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Sample records for stromal-derived factor sdf-1

  1. Role of stromal derived factor-1a (SDF-1a) for spermatogenesis of busulfan-injured rats.

    Science.gov (United States)

    Khanlarkhani, Neda; Mortezaee, Keywan; Amidi, Fardin; Kharazinejad, Ebrahim; Beyer, Cordian; Baazm, Maryam; Pasbakhsh, Parichehr; Pazhohan, Azar; Sobhani, Aligholi; Zendedel, Adib

    2017-10-01

    SDF-1a is a member of CXC chemokine family that plays a crucial role in stem cell migration, cell apoptosis and development. The role of intra-scrotal administration of SDF-1a in spermatogenesis of busulfan-treated rats was investigated in this study. Two injections of busulfan (15mg/kg) with a 14days interval between were given intraperitoneally to male Wistar rats. Rats were then treated for seven days with 500ng/mL SDF-1a. Real-time PCR and immunohistochemistry were performed for evaluation of various cell markers for proliferation and spermatogenesis, and sperm parameters were assessed. In the SDF-1a group, there was a significant increase in testis weight, sperm count and viability. DAZL, DDX4, and TP2 showed increased expression levels in the SDF-1a group. PCNA and BrdU revealed highest expression rates in the SDF-1a group (p≤0.0001). These findings showed the protective role of SDF-1a in busulfan-induced testis injury most likely through stimulation of SSCs proliferation. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. A novel recombinant antibody specific to full-length stromal derived factor-1 for potential application in biomarker studies.

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    Daniel I Bromage

    Full Text Available Stromal derived factor-1α (SDF-1α/CXCL12 is a chemokine that is up-regulated in diseases characterised by tissue hypoxia, including myocardial infarction, ischaemic cardiomyopathy and remote ischaemic conditioning (RIC, a technique of cyclical, non-injurious ischaemia applied remote from the heart that protects the heat from lethal ischaemia-reperfusion injury. Accordingly, there is considerable interest in SDF-1α as a potential biomarker of such conditions. However, SDF-1α is rapidly degraded and inactivated by dipeptidyl peptidase 4 and other peptidases, and the kinetics of intact SDF-1α remain unknown.To facilitate investigation of full-length SDF-1α we established an ELISA using a novel recombinant human antibody we developed called HCI.SDF1. HCI.SDF1 is specific to the N-terminal sequence of all isoforms of SDF-1 and has a comparable KD to commercially available antibodies. Together with a detection antibody specific to the α-isoform, HCI.SDF1 was used to specifically quantify full-length SDF-1α in blood for the first time. Using RIC applied to the hind limb of Sprague-Dawley rats or the arms of healthy human volunteers, we demonstrate an increase in SDF-1α using a commercially available antibody, as previously reported, but an unexpected decrease in full-length SDF-1α after RIC in both species.We report for the first time the development of a novel recombinant antibody specific to full-length SDF-1. Applied to RIC, we demonstrate a significant decrease in SDF-1α that is at odds with the literature and suggests a need to investigate the kinetics of full-length SDF-1α in conditions characterised by tissue hypoxia.

  3. Stromal cell-derived factor 1α (SDF-1α)

    DEFF Research Database (Denmark)

    Li, Dana; Bjørnager, Louise; Langkilde, Anne

    2016-01-01

    OBJECTIVES: Stromal cell-derived factor 1a (SDF-1α), is a chemokine and is able to home hematopoietic progenitor cells to injured areas of heart tissue for structural repair. Previous studies have found increased levels of SDF-1α in several cardiac diseases, but only few studies have investigated...... SDF-1α in patients with atrial fibrillation (AF). We aimed to test SDF-1α in a large cohort of patients with AF and its role as a prognostic marker. DESIGN: Between January 1st 2008 to December 1st 2012, 290 patients with ECG documented AF were enrolled from the in- and outpatient clinics...... at the Department of Cardiology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark. Plasma levels of SDF-1α were measured using ELISA technique. Clinical data were registered and patient follow-up was conducted. RESULTS: Patients with permanent AF had significantly higher SDF-1α levels (2199.5 pg...

  4. Transforming growth factor β-activated kinase 1 negatively regulates interleukin-1α-induced stromal-derived factor-1 expression in vascular smooth muscle cells

    International Nuclear Information System (INIS)

    Yang, Bin; Li, Wei; Zheng, Qichang; Qin, Tao; Wang, Kun; Li, Jinjin; Guo, Bing; Yu, Qihong; Wu, Yuzhe; Gao, Yang; Cheng, Xiang; Hu, Shaobo; Kumar, Stanley Naveen; Liu, Sanguang; Song, Zifang

    2015-01-01

    Stromal-derived Factor-1 (SDF-1) derived from vascular smooth muscle cells (VSMCs) contributes to vascular repair and remodeling in various vascular diseases. In this study, the mechanism underlying regulation of SDF-1 expression by interleukin-1α (IL-1α) was investigated in primary rat VSMCs. We found IL-1α promotes SDF-1 expression by up-regulating CCAAT-enhancer-binding protein β (C/EBPβ) in an IκB kinase β (IKKβ) signaling-dependent manner. Moreover, IL-1α-induced expression of C/EBPβ and SDF-1 was significantly potentiated by knockdown of transforming growth factor β-activated kinase 1 (TAK1), an upstream activator of IKKβ signaling. In addition, we also demonstrated that TAK1/p38 mitogen-activated protein kinase (p38 MAPK) signaling exerted negative effect on IL-1α-induced expression of C/EBPβ and SDF-1 through counteracting ROS-dependent up-regulation of nuclear factor erythroid 2-related factor 2 (NRF2). In conclusion, TAK1 acts as an important regulator of IL-1α-induced SDF-1 expression in VSMCs, and modulating activity of TAK1 may serve as a potential strategy for modulating vascular repair and remodeling. - Highlights: • IL-1α induces IKKβ signaling-dependent SDF-1 expression by up-regulating C/EBPβ. • Activation of TAK1 by IL-1α negatively regulates C/EBPβ-dependent SDF-1 expression. • IL-1α-induced TAK1/p38 MAPK signaling counteracts ROS-dependent SDF-1 expression. • TAK1 counteracts IL-1α-induced SDF-1 expression by attenuating NRF2 up-regulation

  5. Transforming growth factor β-activated kinase 1 negatively regulates interleukin-1α-induced stromal-derived factor-1 expression in vascular smooth muscle cells

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Bin [Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huangzhong University of Science and Technology, Wuhan 430022 (China); Li, Wei [Department of Gerontology, Union Hospital, Tongji Medical College, Huangzhong University of Science and Technology, Wuhan 430022 (China); Zheng, Qichang [Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huangzhong University of Science and Technology, Wuhan 430022 (China); Qin, Tao [Department of Hepatobiliary Pancreatic Surgery, People' s Hospital of Zhengzhou University, School of Medicine, Zhengzhou University, Zhengzhou 450003 (China); Wang, Kun; Li, Jinjin; Guo, Bing; Yu, Qihong; Wu, Yuzhe; Gao, Yang; Cheng, Xiang; Hu, Shaobo; Kumar, Stanley Naveen [Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huangzhong University of Science and Technology, Wuhan 430022 (China); Liu, Sanguang, E-mail: sanguang1998@sina.com [Department of Hepatobiliary Surgery, The Second Hospital, Hebei Medical University, Shijiazhuang 050000 (China); Song, Zifang, E-mail: zsong@hust.edu.cn [Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huangzhong University of Science and Technology, Wuhan 430022 (China)

    2015-07-17

    Stromal-derived Factor-1 (SDF-1) derived from vascular smooth muscle cells (VSMCs) contributes to vascular repair and remodeling in various vascular diseases. In this study, the mechanism underlying regulation of SDF-1 expression by interleukin-1α (IL-1α) was investigated in primary rat VSMCs. We found IL-1α promotes SDF-1 expression by up-regulating CCAAT-enhancer-binding protein β (C/EBPβ) in an IκB kinase β (IKKβ) signaling-dependent manner. Moreover, IL-1α-induced expression of C/EBPβ and SDF-1 was significantly potentiated by knockdown of transforming growth factor β-activated kinase 1 (TAK1), an upstream activator of IKKβ signaling. In addition, we also demonstrated that TAK1/p38 mitogen-activated protein kinase (p38 MAPK) signaling exerted negative effect on IL-1α-induced expression of C/EBPβ and SDF-1 through counteracting ROS-dependent up-regulation of nuclear factor erythroid 2-related factor 2 (NRF2). In conclusion, TAK1 acts as an important regulator of IL-1α-induced SDF-1 expression in VSMCs, and modulating activity of TAK1 may serve as a potential strategy for modulating vascular repair and remodeling. - Highlights: • IL-1α induces IKKβ signaling-dependent SDF-1 expression by up-regulating C/EBPβ. • Activation of TAK1 by IL-1α negatively regulates C/EBPβ-dependent SDF-1 expression. • IL-1α-induced TAK1/p38 MAPK signaling counteracts ROS-dependent SDF-1 expression. • TAK1 counteracts IL-1α-induced SDF-1 expression by attenuating NRF2 up-regulation.

  6. Defining an optimal stromal derived factor-1 presentation for effective recruitment of mesenchymal stem cells in 3D.

    Science.gov (United States)

    Iannone, Maria; Ventre, Maurizio; Pagano, Gemma; Giannoni, Paolo; Quarto, Rodolfo; Netti, Paolo Antonio

    2014-11-01

    In "situ" tissue engineering is a promising approach in regenerative medicine, envisaging to potentiate the physiological tissue repair processes by recruiting the host's own cellular progenitors at the lesion site by means of bioactive materials. Despite numerous works focused the attention in characterizing novel chemoattractant molecules, only few studied the optimal way to present signal in the microenvironment, in order to recruit cells more effectively. In this work, we have analyzed the effects of gradients of stromal derived factor-1 (SDF-1) on the migratory behavior of human mesenchymal stem cells (MSCs). We have characterized the expression of the chemokine-associated receptor, CXCR4, using cytofluorimetric and real-time PCR analyses. Gradients of SDF-1 were created in 3D collagen gels in a chemotaxis chamber. Migration parameters were evaluated using different chemoattractant concentrations. Our results show that cell motion is strongly affected by the spatio-temporal features of SDF-1 gradients. In particular, we demonstrated that the presence of SDF-1 not only influences cell motility but alters the cell state in terms of SDF-1 receptor expression and productions, thus modifying the way cells perceive the signal itself. Our observations highlight the importance of a correct stimulation of MSCs by means of SDF-1 in order to implement on effective cell recruitment. Our results could be useful for the creation of a "cell instructive material" that is capable to communicate with the cells and control and direct tissue regeneration. Biotechnol. Bioeng. 2014;111: 2303-2316. © 2014 Wiley Periodicals, Inc. © 2014 Wiley Periodicals, Inc.

  7. The Expanding Family of Bone Marrow Homing Factors for Hematopoietic Stem Cells: Stromal Derived Factor 1 Is Not the Only Player in the Game

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    Mariusz Z. Ratajczak

    2012-01-01

    Full Text Available The α-chemokine stromal derived factor 1 (SDF-1, which binds to the CXCR4 and CXCR7 receptors, directs migration and homing of CXCR4+ hematopoietic stem/progenitor cells (HSPCs to bone marrow (BM and plays a crucial role in retention of these cells in stem cell niches. However, this unique role of SDF-1 has been recently challenged by several observations supporting SDF-1-CXCR4-independent BM homing. Specifically, it has been demonstrated that HSPCs respond robustly to some bioactive lipids, such as sphingosine-1-phosphate (S1P and ceramide-1-phosphate (C1P, and migrate in response to gradients of certain extracellular nucleotides, including uridine triphosphate (UTP and adenosine triphosphate (ATP. Moreover, the responsiveness of HSPCs to an SDF-1 gradient is enhanced by some elements of innate immunity (e.g., C3 complement cascade cleavage fragments and antimicrobial cationic peptides, such as cathelicidin/LL-37 or β2-defensin as well as prostaglandin E2 (PGE2. Since all these factors are upregulated in BM after myeloblative conditioning for transplantation, a more complex picture of homing emerges that involves several factors supporting, and in some situations even replacing, the SDF-1-CXCR4 axis.

  8. Covalent immobilization of stem cell factor and stromal derived factor 1α for in vitro culture of hematopoietic progenitor cells.

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    Cuchiara, Maude L; Horter, Kelsey L; Banda, Omar A; West, Jennifer L

    2013-12-01

    Hematopoietic stem cells (HSCs) are currently utilized in the treatment of blood diseases, but widespread application of HSC therapeutics has been hindered by the limited availability of HSCs. With a better understanding of the HSC microenvironment and the ability to precisely recapitulate its components, we may be able to gain control of HSC behavior. In this work we developed a novel, biomimetic PEG hydrogel material as a substrate for this purpose and tested its potential with an anchorage-independent hematopoietic cell line, 32D clone 3 cells. We immobilized a fibronectin-derived adhesive peptide sequence, RGDS; a cytokine critical in HSC self-renewal, stem cell factor (SCF); and a chemokine important in HSC homing and lodging, stromal derived factor 1α (SDF1α), onto the surfaces of poly(ethylene glycol) (PEG) hydrogels. To evaluate the system's capabilities, we observed the effects of the biomolecules on 32D cell adhesion and morphology. We demonstrated that the incorporation of RGDS onto the surfaces promotes 32D cell adhesion in a dose-dependent fashion. We also observed an additive response in adhesion on surfaces with RGDS in combination with either SCF or SDF1α. In addition, the average cell area increased and circularity decreased on gel surfaces containing immobilized SCF or SDF1α, indicating enhanced cell spreading. By recapitulating aspects of the HSC microenvironment using a PEG hydrogel scaffold, we have shown the ability to control the adhesion and spreading of the 32D cells and demonstrated the potential of the system for the culture of primary hematopoietic cell populations. Copyright © 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  9. SDF-1 is an Autocrine Insulin-Desensitizing Factor in Adipocytes.

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    Shin, Jihoon; Fukuhara, Atsunori; Onodera, Toshiharu; Kita, Shunbun; Yokoyama, Chieko; Otsuki, Michio; Shimomura, Iichiro

    2018-03-26

    Insulin desensitization occurs not only under obese diabetic condition, but also in the fasting state. However, little is known about the common secretory factor(s) that are regulated under these two insulin-desensitized conditions. Here, using database analysis, in vitro , and in vivo experiments, we identified SDF-1 as an insulin-desensitizing factor in adipocytes, overexpressed in both fasting and obese adipose tissues. Exogenously added SDF-1 induced ERK signal, which phosphorylated and degraded IRS-1 protein in adipocytes, decreasing insulin-mediated signaling and glucose uptake. In contrast, knockdown of endogenous SDF-1 or inhibition of its receptor in adipocytes markedly increased IRS-1 protein levels and enhanced insulin sensitivity, indicating the autocrine action of SDF-1. In agreement with these findings, adipocyte-specific ablation of SDF-1 enhanced insulin sensitivity in adipose tissues and whole body. These results point to a novel regulatory mechanism of insulin sensitivity mediated by adipose autocrine SDF-1 action, and provide a new insight into the process of insulin desensitization in adipocytes. © 2018 by the American Diabetes Association.

  10. Regulation of SDF-1 (CXCL12) production by osteoblasts; a possible mechanism for stem cell homing.

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    Jung, Y; Wang, J; Schneider, A; Sun, Y-X; Koh-Paige, A J; Osman, N I; McCauley, L K; Taichman, R S

    2006-04-01

    Stromal derived factor-1 (SDF-1 or CXCL12) controls many aspects of stem cell function including trafficking and proliferation. Previously, it was demonstrated that DNA-damaging agents such as irradiation, cyclophosphamide or 5-fluorouracil increase the expression of SDF-1 by osteoblasts in murine marrow. Here, the production of SDF-1 by osteoblasts in vitro in response to cytokines known to be particularly important in bone physiology was examined using primary human osteoblasts (HOBs), mixed marrow stromal cells (BMSCs), and by, mouse, rat and human osteoblast-like cell lines. From these studies, it was determined that the expression of SDF-1 is an early feature of osteoblastic induction that may be modulated by IL-1beta, PDGF-BB, VEGF, TNF-alpha and PTH. Each of these factors increased SDF-1 synthesis, while TGF-beta1 decreased SDF-1 secretion. Of note, the biodistribution of SDF-1 in culture was equally distributed between the medium and detergent-soluble and -insoluble fractions of the cultures. Immunohistochemistry of developing bones demonstrated that SDF-1 was also a feature of early bone development first beginning in the perichondrium and moving into the marrow cavity of the developing bone analogue. As SDF-1 expression increases in response to PTH in vitro, animals were treated with an anabolic regime of PTH for 21 days. Under these conditions, significant increases in SDF-1 mRNA expression were observed near the growth plate and epiphysis regions of the long bones. Yet, in serum, immunodetectable SDF-1 levels were significantly reduced (24%) in the PTH-treated animals (Vehicle: 408 +/- 25 vs. PTH 308 +/- 20 SDF-1 pg/ml). Together, these data suggest a possible mechanism for localizing stem cells into a developing marrow where increased expression of SDF-1 in the local marrow environment along with decreased SDF-1 in the serum may create a homing gradient.

  11. Stromal cell-derived factor 1α (SDF-1α): A marker of disease burden in patients with atrial fibrillation.

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    Li, Dana; Bjørnager, Louise; Langkilde, Anne; Andersen, Ove; Jøns, Christian; Agner, Bue F R; Dixen, Ulrik; Landex, Nadia L

    2016-01-01

    Stromal cell-derived factor 1a (SDF-1α), is a chemokine and is able to home hematopoietic progenitor cells to injured areas of heart tissue for structural repair. Previous studies have found increased levels of SDF-1α in several cardiac diseases, but only few studies have investigated SDF-1α in patients with atrial fibrillation (AF). We aimed to test SDF-1α in a large cohort of patients with AF and its role as a prognostic marker. Between January 1st 2008 to December 1st 2012, 290 patients with ECG documented AF were enrolled from the in- and outpatient clinics at the Department of Cardiology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark. Plasma levels of SDF-1α were measured using ELISA technique. Clinical data were registered and patient follow-up was conducted. Patients with permanent AF had significantly higher SDF-1α levels (2199.5 pg/ml) than the patients with paroxysmal AF (1982.0 pg/ml) and persistent AF (1906.0 pg/ml), p SDF-1α level was associated with longer time spent in the hospital per readmission, p SDF-1α level was found in patients with a more progressive state of arrhythmia and was associated with longer hospitalizations. These findings suggest that SDF-1α could prove valuable in risk stratification and evaluating the disease burden in AF patients.

  12. Stromal cell-derived factor-1 alpha (SDF-1 alpha) improves neural recovery after spinal cord contusion in rats

    NARCIS (Netherlands)

    Zendedel, A.; Nobakht, M.; Bakhtiyari, M.; Beyer, C.; Kipp, M.; Baazm, M.; Joghataie, M.T.

    2012-01-01

    Stromal cell-derived factor-1 alpha (SDF-1α) is an important cytokine, implicated in the control of stem cell trafficking and bone marrow-derived stem cell mobilization. Generally, SDF-1α regulates multiple physiological processes such as embryonic development and organ homeostasis. There is also

  13. Stem cells migration during skeletal muscle regeneration - the role of Sdf-1/Cxcr4 and Sdf-1/Cxcr7 axis.

    Science.gov (United States)

    Kowalski, Kamil; Kołodziejczyk, Aleksandra; Sikorska, Maria; Płaczkiewicz, Jagoda; Cichosz, Paulina; Kowalewska, Magdalena; Stremińska, Władysława; Jańczyk-Ilach, Katarzyna; Koblowska, Marta; Fogtman, Anna; Iwanicka-Nowicka, Roksana; Ciemerych, Maria A; Brzoska, Edyta

    2017-07-04

    The skeletal muscle regeneration occurs due to the presence of tissue specific stem cells - satellite cells. These cells, localized between sarcolemma and basal lamina, are bound to muscle fibers and remain quiescent until their activation upon muscle injury. Due to pathological conditions, such as extensive injury or dystrophy, skeletal muscle regeneration is diminished. Among the therapies aiming to ameliorate skeletal muscle diseases are transplantations of the stem cells. In our previous studies we showed that Sdf-1 (stromal derived factor -1) increased migration of stem cells and their fusion with myoblasts in vitro. Importantly, we identified that Sdf-1 caused an increase in the expression of tetraspanin CD9 - adhesion protein involved in myoblasts fusion. In the current study we aimed to uncover the details of molecular mechanism of Sdf-1 action. We focused at the Sdf-1 receptors - Cxcr4 and Cxcr7, as well as signaling pathways induced by these molecules in primary myoblasts, as well as various stem cells - mesenchymal stem cells and embryonic stem cells, i.e. the cells of different migration and myogenic potential. We showed that Sdf-1 altered actin organization via FAK (focal adhesion kinase), Cdc42 (cell division control protein 42), and Rac-1 (Ras-Related C3 Botulinum Toxin Substrate 1). Moreover, we showed that Sdf-1 modified the transcription profile of genes encoding factors engaged in cells adhesion and migration. As the result, cells such as primary myoblasts or embryonic stem cells, became characterized by more effective migration when transplanted into regenerating muscle.

  14. Enhanced Healing of Diabetic Wounds by Topical Administration of Adipose Tissue-Derived Stromal Cells Overexpressing Stromal-Derived Factor-1: Biodistribution and Engraftment Analysis by Bioluminescent Imaging

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    Giuliana Di Rocco

    2011-01-01

    Full Text Available Chronic ulcers represent a major health problem in diabetic patients resulting in pain and discomfort. Conventional therapy does not guarantee adequate wound repair. In diabetes, impaired healing is partly due to poor endothelial progenitor cells mobilisation and homing, with altered levels of the chemokine stromal-derived factor-1 (SDF-1 at the wound site. Adipose tissue-associated stromal cells (AT-SCs can provide an accessible source of progenitor cells secreting proangiogenic factors and differentiating into endothelial-like cells. We demonstrated that topical administration of AT-SCs genetically modified ex vivo to overexpress SDF-1, promotes wound healing into diabetic mice. In particular, by in vivo bioluminescent imaging analysis, we monitored biodistribution and survival after transplantation of luciferase-expressing cells. In conclusion, this study indicates the therapeutic potential of AT-SCs administration in wound healing, through cell differentiation, enhanced cellular recruitment at the wound site, and paracrine effects associated with local growth-factors production.

  15. The role of Sdf-1α signaling in Xenopus laevis somite morphogenesis

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    Leal, Marisa A.; Fickel, Sarah R.; Sabillo, Armbien; Ramirez, Julio; Vergara, Hernando Martínez; Nave, Ceazar; Saw, Daniel; Domingo, Carmen R.

    2014-01-01

    Background Stromal derived factor-1α (sdf-1α), a chemoattractant chemokine, plays a major role in tumor growth, angiogenesis, metastasis and in embryogenesis. The sdf-1α signaling pathway has also been shown to be important for somite rotation in zebrafish (Hollway, et al 2007). Given the known similarities and differences between zebrafish and Xenopus laevis somitogenesis, we sought to determine whether the role of sdf-1α is conserved in Xenopus laevis. Results Using a morpholino approach, we demonstrate that knockdown of sdf-1α or its receptor, cxcr4, leads to a significant disruption in somite rotation and myotome alignment. We further show that depletion of sdf-1α or cxcr4 leads to the near absence of β-dystroglycan and laminin expression at the intersomitic boundaries. Finally, knockdown of sdf-1α decreases the level of activated RhoA, a small GTPase known to regulate cell shape and movement. Conclusion Our results show that sdf-1α signaling regulates somite cell migration, rotation and myotome alignment by directly or indirectly regulating dystroglycan expression and RhoA activation. These findings support the conservation of sdf-1α signaling in vertebrate somite morphogenesis; however, the precise mechanism by which this signaling pathway influences somite morphogenesis is different between the fish and the frog. PMID:24357195

  16. Effect of SDF-1/Cxcr4 Signaling Antagonist AMD3100 on Bone Mineralization in Distraction Osteogenesis.

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    Xu, Jia; Chen, Yuanfeng; Liu, Yang; Zhang, Jinfang; Kang, Qinglin; Ho, Kiwai; Chai, Yimin; Li, Gang

    2017-06-01

    Distraction osteogenesis (DO) is a widely applied technique in orthopedics surgery, which involves rapid stem cell migration, homing, and differentiation. Interactions between the chemokine receptor Cxcr4 and its ligand, stromal derived factor-1 (SDF-1), regulate hematopoietic stem cell trafficking to the ischemic area and induce their subsequent differentiation. Here, we examined SDF-1 expression and further investigated the role of SDF-1/Cxcr4 signaling antagonist AMD3100 during bone regeneration in rat DO model. The results showed that expression levels of SDF-1 and osteogenic genes were higher in DO zones than in the fracture zones, and SDF-1 expression level was the highest at the termination of the distraction phase. Radiological, mechanical, and histological analyses demonstrated that the local administration of AMD3100 (400 μM) to DO rats significantly inhibited new bone formation. In the rat bone marrow mesenchymal stem cells culture, comparing to the group treated with osteogenic induction medium, AMD3100 supplement led to a considerable decrease in the expression of alkaline phosphatase and early osteogenic marker genes. However, the amount of calcium deposits in rat MSCs did not differ between the groups. Therefore, our study demonstrated that the DO process induced higher expression of SDF-1, which collated to rapid induction of callus formation. Local application of SDF-1/Cxcr4 signaling antagonist AMD3100 significantly inhibited bone mineralization and osteogenesis in DO, which may represent a potential therapeutic approach to the enhancement of bone consolidation in patients undergoing DO.

