miR-141-3p inhibits human stromal (mesenchymal) stem cell proliferation and differentiation

    DEFF Research Database (Denmark)

    Qiu, Weimin; Kassem, Moustapha

    2014-01-