  17. Inhibition of SDF-1/CXCR4-induced epithelial-mesenchymal transition by kisspeptin-10.

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    Gründker, Carsten; Bauerschmitz, Gerd; Knapp, Juliane; Schmidt, Elena; Olbrich, Theresa; Emons, Günter

    2015-07-01

    Recently we have shown that breast cancer cell invasion was dramatically increased when co-cultured with MG63 cells. In addition we have generated mesenchymal transformed MCF-7 breast cancer cells (MCF-7-EMT), showing significantly increased invasion in contrast to wild type MCF-7 cells (MCF-7 WT). In this study we have analyzed whether stromal derived factor-1 (SDF-1) is responsible for MCF-7 and T-47-D breast cancer cell invasion and epithelial-mesenchymal-transition (EMT). In addition we have analyzed whether kisspeptin-10 (KP-10) treatment affects SDF-1-induced invasion and EMT. Invasion was quantified by assessment of MCF-7 and T-47-D breast cancer cell migration rate through an artificial basement membrane in a modified Boyden chamber during co-culture with MG63 cells or after treatment with SDF-1α, SDF-1β or the combination of both isoforms. Induction of EMT was verified by analysis of protein expression of epithelial marker E-cadherin (CDH1) and mesenchymal markers N-cadherin (CDH2) and Vimentin (VIM). The role of SDF-1 for invasion and induction of EMT in breast cancer cells was analyzed by blocking SDF-1 secretion during co-culture with MG63 cells. In addition effects of KP-10 treatment on SDF-1-induced invasion and EMT were analyzed. Breast cancer cell invasion was significantly increased when co-cultured with MG63 cells. During co-culture SDF-1 protein expression of MG63 cells was significantly induced. The increased breast cancer cell invasion could be blocked by anti-SDF-1 antibodies. Treatment of breast cancer cells in monoculture (without MG63) with SDF-1α, SDF-1β or the combination of both isoforms resulted in a significant escalation of breast cancer cell invasion and induction of EMT. Protein expression of mesenchymal markers CDH2 and VIM was clearly elevated, whereas protein expression of epithelial marker CDH1 was clearly decreased. The SDF-1-induced increase of cell invasion was significantly reduced after treatment with KP-10. In addition

  18. Low intensity pulsed ultrasound enhanced mesenchymal stem cell recruitment through stromal derived factor-1 signaling in fracture healing.

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    Fang-Yuan Wei

    Full Text Available Low intensity pulsed ultrasound (LIPUS has been proven effective in promoting fracture healing but the underlying mechanisms are not fully depicted. We examined the effect of LIPUS on the recruitment of mesenchymal stem cells (MSCs and the pivotal role of stromal cell-derived factor-1/C-X-C chemokine receptor type 4 (SDF-1/CXCR4 pathway in response to LIPUS stimulation, which are essential factors in bone fracture healing. For in vitro study, isolated rat MSCs were divided into control or LIPUS group. LIPUS treatment was given 20 minutes/day at 37 °C for 3 days. Control group received sham LIPUS treatment. After treatment, intracellular CXCR4 mRNA, SDF-1 mRNA and secreted SDF-1 protein levels were quantified, and MSCs migration was evaluated with or without blocking SDF-1/CXCR4 pathway by AMD3100. For in vivo study, fractured 8-week-old young rats received intracardiac administration of MSCs were assigned to LIPUS treatment, LIPUS+AMD3100 treatment or vehicle control group. The migration of transplanted MSC to the fracture site was investigated by ex vivo fluorescent imaging. SDF-1 protein levels at fracture site and in serum were examined. Fracture healing parameters, including callus morphology, micro-architecture of the callus and biomechanical properties of the healing bone were investigated. The in vitro results showed that LIPUS upregulated SDF-1 and CXCR4 expressions in MSCs, and elevated SDF-1 protein level in the conditioned medium. MSCs migration was promoted by LIPUS and partially inhibited by AMD3100. In vivo study demonstrated that LIPUS promoted MSCs migration to the fracture site, which was associated with an increase of local and serum SDF-1 level, the changes in callus formation, and the improvement of callus microarchitecture and mechanical properties; whereas the blockade of SDF-1/CXCR4 signaling attenuated the LIPUS effects on the fractured bones. These results suggested SDF-1 mediated MSCs migration might be one of the

  19. Dermal fibroblast expression of stromal cell-derived factor-1 (SDF-1) promotes epidermal keratinocyte proliferation in normal and diseased skin.

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    Quan, Chunji; Cho, Moon Kyun; Shao, Yuan; Mianecki, Laurel E; Liao, Eric; Perry, Daniel; Quan, Taihao

    2015-12-01

    Stromal cells provide a crucial microenvironment for overlying epithelium. Here we investigated the expression and function of a stromal cell-specific protein, stromal cell-derived factor-1 (SDF-1), in normal human skin and in the tissues of diseased skin. Immunohistology and laser capture microdissection (LCM)-coupled quantitative real-time RT-PCR revealed that SDF-1 is constitutively and predominantly expressed in dermal stromal cells in normal human skin in vivo. To our surprise, an extremely high level of SDF-1 transcription was observed in the dermis of normal human skin in vivo, evidenced by much higher mRNA expression level than type I collagen, the most abundant and highly expressed protein in human skin. SDF-1 was also upregulated in the tissues of many human skin disorders including psoriasis, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). Double immunostaining for SDF-1 and HSP47 (heat shock protein 47), a marker of fibroblasts, revealed that fibroblasts were the major source of stroma-cell-derived SDF-1 in both normal and diseased skin. Functionally, SDF-1 activates the ERK (extracellular-signal-regulated kinases) pathway and functions as a mitogen to stimulate epidermal keratinocyte proliferation. Both overexpression of SDF-1 in dermal fibroblasts and treatment with rhSDF-1 to the skin equivalent cultures significantly increased the number of keratinocyte layers and epidermal thickness. Conversely, the stimulative function of SDF-1 on keratinocyte proliferation was nearly completely eliminated by interfering with CXCR4, a specific receptor of SDF-1, or by knock-down of SDF-1 in fibroblasts. Our data reveal that extremely high levels of SDF-1 provide a crucial microenvironment for epidermal keratinocyte proliferation in both physiologic and pathologic skin conditions.

  20. Cathepsin K cleavage of SDF-1α inhibits its chemotactic activity towards glioblastoma stem-like cells.

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    Hira, Vashendriya V V; Verbovšek, Urška; Breznik, Barbara; Srdič, Matic; Novinec, Marko; Kakar, Hala; Wormer, Jill; der Swaan, Britt Van; Lenarčič, Brigita; Juliano, Luiz; Mehta, Shwetal; Van Noorden, Cornelis J F; Lah, Tamara T

    2017-03-01

    Glioblastoma (GBM) is the most aggressive primary brain tumor with poor patient survival that is at least partly caused by malignant and therapy-resistant glioma stem-like cells (GSLCs) that are protected in GSLC niches. Previously, we have shown that the chemo-attractant stromal-derived factor-1α (SDF-1α), its C-X-C receptor type 4 (CXCR4) and the cysteine protease cathepsin K (CatK) are localized in GSLC niches in glioblastoma. Here, we investigated whether SDF-1α is a niche factor that through its interactions with CXCR4 and/or its second receptor CXCR7 on GSLCs facilitates their homing to niches. Furthermore, we aimed to prove that SDF-1α cleavage by CatK inactivates SDF-1α and inhibits the invasion of GSLCs. We performed mass spectrometric analysis of cleavage products of SDF-1α after proteolysis by CatK. We demonstrated that CatK cleaves SDF-1α at 3 sites in the N-terminus, which is the region of SDF-1α that binds to its receptors. Confocal imaging of human GBM tissue sections confirmed co-localization of SDF-1α and CatK in GSLC niches. In accordance, 2D and 3D invasion experiments using CXCR4/CXCR7-expressing GSLCs and GBM cells showed that SDF-1α had chemotactic activity whereas CatK cleavage products of SDF-1α did not. Besides, CXCR4 inhibitor plerixafor inhibited invasion of CXCR4/CXCR7-expressing GSLCs. In conclusion, CatK can cleave and inactivate SDF-1α. This implies that CatK activity facilitates migration of GSLCs out of niches. We propose that activation of CatK may be a promising strategy to prevent homing of GSLCs in niches and thus render these cells sensitive to chemotherapy and radiation. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Stromal Derived Factor-1/CXCR4 Axis Involved in Bone Marrow Mesenchymal Stem Cells Recruitment to Injured Liver

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    Kuai Xiao Ling

    2016-01-01

    Full Text Available The molecular mechanism of bone marrow mesenchymal stromal stem cells (BMSCs mobilization and migration to the liver was poorly understood. Stromal cell-derived factor-1 (SDF-1 participates in BMSCs homing and migration into injury organs. We try to investigate the role of SDF-1 signaling in BMSCs migration towards injured liver. The expression of CXCR4 in BMSCs at mRNA level and protein level was confirmed by RT-PCR, flow cytometry, and immunocytochemistry. The SDF-1 or liver lysates induced BMSCs migration was detected by transwell inserts. CXCR4 antagonist, AMD3100, and anti-CXCR4 antibody were used to inhibit the migration. The Sprague-Dawley rat liver injury model was established by intraperitoneal injection of thioacetamide. The concentration of SDF-1 increased as modeling time extended, which was determined by ELISA method. The Dir-labeled BMSCs were injected into the liver of the rats through portal vein. The cell migration in the liver was tracked by in vivo imaging system and the fluorescent intensity was measured. In vivo, BMSCs migrated into injured liver which was partially blocked by AMD3100 or anti-CXCR4 antibody. Taken together, the results demonstrated that the migration of BMSCs was regulated by SDF-1/CXCR4 signaling which involved in BMSCs recruitment to injured liver.

  2. Modulation of stromal cell-derived factor 1 alpha (SDF-1α) and its receptor CXCR4 in Porphyromonas gingivalis-induced periodontal inflammation.

    Science.gov (United States)

    Sun, Jiang; Nemoto, Eiji; Hong, Guang; Sasaki, Keiichi

    2016-07-22

    The production of chemokines by tissue resident cells during inflammation is considered one of the main mechanisms involved in the formation of inflammatory infiltrates. Fibroblasts are the main resident cell type in gingival and periodontal ligament tissues, and their ability to produce chemokine stromal cell-derived factor 1 alpha (SDF-1α) and its receptor CXCR4 under stimulation by gram negative bacteria, Porphyromonas gingivalis, commonly found in periodontal infections was investigated. Western blots were used to assess SDF-1α and CXCR4 protein expression levels in human gingival fibroblast cells (HGF-1) induced by Lipopolysaccharide (LPS) from P. gingivalis in the presence or absence of LY294002, a highly selective inhibitor of PI-3K/Akt. RT-PCR and quantitative Real-time PCR was performed using gingival mRNAs from periodontitis patients. Immunohistochemistry was performed to analyze the expression and subcellular localization of SDF-1α and CXCR4, together with NF-kβ phosphorylation, in specimens from patients with periodontitis and in an experimental rat periodontitis model. We found that P. gingivalis LPS up-regulated SDF-1α and CXCR4 protein levels and elevated phosphorylation of the SDF-1α-responsive NF-kβ and Akt at 24 h in HGF-1 cells. SDF-1α and CXCR4 mRNA and protein expression levels were high in all patients with periodontitis. In the P. gingivalis-induced rat experimental periodontitis model, SDF-1α and CXCR4 immunoreactivity was higher in gingival and periodontal ligament tissues compared to the control. Our data showed that PI-3K/Akt is an upstream participant in the P. gingivalis LPS-mediated induction of SDF-1α. Taken together, these results suggest that the chemokine SDF-1α and its receptor CXCR4 contribute to P. gingivalis-induced periodontal inflammation.

  3. Modulation of Selectin-Mediated Adhesion of Flowing Lymphoma and Bone Marrow Cells by Immobilized SDF-1

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    Elizabeth A. Hedges

    2014-08-01

    Full Text Available The α-chemokine, stromal-derived factor-1 (SDF-1, has been linked to the homing of circulating tumor cells to bone. SDF-1 is expressed by bone microvascular cells and osteoblasts and normally functions to attract blood-borne hematopoietic stem and progenitor cells to marrow. It has been shown that treatment of cancer cells with soluble SDF-1 results in a more aggressive phenotype; however, the relevance of the administration of the soluble protein is unclear. As such, a flow device was functionalized with P-selectin and SDF-1 to mimic the bone marrow microvasculature and the initial steps of cell adhesion. The introduction of SDF-1 onto the adhesive surface was found to significantly enhance the adhesion of lymphoma cells, as well as low-density bone marrow cells (LDBMC, both in terms of the number of adherent cells and the strength of cell adhesion. Thus, SDF-1 has a synergistic effect with P-selectin on cancer cell adhesion and may be sufficient to promote preferential metastasis to bone.

  4. Impaired colonization of the gonads by primordial germ cells in mice lacking a chemokine, stromal cell-derived factor-1 (SDF-1)

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    Ara, Toshiaki; Nakamura, Yuri; Egawa, Takeshi; Sugiyama, Tatsuki; Abe, Kuniya; Kishimoto, Tadamitsu; Matsui, Yasuhisa; Nagasawa, Takashi

    2003-01-01

    Primordial germ cells (PGCs) are the founders of sperm or oocytes. PGCs migrate through the tissues of the embryos and colonize the gonads during development. However, the cytokines essential for colonization of the gonads by PGCs in mammals remain unclear. Stromal cell-derived factor-1 (SDF-1, also called PBSF and CXCL12) is a member of chemokines, a family of structurally related chemoattractive cytokines. SDF-1 and its primary physiologic receptor CXCR4 have multiple essential functions in...

  5. The neuroblast and angioblast chemotaxic factor SDF-1 (CXCL12 expression is briefly up regulated by reactive astrocytes in brain following neonatal hypoxic-ischemic injury

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    Walker Aisha L

    2005-10-01

    Full Text Available Abstract Background Stromal cell-derived factor 1 (SDF-1 or CXCL12 is chemotaxic for CXCR4 expressing bone marrow-derived cells. It functions in brain embryonic development and in response to ischemic injury in helping guide neuroblast migration and vasculogenesis. In experimental adult stroke models SDF-1 is expressed perivascularly in the injured region up to 30 days after the injury, suggesting it could be a therapeutic target for tissue repair strategies. We hypothesized that SDF-1 would be expressed in similar temporal and spatial patterns following hypoxic-ischemic (HI injury in neonatal brain. Results Twenty-five 7-day-old C57BL/J mice underwent HI injury. SDF-1 expression was up regulated up to 7 days after the injury but not at the later time points. The chief sites of SDF-1 up regulation were astrocytes, their foot processes along blood vessels and endothelial cells. Conclusion The localization of SDF-1 along blood vessels in the HI injury zone suggests that these perivascular areas are where chemotaxic signaling for cellular recruitment originates and that reactive astrocytes are major mediators of this process. The associated endothelium is likely to be the site for vascular attachment and diapedesis of CXCR4 receptor expressing cells to enter the injured tissue. Here we show that, relative to adults, neonates have a significantly smaller window of opportunity for SDF-1 based vascular chemotaxic recruitment of bone marrow-derived cells. Therefore, without modification, following neonatal HI injury there is only a narrow period of time for endogenous SDF-1 mediated chemotaxis and recruitment of reparative cells, including exogenously administered stem/progenitor cells.

  6. Stromal cell-derived factor-1α (SDF-1α/CXCL12) stimulates ovarian cancer cell growth through the EGF receptor transactivation

    International Nuclear Information System (INIS)

    Porcile, Carola; Bajetto, Adriana; Barbieri, Federica; Barbero, Simone; Bonavia, Rudy; Biglieri, Marianna; Pirani, Paolo; Florio, Tullio; Schettini, Gennaro

    2005-01-01

    Ovarian cancer (OC) is the leading cause of death in gynecologic diseases in which there is evidence for a complex chemokine network. Chemokines are a family of proteins that play an important role in tumor progression influencing cell proliferation, angiogenic/angiostatic processes, cell migration and metastasis, and, finally, regulating the immune cells recruitment into the tumor mass. We previously demonstrated that astrocytes and glioblastoma cells express both the chemokine receptor CXCR4 and its ligand stromal cell-derived factor-1 (SDF-1), and that SDF-1α treatment induced cell proliferation, supporting the hypothesis that chemokines may play an important role in tumor cells' growth in vitro. In the present study, we report that CXCR4 and SDF-1 are expressed in OC cell lines. We demonstrate that SDF-1α induces a dose-dependent proliferation in OC cells, by the specific interaction with CXCR4 and a biphasic activation of ERK1/2 and Akt kinases. Our results further indicate that CXCR4 activation induces EGF receptor (EGFR) phosphorylation that in turn was linked to the downstream intracellular kinases activation, ERK1/2 and Akt. In addition, we provide evidence for cytoplasmic tyrosine kinase (c-Src) involvement in the SDF-1/CXCR4-EGFR transactivation. These results suggest a possible important 'cross-talk' between SDF-1/CXCR4 and EGFR intracellular pathways that may link signals of cell proliferation in ovarian cancer

  7. SDF1-3'A polymorphism is associated with size but not occurrence of abdominal aortic aneurysm in a Chinese population.

    Science.gov (United States)

    Zhang, Wenwen; Liu, Zhao; Zhou, Min; Yi, Long; Liu, Changjian

    2016-08-01

    Previous studies have suggested that stromal-derived factor 1 (SDF1) plays a pivotal role in abdominal aortic aneurysm (AAA) development. The SDF1-3'A polymorphism (G to A, rs1801157), located in the 3' untranslated region, could influence the expression of SDF1. The aim of our study was to investigate the relationship of SDF1-3'A polymorphism with the risk of AAA occurrence and size. A total of 205 AAA patients and 216 age- and sex-matched controls were recruited. The SDF1-3'A polymorphism was evaluated by polymerase chain reaction, followed by restriction enzyme analysis. The frequency of A allele was similar between groups. The genotype distribution also displayed no statistically significant differences under both the dominant model (odds ratio [OR], 0.922; P = .678) and the recessive model (OR, 1.617; P = .300). The multiple logistic regression analysis indicated that the association between the polymorphism and AAA remained insignificant when applied to the dominant model. However, AAA patients with GG genotype were more likely to develop aneurysms larger than 50 mm (OR, 0.497; P = .014). AAA patients with SDF1-3'A allele have reduced plasma SDF1α levels. In addition, plasma SDF1α levels were positively correlated with AAA size. Our study suggests that SDF1-3'A polymorphism is associated with size but not occurrence of AAA, providing further evidence that SDF1 is implicated in AAA progression. Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

  8. SDF-1 overexpression by mesenchymal stem cells enhances GAP-43-positive axonal growth following spinal cord injury.

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    Stewart, Andrew Nathaniel; Matyas, Jessica Jane; Welchko, Ryan Matthew; Goldsmith, Alison Delanie; Zeiler, Sarah Elizabeth; Hochgeschwender, Ute; Lu, Ming; Nan, Zhenhong; Rossignol, Julien; Dunbar, Gary Leo

    2017-01-01

    Utilizing genetic overexpression of trophic molecules in cell populations has been a promising strategy to develop cell replacement therapies for spinal cord injury (SCI). Over-expressing the chemokine, stromal derived factor-1 (SDF-1α), which has chemotactic effects on many cells of the nervous system, offers a promising strategy to promote axonal regrowth following SCI. The purpose of this study was to explore the effects of human SDF-1α, when overexpressed by mesenchymal stem cells (MSCs), on axonal growth and motor behavior in a contusive rat model of SCI. Using a transwell migration assay, the paracrine effects of MSCs, which were engineered to secrete human SDF-1α (SDF-1-MSCs), were assessed on cultured neural stem cells (NSCs). For in vivo analyses, the SDF-1-MSCs, unaltered MSCs, or Hanks Buffered Saline Solution (vehicle) were injected into the lesion epicenter of rats at 9-days post-SCI. Behavior was analyzed for 7-weeks post-injury, using the Basso, Beattie, and Bresnahan (BBB) scale of locomotor functions. Immunohistochemistry was performed to evaluate major histopathological outcomes, including gliosis, inflammation, white matter sparing, and cavitation. New axonal outgrowth was characterized using immunohistochemistry against the neuron specific growth-associated protein-43 (GAP-43). The results of these experiments demonstrate that the overexpression of SDF-1α by MSCs can enhance the migration of NSCs in vitro. Although only modest functional improvements were observed following transplantation of SDF-1-MSCs, a significant reduction in cavitation surrounding the lesion, and an increased density of GAP-43-positive axons inside the SCI lesion/graft site were found. The results from these experiments support the potential role for utilizing SDF-1α as a treatment for enhancing growth and regeneration of axons after traumatic SCI.

  9. A Simple Model for Inducing Optimal Increase of SDF-1 with Aminoglycoside Ototoxicity

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    Hyun Mi Ju

    2017-01-01

    Full Text Available Objectives. As a homing factor of stem cell, stromal derived factor-1 (SDF-1 is important for the regenerative research in ototoxicity. Mice models with aminoglycoside ototoxicity have been widely used to study the regeneration capacity of MSCs in repair of cochlear injury. We developed a mouse model with maximal increase in SDF-1 levels in the inner ear, according to the “one-shot” doses of kanamycin and furosemide. Methods. C57BL/6 mice had kanamycin (420, 550, and 600 mg/kg dissolved in PBS, followed by an intraperitoneal injection of furosemide (130 mg/kg. The injuries of inner ear were measured with hearing thresholds, histology, and outer hair cell counts at 0, 3, 5, 7, 10, and 14 days before the sacrifice. The levels of SDF-1 in the inner ear were tested by real-time RT-PCR and immunohistochemistry. Results. There were a significant reduction in hearing thresholds and a maximal increase of SDF-1 levels in the furosemide 130 mg/kg + kanamycin 550 mg/kg group, but severe hearing deterioration over time was observed in the furosemide 130 mg/kg + kanamycin 600 mg/kg group and four mice were dead. SDF-1 was detected mostly in the stria vascularis and organ of Corti showing the highest increase in expression. Conclusion. We observed optimal induction of the stem cell homing factor in the newly generated aminoglycoside-induced ototoxicity mouse model using a “one-shot” protocol. This study regarding high SDF-1 levels in our mouse model of ototoxicity would play a major role in the development of therapeutic agents using MSC homing.

  10. Omega-3 Fatty Acids Supplementation Differentially Modulates the SDF-1/CXCR-4 Cell Homing Axis in Hypertensive and Normotensive Rats.

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    Halmenschlager, Luiza; Lehnen, Alexandre Machado; Marcadenti, Aline; Markoski, Melissa Medeiros

    2017-08-01

    We assessed the effect of acute and chronic dietary supplementation of ω-3 on lipid metabolism and cardiac regeneration, through its influence on the Stromal Derived Factor-1 (SDF-1) and its receptor (CXCR4) axis in normotensive and hypertensive rats. Male Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) were allocated in eight groups (of eight animals each), which received daily orogastric administration of ω-3 (1 g) for 24 h, 72 h or 2 weeks. Blood samples were collected for the analysis of the lipid profile and SDF-1 systemic levels (ELISA). At the end of the treatment period, cardiac tissue was collected for CXCR4 expression analysis (Western blot). The use of ω-3 caused a reduction in total cholesterol levels ( p = 0.044), and acutely activated the SDF-1/CXCR4 axis in normotensive animals ( p = 0.037). In the presence of the ω-3, after 72 h, SDF-1 levels decreased in WKY and increased in SHR ( p = 0.017), and tissue expression of the receptor CXCR4 was higher in WKY than in SHR ( p = 0.001). The ω-3 fatty acid supplementation differentially modulates cell homing mediators in normotensive and hypertensive animals. While WKY rats respond acutely to omega-3 supplementation, showing increased release of SDF-1 and CXCR4, SHR exhibit a weaker, delayed response.

  11. Crosstalk between SDF-1/CXCR4 and SDF-1/CXCR7 in cardiac stem cell migration.

    Science.gov (United States)

    Chen, Dong; Xia, Yanli; Zuo, Ke; Wang, Ying; Zhang, Shiying; Kuang, Dong; Duan, Yaqi; Zhao, Xia; Wang, Guoping

    2015-11-18

    Stromal cell-derived factor 1 (SDF-1) is a chemokine that can be expressed in injured cardiomyocytes after myocardial infarction (MI). By combining with its receptor CXCR4, SDF-1 induced stem and progenitor cells migration. CXCR7, a novel receptor for SDF-1, has been identified recently. We aimed to explore the roles of SDF-1/CXCR4 and SDF-1/CXCR7 pathway and their crosstalk in CSCs migration. In the present study, CXCR4 and CXCR7 expression were identified in CSCs. Transwell assay showed that SDF-1 caused CSCs migration in a dose- and time-dependent manner, which could be significantly suppressed by CXCR4 or CXCR7 siRNA. Phospho-ERK, phospho-Akt and Raf-1 significantly elevated in CSCs with SDF-1 stimulation. Knockdown of CXCR4 or CXCR7 significantly decreased phospho-ERK or phospho-Akt, respectively, and eventually resulted in the inhibition of CSCs migration. Moreover, western blot showed that MK2206 (Akt inhibitor) increased the expression of phospho-ERK and Raf-1, whereas PD98059 (ERK inhibitor) had no effect on phospho-Akt and Raf-1. GW5074 (Raf-1 inhibitor) upregulated the expression of phospho-ERK, but had no effect on phospho-Akt. The present study indicated that SDF-1/CXCR7/Akt and SDF-1/CXCR4/ERK pathway played important roles in CSCs migration. Akt phosphorylation inhibited Raf-1 activity, which in turn dephosphorylated ERK and negatively regulated CSCs migration.

  12. CXCR7 is induced by hypoxia and mediates glioma cell migration towards SDF-1α

    International Nuclear Information System (INIS)

    Esencay, Mine; Sarfraz, Yasmeen; Zagzag, David

    2013-01-01

    Glioblastomas, the most common and malignant brain tumors of the central nervous system, exhibit high invasive capacity, which hinders effective therapy. Therefore, intense efforts aimed at improved therapeutics are ongoing to delineate the molecular mechanisms governing glioma cell migration and invasion. In order to perform the studies, we employed optimal cell culture methods and hypoxic conditions, lentivirus-mediated knockdown of protein expression, Western Blot analysis, migration assays and immunoprecipitation. We determined statistical significance by unpaired t-test. In this report, we show that U87MG, LN229 and LN308 glioma cells express CXCR7 and that exposure to hypoxia upregulates CXCR7 protein expression in these cell lines. CXCR7-expressing U87MG, LN229 and LN308 glioma cells migrated towards stromal-derived factor (SDF)-1α/CXCL12 in hypoxic conditions in the Boyden chamber assays. While shRNA-mediated knockdown of CXCR7 expression did not affect the migration of any of the three cell lines in normoxic conditions, we observed a reduction in the migration of LN229 and LN308, but not U87MG, glioma cells towards SDF-1α in hypoxic conditions. In addition, knockdown of CXCR7 expression in LN229 and LN308 glioma cells decreased levels of SDF-1α-induced phosphorylation of ERK1/2 and Akt. Inhibiting CXCR4 in LN229 and LN308 glioma cells that were knocked down for CXCR7 did not further reduce migration towards SDF-1α in hypoxic conditions and did not affect the levels of phosphorylated ERK1/2 and Akt. Analysis of immunoprecipitated CXCR4 from LN229 and LN308 glioma cells revealed co-precipitated CXCR7. Taken together, our findings indicate that both CXCR4 and CXCR7 mediate glioma cell migration towards SDF-1α in hypoxic conditions and support the development of therapeutic agents targeting these receptors

  13. Spatially localized recruitment of anti-inflammatory monocytes by SDF-1α-releasing hydrogels enhances microvascular network remodeling.

    Science.gov (United States)

    Krieger, J R; Ogle, M E; McFaline-Figueroa, J; Segar, C E; Temenoff, J S; Botchwey, E A

    2016-01-01

    Tissue repair processes are characterized by the biphasic recruitment of distinct subpopulations of blood monocytes, including classical ("inflammatory") monocytes (IMs, Ly6C(hi)Gr1(+)CX3CR1(lo)) and non-classical anti-inflammatory monocytes (AMs, Ly6C(lo)Gr1(-)CX3CR1(hi)). Drug-eluting biomaterial implants can be used to tune the endogenous repair process by the preferential recruitment of pro-regenerative cells. To enhance recruitment of AMs during inflammatory injury, a novel N-desulfated heparin-containing poly(ethylene glycol) diacrylate (PEG-DA) hydrogel was engineered to deliver exogenous stromal derived factor-1α (SDF-1α), utilizing the natural capacity of heparin to sequester and release growth factors. SDF-1α released from the hydrogels maintained its bioactivity and stimulated chemotaxis of bone marrow cells in vitro. Intravital microscopy and flow cytometry demonstrated that SDF-1α hydrogels implanted in a murine dorsal skinfold window chamber promoted spatially-localized recruitment of AMs relative to unloaded internal control hydrogels. SDF-1α delivery stimulated arteriolar remodeling that was correlated with AM enrichment in the injury niche. SDF-1α, but not unloaded control hydrogels, supported sustained arteriogenesis and microvascular network growth through 7 days. The recruitment of AMs correlated with parameters of vascular remodeling suggesting that tuning the innate immune response by biomaterial SDF-1α release is a promising strategy for promoting vascular remodeling in a spatially controlled manner. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. SDF-1 improves wound healing ability of glucocorticoid-treated adipose tissue-derived mesenchymal stem cells.

    Science.gov (United States)

    Kato, Toshiki; Khanh, Vuong Cat; Sato, Kazutoshi; Takeuchi, Kosuke; Carolina, Erica; Yamashita, Toshiharu; Sugaya, Hisashi; Yoshioka, Tomokazu; Mishima, Hajime; Ohneda, Osamu

    2017-11-18

    Glucocorticoids cause the delayed wound healing by suppressing inflammation that is required for wound healing process. Adipose tissue-derived mesenchymal stem cells (AT-MSCs) play an important role for wound healing by their cytokine productions including stromal derived factor 1 (SDF-1). However, it has not been clear how glucocorticoids affect the wound healing ability of AT-MSCs. In this study, we found that glucocorticoid downregulated SDF-1 expression in AT-MSCs. In addition, glucocorticoid-treated AT-MSCs induced less migration of inflammatory cells and impaired wound healing capacity compared with glucocorticoid-untreated AT-MSCs. Of note, prostaglandin E2 (PGE2) synthesis-related gene expression was downregulated by glucocorticoid and PGE2 treatment rescued not only SDF-1 expression in the presence of glucocorticoid but also their wound healing capacity in vivo. Furthermore, we found SDF-1-overexpressed AT-MSCs restored wound healing capacity even after treatment of glucocorticoid. Consistent with the results obtained from glucocorticoid-treated AT-MSCs, we found that AT-MSCs isolated from steroidal osteonecrosis donors (sAT-MSCs) who received chronic glucocorticoid therapy showed less SDF-1 expression and impaired wound healing capacity compared with traumatic osteonecrosis donor-derived AT-MSCs (nAT-MSCs). Moreover, the SDF-1 level was also reduced in plasma derived from steroidal osteonecrosis donors compared with traumatic osteonecrosis donors. These results provide the evidence that concomitant application of AT-MSCs with glucocorticoid shows impaired biological modulatory effects that induce impaired wound healing. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Spatiotemporal presentation of exogenous SDF-1 with PLGA nanoparticles modulates SDF-1/CXCR4 signaling axis in the rodent cortex.

    Science.gov (United States)

    Dutta, D; Hickey, K; Salifu, M; Fauer, C; Willingham, C; Stabenfeldt, S E

    2017-07-25

    Stromal cell-derived factor-1 (SDF-1) and its key receptor CXCR4 have been implicated in directing cellular recruitment for several pathological/disease conditions thus also gained considerable attention for regenerative medicine. One regenerative approach includes sustained release of SDF-1 to stimulate prolonged stem cell recruitment. However, the impact of SDF-1 sustained release on the endogenous SDF-1/CXCR4 signaling axis is largely unknown as auto-regulatory mechanisms typically dictate cytokine/receptor signaling. We hypothesize that spatiotemporal presentation of exogenous SDF-1 is a key factor in achieving long-term manipulation of endogenous SDF-1/CXCR4 signaling. Here in the present study, we sought to probe our hypothesis using a transgenic mouse model to contrast the spatial activation of endogenous SDF-1 and CXCR4 in response to exogenous SDF-1 injected in bolus or controlled release (PLGA nanoparticles) form in the adult rodent cortex. Our data suggests that the manner of SDF-1 presentation significantly affected initial CXCR4 cellular activation/recruitment despite having similar protein payloads over the first 24 h (∼30 ng for both bolus and sustained release groups). Yet, one week post-injection, this response was negligible. Therefore, the transient nature CXCR4 recruitment/activation in response to bolus or controlled release SDF-1 indicated that cytokine/receptor auto-regulatory mechanisms may demand more complex release profiles (i.e. delayed and/or pulsed release) to achieve sustained cellular response.

  16. Increased Platelet Content of SDF-1alpha is Associated with Worse Prognosis in Patients with Pulmonary Arterial Hypertension.

    Science.gov (United States)

    Kazimierczyk, Remigiusz; Blaszczak, Piotr; Jasiewicz, Małgorzata; Knapp, Małgorzata; Ptaszynska-Kopczynska, Katarzyna; Sobkowicz, Bozena; Waszkiewicz, Ewa; Grzywna, Ryszard; Musial, Wlodzimierz J; Kaminski, Karol A

    2018-04-04

    Inflammatory processes and platelet activity play an important role in the pathophysiology of pulmonary arterial hypertension (PAH). Enhanced IL-6 signaling and higher concentration of stromal-derived factor alpha (SDF-1) have been previously shown to be linked with prognosis in PAH. We hypothesized that platelets of PAH patients have higher content of IL-6 and SDF-1 and thus are involved in disease progression. We enrolled into study 22 PAH patients and 18 healthy controls. Patients with PAH presented significantly higher plasma concentrations and platelet contents of IL-6, sIL-6R, and SDF-1 than healthy subjects (platelet content normalized to protein concentration: IL-6 (0.85*10 -10 [0.29 - 1.37] vs. 0.45*10 -10 [0.19-0.65], sIL-6R 1.54*10 -7 [1.32-2.21] vs. 1.14*10 -7 [1.01-1.28] and SDF-1 (2.72*10 -7 [1.85-3.23] vs. 1.70*10 -7 [1.43-2.60], all p SDF-1/total platelet protein ratio (3.68*10 -7 [2.45-4.62] vs. 1.69*10 -7 [1.04-2.28], p = 0.001), with no significant differences between plasma levels. Kaplan-Meier analysis revealed that patients with higher platelet SDF-1/total platelet protein ratio had more frequently deterioration of PAH in the follow-up (15.24 ± 4.26 months, log-rank test, p = 0.01). Concentrations of IL-6, sIL-6 receptor and SDF-1 in plasma and platelets are elevated in PAH patients. Higher content of SDF-1 in platelets is associated with poorer prognosis. Our study, despite of limitation due to small number of enrolled patients, suggests that activated platelets may be an important source of cytokines at the site of endothelial injury, but their exact role in the pathogenesis of PAH requires further investigation.

  17. SDF-1/CXCL12 and CXCR4 gene variants, and elevated serum SDF-1 levels are associated with preeclampsia.

    Science.gov (United States)

    Karakus, Savas; Bagci, Binnur; Bagci, Gokhan; Sancakdar, Enver; Yildiz, Caglar; Akkar, Ozlem; Cetin, Ali

    2017-05-01

    We aimed to compare the frequencies of stromal cell-derived factor-1 (SDF-1) 3'A and CXCR4 single-nucleotide polymorphisms (SNPs) and serum SDF-1 levels in patients with preeclampsia (PE). In total, 89 women with PE and 89 control women were included in the study. Genotyping was done by polymerase chain reaction-restriction fragment length polymorphism method. Enzyme-linked immunosorbent assay method was used to measure serum SDF-1 level. For SDF-1 3'A SNP, the frequency of GA genotype, total number of GA and AA genotypes, and the A allele frequency was higher in PE patients than controls (p = 0.04, 0.023, and 0.029, respectively). For CXCR4 SNP, the frequency of CT genotype, total number of CT and TT genotypes, and the T allele frequency were higher in PE patients than controls (p = 0.04, 0.006, and 0.005, respectively). SDF-1 serum level was detected higher in preeclamptic women compared with controls (p = 0.001). In PE patients, there was no significant association between serum SDF-1 levels and genotypes of SDF-1 3'A SNP. SDF-1 level was significantly higher in patients bearing CXCR4 CT genotype than CC genotype (p = 0.001). Furthermore, SDF-1 levels in patients bearing CT+TT genotype were found higher than that of patients with CC genotypes (p = 0.001). Results of our study suggest that SDF-1 3'A and CXCR4 polymorphisms and elevated serum SDF-1 levels may have a role in the development of PE.

  18. SDF-1α (Stromal Cell-Derived Factor 1α) Induces Cardiac Fibroblasts, Renal Microvascular Smooth Muscle Cells, and Glomerular Mesangial Cells to Proliferate, Cause Hypertrophy, and Produce Collagen.

    Science.gov (United States)

    Jackson, Edwin K; Zhang, Yumeng; Gillespie, Delbert D; Zhu, Xiao; Cheng, Dongmei; Jackson, Travis C

    2017-11-07

    Activated cardiac fibroblasts (CFs), preglomerular vascular smooth muscle cells (PGVSMCs), and glomerular mesangial cells (GMCs) proliferate, cause hypertrophy, and produce collagen; in this way, activated CFs contribute to cardiac fibrosis, and activated PGVSMCs and GMCs promote renal fibrosis. In heart and kidney diseases, SDF-1α (stromal cell-derived factor 1α; endogenous CXCR4 [C-X-C motif chemokine receptor 4] receptor agonist) levels are often elevated; therefore, it is important to know whether and how the SDF-1α/CXCR4 axis activates CFs, PGVSMCs, or GMCs. Here we investigated whether SDF-1α activates CFs, PGVSMCs, and GMCs to proliferate, hypertrophy, or produce collagen. DPP4 (dipeptidyl peptidase 4) inactivates SDF-1α and previous experiments show that growth-promoting peptides have greater effects in cells from genetically-hypertensive animals. Therefore, we performed experiments in the absence and presence of sitagliptin (DPP4 inhibitor) and in cells from normotensive Wistar-Kyoto rats and spontaneously hypertensive rats. Our studies show (1) that spontaneously hypertensive and Wistar-Kyoto rat CFs, PGVSMCs, and GMCs express CXCR4 receptors and DPP4 activity; (2) that chronic treatment with physiologically relevant concentrations of SDF-1α causes concentration-dependent increases in the proliferation (cell number) and hypertrophy ( 3 H-leucine incorporation) of and collagen production ( 3 H-proline incorporation) by CFs, PGVSMCs, and GMCs; (3) that sitagliptin augments these effects of SDF-1α; (4) that interactions between SDF-1α and sitagliptin are greater in spontaneously hypertensive rat cells; (5) that CXCR4 antagonism (AMD3100) blocks all effects of SDF-1α; and (6) that SDF-1α/CXCR4 signal transduction likely involves the RACK1 (receptor for activated C kinase 1)/Gβγ/PLC (phospholipase C)/PKC (protein kinase C) signaling complex. The SDF-1α/CXCR4 axis drives proliferation and hypertrophy of and collagen production by CFs, PGVSMCs, and

  19. The effect of SDF-1α on low dose BMP-2 mediated bone regeneration by release from heparinized mineralized collagen type I matrix scaffolds in a murine critical size bone defect model.

    Science.gov (United States)

    Zwingenberger, Stefan; Langanke, Robert; Vater, Corina; Lee, Geoffrey; Niederlohmann, Eik; Sensenschmidt, Markus; Jacobi, Angela; Bernhardt, Ricardo; Muders, Michael; Rammelt, Stefan; Knaack, Sven; Gelinsky, Michael; Günther, Klaus-Peter; Goodman, Stuart B; Stiehler, Maik

    2016-09-01

    The treatment of critical size bone defects represents a challenge. The growth factor bone morphogenetic protein 2 (BMP-2) is clinically established but has potentially adverse effects when used at high doses. The aim of this study was to evaluate if stromal derived factor-1 alpha (SDF-1α) and BMP-2 released from heparinized mineralized collagen type I matrix (MCM) scaffolds have a cumulative effect on bone regeneration. MCM scaffolds were functionalized with heparin, loaded with BMP-2 and/or SDF-1α and implanted into a murine critical size femoral bone defect (control group, low dose BMP-2 group, low dose BMP-2 + SDF-1α group, and high dose BMP-2 group). After 6 weeks, both the low dose BMP-2 + SDF-1α group (5.8 ± 0.6 mm³, p = 0.0479) and the high dose BMP-2 group (6.5 ± 0.7 mm³, p = 0.008) had a significantly increased regenerated bone volume compared to the control group (4.2 ± 0.5 mm³). There was a higher healing score in the low dose BMP-2 + SDF-1α group (median grade 8; Q1-Q3 7-9; p = 0.0357) than in the low dose BMP-2 group (7; Q1-Q3 5-9) histologically. This study showed that release of BMP-2 and SDF-1α from heparinized MCM scaffolds allows for the reduction of the applied BMP-2 concentration since SDF-1α seems to enhance the osteoinductive potential of BMP-2. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2126-2134, 2016. © 2016 Wiley Periodicals, Inc.

  20. Exogenous stromal derived factor-1 releasing silk scaffold combined with intra-articular injection of progenitor cells promotes Bone-Ligament-Bone regeneration.

    Science.gov (United States)

    Hu, Yejun; Ran, Jisheng; Zheng, Zefeng; Jin, Zhangchu; Chen, Xiao; Yin, Zi; Tang, Chenqi; Chen, Yangwu; Huang, Jiayun; Le, Huihui; Yan, Ruijian; Zhu, Ting; Wang, Junjuan; Lin, Junxin; Xu, Kan; Zhou, Yiting; Zhang, Wei; Cai, Youzhi; Dominique, Pioletti; Chin Heng, Boon; Chen, Weishan; Shen, Weiliang; Ouyang, Hong-Wei

    2018-03-07

    Anterior cruciate ligament (ACL) is one of the most difficult tissues to heal once injured. Ligament regeneration and tendon-bone junction healing are two major goals of ACL reconstruction. This study aimed to investigate the synergistic therapeutic effects of Stromal cell-derived factor 1(SDF-1)-releasing collagen-silk (CSF) scaffold combined with intra-articular injection of ligament-derived stem/progenitor cells (LSPCs) for ACL regeneration and the amelioration in the long-term complication of osteoarthritis (OA). The stem cell recruitment ability of CSF scaffold and the multipotency, particularly the tendon forming ability of LSPCs from rabbits were characterized in vitro, while the synergistic effect of the CSF scaffold and LSPCs for ACL regeneration and OA amelioration were investigated in vivo at 1, 3, and 6 months with a rabbit ACL reconstruction model. The CSF scaffold was used as a substitute for the ACL, and LSPCs were injected into the joint cavity after 7 days of the ACL reconstruction. CSF scaffold displayed a controlled release pattern for the encapsulated protein for up to 7 days with an increased stiffness in the mechanical property. LSPCs, which exhibited highly I Collagen and CXCR4 expression, were attracted by SDF-1 and successfully relocated into the CSF scaffold at 1 month in vivo. At 3 and 6 months post-treatment, the CSF scaffold combined with LSPCs (CSFL group) enhanced the regeneration of ACL tissue, and promoted bone tunnel healing. Furthermore, the OA progression was impeded efficiently. Our findings here provided a new strategy that using stem cell recruiting CSF scaffold with tissue-specific stem cells, could be a promising solution for ACL regeneration. In this study, we developed a silk scaffold with increased stiffness and SDF-1 controlled release capacity for ligament repair. This advanced scaffold transplantation combined with intra-articular injection of LSPCs (which was isolated from rabbit ligament for the first time in this

  1. Experimental study on relationship between expression of SDF-1 and homing of hematopoietic cells

    International Nuclear Information System (INIS)

    Sun Suping; Cai Jianming; Xiang Yingsong; Zhao Fang; Huang Dingde; Gao Jianguo; Yang Rujun

    2002-01-01

    Objective: To investigate the role of chemo-attractant SDF-1 in of homing hematopoietic cells. Methods: A mouse allogeneic bone marrow transplantation model and double staining of immunohistochemistry were used in this study. Relationship between expression of chemo-attractant SDF-1 and of homing hematopoietic cells was observed. Results: In bone marrow, SDF-1 was mainly expressed at sites near endosteum, in microvessel endothelium, osteocytes and around donor cells. Contrast to non-irradiation group, SDF-1 was significantly expressed by osteocytes, and at sites near endosteum in the irradiation group, suggesting that pretreatment with irradiation might enhance secretion of SDF-1 by bone marrow stromal cells and SDF-1 could have a close relation with homing cells. Conclusion: Pretreatment with irradiation might be one of the stimulating factors significantly increasing the level of SDF-1 produced by bone marrow stromal cells and the chemo-attractant SDF-1 could play an important role in homing of hematopoietic cells

  2. Transcript analyses of stromal cell derived factors (SDFs): SDF-2, SDF-4 and SDF-5 reveal a different pattern of expression and prognostic association in human breast cancer

    OpenAIRE

    Kang, H.; Escudero-Esparza, Astrid; Douglas-Jones, A.; Mansel, Robert Edward; Jiang, Wen G.

    2009-01-01

    Stromal derived factors, SDFs, are a loosely defined group of molecules that may be generated by stromal cells. Two of the stromal derived factors, SDF-1 and SDF-4 belong to the chemokine family. Other SDFs, such as SDF-2 and SDF-5 are not well defined and their biological functions are less known. Although SDF-1 and its receptor have been strongly indicated in the progression of various cancers including breast cancer, little is known with regard to the role of other SDFs in malignant condit...

  3. SDF-1 Expression is Associated with Poor Prognosis in Osteosarcoma.

    Science.gov (United States)

    Yu, Dangen; Lv, Fei; Zhang, Jianhe; Li, Hongjie

    2016-09-01

    Stromal cell-derived factor-1 (SDF-1) expression has been reported to be a predictor of poor clinical symptoms in certain types of cancer. Vascular endothelial growth factor (VEGF) is a well-known factor that mediates the micro-angiogenesis of solid tumors, and SDF-1 mediated expression of VEGF may promote tumor growth and metastasis, resulting in poor clinical outcome. Therefore, we explored the expression levels of SDF-1 and VEGF in patients with osteosarcoma in order to determine the association between their expression levels and unfavorable outcomes. A total of 54 patients with osteosarcoma were included in the current study. The protein expression levels of SDF-1 and VEGF were evaluated on immunohistochemical and immunofluorescence staining. The correlation between the expression levels of SDF-1 and VEGF and their association with clinical parameters were analyzed using the Pearson chi-square test and the Spearman-rho test. Univariate and multivariate Cox regression analyses were used to identify potential prognostic factors. The Kaplan-Meier method was employed to analyze overall survival. Low SDF-1 and VEGF expression levels were detected in 20.4% (11 of 54) and 22.2% (12 of 54) of the patients with osteosarcoma, respectively; moderate expression was detected in 35.2% (19 of 54) and 37.0% (20 of 54) of the patients, respectively; and high expression was detected in 44.4% (24 of 54) and 40.7% (22 of 54) of the patients, respectively. Protein levels of both SDF-1 and VEGF were significantly associated with the histologic grade (p=0.004 and p=0.042 respectively), the presence of metastasis (p=0.009 and p=0.028 respectively), and Enneking staging (pSDF-1and VEGF had a significantly positive correlation (pSDF-1 and VEGF were significantly associated with shorter overall survival on univariate analysis; however, the association was significant for SDF-1 expression alone in the multivariate analysis (p=0.26, hazard ratio =2.640 [1.124-6.200]). SDF-1 and VEGF

  4. SDF-1α peptide tethered polyester facilitates tissue repair by endogenous cell mobilization and recruitment.

    Science.gov (United States)

    Shafiq, Muhammad; Kong, Deling; Kim, Soo Hyun

    2017-10-01

    The design of bioactive scaffolds that can invoke host's own regenerative capabilities and facilitate endogenous tissue repair hold great promise. This study aims to evaluate the potential of stromal cell-derived factor 1 alpha (SDF-1α)-derived peptide and heparin tethered poly(L-lactide-co-ε-caprolactone) (PLCL) copolymers for blood vessel regeneration applications. Amino acid analysis and toluidine blue assays confirm successful conjugation of SDF-1α peptide and heparin with the PLCL copolymers. Assessment of biocompatibility after subcutaneous implantation in rats discloses higher cell infiltration in SDF-1α peptide (SDF-1 group) or SDF-1 peptide and heparin (SDF-1/heparin group) than the control group. SDF-1 and SDF-1/heparin grafts also show more numbers of laminin + blood vessels, CD90 + stem cells, and alpha smooth muscle actin + cells than the control group. However, SDF-1 and SDF-1/heparin groups did not significantly differ in terms of blood vessel regeneration and stem cell recruitment. Evaluation of the inflammatory response reveal less numbers of CD68 + macrophages in SDF-1 and SDF-1/heparin groups compared with the control group; whereas three groups show similar numbers of CD206 + macrophages. These results indicate that completely synthetic, cell-free grafts can attract endogenous cells and enhance tissue repair. Bioactive polyesters can be fabricated into different shapes and structures for various tissue engineering applications. © 2017 Wiley Periodicals, Inc. J Biomater Res Part A: 105A: 2670-2684, 2017. © 2017 Wiley Periodicals, Inc.

  5. High Expression of Stromal Cell-Derived Factor 1 (SDF-1) and NF-κB Predicts Poor Prognosis in Cervical Cancer.

    Science.gov (United States)

    Song, Zhiwang; Zhang, Xia; Ye, Xiaojuan; Feng, Chan; Yang, Guang; Lu, Yonglin; Lin, Yun; Dong, Chunyan

    2017-01-11

    BACKGROUND SDF-1 and NF-κB are associated with the prognosis of a wide range of cancers, but their value in cervical cancer remains controversial. The aim of this study was to investigate the expression of SDF-1and NF-κB in cervical cancer and their significance in clinical prognosis. MATERIAL AND METHODS The expression of SDF-1and NF-κB in 105 formalin-fixed, paraffin-embedded cervical cancer tissues and the adjacent tissues was examined by immunohistochemistry (IHC). The results were semi-quantitatively scored and analyzed by chi-square test. The overall survival times (OS) were collected by follow-up and analyzed by Kaplan-Meier analysis. RESULTS The expression level of both SDF-1and NF-κB in cervical cancer are higher than that in the adjacent tissues (PSDF-1 expression are correlated with tumor size and FIGO histology grade (PSDF-1or NF-κB tended to have much shorter survival time than patients with negative expression. In addition, multivariate Cox regression analysis demonstrated that SDF-1 expression and lymph node metastasis are independent predictors of the OS in cervical cancer patients. CONCLUSIONS The expression of SDF-1 is significantly associated with tumor size and FIGO histology grade. The expression of NF-κB is significantly associated with tumor size, FIGO histology grade, and lymph node metastasis. The positive SDF-1or NF-κB expression is significantly correlated with poor prognosis. These may be valuable biomarkers for the prognosis and the potential therapeutic targets of cervical cancer.

  6. SDF-1 induces TNF-mediated apoptosis in cardiac myocytes.

    Science.gov (United States)

    Jarrah, Andrew A; Schwarskopf, Martina; Wang, Edward R; LaRocca, Thomas; Dhume, Ashwini; Zhang, Shihong; Hadri, Lahouria; Hajjar, Roger J; Schecter, Alison D; Tarzami, Sima T

    2018-01-01

    Chemokines are small secreted proteins with chemoattractant properties that play a key role in inflammation. One such chemokine, Stromal cell-derived factor-1 (SDF-1) also known as CXCL12, and its receptor, CXCR4, are expressed and functional in cardiac myocytes. SDF-1 both stimulates and enhances the cellular signal which attracts potentially beneficial stem cells for tissue repair within the ischemic heart. Paradoxically however, this chemokine is known to act in concert with the inflammatory cytokines of the innate immune response which contributes to cellular injury through the recruitment of inflammatory cells during ischemia. In the present study, we have demonstrated that SDF-1 has dose dependent effects on freshly isolated cardiomyocytes. Using Tunnel and caspase 3-activation assays, we have demonstrated that the treatment of isolated adult rat cardiac myocyte with SDF-1 at higher concentrations (pathological concentrations) induced apoptosis. Furthermore, ELISA data demonstrated that the treatment of isolated adult rat cardiac myocyte with SDF-1 at higher concentrations upregulated TNF-α protein expression which directly correlated with subsequent apoptosis. There was a significant reduction in SDF-1 mediated apoptosis when TNF-α expression was neutralized which suggests that SDF-1 mediated apoptosis is TNF-α-dependent. The fact that certain stimuli are capable of driving cardiomyocytes into apoptosis indicates that these cells are susceptible to clinically relevant apoptotic triggers. Our findings suggest that the elevated SDF-1 levels seen in a variety of clinical conditions, including ischemic myocardial infarction, may either directly or indirectly contribute to cardiac cell death via a TNF-α mediated pathway. This highlights the importance of this receptor/ligand in regulating the cardiomyocyte response to stress conditions.

  7. Cloning and expression pattern of dog SDF-1 and the implications of altered expression of SDF-1 in ischemic myocardium.

    Science.gov (United States)

    Wei, Ying-jie; Tang, Yi; Li, Jun; Cui, Chuan-jue; Zhang, Hong; Zhang, Xiao-ling; Zhang, Hao; Hu, Sheng-shou

    2007-10-01

    Stromal cell derived factor-1 (SDF-1) plays a pivotal role in the mobilization and homing of stem cells, indicative of its potential in myocardial regeneration after heart damage. The use of large animal models in cardiac surgery research plays an essential role in the translation of results from basic studies into clinical trials. Considering the aforesaid two reasons, for the first time, we cloned dog SDF-1 cDNA and characterized the constitutive expression pattern of SDF-1 gene in normal dog tissues and the dynamic expression pattern in a dog model of myocardial infarction (MI) by means of ELISA test, real-time RT-PCR, and Western blotting. In a dog model of MI, We also examined and compared the differentially expressed pattern of SDF-1 between infarct area and border zone of myocardium in order to explore the implication of differentially distribution of SDF-1 in the mobilization and homing of stem cells to the damaged heart. Our results provide insights into expression pattern and pathophysiologic significance of dog SDF-1 in normal and heart-damaged dogs.

  8. Myocardial Ischemia Induces SDF-1α Release in Cardiac Surgery Patients.

    Science.gov (United States)

    Kim, Bong-Sung; Jacobs, Denise; Emontzpohl, Christoph; Goetzenich, Andreas; Soppert, Josefin; Jarchow, Mareike; Schindler, Lisa; Averdunk, Luisa; Kraemer, Sandra; Marx, Gernot; Bernhagen, Jürgen; Pallua, Norbert; Schlemmer, Heinz-Peter; Simons, David; Stoppe, Christian

    2016-06-01

    In the present observational study, we measured serum levels of the chemokine stromal cell-derived factor-1α (SDF-1α) in 100 patients undergoing cardiac surgery with cardiopulmonary bypass at seven distinct time points including preoperative values, myocardial ischemia, reperfusion, and the postoperative course. Myocardial ischemia triggered a marked increase of SDF-1α serum levels whereas cardiac reperfusion had no significant influence. Perioperative SDF-1α serum levels were influenced by patients' characteristics (e.g., age, gender, aspirin intake). In an explorative analysis, we observed an inverse association between SDF-1α serum levels and the incidence of organ dysfunction. In conclusion, time of myocardial ischemia was identified as the key stimulus for a significant upregulation of SDF-1α, indicating its role as a marker of myocardial injury. The inverse association between SDF-1α levels and organ dysfunction association encourages further studies to evaluate its organoprotective properties in cardiac surgery patients.

  9. SDF-1 controls the muscle and blood vessel formation of the somite.

    Science.gov (United States)

    Abduelmula, Aisha; Huang, Ruijin; Pu, Qin; Tamamura, Hirokazu; Morosan-Puopolo, Gabriela; Brand-Saberi, Beate

    2016-01-01

    Stromal-cell-derived factor-1 (SDF-1), the only ligand of the chemokine receptor CXCR4, is involved in skeletal muscle development. However, its role in the proliferation, differentiation and migration of somite cells is not well understood. Here, we investigated its function during somite development in chicken embryos by using gain-of-function and loss-of-function experiments. Overexpression of SDF-1 was performed by electroporating SDF-1 constructs into the ventrolateral part of the somite, or by injecting SDF-1-expressing cells into the somites of stages HH14-16 chicken embryos. We found that enhanced SDF-1 signaling induced cell proliferation in the somite. This resulted in an increase in number of both myotomal and endothelial cells. In contrast, inhibition of SDF-1/CXCR4 signaling led to a reduction of myotomal cells. Injection of SDF-1 producing cells into the somite induced ectopic localization of myotomal cells in the sclerotome. Although many SDF-1-expressing somite cells colonized the limb, only a few of them developed into muscle cells. This resulted in a reduction of the limb muscle mass. This means that most myogenic progenitors were stopped on their migration towards the limb due to the high concentration of the SDF-1 signal in the somite. Most of the SDF-1-expressing somite cells found in the limb were of endothelial cell fate and they contributed to the increase in limb blood vessels. These results reveal that SDF-1 promotes the proliferation of both myogenic and angiogenic progenitor cells of the somite and controls myotome formation. Furthermore, SDF-1 controls muscle and blood vessel formation in the limb in different ways.

  10. The role of SDF-1/CXCR4 in the vasculogenesis and remodeling of cerebral arteriovenous malformation.

    Science.gov (United States)

    Wang, Lingyan; Guo, Shaolei; Zhang, Nu; Tao, Yuqian; Zhang, Heng; Qi, Tiewei; Liang, Feng; Huang, Zhengsong

    2015-01-01

    Cerebral arteriovenous malformation (AVM) involves the vasculogenesis of cerebral blood vessels and can cause severe intracranial hemorrhage. Stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4, are believed to exert multiple physiological functions including angiogenesis. Thus, we investigated the role of SDF-1/CXCR4 in the vasculogenesis of cerebral AVM. Brain AVM lesions from surgical resections were analyzed for the expression of SDF-1, CXCR4, VEGF-A, and HIF-1 by using immunohistochemical staining. Flow cytometry was used to quantify the level of circulating endothelial progenitor cells (EPCs). Further, in an animal study, chronic cerebral hypoperfusion model rats were analyzed for the expression of SDF-1 and HIF-1. CXCR4 antagonist, AMD3100, was also used to detect its effects on cerebral vasculogenesis and SDF-1 expression. Large amounts of CXCR4-positive CD45(+) cells were found in brain AVM lesion blood vessel walls, which also have higher SDF-1 expression. Cerebral AVM patients also had higher level of EPCs and SDF-1. In chronic cerebral hypoperfusion rats, SDF-1, HIF-1, and CD45 expressions were elevated. The application of AMD3100 effectively suppressed angiogenesis and infiltration of CXCR4-positive CD45(+) cells in hypoperfusion rats compared to controls. The SDF-1/CXCR4 axis plays an important role in the vasculogenesis and migration of inflammatory cells in cerebral AVM lesions, possibly via the recruitment of bone marrow EPCs.

  11. Effects of SDF-1/CXCR4 on Acute Lung Injury Induced by Cardiopulmonary Bypass.

    Science.gov (United States)

    Shi, Hai; Lu, Rujian; Wang, Shuo; Chen, Honglin; Wang, Fei; Liu, Kun

    2017-06-01

    Acute lung injury (ALI) is one of the most important complications after cardiopulmonary bypass (CPB) and the complex pathophysiology remains to be resolved incomplete. SDF-1/CXCR4 chemokine axis can chemotactically accumulate inflammatory cell to local tissue and regulate the release of inflammatory factors, and SDF-1 has a strong chemotaxis effect on neutrophils with CXCR4. Since CPB animal model was difficult to establish, there was still no report about the effect of SDF-1/CXCR4 on neutrophil chemotaxis in ALI after CPB. Here, a stable CPB rat model was constructed to clarify the role of SDF-1/CXCR4 axis in the CPB-induced ALI. Real-time quantitative PCR (RT-qPCR), Western blot analysis, and enzyme-linked immunosorbent assay (ELISA) were used to detect the changes of SDF-1 and CXCR4 in lung tissues, blood, bronchoalveolar lavage (BALF), and/or isolated neutrophils. SDF-1/CXCR4 was increased after CPB, both of that were increased in blood; CXCR4 was increased in neutrophils; SDF-1/CXCR4 was also increased in BALF of CPB model. Results indicated that SDF-1/CXCR4 axis played a key role in the process of early ALI after CPB, also showed that lung injury was significantly reduce after blocking SDF-1/CXCR4 axis, suggest that CXCR4 might be a new target for ALI treatment.

  12. Controlled Release of Collagen-Binding SDF-1α Improves Cardiac Function after Myocardial Infarction by Recruiting Endogenous Stem Cells.

    Science.gov (United States)

    Sun, Jie; Zhao, Yannan; Li, Qingguo; Chen, Bing; Hou, Xianglin; Xiao, Zhifeng; Dai, Jianwu

    2016-05-26

    Stromal cell-derived factor-1α (SDF-1α) is a well-characterized chemokine that mobilizes stem cells homing to the ischemic heart, which is beneficial for cardiac regeneration. However, clinically administered native SDF-1α diffuses quickly, thus decreasing its local concentration, and results in side effects. Thus, a controlled release system for SDF-1α is required to produce an effective local concentration in the ischemic heart. In this study, we developed a recombinant chemokine, consisting of SDF-1α and a collagen-binding domain, which retains both the SDF-1α and collagen-binding activity (CBD-SDF-1α). In an in vitro assay, CBD-SDF-1α could specifically bind to a collagen gel and achieve sustained release. An intramyocardial injection of CBD-SDF-1α after acute myocardial infarction demonstrated that the protein was largely tethered in the ischemic area and that controlled release had been achieved. Furthermore, CBD-SDF-1α enhanced the recruitment of c-kit positive (c-kit(+)) stem cells, increased capillary density and improved cardiac function, whereas NAT-SDF-1α had no such beneficial effects. Our findings demonstrate that CBD-SDF-1α can specifically bind to collagen and achieve controlled release both in vitro and in vivo. Local delivery of this protein could mobilize endogenous stem cells homing to the ischemic heart and improve cardiac function after myocardial infarction.

  13. Endomyocardial expression of SDF-1 predicts mortality in patients with suspected myocarditis.

    Science.gov (United States)

    Zuern, Christine S; Walker, Britta; Sauter, Martina; Schaub, Malte; Chatterjee, Madhumita; Mueller, Karin; Rath, Dominik; Vogel, Sebastian; Tegtmeyer, Roland; Seizer, Peter; Geisler, Tobias; Kandolf, Reinhard; Lang, Florian; Klingel, Karin; Gawaz, Meinrad; Borst, Oliver

    2015-12-01

    Risk stratification in patients with suspected myocarditis is pivotal for optimizing therapy. Stromal cell-derived factor 1 (SDF-1) is an inflammatory chemokine expressed in the inflamed and failing myocardium. Therefore, we aimed to investigate whether endomyocardial expression of SDF-1 identifies high-risk patients with suspected myocarditis. We prospectively enrolled 174 patients with non-ischemic HF who underwent endomyocardial biopsy for suspected myocarditis. Biopsies were analyzed using established histopathological and immunohistological criteria together with SDF-1 staining. SDF-1 was significantly enhanced in patients with inflammatory cardiomyopathy (65.4 % positive biopsies) as compared to patients with non-inflammatory cardiomyopathy (19.1 %, p SDF-1 expression levels correlated significantly with the degree of myocardial fibrosis (correlation coefficient r = 0.196; p = 0.010) since patients with severe myocardial fibrosis displayed high myocardial SDF-1 expression. During a mean follow-up of 27.5 months, 20 patients (11.5 %) died. The 4-year mortality rate was 26.0 % among the 92 SDF-1-positive patients vs. 9.5 % among the 82 SDF-1-negative patients (p = 0.001). On multivariable analysis which considered clinical (NYHA functional class, left ventricular ejection fraction), laboratory (brain natriuretic peptide, troponin I) and biopsy staining, SDF-1 was the strongest independent predictor of mortality (hazard ratio 6.1; 95 % confidence interval 1.4-27.5; p = 0.018). Subgroup analysis revealed SDF-1 as a predictor of mortality in both patients with inflammatory and non-inflammatory cardiomyopathy. Endomyocardial expression of SDF-1 is enhanced in inflammatory cardiomyopathy, positively correlates with myocardial fibrosis and identifies high-risk patients with suspected myocarditis.

  14. SDF-1 dynamically mediates megakaryocyte niche occupancy and thrombopoiesis at steady state and following radiation injury

    Science.gov (United States)

    Niswander, Lisa M.; Fegan, Katherine H.; Kingsley, Paul D.; McGrath, Kathleen E.

    2014-01-01

    Megakaryocyte (MK) development in the bone marrow progresses spatially from the endosteal niche, which promotes MK progenitor proliferation, to the sinusoidal vascular niche, the site of terminal maturation and thrombopoiesis. The chemokine stromal cell-derived factor-1 (SDF-1), signaling through CXCR4, is implicated in the maturational chemotaxis of MKs toward sinusoidal vessels. Here, we demonstrate that both IV administration of SDF-1 and stabilization of endogenous SDF-1 acutely increase MK-vasculature association and thrombopoiesis with no change in MK number. In the setting of radiation injury, we find dynamic fluctuations in marrow SDF-1 distribution that spatially and temporally correlate with variations in MK niche occupancy. Stabilization of altered SDF-1 gradients directly affects MK location. Importantly, these SDF-1-mediated changes have functional consequences for platelet production, as the movement of MKs away from the vasculature decreases circulating platelets, while MK association with the vasculature increases circulating platelets. Finally, we demonstrate that manipulation of SDF-1 gradients can improve radiation-induced thrombocytopenia in a manner additive with earlier TPO treatment. Taken together, our data support the concept that SDF-1 regulates the spatial distribution of MKs in the marrow and consequently circulating platelet numbers. This knowledge of the microenvironmental regulation of the MK lineage could lead to improved therapeutic strategies for thrombocytopenia. PMID:24735964

  15. SDF-1 and CXCR4 play an important role in adult SVZ lineage cell proliferation and differentiation.

    Science.gov (United States)

    Zhu, Chang; Yao, Wen-Long; Tan, Wei; Zhang, Chuan-Han

    2017-02-15

    Evidence has shown that stromal cell-derived factor (SDF-1/CXCL12) plays an important role in maintaining adult neural progenitor cells (NPCs). SDF-1 is also known to enhance recovery by recruiting NPCs to damaged regions and recent studies have revealed that SDF-1α exhibits pleiotropism, thereby differentially affecting NPC subpopulations. In this study, we investigated the role of SDF-1 in in vitro NPC self-renewal, proliferation and differentiation, following treatment with different concentrations of SDF-1 or a CXCR4 antagonist, AMD3100. We observed that AMD3100 inhibited the formation of primary neurospheres. However, SDF-1 and AMD3100 exhibited no effect on proliferation upon inclusion of growth factors in the media. Following growth factor withdrawal, AMD3100 and SDF-1 treatment resulted in differential effects on NPC proliferation. SDF-1, at a concentration of 500ng/ml, resulted in an increase in the relative proportion of oligodendrocytes following growth factor withdrawal-induced differentiation. Using CXCR4 knockout mice, we observed that SDF-1 affected NPC proliferation in the sub-ventricular zone (SVZ). We also investigated the occurrence of differential CXCR4 expression at different stages during lineage progression. These results clearly indicate that signaling interactions between SDF-1 and CXCR4 play an important role in adult SVZ lineage cell proliferation and differentiation. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. The MCP-1, CCL-5 and SDF-1 chemokines as pro-inflammatory markers in generalized anxiety disorder and personality disorders.

    Science.gov (United States)

    Ogłodek, Ewa A; Szota, Anna M; Just, Marek J; Moś, Danuta M; Araszkiewicz, Aleksander

    2015-02-01

    The co-occurrence of generalized anxiety disorder and personality disorders suggests the existence of association between the neurobiological predispositions leading to the development of these disorders and activation of cytokine system. Pro-inflammatory chemokines such as CCL-5/RANTES (regulated upon activation normal T cell expressed and secreted) and CXCL12/SDF-1 (stromal derived factor) play an important role in immune response. A total of 160 participants were enrolled in the study, 120 of whom comprised the study group (people with the dual diagnosis of personality disorder and generalized anxiety disorder). The mean age was 41.4 ± 3.5 years (range: 20-44 years). The control group consisted of 40 healthy individuals in the mean age of 40.8 ± 3.1 years (range: 20-43 years). A blood sample was collected from each participant and the plasma levels of the CCL-2/MCP-1 (monocyte chemoattractant protein-1), RANTES and SDF-1 chemokines were determined by ELISA. Increased levels of MCP-1 and SDF-1 were found both in women and in men versus the control group for all types of personality disorders. The levels of CCL-5 in men were significantly increased versus the control group and significantly higher in women than in men. Neither women nor men with avoidant or obsessive-compulsive personality disorder showed any significant differences in MCP-1 or SFD-1 levels. In subjects with borderline personality disorder, the levels of the study chemokines were higher in women than in men. Our study has shown the need for determination of proinflammatory interleukins which are considered as biomarkers of personality disorders and generalized anxiety disorders. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  17. Effect of Dual Treatment with SDF-1 and BMP-2 on Ectopic and Orthotopic Bone Formation

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    Jung, Hong-Moon; Lee, Jung-Tae; Kwon, Tae-Geon

    2015-01-01

    Purposes The potent stem cell homing factor stromal cell-derived factor-1 (SDF-1) actively recruits mesenchymal stem cells from circulation and from local bone marrow. It is well established that bone morphogenetic protein-2 (BMP-2) induces ectopic and orthotopic bone formation. However, the exact synergistic effects of BMP-2 and SDF-1 in ectopic and orthotopic bone regeneration models have not been fully investigated. The purpose of this study was to evaluate the potential effects of simultaneous SDF-1 and BMP-2 treatment on bone formation. Materials and Methods Various doses of SDF-1 were loaded onto collagen sponges with or without BMP-2.These sponges were implanted into subcutaneous pockets and critical-size calvarial defects in C57BL/6 mice. The specimens were harvested 4 weeks post-surgery and the degree of bone formation in specimens was evaluated by histomorphometric and radiographic density analyses. Osteogenic potential and migration capacity of mesenchymal cells and capillary tube formation of endothelial cells following dual treatment with SDF-1 and BMP-2 were evaluated with in vitro assays. Results SDF-1-only-treated implants did not yield significant in vivo bone formation and SDF-1 treatment did not enhance BMP-2-induced ectopic and orthotopic bone regeneration. In vitro experiments showed that concomitant use of BMP-2 and SDF-1 had no additive effect on osteoblastic differentiation, cell migration or angiogenesis compared to BMP-2 or SDF-1 treatment alone. Conclusions These findings imply that sequence-controlled application of SDF-1 and BMP-2 must be further investigated for the enhancement of robust osteogenesis in bone defects. PMID:25781922

  18. TPL2 (Therapeutic Targeting Tumor Progression Locus-2)/ATF4 (Activating Transcription Factor-4)/SDF1α (Chemokine Stromal Cell-Derived Factor-α) Axis Suppresses Diabetic Retinopathy.

    Science.gov (United States)

    Lai, De-Wei; Lin, Keng-Hung; Sheu, Wayne Huey-Herng; Lee, Maw-Rong; Chen, Chung-Yu; Lee, Wen-Jane; Hung, Yi-Wen; Shen, Chin-Chang; Chung, Tsung-Ju; Liu, Shing-Hwa; Sheu, Meei-Ling

    2017-09-01

    Diabetic retinopathy is characterized by vasopermeability, vascular leakage, inflammation, blood-retinal barrier breakdown, capillary degeneration, and neovascularization. However, the mechanisms underlying the association between diabetes mellitus and progression retinopathy remain unclear. TPL2 (tumor progression locus 2), a serine-threonine protein kinase, exerts a pathological effect on vascular angiogenesis. This study investigated the role of N ε -(carboxymethyl)lysine, a major advanced glycation end products, and the involved TPL2-related molecular signals in diabetic retinopathy using models of in vitro and in vivo and human samples. Serum N ε -(carboxymethyl)lysine levels and TPL2 kinase activity were significantly increased in clinical patients and experimental animals with diabetic retinopathy. Intravitreal administration of pharmacological blocker or neutralizing antibody inhibited TPL2 and effectively suppressed the pathological characteristics of retinopathy in streptozotocin-induced diabetic animal models. Intravitreal VEGF (vascular endothelial growth factor) neutralization also suppressed the diabetic retinopathy in diabetic animal models. Mechanistic studies in primary human umbilical vein endothelial cells and primary retinal microvascular endothelial cells from streptozotocin-diabetic rats, db/db mice, and samples from patients with diabetic retinopathy revealed a positive parallel correlation between N ε -(carboxymethyl)lysine and the TPL2/chemokine SDF1α (stromal cell-derived factor-α) axis that is dependent on endoplasmic reticulum stress-related molecules, especially ATF4 (activating transcription factor-4). This study demonstrates that inhibiting the N ε -(carboxymethyl)lysine-induced TPL2/ATF4/SDF1α axis can effectively prevent diabetes mellitus-mediated retinal microvascular dysfunction. This signaling axis may include the therapeutic potential for other diseases involving pathological neovascularization or macular edema. © 2017

  19. Role of SDF-1 and Wnt signaling pathway in the myocardial fibrosis of hypertensive rats.

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    Shao, Shuai; Cai, Wenwei; Sheng, Jing; Yin, Lingni

    2015-01-01

    To investigate the effects of stromal cell-derived factor-1 (SDF-1) and Wnt signaling pathway on the bioactivities of myofibroblasts (MFs) and the expressions of SDF-1 and components of Wnt signaling pathway in the myocardium of spontaneously hypertensive rats (SHR). BMSCs were induced to differentiate into MFs in vitro, and SDF-1 and Wnt signaling pathway were independently or simultaneously blocked. Then, the migration of MFs and the secretion of Col I and α-SMA were determined in MFs. Heart function, progression of myocardial fibrosis and structure of the heart were evaluated. The expression of SDF-1 and components of Wnt signaling pathway in SHR was detected. TGF-β could induce the differentiation of BMSCs into B-MFs; Blocking SDF-1/CXCR4 axis and/or Wnt signaling pathway was able to inhibit the MFs migration and Col I secretion; Blocking Wnt signaling pathway inhibited the differentiation of BMSCs into MFs; Serum SDF-1 increased with the increase in blood pressure, and serum β-catenin elevated with the fluctuation of blood pressure; Protein and mRNA expressions of SDF-1 in the myocardium increased, and those of DKK-1 (an inhibitor of Wnt signaling pathway) and GSK-3 reduced in SHR. SDF-1 and Wnt signaling pathway are involved in the differentiation of BMSCs into MFs, as well as the migration and collagen secretion of MFs; Hypertension affects the expressions of SDF-1 and components of Wnt signaling pathway. In the myocardium of SHR, SDF-1 expression increases, but the expression of inhibitor of Wnt signaling pathway reduces.

  20. The role of SDF-1/CXCR4 in the vasculogenesis and remodeling of cerebral arteriovenous malformation

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    Wang L

    2015-09-01

    Full Text Available Lingyan Wang,1 Shaolei Guo,2 Nu Zhang,2 Yuqian Tao,3 Heng Zhang,1 Tiewei Qi,2 Feng Liang,2 Zhengsong Huang2 1Department of Neurosurgery ICU, 2Department of Neurosurgery, 3Department of Neurology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China Background: Cerebral arteriovenous malformation (AVM involves the vasculogenesis of cerebral blood vessels and can cause severe intracranial hemorrhage. Stromal cell-derived factor-1 (SDF-1 and its receptor, CXCR4, are believed to exert multiple physiological functions including angiogenesis. Thus, we investigated the role of SDF-1/CXCR4 in the vasculogenesis of cerebral AVM.Methods: Brain AVM lesions from surgical resections were analyzed for the expression of SDF-1, CXCR4, VEGF-A, and HIF-1 by using immunohistochemical staining. Flow cytometry was used to quantify the level of circulating endothelial progenitor cells (EPCs. Further, in an animal study, chronic cerebral hypoperfusion model rats were analyzed for the expression of SDF-1 and HIF-1. CXCR4 antagonist, AMD3100, was also used to detect its effects on cerebral vasculogenesis and SDF-1 expression.Results: Large amounts of CXCR4-positive CD45+ cells were found in brain AVM lesion blood vessel walls, which also have higher SDF-1 expression. Cerebral AVM patients also had higher level of EPCs and SDF-1. In chronic cerebral hypoperfusion rats, SDF-1, HIF-1, and CD45 expressions were elevated. The application of AMD3100 effectively suppressed angiogenesis and infiltration of CXCR4-positive CD45+ cells in hypoperfusion rats compared to controls.Conclusion: The SDF-1/CXCR4 axis plays an important role in the vasculogenesis and migration of inflammatory cells in cerebral AVM lesions, possibly via the recruitment of bone marrow EPCs. Keywords: cerebral arteriovenous malformation, SDF-1/CXCR4, chronic cerebral hypoperfusion, endothelial progenitor cells

  1. Hypoxia-inducible factor 1α (HIF-1α) and reactive oxygen species (ROS) mediates radiation-induced invasiveness through the SDF-1α/CXCR4 pathway in non-small cell lung carcinoma cells.

    Science.gov (United States)

    Gu, Qing; He, Yan; Ji, Jianfeng; Yao, Yifan; Shen, Wenhao; Luo, Jialin; Zhu, Wei; Cao, Han; Geng, Yangyang; Xu, Jing; Zhang, Shuyu; Cao, Jianping; Ding, Wei-Qun

    2015-05-10

    Radiotherapy is an important procedure for the treatment of inoperable non-small cell lung cancer (NSCLC). However, recent evidence has shown that irradiation can promote the invasion and metastasis of several types of cancer, and the underlying mechanisms are not fully understood. This study aimed to investigate the molecular mechanism by which radiation enhances the invasiveness of NSCLC cells. We found that after irradiation, hypoxia-inducible factor 1α (HIF-1α) was increased and translocated into the nucleus, where it bound to the hypoxia response element (HRE) in the CXCR4 promoter and promoted the transcription of CXCR4. Furthermore, reactive oxygen species (ROS) also plays a role in the radiation-induced expression of CXCR4. Our results revealed that 2 Gy X-ray irradiation promoted the metastasis and invasiveness of H1299, A549 and H460 cells, which were significantly enhanced by SDF-1α treatment. Blocking the SDF-1α/CXCR4 interaction could suppress the radiation-induced invasiveness of NSCLC cells. The PI3K/pAkt and MAPK/pERK1/2 pathways were found to be involved in radiation-induced matrix metalloproteinase (MMP) expression. In vivo, irradiation promoted the colonization of H1299 cells in the liver and lung, which was mediated by CXCR4. Altogether, our findings have elucidated the underlying mechanisms of the irradiation-enhanced invasiveness of NSCLC cells.

  2. SDF-1/CXCR4 mediates acute protection of cardiac function through myocardial STAT3 signaling following global ischemia/reperfusion injury

    Science.gov (United States)

    Huang, Chunyan; Gu, Hongmei; Zhang, Wenjun; Manukyan, Mariuxi C.; Shou, Weinian

    2011-01-01

    Stromal cell-derived factor-1α (SDF-1) has been reported to mediate cardioprotection through the mobilization of stem cells into injured tissue and an increase in local angiogenesis after myocardial infarction. However, little is known regarding whether SDF-1 induces acute protection following global myocardial ischemia/reperfusion (I/R) injury and if so, by what molecular mechanism. SDF-1 binding to its cognate receptor CXCR4 has been shown to activate STAT3 in a variety of cells. STAT3 is a cardioprotective factor and may mediate SDF-1/CXCR4-induced acute protection. We hypothesized that SDF-1 would improve myocardial function through CXCR4-increased STAT3 activation following acute I/R. Isolated mouse hearts were subjected to 25-min global ischemia/40-min reperfusion and divided into groups of 1) vehicle; 2) SDF-1; 3) AMD3100, a CXCR4 inhibitor; 4) SDF-1 + AMD3100; 5) Stattic, a STAT3 inhibitor; 6) SDF-1 + Stattic; 7) cardiomyocyte-restricted ablation of STAT3 (STAT3KO); 8) STAT3KO + SDF-1; 9) Ly294002, an inhibitor of the Akt pathway; and 10) SDF-1 + Ly294002. Reagents were infused into hearts within 5 min before ischemia. SDF-1 administration significantly improved postischemic myocardial functional recovery in a dose-dependent manner. Additionally, pretreatment with SDF-1 reduced cardiac apoptotic signaling and increased myocardial STAT3 activation following acute I/R. Inhibition of the SDF-1 receptor CXCR4 neutralized these protective effects by SDF-1 in hearts subjected to I/R. Notably, inhibition of the STAT3 pathway or use of STAT3KO hearts abolished SDF-1-induced acute protection following myocardial I/R. Our results represent the first evidence that the SDF-1/CXCR4 axis upregualtes myocardial STAT3 activation and, thereby, mediates acute cardioprotection in response to global I/R. PMID:21821779

  3. Hypercholesterolemia promotes bone marrow cell mobilization by perturbing the SDF-1:CXCR4 axis.

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    Gomes, Ana L; Carvalho, Tânia; Serpa, Jacinta; Torre, Cheila; Dias, Sérgio

    2010-05-13

    Hypercholesterolemia is associated with elevated peripheral blood leukocytes and increased platelet levels, generally attributed to cholesterol-induced proinflammatory cytokines. Bone marrow (BM) cell mobilization and platelet production is achieved by disrupting the SDF-1:CXCR4 axis, namely with granulocyte colony-stimulating factor and/or CXCR4 antagonists. Here we show that high cholesterol disrupts the BM SDF-1:CXCR4 axis; promotes the mobilization of B cells, neutrophils, and progenitor cells (HPCs); and creates thrombocytosis. Hypercholesterolemia was achieved after a 30-day high-cholesterol feeding trial, resulting in elevated low-density lipoprotein (LDL) cholesterol levels and inversion of the LDL to high-density lipoprotein cholesterol ratio. Hypercholesterolemic mice displayed lymphocytosis, increased neutrophils, HPCs, and thrombocytosis with a lineage-specific decrease in the BM. Histologic analysis revealed that megakaryocyte numbers remained unaltered but, in high-cholesterol mice, they formed large clusters in contact with BM vessels. In vitro, LDL induced stromal cell-derived factor-1 (SDF-1) production, suggesting that megakaryocyte delocalization resulted from an altered SDF-1 gradient. LDL also stimulated B cells and HPC migration toward SDF-1, which was blocked by scavenger receptor class B type I (cholesterol receptor) inhibition. Accordingly, hypercholesterolemic mice had increased peripheral blood SDF-1 levels, increased platelets, CXCR4-positive B lymphocytes, neutrophils, and HPCs. High cholesterol interferes with the BM SDF-1:CXCR4 axis, resulting in lymphocytosis, thrombocytosis, and HPC mobilization.

  4. Expression of chemokine receptor-4 in bone marrow mesenchymal stem cells on experimental rat abdominal aortic aneurysms and the migration of bone marrow mesenchymal stem cells with stromal-derived factor-1

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    Miao-Yun Long

    2014-05-01

    Full Text Available This study investigated the expression and role of chemokine receptor-4 (CXCR4 in bone marrow mesenchymal stem cells (BMSCs from experimental rats with abdominal aortic aneurysms (AAA for migration of BMSCs. Sprague–Dawley rats were divided into an experimental group and control group (n = 18 each. AAA was induced with 0.75 M solution infiltrate for 30 minutes, after which the abdomen was rinsed and closed. Saline was used in place of CaCl2 in the control group. CD34 and CD29 were detected by flow cytometry, the gene and protein expression of CXCR4 were detected by real-time polymerase chain reaction and western blot, respectively. The migration of BMSCs with stromal-derived factor-1 was detected by Transwell chamber. CD34 expression was negative and CD29 expression was positive. The gene and protein expression of CXCR4 were significantly higher in experimental group than them in control group (p < 0.05, the migration ability of BMSCs from the experimental group was significantly higher than that from the control group (p < 0.05. Stromal-derived factor -1/CXCR4 can enhance the migration of BMSCs in vitro in a rat AAA model.

  5. Expression patterns and role of SDF-1/CXCR4 axis in boar spermatogonial stem cells.

    Science.gov (United States)

    Park, Hyun Jung; Lee, Won-Yong; Kim, Jin Hoi; Park, Chankyu; Song, Hyuk

    2018-03-15

    The signaling of chemokine stromal cell-derived factor (SDF)-1 and its receptor C-X-C motif chemokine receptor 4 (CXCR4) is involved in the cellular proliferation, survival, and migration of various cell types. Although SDF-1/CXCR4 has been implicated in the maintenance of the spermatogonial population during mouse testis development, their expression patterns and functions in boar testis remain unclear. In the present study, the expression pattern of SDF-1 and CXCR4 was determined during pre-pubertal and post-pubertal stage boar testes and in vitro cultured porcine spermatogonial stem cells (pSSCs). The role of these proteins in colony formation in cultured pSSCs was also investigated. Interestingly, SDF-1 expression was observed in PGP 9.5-positve spermatogonia in all developing stages of boar testis; however, CXCR4 expression was only detected in spermatogonia from 5-day-old boar testis. In addition, SDF-1 and CXCR4 expression was observed in cultured pSSCs from 5-day-old boar testes, and inhibition of the CXCR4 receptor signaling pathway by AMD3100 significantly decreased the colony formation of pSSCs. These results suggest that SDF-1 and CXCR4 are useful markers for detecting stage-specific spermatogonia in boar testis. Our results reveal the role of the SDF-1/CXCR4 axis in pSSC in vitro culture. Copyright © 2018. Published by Elsevier Inc.

  6. SDF-1/CXCR4 Signaling Maintains Stemness Signature in Mouse Neural Stem/Progenitor Cells.

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    Ho, Shih-Yin; Ling, Thai-Yen; Lin, Hsing-Yu; Liou, Jeffrey Tsai-Jui; Liu, Fei-Chih; Chen, I-Chun; Lee, Sue-Wei; Hsu, Yu; Lai, Dar-Ming; Liou, Horng-Huei

    2017-01-01

    SDF-1 and its primary receptor, CXCR4, are highly expressed in the embryonic central nervous system (CNS) and play a crucial role in brain architecture. Loss of SDF-1/CXCR4 signaling causes abnormal development of neural stem/progenitor cells (NSCs/NPCs) in the cerebellum, hippocampus, and cortex. However, the mechanism of SDF-1/CXCR4 axis in NSCs/NPCs regulation remains unknown. In this study, we found that elimination of SDF-1/CXCR4 transduction caused NSCs/NPCs to lose their stemness characteristics and to encounter neurogenic differentiation. Moreover, Notch and RE1 silencing transcription factor (REST) both play an essential role in NSCs/NPCs maintenance and neuronal differentiation and were dramatically downregulated following SDF-1/CXCR4 cascade inhibition. Finally, we demonstrated that the expression of achaete-scute homolog 1 (Ascl1), a proneural gene, and p27, an antiproliferative gene, were significantly increased after genetic elimination of SDF-1 alleles. Our results support that the loss of functional SDF-1/CXCR4 signaling pathway in NSCs/NPCs induces exit of cell cycle and promotes premature neural differentiation.

  7. SDF-1/CXCR4 Signaling Maintains Stemness Signature in Mouse Neural Stem/Progenitor Cells

    Directory of Open Access Journals (Sweden)

    Shih-Yin Ho

    2017-01-01

    Full Text Available SDF-1 and its primary receptor, CXCR4, are highly expressed in the embryonic central nervous system (CNS and play a crucial role in brain architecture. Loss of SDF-1/CXCR4 signaling causes abnormal development of neural stem/progenitor cells (NSCs/NPCs in the cerebellum, hippocampus, and cortex. However, the mechanism of SDF-1/CXCR4 axis in NSCs/NPCs regulation remains unknown. In this study, we found that elimination of SDF-1/CXCR4 transduction caused NSCs/NPCs to lose their stemness characteristics and to encounter neurogenic differentiation. Moreover, Notch and RE1 silencing transcription factor (REST both play an essential role in NSCs/NPCs maintenance and neuronal differentiation and were dramatically downregulated following SDF-1/CXCR4 cascade inhibition. Finally, we demonstrated that the expression of achaete-scute homolog 1 (Ascl1, a proneural gene, and p27, an antiproliferative gene, were significantly increased after genetic elimination of SDF-1 alleles. Our results support that the loss of functional SDF-1/CXCR4 signaling pathway in NSCs/NPCs induces exit of cell cycle and promotes premature neural differentiation.

  8. NADPH oxidase- generated ROS are required for SDF-1α-stimulated angiogenesis Short title: NOX is an angiogenic regulator

    Science.gov (United States)

    Pi, Xinchun; Xie, Liang; Portbury, Andrea L.; Kumar, Sarayu; Lockyer, Pamela; Li, Xi; Patterson, Cam

    2014-01-01

    Objective Reactive oxygen species (ROS) act as signaling molecules during angiogenesis, however, the mechanisms used for such signaling events remain unclear. Stromal cell-derived factor-1α (SDF-1α) is one of the most potent angiogenic chemokines. Here we examined the role of ROS in the regulation of SDF-1α-dependent angiogenesis. Approach and results Bovine aortic endothelial cells (BAECs) were treated with SDF-1α and intracellular ROS generation was monitored. SDF-1α treatment induced BAEC migration and ROS generation, with the majority of ROS generated by BAECs at the leading edge of the migratory cells. Antioxidants and NADPH oxidase (NOX) inhibitors blocked SDF-1α-induced endothelial migration. Furthermore, knockdown of either NOX5 or p22phox (a requisite subunit for NOX1/2/4 activation) significantly impaired endothelial motility and tube formation, suggesting that multiple NOXs regulate SDF-1α-dependent angiogenesis. Our previous study demonstrated that JNK3 activity is essential for SDF-1α-dependent angiogenesis. Here, we identified that NOX5 is the dominant NOX required for SDF-1α-induced JNK3 activation and that NOX5 and MKP7 (the JNK3 phosphatase) associate with one another but decrease this interaction upon SDF-1α treatment. Furthermore, MKP7 activity was inhibited by SDF-1α and this inhibition was relieved by NOX5 knockdown, indicating that NOX5 promotes JNK3 activation by blocking MKP7 activity. Conclusions We conclude that NOX is required for SDF-1α signaling and that intracellular redox balance is critical for SDF-1α-induced endothelial migration and angiogenesis. PMID:24990230

  9. Role of SDF-1:CXCR4 in Impaired Post-Myocardial Infarction Cardiac Repair in Diabetes.

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    Mayorga, Maritza E; Kiedrowski, Matthew; McCallinhart, Patricia; Forudi, Farhad; Ockunzzi, Jeremiah; Weber, Kristal; Chilian, William; Penn, Marc S; Dong, Feng

    2018-01-01

    Diabetes is a risk factor for worse outcomes following acute myocardial infarction (AMI). In this study, we tested the hypothesis that SDF-1:CXCR4 expression is compromised in post-AMI in diabetes, and that reversal of this defect can reverse the adverse effects of diabetes. Mesenchymal stem cells (MSC) isolated from green fluorescent protein (GFP) transgenic mice (control MSC) were induced to overexpress stromal cell-derived factor-1 (SDF-1). SDF-1 expression in control MSC and SDF-1-overexpressing MSC (SDF-1:MSC) were quantified using enzyme-linked immunosorbent assay (ELISA). AMI was induced on db/db and control mice. Mice were randomly selected to receive infusion of control MSC, SDF-1:MSC, or saline into the border zone after AMI. Serial echocardiography was used to assess cardiac function. SDF-1 and CXCR4 mRNA expression in the infarct zone of db/db mice and control mice were quantified. Compared to control mice, SDF-1 levels were decreased 82%, 91%, and 45% at baseline, 1 day and 3 days post-AMI in db/db mice, respectively. CXCR4 levels are increased 233% at baseline and 54% 5 days post-AMI in db/db mice. Administration of control MSC led to a significant improvement in ejection fraction (EF) in control mice but not in db/db mice 21 days after AMI. In contrast, administration of SDF-1:MSC produced a significant improvement in EF in both control mice and db/db mice 21 days after AMI. The SDF-1:CXCR4 axis is compromised in diabetes, which appears to augment the deleterious consequences of AMI. Over-express of SDF-1 expression in diabetes rescues cardiac function post AMI. Our results suggest that modulation of SDF-1 may improve post-AMI cardiac repair in diabetes. Stem Cells Translational Medicine 2018;7:115-124. © 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

  10. Analysis of the expression of SDF-1 splicing variants in human colorectal cancer and normal mucosa tissues.

    Science.gov (United States)

    Allami, Risala Hussain; Graf, Claudine; Martchenko, Ksenia; Voss, Beatrice; Becker, Marc; Berger, Martin R; Galle, Peter R; Theobald, Matthias; Wehler, Thomas C; Schimanski, Carl C

    2016-03-01

    C-X-C motif chemokine ligand 12 (CXCL12), also termed stromal cell-derived factor-1 (SDF-1) is a small protein 8-14 kDa in length that is expressed as six isoforms, consisting of SDF-1α, SDF-1β, SDF-1γ, SDF-1δ, SDF-1ε and SDF-1θ. All six isoforms are encoded by the single CXCL12 gene on chromosome 10. This gene regulates leukocyte trafficking and is variably expressed in a number of normal and cancer tissues. The potential role of the novel CXCL12 splice variants as components of the CXCR4 axis in cancer development is not fully understood. The present study aimed to analyze the expression profile of the various SDF-1 isoforms and SDF-1 polymorphisms, and the association with the clinicopathological features and overall survival of patients with colorectal cancer (CRC). SDF-1 polymorphism analysis was performed using restriction fragment length polymorphism (RFLP) analysis in 73 histologically confirmed human CRC tissue samples at various stages of disease. The expression pattern of the SDF-1 isoforms was analyzed by reverse transcription-polymerase chain reaction in 40 histologically confirmed human CRC tissue samples obtained at various stages of disease, as well as in matched adjacent normal mucosa samples. The presence of the CXCL12 gene polymorphism rs1801157 demonstrated an association with local progression of the primary tumor, as indicated by the T stage. The frequency of the GG genotype was slightly increased in patients with stage 3 and 4 tumors (78.0%) compared with the incidence of the GA/AA genotype (69.5%; P=0.067). The expression of SDF-1β was associated with the presence of metastases (P=0.0656) and the expression of SDF-1γ was significantly associated with tumor size (P=0.0423). The present study is the first to analyze the association between the expression profile of the chemokine CXCL12 splice variants in human CRC tissues and their clinical relevance. The present results reveal that the CXCL12 G801A polymorphism is a low

  11. Platelet surface expression of SDF-1 is associated with clinical outcomes in the patients with cardiovascular disease.

    Science.gov (United States)

    Rath, Dominik; Chatterjee, Madhumita; Bongartz, Angela; Müller, Karin; Droppa, Michal; Stimpfle, Fabian; Borst, Oliver; Zuern, Christine; Vogel, Sebastian; Gawaz, Meinrad; Geisler, Tobias

    2017-01-01

    Platelet surface expression levels of stromal cell derived factor 1 (SDF-1) are elevated in acute coronary syndrome and associated with LVEF% improvement after myocardial infarction (MI). Platelet SDF-1 might facilitate thrombus formation and endomyocardial expression of SDF-1 is enhanced in inflammatory cardiomyopathy and positively correlates with myocardial fibrosis. The influence of platelet SDF-1 on outcome in the patients with symptomatic coronary artery disease (CAD) is to the best of our knowledge unknown. Blood samples of 608 consecutive CAD patients were collected during the percutaneous coronary intervention and analyzed for surface expression of SDF-1 by flow cytometry. The primary combined endpoint was defined as the composite of either MI, or ischemic stroke, or all-cause death. Secondary endpoints were defined as the aforementioned single events. The patients with baseline platelet SDF-1 levels above the third quartile showed a significantly worse cumulative event-free survival when compared to the patients with lower baseline SDF-1 levels (first to third quartile) (log rank 0.009 for primary combined endpoint and log rank 0.016 for secondary endpoint all-cause death). Multivariate Cox regression analysis showed that SDF-1 levels above the third quartile were independently associated with the primary combined endpoint and the secondary endpoint all-cause death. We provide first clinical evidence that high platelet expression levels of SDF-1 influence clinical outcomes in CAD patients in a negative way.

  12. Sequential Treatment with SDF-1 and BMP-2 Potentiates Bone Formation in Calvarial Defects.

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    Hwang, Hee-Don; Lee, Jung-Tae; Koh, Jeong-Tae; Jung, Hong-Moon; Lee, Heon-Jin; Kwon, Tae-Geon

    2015-07-01

    Stromal cell-derived factor-1 (SDF-1) protein and its receptor, CXCR-4, play an important role in tissue repair and regeneration in various organs, including the bone. SDF-1 is indispensable for bone morphogenetic protein-2 (BMP-2)-induced osteogenic differentiation. However, SDF-1 is not needed after the osteogenic induction has been activated. Since the precise condition for the additive effects of combined DF-1 and BMP-2 in bone healing had not been fully investigated, we aimed to determine the optimal conditions for SDF-1- and BMP-2-mediated bone regeneration. We examined the in vitro osteoblastic differentiation and cell migration after sequential treatments with SDF-1 and BMP-2. Based on the in vitro additive effects of SDF-1 and BMP-2, the critical size defects of mice calvaria were treated with these cytokines in various sequences. Phosphate buffered saline (PBS)-, SDF-1-, or BMP-2-soaked collagen scaffolds were implanted into the calvarial defects (n=36). Periodic percutaneous injections of PBS or the cytokine SDF-1 and BMP-2 into the implanted scaffolds were performed on days 3 and 6, postoperatively. Six experimental groups were used according to the types and sequences of the cytokine treatments. After 28 days, the mice were euthanized and bone formation was evaluated with microcomputed tomography and histology. The molecular mechanism of the additive effect of SDF-1 and BMP-2 was evaluated by analyzing intracellular signal transduction through Smad and Erk phosphorylation. The in vitro experiments revealed that, among all the treatments, the treatment with BMP-2 after SDF-1 showed the strongest osteoblastic differentiation and enhanced cell migration. Similarly, in the animal model, the treatment with SDF-1 followed by BMP-2 treatment showed the highest degree of new bone regeneration than any other groups, including the one with continuous BMP-2 treatment. This new bone formation can be partially explained by the activation of Smad and Erk pathways

  13. Attenuation of subchondral bone abnormal changes in osteoarthritis by inhibition of SDF-1 signaling.

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    Chen, Y; Lin, S; Sun, Y; Guo, J; Lu, Y; Suen, C W; Zhang, J; Zha, Z; Ho, K W; Pan, X; Li, G

    2017-06-01

    Current conservative treatments for osteoarthritis (OA) are largely symptoms control therapies. Further understanding on the pathological mechanisms of OA is crucial for new pharmacological intervention. In this study, we investigated the role of Stromal cell-derived factor-1(SDF-1) in regulating subchondral bone changes during the progression of OA. Clinical samples of different stages of OA severity were analyzed by histology staining, micro-CT, enzyme-linked immunosorbent assay (ELISA) and western blotting, to compare SDF-1 level in subchondral bone. The effects of SDF-1 on human mesenchymal stem cells (MSCs) osteogenic differentiation were evaluated. In vivo assessment was performed in an anterior cruciate ligament transaction plus medial meniscus resection in the SD rats. The OA rats received continuous infusion of AMD3100 (SDF-1 receptor blocker) in osmotic mini-pump implanted subcutaneously for 6 weeks. These rats were then terminated and subjected to the same in vitro assessments as human OA samples. SDF-1 level was significantly elevated in the subchondral bone of human OA samples. In the cell studies, the results showed SDF-1 plays an important role in osteogenic differentiation of MSCs. In the OA animal studies, there were less cartilage damage in the AMD3100-treated group; microCT results showed that the subchondral bone formation was significantly reduced and so did the number of positive Nestin or Osterix cells in the subchondral bone region. Higher level of SDF-1 may induce the subchondral bone abnormal changes in OA and inhibition of SDF-1 signaling could be a potential therapeutic approach for OA. Copyright © 2017 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

  14. Heterogeneity in SDF-1 expression defines the vasculogenic potential of adult cardiac progenitor cells.

    Directory of Open Access Journals (Sweden)

    Claudia O Rodrigues

    Full Text Available The adult myocardium has been reported to harbor several classes of multipotent progenitor cells (CPCs with tri-lineage differentiation potential. It is not clear whether c-kit+CPCs represent a uniform precursor population or a more complex mixture of cell types.To characterize and understand vasculogenic heterogeneity within c-kit+presumptive cardiac progenitor cell populations.c-kit+, sca-1+ CPCs obtained from adult mouse left ventricle expressed stem cell-associated genes, including Oct-4 and Myc, and were self-renewing, pluripotent and clonogenic. Detailed single cell clonal analysis of 17 clones revealed that most (14/17 exhibited trilineage differentiation potential. However, striking morphological differences were observed among clones that were heritable and stable in long-term culture. 3 major groups were identified: round (7/17, flat or spindle-shaped (5/17 and stellate (5/17. Stellate morphology was predictive of vasculogenic differentiation in Matrigel. Genome-wide expression studies and bioinformatic analysis revealed clonally stable, heritable differences in stromal cell-derived factor-1 (SDF-1 expression that correlated strongly with stellate morphology and vasculogenic capacity. Endogenous SDF-1 production contributed directly to vasculogenic differentiation: both shRNA-mediated knockdown of SDF-1 and AMD3100, an antagonist of the SDF-1 receptor CXC chemokine Receptor-4 (CXCR4, reduced tube-forming capacity, while exogenous SDF-1 induced tube formation by 2 non-vasculogenic clones. CPCs producing SDF-1 were able to vascularize Matrigel dermal implants in vivo, while CPCs with low SDF-1 production were not.Clonogenic c-kit+, sca-1+ CPCs are heterogeneous in morphology, gene expression patterns and differentiation potential. Clone-specific levels of SDF-1 expression both predict and promote development of a vasculogenic phenotype via a previously unreported autocrine mechanism.

  15. Role of SDF-1 and CXCR4 in the proliferation, migration and invasion of cervical cancer.

    Science.gov (United States)

    Wang, Chen; Cheng, Hailing; Li, Yanyun

    2016-11-01

    This study was to investigate the role of stromal cell-derived factor 1 (SDF-1) and its corresponding receptor CXCR4 in the proliferation, migration and invasion of cervical cancer HeLa cells. CXCR4 expression in HeLa cells was measured by flow cytometry and Western Blot. Role of SDF-1 and CXCR4 in the HeLa cells proliferation was measured by MTT. Role of SDF-1 and CXCR4 in the migration and invasion of HeLa cell was measured by Boyden chamber. High expression of CXCR4 was observed on the surface of HeLa cells. Proliferation ability of HeLa cells was significantly increased after SDF-1 stimulation, which showed dose-dependent manner. After knock-down of CXCR4 expression by RNAi, SDF-1-stimulated HeLa cells proliferation was significantly blocked (PSDF-1 can induce migration and invasion of Hela cells, SDF-1-stimulated HeLa cells migration and invasion was significantly blocked (P<0.05) after knock-down of CXCR4 expression by RNAi. High expression of surface CXCR4 plays an important role in the proliferation, migration and invasion of HeLa cells.

  16. The role of SDF-1-CXCR4/CXCR7 axis in biological behaviors of adipose tissue-derived mesenchymal stem cells in vitro

    International Nuclear Information System (INIS)

    Li, Qiang; Zhang, Aijun; Tao, Changbo; Li, Xueyang; Jin, Peisheng

    2013-01-01

    Highlights: •SDF-1 pretreating increased the levels of CXCR4, CXCR7 in ADSCs. •SDF-1 improved cells paracrine migration and proliferation abilities. •CXCR4 and CXCR7 could function in ADSCs paracrine, migration and proliferation. -- Abstract: Numerous studies have reported that CXCR4 and CXCR7 play an essential, but differential role in stromal cell-derived factor-1 (SDF-1)-inducing cell chemotaxis, viability and paracrine actions of BMSCs. Adipose tissue-derived mesenchymal stem cells (ADSCs) have been suggested to be potential seed cells for clinical application instead of bone marrow derived stroma cell (BMSCs). However, the function of SDF-1/CXCR4 and SDF-1/CXCR7 in ADSCs is not well understood. This study was designed to analyze the effect of SDF-1/CXCR4 and SDF-1/CXCR7 axis on ADSCs biological behaviors in vitro. Using Flow cytometry and Western blot methods, we found for the first time that CXCR4/CXCR7 expression was increased after treatment with SDF-1 in ADSCs. SDF-1 promoted ADSCs paracrine, proliferation and migration abilities. CXCR4 or CXCR7 antibody suppressed ADSCs paracrine action induced by SDF-1. The migration of ADSCs can be abolished by CXCR4 antibody, while the proliferation of ADSCs was only downregulated by CXCR7 antibody. Our study indicated that the angiogenesis of ADSCs is, at least partly, mediated by SDF-1/CXCR4 and SDF-1/CXCR7 axis. However, only binding of SDF-1/CXCR7 was required for proliferation of ADSCs, and CXCR7 was required for migration of ADSCs induced by SDF-1. Our studies provide evidence that the activation of either axis may be helpful to improve the effectiveness of ADSCs-based stem cell therapy

  17. The role of SDF-1-CXCR4/CXCR7 axis in biological behaviors of adipose tissue-derived mesenchymal stem cells in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Li, Qiang; Zhang, Aijun; Tao, Changbo; Li, Xueyang; Jin, Peisheng, E-mail: jinps2006@163.com

    2013-11-22

    Highlights: •SDF-1 pretreating increased the levels of CXCR4, CXCR7 in ADSCs. •SDF-1 improved cells paracrine migration and proliferation abilities. •CXCR4 and CXCR7 could function in ADSCs paracrine, migration and proliferation. -- Abstract: Numerous studies have reported that CXCR4 and CXCR7 play an essential, but differential role in stromal cell-derived factor-1 (SDF-1)-inducing cell chemotaxis, viability and paracrine actions of BMSCs. Adipose tissue-derived mesenchymal stem cells (ADSCs) have been suggested to be potential seed cells for clinical application instead of bone marrow derived stroma cell (BMSCs). However, the function of SDF-1/CXCR4 and SDF-1/CXCR7 in ADSCs is not well understood. This study was designed to analyze the effect of SDF-1/CXCR4 and SDF-1/CXCR7 axis on ADSCs biological behaviors in vitro. Using Flow cytometry and Western blot methods, we found for the first time that CXCR4/CXCR7 expression was increased after treatment with SDF-1 in ADSCs. SDF-1 promoted ADSCs paracrine, proliferation and migration abilities. CXCR4 or CXCR7 antibody suppressed ADSCs paracrine action induced by SDF-1. The migration of ADSCs can be abolished by CXCR4 antibody, while the proliferation of ADSCs was only downregulated by CXCR7 antibody. Our study indicated that the angiogenesis of ADSCs is, at least partly, mediated by SDF-1/CXCR4 and SDF-1/CXCR7 axis. However, only binding of SDF-1/CXCR7 was required for proliferation of ADSCs, and CXCR7 was required for migration of ADSCs induced by SDF-1. Our studies provide evidence that the activation of either axis may be helpful to improve the effectiveness of ADSCs-based stem cell therapy.

  18. Controlled delivery of SDF-1α and IGF-1: CXCR4+ cell recruitment and functional skeletal muscle recovery

    Science.gov (United States)

    Rybalko, Viktoriya Y.; Pham, Chantal B.; Hsieh, Pei-Ling; Hammers, David W.; Merscham-Banda, Melissa; Suggs, Laura J.; Farrar, Roger P.

    2017-01-01

    Therapeutic delivery of regeneration-promoting biological factors directly to the site of injury has demonstrated its efficacy in various injury models. Several reports describe improved tissue regeneration following local injection of tissue specific growth factors, cytokines and chemokines. Evidence exists that combined cytokine/growth factor treatment is superior for optimizing tissue repair by targeting different aspects of the regeneration response. The purpose of this study was to evaluate the therapeutic potential of the controlled delivery of stromal cell-derived factor-1alpha (SDF-1α) alone or in combination with insulin-like growth factor-I (SDF-1α/IGF-I) for the treatment of tourniquet-induced ischemia/reperfusion injury (TK-I/R) of skeletal muscle. We hypothesized that SDF-1α will promote sustained stem cell recruitment to the site of muscle injury, while IGF-I will induce progenitor cell differentiation to effectively restore muscle contractile function after TK-I/R injury while concurrently reducing apoptosis. Utilizing a novel poly-ethylene glycol PEGylated fibrin gel matrix (PEG-Fib), we incorporated SDF-1α alone (PEG-Fib/SDF-1α) or in combination with IGF-I (PEG-Fib/SDF-1α/IGF-I) for controlled release at the site of acute muscle injury. Despite enhanced cell recruitment and revascularization of the regenerating muscle after SDF-1α treatment, functional analysis showed no benefit from PEG-Fib/SDF-1α therapy, while dual delivery of PEG-Fib/SDF-1α/IGF-I resulted in IGF-I-mediated improvement of maximal force recovery and SDF-1α-driven in vivo neovasculogenesis. Histological data supported functional data, as well as highlighted the important differences in the regeneration process among treatment groups. This study provides evidence that while revascularization may be necessary for maximizing muscle force recovery, without modulation of other effects of inflammation it is insufficient. PMID:26247892

  19. Controlled delivery of SDF-1α and IGF-1: CXCR4(+) cell recruitment and functional skeletal muscle recovery.

    Science.gov (United States)

    Rybalko, Viktoriya Y; Pham, Chantal B; Hsieh, Pei-Ling; Hammers, David W; Merscham-Banda, Melissa; Suggs, Laura J; Farrar, Roger P

    2015-11-01

    Therapeutic delivery of regeneration-promoting biological factors directly to the site of injury has demonstrated its efficacy in various injury models. Several reports describe improved tissue regeneration following local injection of tissue specific growth factors, cytokines and chemokines. Evidence exists that combined cytokine/growth factor treatment is superior for optimizing tissue repair by targeting different aspects of the regeneration response. The purpose of this study was to evaluate the therapeutic potential of the controlled delivery of stromal cell-derived factor-1alpha (SDF-1α) alone or in combination with insulin-like growth factor-I (SDF-1α/IGF-I) for the treatment of tourniquet-induced ischemia/reperfusion injury (TK-I/R) of skeletal muscle. We hypothesized that SDF-1α will promote sustained stem cell recruitment to the site of muscle injury, while IGF-I will induce progenitor cell differentiation to effectively restore muscle contractile function after TK-I/R injury while concurrently reducing apoptosis. Utilizing a novel poly-ethylene glycol PEGylated fibrin gel matrix (PEG-Fib), we incorporated SDF-1α alone (PEG-Fib/SDF-1α) or in combination with IGF-I (PEG-Fib/SDF-1α/IGF-I) for controlled release at the site of acute muscle injury. Despite enhanced cell recruitment and revascularization of the regenerating muscle after SDF-1α treatment, functional analysis showed no benefit from PEG-Fib/SDF-1α therapy, while dual delivery of PEG-Fib/SDF-1α/IGF-I resulted in IGF-I-mediated improvement of maximal force recovery and SDF-1α-driven in vivo neovasculogenesis. Histological data supported functional data, as well as highlighted the important differences in the regeneration process among treatment groups. This study provides evidence that while revascularization may be necessary for maximizing muscle force recovery, without modulation of other effects of inflammation it is insufficient.

  20. Tunable Controlled Release of Bioactive SDF-1α via Protein Specific Interactions within Fibrin/Nanoparticle Composites.

    Science.gov (United States)

    Dutta, D; Fauer, C; Mulleneux, H L; Stabenfeldt, S E

    2015-10-31

    The chemokine, stromal cell-derived factor 1α (SDF-1α), is a key regulator of the endogenous neural progenitor/stem cell-mediated regenerative response after neural injury. Increased and sustained bioavailability of SDF-1α in the peri-injury region is hypothesized to modulate this endogenous repair response. Here, we describe poly(lactic-co-glycolic) acid (PLGA) nanoparticles capable of releasing bioactive SDF-1α in a sustained manner over 60days after a burst of 23%. Moreover, we report a biphasic cellular response to SDF-1α concentrations thus the large initial burst release in an in vivo setting may result in supratherapeutic concentrations of SDF-1α. Specific protein-protein interactions between SDF-1α and fibrin (as well as its monomer, fibrinogen) were exploited to control the magnitude of the burst release. Nanoparticles embedded in fibrin significantly reduced the amount of SDF-1α released after 72 hrs as a function of fibrin density. Therefore, the nanoparticle/fibrin composites represented a means to independently tune the magnitude of the burst phase release from the nanoparticles while perserving a bioactive depot of SDF-1α for release over 60days.

  1. Role of SDF-1α/CXCR4 signaling pathway in clinicopathological features and prognosis of patients with nasopharyngeal carcinoma.

    Science.gov (United States)

    Li, Yun-Ling; Li, Yu-Fen; Li, Hua-Feng; Lv, Huai-Qing; Sun, De-Zhong

    2017-08-31

    The present study aims to explore the role of stromal cell-derived factor-1α (SDF-1α)/stromal cell-derived factor receptor-4 (CXCR4) signaling pathway to the clinicopathological features and prognosis of patients with nasopharyngeal carcinoma (NPC). From January 2009 to December 2010, 102 patients with NPC and 80 patients with chronic nasopharyngitis were enrolled for the study. Immunohistochemical staining, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting were employed to determine the expressions of SDF-1α and CXCR4 proteins in NPC tissues and chronic nasopharyngitis tissues. Chi-square test was conducted to analyze the associations of the expressions of SDF-1α and CXCR4 proteins with the clinicopathological features of NPC patients. Spearman rank correlation analysis was used to analyze the correlation between the SDF-1α protein expression and CXCR4 protein expression. The mRNA and protein expressions of SDF-1α and CXCR4 in NPC tissues were significantly higher than those in chronic nasopharyngitis tissues. The expressions of SDF-1α and CXCR4 proteins showed associations with T staging, N staging, tumor node metastasis (TNM) staging, skull base invasion, and cervical lymph node metastasis of NPC patients. Compared with NPC patients showing negative expressions of SDF-1α and CXCR4 proteins, those with positive expressions of SDF-1α and CXCR4 proteins had a significantly shorter survival time. SDF-1α protein, CXCR4 protein, EBV-IgG status, T staging, N staging, TNM staging, skull base invasion, and cervical lymph node metastasis were independent risk factors for the prognosis of NPC. The findings indicated that SDF-1α/CXCR4 signaling pathway might be associated with the clinicopathological features and prognosis of patients with NPC. © 2017 The Author(s).

  2. Effect of combined VEGF165/ SDF-1 gene therapy on vascular remodeling and blood perfusion in cerebral ischemia.

    Science.gov (United States)

    Hu, Guo-Jie; Feng, Yu-Gong; Lu, Wen-Peng; Li, Huan-Ting; Xie, Hong-Wei; Li, Shi-Fang

    2017-09-01

    OBJECTIVE Therapeutic neovascularization is a promising strategy for treating patients after an ischemic stroke; however, single-factor therapy has limitations. Stromal cell-derived factor 1 (SDF-1) and vascular endothelial growth factor (VEGF) proteins synergistically promote angiogenesis. In this study, the authors assessed the effect of combined gene therapy with VEGF 165 and SDF-1 in a rat model of cerebral infarction. METHODS An adenoviral vector expressing VEGF 165 and SDF-1 connected via an internal ribosome entry site was constructed (Ad- VEGF 165 -SDF-1). A rat model of middle cerebral artery occlusion (MCAO) was established; either Ad- VEGF 165 -SDF-1 or control adenovirus Ad- LacZ was stereotactically microinjected into the lateral ventricle of 80 rats 24 hours after MCAO. Coexpression and distribution of VEGF 165 and SDF-1 were examined by reverse-transcription polymerase chain reaction, Western blotting, and immunofluorescence. The neurological severity score of each rat was measured on Days 3, 7, 14, 21, and 28 after MCAO. Angiogenesis and vascular remodeling were evaluated via bromodeoxyuridine and CD34 immunofluorescence labeling. Relative cerebral infarction volumes were determined by T2-weighted MRI and triphenyltetrazolium chloride staining. Cerebral blood flow, relative cerebral blood volume, and relative mean transmit time were assessed using perfusion-weighted MRI. RESULTS The Ad- VEGF 165 -SDF-1 vector mediated coexpression of VEGF 165 and SDF-1 in multiple sites around the ischemic core, including the cortex, corpus striatum, and hippocampal granular layer. Coexpression of VEGF 165 and SDF-1 improved neural function, reduced cerebral infarction volume, increased microvascular density and promoted angiogenesis in the ischemic penumbra, and improved cerebral blood flow and perfusion. CONCLUSIONS Combined VEGF 165 and SDF-1 gene therapy represents a potential strategy for improving vascular remodeling and recovery of neural function after

  3. Hydroxysafflor yellow A promotes neovascularization and cardiac function recovery through HO-1/VEGF-A/SDF-1α cascade.

    Science.gov (United States)

    Wei, Guo; Yin, Ying; Duan, Jialin; Guo, Chao; Zhu, Yanrong; Wang, Yanhua; Xi, Miaomiao; Wen, Aidong

    2017-04-01

    The present study was to investigate the proangiogenic and cardioprotective effects of hydroxysafflor yellow A (HSYA) against myocardial infarction (MI) injury and the underlying mechanisms. MI model was induced by ligation of the left coronary artery in normal and heme oxygenase-1 (HO-1) knockout mice and the ones receiving vascular endothelial growth factor-A (VEGF-A) or stromal cell-derived factor-1α (SDF-1α) antagonists. They were treated with three doses or single dose of HSYA for 28days. The cardiac function, endothelial progenitor cells (EPCs) mobilization, angiogenesis, the expression of HO-1, VEGF-A, SDF-1α and apoptosis or fibrosis related proteins in the peri-infarct area were evaluated at respective times. We further examined the effect of HSYA on EPCs CXC chemokiner receptor 4 (CXCR4) expression and the role of SDF-1α on EPCs function in vitro. HSYA could dose dependently reduce left ventricular function impairment, myocardial apoptosis and fibrosis, and promote EPCs mobilization and myocardial neovascularization. Further, HO-1 knockout abolished HSYA-induced up-regulation of HO-1, VEGF-A and SDF-1α. VEGF antagonist significantly reduced HSYA-increased VEGF-A and SDF-1α levels and SDF-1 antagonist abolished HSYA-simulated up-regulation of SDF-1α. Meanwhile, HO-1 knockout, administration of VEGF and SDF-1 antibodies abrogated HSYA-promoted expression of the marker proteins of newborn microvessels and cardiac functional recovery. In vitro, HSYA dose dependently promoted (CXCR4) expression on EPCs. SDF-1α significantly accelerated EPCs function which was reversed by CXCR4 antagonist. HSYA could promote EPCs function through the HO-1/VEGF-A/SDF-1α signaling cascade, which contributed largely to myocardial neovascularization and further improved cardiac function in MI mice. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  4. Crude Fucoidan Extracts Impair Angiogenesis in Models Relevant for Bone Regeneration and Osteosarcoma via Reduction of VEGF and SDF-1

    Directory of Open Access Journals (Sweden)

    Fanlu Wang

    2017-06-01

    Full Text Available The marine origin polysaccharide fucoidan combines multiple biological activities. As demonstrated by various studies in vitro and in vivo, fucoidans show anti-viral, anti-tumor, anti-oxidant, anti-inflammatory and anti-coagulant properties, although the detailed molecular action remains to be elucidated. The aim of the present study is to assess the impact of crude fucoidan extracts, on the formation of vascular structures in co-culture models relevant for bone vascularization during bone repair and for vascularization processes in osteosarcoma. The co-cultures consisted of bone marrow derived mesenchymal stem cells, respectively the osteosarcoma cell line MG63, and human blood derived outgrowth endothelial cells (OEC. The concentration dependent effects on the metabolic activity on endothelial cells and osteoblast cells were first assessed using monocultures of OEC, MSC and MG63 suggesting a concentration of 100 µg/mL as a suitable concentration for further experiments. In co-cultures fucoidan significantly reduced angiogenesis in MSC/OEC but also in MG63/OEC co-cultures suggesting a potential application of fucoidan to lower the vascularization in bone tumors such as osteosarcoma. This was associated with a decrease in VEGF (vascular endothelial growth factor and SDF-1 (stromal derived factor-1 on the protein level, both related to the control of angiogenesis and furthermore discussed as crucial factors in osteosarcoma progression and metastasis. In terms of bone formation, fucoidan slightly lowered on the calcification process in MSC monocultures and MSC/OEC co-cultures. In summary, these data suggest the suitability of lower fucoidan doses to limit angiogenesis for instance in osteosarcoma.

  5. Altered expression of SDF-1 and CXCR4 during fracture healing in diabetes mellitus.

    Science.gov (United States)

    Arakura, Michio; Lee, Sang Yang; Takahara, Shunsuke; Okumachi, Etsuko; Iwakura, Takashi; Fukui, Tomoaki; Nishida, Kotaro; Kurosaka, Masahiro; Kuroda, Ryosuke; Niikura, Takahiro

    2017-06-01

    Diabetes mellitus (DM) is known to impair fracture healing. The purpose of this study was to elucidate and compare the gene expression patterns and localization of stromal cell-derived factor 1 (SDF-1) and CXC chemokine receptor 4 (CXCR4) during fracture healing of the femur in rats with and without DM. Closed transverse fractures were created in the femurs of rats equally divided into a DM group and control group; DM was induced by streptozotocin. At post-fracture days five, seven, 11, 14, 21 and 28, total RNA was extracted from the fracture callus and mRNA expression levels of SDF-1 and CXCR4 were measured by real-time polymerase chain reaction. Localization of SDF-1 and CXCR4 proteins at the fracture site was determined by immunohistochemistry at days 21 and 28. SDF-1 expression was significantly lower in the DM group than in the healthy group on days 21 and 28, and showed a significant difference between days 14 and 21 in the healthy group. There was no significant difference in CXCR4 expression levels between the healthy and DM groups at any time point. On day 21 immunoreactivity of SDF-1 and CXCR4 was detected at the fracture site of the healthy group but no immunoreactivity was observed in the DM group. On day 28, immunoreactivity of SDF-1 and CXCR4 was detected at the fracture site in both groups. Gene expression and localization of SDF-1 and CXCR4 was altered during fracture healing, which may contribute to the impaired fracture healing in DM.

  6. The association between SDF-1 G801A polymorphism and non-small cell lung cancer risk in a Chinese Han population.

    Science.gov (United States)

    Xu, Weiguo; Cui, Rong; Yu, Huapeng

    2015-01-01

    SDF-1 G801A polymorphism is reported to correlate with cancer susceptibility. However, the association between SDF-1 G801A polymorphism and non-small cell lung cancer (NSCLC) risk in Chinese populations remains unknown. A total of 408 NSCLC patients and 303 health controls included in this study. Restriction length fragment polymorphism (RFLP) analysis was used to assess the frequencies of SDF-1 G801A polymorphic variant. No significant association was found between SDF-1 G801A polymorphism and NSCLC risk (OR=1.268, 95% CI 0.811-2.583, P=0.361). Furthermore, SDF-1 G801A polymorphism was not correlated with histological type (P=0.697) and TNM stage (P=0.276). SDF-1 G801A polymorphism was not a risk factor for NSCLC in Chinese Han population.

  7. SDF-1 Inhibition Targets the Bone Marrow Niche for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Aldo M. Roccaro

    2014-10-01

    Full Text Available Bone marrow (BM metastasis remains one of the main causes of death associated with solid tumors as well as multiple myeloma (MM. Targeting the BM niche to prevent or modulate metastasis has not been successful to date. Here, we show that stromal cell-derived factor-1 (SDF-1/CXCL12 is highly expressed in active MM, as well as in BM sites of tumor metastasis and report on the discovery of the high-affinity anti-SDF-1 PEGylated mirror-image l-oligonucleotide (olaptesed-pegol. In vivo confocal imaging showed that SDF-1 levels are increased within MM cell-colonized BM areas. Using in vivo murine and xenograft mouse models, we document that in vivo SDF-1 neutralization within BM niches leads to a microenvironment that is less receptive for MM cells and reduces MM cell homing and growth, thereby inhibiting MM disease progression. Targeting of SDF-1 represents a valid strategy for preventing or disrupting colonization of the BM by MM cells.

  8. [ERK activation effects on GABA secretion inhibition induced by SDF-1 in hippocampal neurons of rats].

    Science.gov (United States)

    Zhang, Zi-juan; Guo, Mei-xia; Xing, Ying

    2015-09-01

    To investigate the effect of extracellular regulating kinase (ERK) signaling pathway on the secretion of gamma-aminobutyric acid (GABA) in cultured rat hippocampal neurons induced by stromal cell derived factor-1 (SDF-1). The hippocampal neurons of newborn SD rats were cultured and identified in vitro; the phosphorylation level of ERK1/2 was examined by Western blot; ELISA was used to detect the effect of PD98059, a ERK1/2 specific blocker on GABA secretion of cultured hippocampal neurons and Western blot were adopted to measure the protein expression levels of glutamate decarboxylase (GAD65/67) and gamma aminobutyric acid transporter (GAT); after blocking ERK1/2 signaling pathway with PD98059; RT-PCR was used to detect the mRNA expression levels of GAT-1 and GAD65 after treated with PD98059. The levels of ERKl/2 phosphorylation were increased significantly by SDF1 acting on hippocampal neurons, and CX-CR4 receptor blocker AMD3100, could inhibit SDF-1 induced ERK1/2 activation; SDF-1 could inhibit the secretion of GABA in cultured hippocampal neurons, and ERK1/2 specific inhibitor PD98059, could partly reverse the inhibition of GABA secretion by SDF-1. The effects of SDF-1 on cultured hippocampal neurons was to decrease the mRNA genesis of glutamic acid decarboxylase GAD65 and GABA transporter GAT-1, besides, ERK inhibitor PD98059 could effectively flip the effect of SDF-1. The results of Western blot showed that SDF-1 could inhibit the protein expression of GAT-1 and GAD65/67 in hippocampal neurons and the inhibition of GAT-1 and GAD65/67 protein expression could be partially restored by ERK1/2 blocker. SDF-1 acts on the CXCR4 of hippocampal neurons in vitro, and inhibits the expression of GAD by activating the ERK1/2 signaling pathway, and this may represent one possible pathway of GABA secretion inhibition.

  9. The Role of SDF-1/CXCR4/CXCR7 in Neuronal Regeneration after Cerebral Ischemia

    Science.gov (United States)

    Cheng, Xi; Wang, Huibin; Zhang, Xiuchun; Zhao, Shanshan; Zhou, Zhike; Mu, Xiaopeng; Zhao, Chuansheng; Teng, Weiyu

    2017-01-01

    Stromal cell-derived factor-1 is a chemoattractant produced by bone marrow stromal cell lines. It is recognized as a critical factor in the immune and central nervous systems (CNSs) as well as exerting a role in cancer. SDF-1 activates two G protein-coupled receptors, CXCR4 and CXCR7; these are expressed in both developing and mature CNSs and participate in multiple physiological and pathological events, e.g., inflammatory response, neurogenesis, angiogenesis, hematopoiesis, cancer metastasis, and HIV infection. After an ischemic stroke, SDF-1 levels robustly increase in the penumbra regions and participate in adult neural functional repair. Here we will review recent findings about SDF-1 and its receptor, analyse their functions in neurogeneration after brain ischemic injury: i.e., how the system promotes the proliferation, differentiation and migration of neural precursor cells and mediates axonal elongation and branching. PMID:29123467

  10. Inhibition of SDF-1α/CXCR4 Signalling in Subchondral Bone Attenuates Post-Traumatic Osteoarthritis.

    Science.gov (United States)

    Dong, Yonghui; Liu, Hui; Zhang, Xuejun; Xu, Fei; Qin, Liang; Cheng, Peng; Huang, Hui; Guo, Fengjing; Yang, Qing; Chen, Anmin

    2016-06-16

    Previous studies showed that SDF-1α is a catabolic factor that can infiltrate cartilage, decrease proteoglycan content, and increase MMP-13 activity. Inhibiting the SDF-1α/CXCR4 signalling pathway can attenuate the pathogenesis of osteoarthritis (OA). Recent studies have also shown that SDF-1α enhances chondrocyte proliferation and maturation. These results appear to be contradictory. In the current study, we used a destabilisation OA animal model to investigate the effects of SDF-1α/CXCR4 signalling in the tibial subchondral bone and the OA pathological process. Post-traumatic osteoarthritis (PTOA) mice models were prepared by transecting the anterior cruciate ligament (ACLT), or a sham surgery was performed, in a total of 30 mice. Mice were treated with phosphate buffer saline (PBS) or AMD3100 (an inhibitor of CXCR4) and sacrificed at 30 days post ACLT or sham surgery. Tibial subchondral bone status was quantified by micro-computed tomography (μCT). Knee-joint histology was analysed to examine the articular cartilage and joint degeneration. The levels of SDF-1α and collagen type I c-telopeptidefragments (CTX-I) were quantified by ELISA. Bone marrow mononuclear cells (BMMCs) were used to clarify the effects of SDF-1α on osteoclast formation and activity in vivo. μCT analysis revealed significant loss of trabecular bone from tibial subchondral bone post-ACLT, which was effectively prevented by AMD3100. AMD3100 could partially prevent bone loss and articular cartilage degeneration. Serum biomarkers revealed an increase in SDF-1α and bone resorption, which were also reduced by AMD3100. SDF-1α can promote osteoclast formation and the expression oftartrate resistant acid phosphatase (TRAP), cathepsin K (CK), and matrix metalloproteinase (MMP)-9 in osteoclasts by activating the MAPK pathway, including ERK and p38, but not JNK. In conclusion, inhibition of SDF-1α/CXCR4signalling was able to prevent trabecular bone loss and attenuated cartilage degeneration in

  11. SDF-1 alpha expression during wound healing in the aged is HIF dependent.

    Science.gov (United States)

    Loh, Shang A; Chang, Edward I; Galvez, Michael G; Thangarajah, Hariharan; El-ftesi, Samyra; Vial, Ivan N; Lin, Darius A; Gurtner, Geoffrey C

    2009-02-01

    Age-related impairments in wound healing are associated with decreased neovascularization, a process that is regulated by hypoxia-responsive cytokines, including stromal cell-derived factor (SDF)-1 alpha. Interleukin-1 beta is an important inflammatory cytokine involved in wound healing and is believed to regulate SDF-1 alpha expression independent of hypoxia signaling. Thus, the authors examined the relative importance of interleukin (IL)-1 beta and hypoxia-inducible factor (HIF)-1 alpha on SDF-1 alpha expression in aged wound healing. Young and aged mice (n = 4 per group) were examined for wound healing using a murine excisional wound model. Wounds were harvested at days 0, 1, 3, 5, and 7 for histologic analysis, immunohistochemistry, enzyme-linked immunosorbent assay, and Western blot. An engineered wild-type and mutated SDF luciferase reporter construct were used to determine HIF transactivation. Aged mice demonstrated significantly impaired wound healing, reduced granulation tissue, and increased epithelial gap compared with young controls. Real-time polymerase chain reaction demonstrated reduced SDF-1 alpha levels in aged wounds that correlated with reduced CD31+ neovessels. Western blots revealed decreased HIF-1 alpha protein in aged wounds. However, both IL-1 beta and macrophage infiltrate were unchanged between young and aged animals. Using the wild-type and mutated SDF luciferase reporter construct in which the hypoxia response element was deleted, only young fibroblasts were able to respond to IL-1 beta stimulation, and this response was abrogated by mutating the HIF-binding sites. This suggests that HIF binding is essential for SDF-1 transactivation in response to both inflammatory and hypoxic stimuli. SDF-1 alpha deficiency observed during aged wound healing is attributable predominantly to decreased HIF-1 alpha levels rather than impaired IL-1 beta expression.

  12. Enhancing neural stem cell response to SDF-1α gradients through hyaluronic acid-laminin hydrogels.

    Science.gov (United States)

    Addington, C P; Heffernan, J M; Millar-Haskell, C S; Tucker, E W; Sirianni, R W; Stabenfeldt, S E

    2015-12-01

    Traumatic brain injury (TBI) initiates an expansive biochemical insult that is largely responsible for the long-term dysfunction associated with TBI; however, current clinical treatments fall short of addressing these underlying sequelae. Pre-clinical investigations have used stem cell transplantation with moderate success, but are plagued by staggeringly low survival and engraftment rates (2-4%). As such, providing cell transplants with the means to better dynamically respond to injury-related signals within the transplant microenvironment may afford improved transplantation survival and engraftment rates. The chemokine stromal cell-derived factor-1α (SDF-1α) is a potent chemotactic signal that is readily present after TBI. In this study, we sought to develop a transplantation vehicle to ultimately enhance the responsiveness of neural transplants to injury-induced SDF-1α. Specifically, we hypothesize that a hyaluronic acid (HA) and laminin (Lm) hydrogel would promote 1. upregulated expression of the SDF-1α receptor CXCR4 in neural progenitor/stem cells (NPSCs) and 2. enhanced NPSC migration in response to SDF-1α gradients. We demonstrated successful development of a HA-Lm hydrogel and utilized standard protein and cellular assays to probe NPSC CXCR4 expression and NPSC chemotactic migration. The findings demonstrated that NPSCs significantly increased CXCR4 expression after 48 h of culture on the HA-Lm gel in a manner critically dependent on both HA and laminin. Moreover, the HA-Lm hydrogel significantly increased NPSC chemotactic migration in response to SDF-1α at 48 h, an effect that was critically dependent on HA, laminin and the SDF-1α gradient. Therefore, this hydrogel serves to 1. prime NPSCs for the injury microenvironment and 2. provide the appropriate infrastructure to support migration into the surrounding tissue, equipping cells with the tools to more effectively respond to the injury microenvironment. Copyright © 2015 Elsevier Ltd. All rights

  13. SDF1-CXCR4 Signaling Contributes to the Transition from Acute to Chronic Pain State.

    Science.gov (United States)

    Yang, Fei; Sun, Wei; Luo, Wen-Jun; Yang, Yan; Yang, Fan; Wang, Xiao-Liang; Chen, Jun

    2017-05-01

    Emerging evidence has demonstrated the involvement of stromal cell-derived factor 1 (SDF1, also known as CXCL12)-CXCR4 signaling in a variety of pain state. However, the underlying mechanisms of SDF1-CXCR4 signaling leading to the maintenance of chronic pain states are poorly understood. In the present study, we sought to explore the role of SDF1-CXCR4 signaling in the forming of neuroplasticity by applying a model of the transition from acute to chronic pain state, named as hyperalgesic priming. Utilizing intraplantar bee venom (BV) injection, we successfully established hyperalgesic priming state and found that peripheral treating with AMD3100, a CXCR4 antagonist, or knocking down CXCR4 by intraganglionar CXCR4 small interfering RNA (siRNA) injection could prevent BV-induced primary mechanical hyperalgesia and hyperalgesic priming. Moreover, we showed that single intraplantar active SDF1 protein injection is sufficient to induce acute mechanical hyperalgesia and hyperalgesic priming through CXC4. Intraplantar coinjection of ERK inhibitor, U0126, and PI3K inhibitor, LY294002, as well as two protein translation inhibitors, temsirolimus and cordycepin, prevented the development of SDF1-induced acute mechanical hyperalgesia and hyperalgesic priming. Finally, on the models of complete Freund's adjuvant (CFA)-induced chronic inflammatory pain and spared nerve injury (SNI)-induced chronic neuropathic pain, we observed that knock-down of CXCR4 could both prevent the development and reverse the maintenance of chronic pain state. In conclusion, our present data suggested that through regulating ERK and PI3K-AKT pathways-mediated protein translation SDF1-CXCR4 signaling mediates the transition from acute pain to chronic pain state and finally contributes to the development and maintenance of chronic pain.

  14. Therapeutic strategies utilizing SDF-1α in ischaemic cardiomyopathy.

    Science.gov (United States)

    Ziff, Oliver J; Bromage, Daniel I; Yellon, Derek M; Davidson, Sean M

    2018-03-01

    Heart failure is rapidly increasing in prevalence and will redraw the global landscape for cardiovascular health. Alleviating and repairing cardiac injury associated with myocardial infarction (MI) is key to improving this burden. Homing signals mobilize and recruit stem cells to the ischaemic myocardium where they exert beneficial paracrine effects. The chemoattractant cytokine SDF-1α and its associated receptor CXCR4 are upregulated after MI and appear to be important in this context. Activation of CXCR4 promotes both cardiomyocyte survival and stem cell migration towards the infarcted myocardium. These effects have beneficial effects on infarct size, and left ventricular remodelling and function. However, the timing of endogenous SDF-1α release and CXCR4 upregulation may not be optimal. Furthermore, current ELISA-based assays cannot distinguish between active SDF-1α, and SDF-1α inactivated by dipeptidyl peptidase 4 (DPP4). Current therapeutic approaches aim to recruit the SDF-1α-CXCR4 pathway or prolong SDF-1α life-time by preventing its cleavage by DPP4. This review assesses the evidence supporting these approaches and proposes SDF-1α as an important confounder in recent studies of DPP4 inhibitors.

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

    DEFF Research Database (Denmark)

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

    2012-01-01

    Cell based therapy has been shown to attenuate myocardial dysfunction after myocardial infarction (MI) in different acute and chronic animal models. It has been further shown that stromal-cell derived factor-1a (SDF-1a) facilitates proliferation and migration of endogenous progenitor cells into i...

  16. Use of Amniotic Microparticles Coated With Fibroblasts Overexpressing SDF-1α to Create an Environment Conducive to Neovascularization for Repair of Full-Thickness Skin Defects.

    Science.gov (United States)

    Zhang, Yun-qing; Ji, Shi-zhao; Fang, He; Zheng, Yong-jun; Luo, Peng-fei; Wu, Hai-bin; Wu, Min-juan; Wang, Zhi-hong; Xiao, Shi-chu; Xia, Zhao-fan

    2016-01-01

    As angiogenesis and vasculogenesis involve the complex network structures of various types of cells, extracellular matrix components, and cytokines, it is still difficult to exactly mimic the microenvironment of vascularization in vivo. In our study, we constructed a complex containing highly proliferative fibroblasts that can secrete extracellular matrix components and growth factors to chemotaxize endothelial progenitor cells (EPCs) in an attempt to create an ideal microenvironment for quick vascularization. Amniotic membrane microparticles (mAM) rich in type IV collagen (COL IV) and laminin (LN) were prepared, and human dermal fibroblasts (HDF) were infected with lentivirus (LV) of overexpression of SDF-1α to construct SDF-1α(ov)HDF. Using the rotary cell culture system (RCCS), mAM was loaded with HDF or SDF-1α(ov)HDF to construct HDF-mAM and SDF-1α(ov)HDF-mAM complexes. The complexes were able to secrete various types of active peptides (IL-6, IL-8, TGF-β, and bFGF) during in vitro culture. In addition, SDF-1α(ov)HDF-mAM complex highly expressed SDF-1α. Transwell assay showed SDF-1α(ov)HDF-mAM complex had an apparent chemotactic effect on EPCs. Transplantation of complexes onto full-thickness skin defects of C57BL mice further demonstrated that SDF-1α expression and the number of peripheral EPCs at days 3, 5, and 7 in the SDF-1α(ov)HDF-mAM group were significantly higher than that in other groups (p SDF-1α(ov)HDF-mAM group was significantly higher than that in HDF-mAM group (p SDF-1α could chemotaxize EPCs to reach local wounds, thus further accelerating angiogenesis in the transplant site. The technique described may prove to be a new model for accelerating vascularization of tissue and organ transplants and chronic ischemic wounds.

  17. A critical role of Src family kinase in SDF-1/CXCR4-mediated bone-marrow progenitor cell recruitment to the ischemic heart.

    Science.gov (United States)

    Cheng, Min; Huang, Kai; Zhou, Junlan; Yan, Dewen; Tang, Yao-Liang; Zhao, Ting C; Miller, Richard J; Kishore, Raj; Losordo, Douglas W; Qin, Gangjian

    2015-04-01

    The G protein-coupled receptor CXCR4 and its ligand stromal-cell derived factor 1 (SDF-1) play a crucial role in directing progenitor cell (PC) homing to ischemic tissue. The Src family protein kinases (SFK) can be activated by, and serve as effectors of, G proteins. In this study we sought to determine whether SFK play a role in SDF-1/CXCR4-mediated PC homing. First, we investigated whether SDF-1/CXCR4 signaling activates SFK. Bone-marrow mononuclear cells (BM MNCs) were isolated from WT and BM-specific CXCR4-KO mice and treated with SDF-1 and/or CXCR4 antagonist AMD3100. SDF-1 treatment rapidly induced phosphorylation (activation) of hematopoietic Src (i.e., Lyn, Fgr, and Hck) in WT cells but not in AMD3100-treated cells or CXCR4-KO cells. Then, we investigated whether SFK are involved in SDF-1/CXCR4-mediated PC chemotaxis. In a combined chemotaxis and endothelial-progenitor-cell (EPC) colony assay, Src inhibitor SU6656 dose-dependently inhibited the SDF-1-induced migration of colony-forming EPCs. Next, we investigated whether SFK play a role in SDF-1/CXCR4-mediated BM PC homing to the ischemic heart. BM MNCs from CXCR4BAC:eGFP reporter mice were i.v. injected into WT and SDF-1BAC:SDF1-RFP transgenic mice following surgically-induced myocardial infarction (MI). eGFP(+) MNCs and eGFP(+)c-kit(+) PCs that were recruited in the infarct border zone in SDF-1BAC:SDF1-RFP recipients were significantly more than that in WT recipients. Treatments of mice with SU6656 significantly reduced eGFP(+) and eGFP(+)c-kit(+) cell recruitment in both WT and SDF-1BAC:RFP recipients and abrogated the difference between the two groups. Remarkably, PCs isolated from BM-specific C-terminal Src kinase (CSK)-KO (Src activated) mice were recruited more efficiently than PCs from WT PCs in the WT recipients. In conclusion, SFK are activated by SDF-1/CXCR4 signaling and play an essential role in SDF-1/CXCR4-mediated BM PC chemotactic response and ischemic cardiac recruitment. Copyright © 2015

  18. The role of the SDF-1/ CXCR7 axis on the growth and invasion ability of endometrial cancer cells.

    Science.gov (United States)

    Gu, Hong-Qin; Zhang, Zhen-Bo; Zhang, Jia-Wen; Wang, Qian-Qian; Xi, Xiao-Wei; He, Yin-Yan

    2017-04-01

    Stroma-derived factor-1 (SDF-1) and its receptor C-X-C chemokine receptor-4 (CXCR4) are involved in human endometrial carcinoma (EC) progression. CXCR7 is another important receptor of SDF-1 and has a higher affinity with SDF-1 compared with that of CXCR4. This paper aims to study the effects of the SDF-1/CXCR7 axis on the growth and invasion ability of EC cells. CXCR7 expression was evaluated by quantitative RT-PCR, immunohistochemistry, immunocytochemistry and Western blotting in EC cell lines and 30 cases of primary EC tissue from patients. EC cell line proliferation and migration were assessed following knockdown of CXCR7 by MTT and transwell assays. The results showed that CXCR7 was highly expressed at both mRNA and protein levels in the EC cells and tissue. siCXCR7 effectively silenced CXCR7 in Ishikawa and AN3CA cells. Treatment with 17β-oestradiol (17β-E2) significantly increased the levels of CXCR7 and SDF-1 in Con, siCon and siCXCR7 treated Ishikawa. siCXCR7 persistently inhibited CXCR7 expression, even in cells treated with 17β-E2. Moreover, in vitro functional analyses, silencing CXCR7 resulted in decreased proliferation in Ishikawa and AN3CA cells. Treatment with 17β-E2 and SDF-1 significantly promoted the growth and migration in siCon treated Ishikawa and AN3CA. Interestingly, in response to 17β-E2 and SDF-1 stimulation, siCXCR7 continuously inhibited the growth and invasion of Ishikawa and AN3CA cells. Our results indicate that SDF-1/CXCR7 plays a positive role in the proliferation and invasion of EC cells. CXCR7 inhibition treatment may provide a promising strategy for anti-tumour therapy for EC.

  19. Demineralized Bone Matrix Scaffolds Modified by CBD-SDF-1α Promote Bone Regeneration via Recruiting Endogenous Stem Cells.

    Science.gov (United States)

    Shi, Jiajia; Sun, Jie; Zhang, Wen; Liang, Hui; Shi, Qin; Li, Xiaoran; Chen, Yanyan; Zhuang, Yan; Dai, Jianwu

    2016-10-07

    The reconstruction of bone usually depends on substitute transplantation, which has drawbacks including the limited bone substitutes available, comorbidity, immune rejection, and limited endogenous bone regeneration. Here, we constructed a functionalized bone substitute by combining application of the demineralized bone matrix (DBM) and collagen-binding stromal-cell-derived factor-1α (CBD-SDF-1α). DBM was a poriferous and biodegradable bone substitute, derived from bovine bone and consisting mainly of collagen. CBD-SDF-1α could bind to collagen and be controllably released from the DBM to mobilize stem cells. In a rat femur defect model, CBD-SDF-1α-modified DBM scaffolds could efficiently mobilize CD34 + and c-kit + endogenous stem cells homing to the injured site at 3 days after implantation. According to the data from micro-CT, CBD-SDF-1α-modified DBM scaffolds could help the bone defects rejoin with mineralization accumulated and bone volume expanded. Interestingly, osteoprotegerin (OPG) and osteopontin (OPN) were highly expressed in CBD-SDF-1α group at an early time after implantation, while osteocalcin (OCN) was more expanded. H&E and Masson's trichrome staining showed that the CBD-SDF-1α-modified DBM scaffold group had more osteoblasts and that the bone defect rejoined earlier. The ultimate strength of the regenerated bone was investigated by three-point bending, showing that the CBD-SDF-1α group had superior strength. In conclusion, CBD-SDF-1α-modified DBM scaffolds could promote bone regeneration by recruiting endogenous stem cells.

  20. SDF-1 in Mammary Fibroblasts of Bovine with Mastitis Induces EMT and Inflammatory Response of Epithelial Cells.

    Science.gov (United States)

    He, Guiliang; Ma, Mengru; Yang, Wei; Wang, Hao; Zhang, Yong; Gao, Ming-Qing

    2017-01-01

    Fibroblasts constitute the majority of the stromal cells within bovine mammary gland, yet the functional contributions of these cells to mastitis and fibrosis and the mechanism are poorly understood. In this study, we demonstrate that inflammation-associated fibroblasts (INFs) extracted from bovine mammary glands with clinical mastitis had different expression pattern regarding to several extracellular matrix (ECM) proteins, chemokines and cytokines compared to normal fibroblasts (NFs) from dairy cows during lactation. The INFs induced epithelial-mesenchymal transition (EMT) and inflammatory responses of mammary epithelial cells in a vitro co-culture model. These functional contributions of INFs to normal epithelial cells were mediated through their ability to secrete stromal cell-derived factor 1 (SDF-1). SDF-1 was highly secreted/expressed by INFs, lipopolysaccharide (LPS) -treated NFs, lipoteichoic acid (LTA) -treated NFs, as well as mastitic tissue compared to their counterparts. Exogenous SDF-1 promoted EMT on epithelial cells through activating NF-κB pathway, induced inflammation response and inhibited proliferation of epithelial cells. In addition, SDF-1 was able to induce mastitis and slight fibrosis of mouse mammary gland, which was attenuated by a specific inhibitor of the receptor of SDF-1. Our findings indicate that stromal fibroblasts within mammary glands with mastitis contribute to EMT and inflammatory responses of epithelial cells through the secretion of SDF-1, which could result in the inflammation spread and fibrosis within mammary gland.

  1. All-trans-retinoic acid activates SDF-1/CXCR4/ROCK2 signaling pathway to inhibit chondrogenesis.

    Science.gov (United States)

    Hu, Qin-Xiao; Li, Xue-Dong; Xie, Peng; Wu, Chu-Cheng; Zheng, Gui-Zhou; Lin, Fei-Xiang; Xie, Da; Zhang, Qi-Hao; Liu, De-Zhong; Wang, Yun-Guo; Chang, Bo; Du, Shi-Xin

    2017-01-01

    Recent studies have indicated that ATRA inhibits chondrogenesis and can lead to congenital clubfoot (CCF). The molecular mechanism of ATRA-induced chondrogenesis is not clear. As RhoA/ROCK and SDF-1/CXCR4 signaling play important molecular roles for a variety of cellular processes, we hypothesized that RhoA/ROCK2 and SDF-1/CXCR4 signaling are involved in ATRA-induced chondrogenesis in rat embryo hind limb bud mesenchymal cells (rEHBMCs). We found that ATRA dose-dependently inhibits proliferation and expression of chondrogenic transcription factors (SOX9 and COL2A1) in rEHBMCs. In contrast, ATRA increases the expression of ROCK2, SDF-1 and CXCR4. Pharmacological inhibition of ROCK signaling and SDF-1/CXCR4 signaling by Y27632 and AMD3100, respectively, resulted in elevated expression of SOX9 and COL2A1. In addition, we found that disturbing SDF-1/CXCR4 signaling by AMD3100 decreases ATRA-induced ROCK2 expression. In vivo studies we also confirm that SOX9 expression of early-stage cartilage progenitors in the proliferative zone and COL2A1 expression in prehypertrophic chondrocytes are decreased in ATRA-treated rat embryo hind limb. Together, these results show that ATRA activates SDF-1/CXCR4/ROCK2 signaling to inhibit chondrogenesis to lead to CCF by suppressing differentiation through down-regulation of SOX9 and COL2A1 expression in rat embryo hind limb bud mesenchymal cells.

  2. Analysis on the relation of pterygium with VEGF,SDF-1,Ki-67,PCNA and Survivin

    Directory of Open Access Journals (Sweden)

    Ying Song

    2015-12-01

    Full Text Available AIM:To analyze and study the relation of pterygium with vascular endothelial growth factor(VEGF,stroma cell-derived factor 1(SDF-1,tumor proliferating antigen(Ki-67,proliferating cell nuclear antigen(PCNAand survivin. METHODS:Seventy-nine patients(106 eyeswith pterygium from January 2013 to May 2015 in our hospital were selected as observation group. Seventy-nine persons with normal conjunctiva during the same period were selected as control group. Then the number of positive cells and staining intensity classification of the two groups for VEGF,SDF-1,Ki-67,PCNA and survivin were compared,and the detection results of patients with different gender,stages and types were compared too. Then the relation between pterygium and those indexes were analyzed by the Logistic analysis. RESULTS:The number of positive cells and staining intensity classification of observation group for VEGF,SDF-1,Ki-67,PCNA and survivin were all higher than those of control group,and the detection results of patients with different stages and types had certain differences too(all PP>0.05. All those indexes had close relation to pterygium by the Logistic analysis. CONCLUSION:The expression of VEGF,SDF-1,Ki-67,PCNA and survivin in tissue of patients with pterygium all show abnormal state,and those indexes all have close relation to pterygium.

  3. Association of Plasma SDF-1 with Bone Mineral Density, Body Composition, and Hip Fractures in Older Adults: The Cardiovascular Health Study.

    Science.gov (United States)

    Carbone, Laura D; Bůžková, Petra; Fink, Howard A; Robbins, John A; Bethel, Monique; Hamrick, Mark W; Hill, William D

    2017-06-01

    Aging is associated with an increase in circulating inflammatory factors. One, the cytokine stromal cell-derived factor 1 (SDF-1 or CXCL12), is critical to stem cell mobilization, migration, and homing as well as to bone marrow stem cell (BMSC), osteoblast, and osteoclast function. SDF-1 has pleiotropic roles in bone formation and BMSC differentiation into osteoblasts/osteocytes, and in osteoprogenitor cell survival. The objective of this study was to examine the association of plasma SDF-1 in participants in the cardiovascular health study (CHS) with bone mineral density (BMD), body composition, and incident hip fractures. In 1536 CHS participants, SDF-1 plasma levels were significantly associated with increasing age (p SDF-1 levels were associated with lower total hip BMD (p = 0.02). However, there was no significant association of SDF-1 with hip fractures (p = 0.53). In summary, circulating plasma levels of SDF-1 are associated with increasing age and independently associated with lower total hip BMD in both men and women. These findings suggest that SDF-1 levels are linked to bone homeostasis.

  4. HIV-1-infected macrophages induce astrogliosis by SDF-1α and matrix metalloproteinases

    International Nuclear Information System (INIS)

    Okamoto, Mika; Wang, Xin; Baba, Masanori

    2005-01-01

    Brain macrophages/microglia and astrocytes are known to be involved in the pathogenesis of HIV-1-associated dementia (HAD). To clarify their interaction and contribution to the pathogenesis, HIV-1-infected or uninfected macrophages were used as a model of brain macrophages/microglia, and their effects on human astrocytes in vitro were examined. The culture supernatants of HIV-1-infected or uninfected macrophages induced significant astrocyte proliferation, which was annihilated with a neutralizing antibody to stromal cell-derived factor (SDF)-1α or a matrix metalloproteinase (MMP) inhibitor. In these astrocytes, CXCR4, MMP, and tissue inhibitors of matrix metalloproteinase mRNA expression and SDF-1α production were significantly up-regulated. The supernatants of infected macrophages were always more effective than those of uninfected cells. Moreover, the enhanced production of SDF-1α was suppressed by the MMP inhibitor. These results indicate that the activated and HIV-1-infected macrophages can indirectly induce astrocyte proliferation through up-regulating SDF-1α and MMP production, which implies a mechanism of astrogliosis in HAD

  5. Controlled release of collagen-binding SDF-1α from the collagen scaffold promoted tendon regeneration in a rat Achilles tendon defect model.

    Science.gov (United States)

    Sun, Jie; Mou, Chenchen; Shi, Qin; Chen, Bing; Hou, Xianglin; Zhang, Wen; Li, Xiaoran; Zhuang, Yan; Shi, Jiajia; Chen, Yanyan; Dai, Jianwu

    2018-04-01

    It had been demonstrated that stromal cell-derived factor-1α (SDF-1α) could promote in situ tendon regeneration by recruiting endogenous cells. However, native SDF-1α diffuses too fast in vivo, reducing its local concentration and efficacy. In this study, we prepared a recombinant SDF-1α containing a collagen-binding domain (CBD-SDF-1α) and developed a functional collagen scaffold by tethering CBD-SDF-1α on the collagen scaffold for in situ tendon regeneration. CBD-SDF-1α could induce the migration of mesenchymal stem cells, dermal fibroblasts and Achilles tendon fibroblasts in vitro, and achieve controlled release from the collagen scaffold. In a rat Achilles tendon defect model, the functional scaffold could increase the recruitment of CXCR4 positive fibroblast-like cells and the deposition of Tenascin-C at 7 days after implantation. After 4 and 12 weeks, the functional collagen scaffold could promote the expression of type I collagen, increase the diameters of collagen fibrils and improve the mechanical properties of regenerated tendons. Hence, the functional scaffold increased the efficacy of tendon regeneration by controlling release of SDF-1α, enhancing the recruitment of fibroblast-like cells and providing instructive microenvironment and mechanical support for tendon regeneration. Therefore, CBD-SDF-1α-modified collagen scaffold could serve as a practical application for tendon regeneration. Copyright © 2018 Elsevier Ltd. All rights reserved.

  6. Homing of endogenous bone marrow mesenchymal stem cells to rat infarcted myocardium via ultrasound-mediated recombinant SDF-1α adenovirus in microbubbles.

    Science.gov (United States)

    Su, Gaofeng; Liu, Liyun; Yang, Lingjie; Mu, Yuming; Guan, Lina

    2018-01-02

    Stem cells can promote myocardial regeneration and accelerate the formation of new blood vessels. As such, transplanted stem cells represent a promising treatment modality for acute myocardial infarction (AMI). Stem cells spontaneously home to the infarcted myocardium using chemotaxis, in which the stromal cell-derived factor (SDF-1α) has been shown to be one of the most important chemokines. However, spontaneously secreted SDF-1α is short-lived, and therefore does not meet the needs of tissue repair. In this study, adenoviruses carrying SDF-1α genes were loaded on microbubble carriers and the adenoviruses were released into AMI rats by ultrasound targeted microbubble destruction. The possibility of in vivo self-transplantation of bone marrow mesenchymal stem cells (BMSCs) induced by overexpression of SDF-1α in the infarcted myocardium was explored by detecting the number of BMSCs homing from the peripheral blood to the myocardial infarcts. The concentration of SDF-1α in peripheral blood was significantly higher after transfection, and the number of BMSCs was significantly higher in the peripheral blood and infarcted area. Further analyses indicated that the number of homing BMSCs increased with increased SDF-1α expression. In conclusion, our results suggest that ultrasound mediated transduction of exogenous SDF-1α genes into myocardial infarcted AMI rats can effectively promote the homing of endogenous BMSCs into the heart. Moreover, the number of homing stem cells was controlled by the level of SDF-1α expression.

  7. Cancer-associated fibroblasts promote the progression of endometrial cancer via the SDF-1/CXCR4 axis.

    Science.gov (United States)

    Teng, Fei; Tian, Wen-Yan; Wang, Ying-Mei; Zhang, Yan-Fang; Guo, Fei; Zhao, Jing; Gao, Chao; Xue, Feng-Xia

    2016-02-06

    Cancer-associated fibroblasts (CAFs) are believed to play an essential role in cancer initiation and development. However, little research has been undertaken to evaluate the role of CAFs in endometrial cancer (EC) progression. We aim to detect the functional contributions of CAFs to promote progression of EC. Stromal fibroblasts were isolated from endometrioid adenocarcinomas and normal endometrial tissues. The conditioned media of cultured CAFs and normal fibroblasts (NFs) were collected to detect the level of stromal cell-derived factor-1alpha (SDF-1α), macrophage chemoattractant protein-1 (MCP-1), migration inhibitory factor (MIF), colony stimulating factor-1 (CSF-1), and interleukin-1 (IL-1) by ELISA. The CAFs or NFs were cocultured with EC cell lines to determine the proliferation, migration, and invasion by MTT assays and transwell chambers. Xenograft models were used to observe tumor growth. Matrix metalloproteinases (MMP)-2 and MMP-9 activity was evaluated by zymography. AMD3100 (a chemokine receptor 4 (CXCR4) antagonist) was used to block the SDF-1/CXCR4 axis. Neutralizing antibodies were used to detect PI3K/Akt and MAPK/Erk pathways by western blotting. SDF-1α and CXCR4 expressions were analyzed in xenotransplanted tumors and 348 cases by immunohistochemistry. CAFs promoted proliferation, migration, and invasion as well as in vivo tumorigenesis of admixed EC cells significantly more than NFs by secreting SDF-1α. These effects were significantly inhibited by AMD3100. CAFs promoted EC progression via the SDF-1α/CXCR4 axis to activate the PI3K/Akt and MAPK/Erk signalings in a paracrine-dependent manner or increase MMP-2 and MMP-9 secretion in an autocrine-dependent manner. SDF-1α and CXCR4 expression upregulation accompanied clinical EC development and progression. High SDF-1α expression levels were associated with deep myometrial invasion, lymph node metastasis, and poor prognosis in EC. Our data indicated that CAFs derived from EC tissues promoted

  8. Central SDF-1/CXCL12 expression and its cardiovascular and sympathetic effects: the role of angiotensin II, TNF-α, and MAP kinase signaling

    Science.gov (United States)

    Wei, Shun-Guang; Zhang, Zhi-Hua; Yu, Yang

    2014-01-01

    The chemokine stromal cell-derived factor-1 (SDF-1/CXCL12) and its receptors are expressed by neurons and glial cells in cardiovascular autonomic regions of the brain, including the hypothalamic paraventricular nucleus (PVN), and contribute to neurohumoral excitation in rats with ischemia-induced heart failure. The present study examined factors regulating the expression of SDF-1 in the PVN and mechanisms mediating its sympatho-excitatory effects. In urethane anesthetized rats, a 4-h intracerebroventricular (ICV) infusion of angiotensin II (ANG II) or tumor necrosis factor-α (TNF-α) in doses that increase mean blood pressure (MBP) and sympathetic drive increased the expression of SDF-1 in PVN. ICV administration of SDF-1 increased the phosphorylation of p44/42 mitogen-activated protein kinase (MAPK), JNK, and p38 MAPK in PVN, along with MBP, heart rate (HR), and renal sympathetic nerve activity (RSNA), but did not affect total p44/42 MAPK, JNK, and p38 MAPK levels. ICV pretreatment with the selective p44/42 MAPK inhibitor PD98059 prevented the SDF-1-induced increases in MBP, HR, and RSNA; ICV pretreatment with the selective JNK and p38 MAPK inhibitors attenuated but did not block these SDF-1-induced excitatory responses. ICV PD98059 also prevented the sympatho-excitatory response to bilateral PVN microinjections of SDF-1. ICV pretreatment with SDF-1 short-hairpin RNA significantly reduced ANG II- and TNF-α-induced phosphorylation of p44/42 MAPK in PVN. These findings identify TNF-α and ANG II as drivers of SDF-1 expression in PVN and suggest that the full expression of their cardiovascular and sympathetic effects depends upon SDF-1-mediated activation of p44/42 MAPK signaling. PMID:25260613

  9. The molecular biological expression of SDF-1 and VEGF in rat diabetic retinopathy and the intervention effect of AMD3100

    Directory of Open Access Journals (Sweden)

    Yi-An You

    2013-10-01

    Full Text Available AIM: To measure the expression of stromal cell derived factor-1(SDF-1and vascular endothelial growth factor(VEGFin retina of diabetic rats model at the different stage and explore the inhibitory effect of AMD3100 on the expression of SDF-1 and VEGF mRNA by RT-PCR and Western-Blot test.METHODS: RT-PCR and Western-Blot tests were carried out. In RT-PCR test, 60 adult SD rats were divided into normal group, antagonist group, and diabetes group. After diabetic rat model was induced using streptozotocin and antagonist group and diabetic group were injected intravitreously and postocularly with AMD3100 and PBS respectively. All rats were killed and the retina was extracted. after 1,3,5 months and the HE stain of paraffin sections was used and the expression of SDF-1 and VEGF mRNA were measured with RT-PCR. In Western-Blot test, 18 rats were divided into normal group, diabetes group and four antagonist groups which were using different concentration of AMD3100, and killed after 3 months.RESULTS: SDF-1 and VEGF mRNA were expressed in normal group, antagonist group and diabetes group. At the same age group(1, 3 and 5 monthsand among the normal group, antagonist group and diabetes group, the difference of expression of SDF-1 and VEGF mRNA were significant. The expressions in diabetic group were always highest and antagonist group lower than diabetic group. The expression of SDF-1 and VEGF mRNA was increased significantly with the extension of disease. The HE Stain of paraffin sections showed DM group had more cell nucleus which protruded internal limited membranes than normal control group and antagonist group. The Western-Blot test showed in 4 antagonist groups the SDF -1 and VEGF protein expression levels gradually decreased with the increases of SDF-1 antagonist AMD3100 concentration, the difference was significant. When intravitreous injected concentration of AMD3100 increased over 10μg/μL, the expression of SDF-1 and VEGF protein did not change

  10. Activation and Regulation of NLRP3 Inflammasome by Intrathecal Application of SDF-1a in a Spinal Cord Injury Model.

    Science.gov (United States)

    Zendedel, Adib; Johann, Sonja; Mehrabi, Soraya; Joghataei, Mohammad-Taghi; Hassanzadeh, Gholamreza; Kipp, Markus; Beyer, Cordian

    2016-07-01

    Stromal cell-derived factor-1 alpha (SDF-1a) or CXCL12 is an important cytokine with multiple functions in the brain during development and in adulthood. The inflammatory response initiated by spinal cord injury (SCI) involves the processing of interleukin-1beta (IL-1ß) and IL-18 mediated by caspase-1 which is under the control of an intracellular multiprotein complex termed inflammasome. Using an SCI rat model, we found improved functional long-term recovery which is paralleled by a reduction of apoptosis after intrathecal treatment with SDF-1a. An intriguing aspect is that SDF-1a changed the number of neuroinflammatory cells in the damaged area. We further examined the cellular localization and sequential expression of several inflammasomes during SCI at 6 h, 24 h, 3 days, and 7 days as well as the role of SDF-1a as a regulatory factor for inflammasomes. Using 14-week old male Wistar rats, spinal cord contusion was applied at the thoracic segment 9, and animals were subsequently treated with SDF-1a via intrathecal application through an osmotic pump. SCI temporally increased the expression of the inflammasomes NLRP3, ASC, the inflammatory marker tumor necrosis factor-a (TNF-a), interleukin-1ß (IL-1β) and IL-18. SDF-1a significantly reduced the levels of IL-18, IL-1b, TNF-a, NLRP3, ASC, and caspase-1. Immunofluorescence double-labeling demonstrated that microglia and neurons are major sources of the ASC and NLRP3 respectivley. Our data provide clear evidence that SCI stimulates a complex scenario of inflammasome activation at the injured site and that SDF-1a-mediated neuroprotection presumably depends on the attenuation of the inflammasome complex.

  11. High expression of SDF-1 and VEGF is associated with poor prognosis in patients with synovial sarcomas.

    Science.gov (United States)

    Feng, Qi; Guo, Peng; Wang, Jin; Zhang, Xiaoyu; Yang, Hui-Chai; Feng, Jian-Gang

    2018-03-01

    Stromal cell-derived factor-1 (SDF-1) predicts poor clinical outcomes of certain types of cancer. Furthermore, vascular endothelial growth factor (VEGF) promotes the growth and metastasis of solid tumors. The aim of the present study was to examine the expression of SDF-1 and VEGF in patients with synovial sarcoma and to determine their expression is correlated with unfavorable outcomes. Levels of SDF-1 and VEGF proteins were evaluated in 54 patients with synovial sarcoma using immunohistochemical and immunofluorescence staining. Potential associations between the expression of SDF-1 and VEGF and various clinical parameters were analyzed using Pearson's χ 2 test and the Spearman-rho test. Additionally, univariate and multivariate Cox regression analyses were used to identify potential prognostic factors, and the Kaplan-Meier method was used to analyze the overall survival rates of patients. Low SDF-1 and VEGF expression was detected in 20.4% (11/54) and 22.2% (12/54) of patients with synovial sarcoma; moderate expression was detected in 35.2% (19/54) and 37.0% (20/54) of patients and high expression was detected in 44.4% (24 of 54) and 40.7% (22 of 54) of patients, respectively. Levels of SDF-1 and VEGF proteins were significantly associated with histological grade (PSDF-1 and VEGF expression were positively correlated with each other (PSDF-1 expression was associated with shorter patient survival rates (PSDF-1 and VEGF expression were associated with various characteristics of synovial sarcoma. Therefore, SDF-1 expression may be a potential independent prognostic indicator in patients with synovial sarcomas.

  12. Quantitative phosphoproteomic analysis reveals system-wide signaling pathways downstream of SDF-1/CXCR4 in breast cancer stem cells

    Science.gov (United States)

    Yi, Tingfang; Zhai, Bo; Yu, Yonghao; Kiyotsugu, Yoshikawa; Raschle, Thomas; Etzkorn, Manuel; Seo, Hee-Chan; Nagiec, Michal; Luna, Rafael E.; Reinherz, Ellis L.; Blenis, John; Gygi, Steven P.; Wagner, Gerhard

    2014-01-01

    Breast cancer is the leading cause of cancer-related mortality in women worldwide, with an estimated 1.7 million new cases and 522,000 deaths around the world in 2012 alone. Cancer stem cells (CSCs) are essential for tumor reoccurrence and metastasis which is the major source of cancer lethality. G protein-coupled receptor chemokine (C-X-C motif) receptor 4 (CXCR4) is critical for tumor metastasis. However, stromal cell-derived factor 1 (SDF-1)/CXCR4–mediated signaling pathways in breast CSCs are largely unknown. Using isotope reductive dimethylation and large-scale MS-based quantitative phosphoproteome analysis, we examined protein phosphorylation induced by SDF-1/CXCR4 signaling in breast CSCs. We quantified more than 11,000 phosphorylation sites in 2,500 phosphoproteins. Of these phosphosites, 87% were statistically unchanged in abundance in response to SDF-1/CXCR4 stimulation. In contrast, 545 phosphosites in 266 phosphoproteins were significantly increased, whereas 113 phosphosites in 74 phosphoproteins were significantly decreased. SDF-1/CXCR4 increases phosphorylation in 60 cell migration- and invasion-related proteins, of them 43 (>70%) phosphoproteins are unrecognized. In addition, SDF-1/CXCR4 upregulates the phosphorylation of 44 previously uncharacterized kinases, 8 phosphatases, and 1 endogenous phosphatase inhibitor. Using computational approaches, we performed system-based analyses examining SDF-1/CXCR4–mediated phosphoproteome, including construction of kinase–substrate network and feedback regulation loops downstream of SDF-1/CXCR4 signaling in breast CSCs. We identified a previously unidentified SDF-1/CXCR4-PKA-MAP2K2-ERK signaling pathway and demonstrated the feedback regulation on MEK, ERK1/2, δ-catenin, and PPP1Cα in SDF-1/CXCR4 signaling in breast CSCs. This study gives a system-wide view of phosphorylation events downstream of SDF-1/CXCR4 signaling in breast CSCs, providing a resource for the study of CSC-targeted cancer therapy. PMID

  13. Serum SDF-1 levels are a reliable diagnostic marker of feline mammary carcinoma, discriminating HER2-overexpressing tumors from other subtypes.

    Science.gov (United States)

    Marques, Cláudia S; Soares, Maria; Santos, Ana; Correia, Jorge; Ferreira, Fernando

    2017-12-01

    The feline mammary carcinoma (FMC) is the third most common tumor in cat, sharing many clinicopathological features with human breast cancer and thus, considered a suitable model for comparative oncology. Due to its poor prognosis, further studies are required to improve the diagnostic accuracy and treatment of cats with spontaneous mammary carcinoma. Recently, it was reported that the overexpression of stromal cell-derived factor-1 (SDF-1) has great value in human breast cancer diagnosis, suggesting that diagnostic tools and therapies targeting the SDF-1 ligand can improve the clinical outcome. In this study, we aimed to evaluate if serum SDF-1 levels can also be used as a biomarker of mammary carcinoma in cats and to analyze if serum SDF-1 levels are associated with clinicopathological features, linked to a specific FMC subtype or correlated with the tumor expression of SDF-1 receptor, the chemokine C-X-C motif receptor 4 (CXCR4). Results showed that cats with mammary carcinoma had significantly higher serum SDF-1 levels than healthy controls ( p =0.035) and ROC analysis revealed that the best cut-off value to differentiate sick from healthy animals was 2 ng/ml (specificity: 80%; sensitivity: 57%; AUC=0.715). Significant associations were also found between cats with elevated serum SDF-1 concentrations (≥ 2 ng/ml) and HER2-overexpressing mammary carcinomas (Luminal B-like and HER2-positive subtypes, p SDF-1 levels and overall or disease-free survival. In summary, our results show that serum SDF-1 levels can be used as a biomarker of feline mammary carcinoma, especially in cats with HER2-overexpressing mammary tumors. Data suggest that targeted therapies against the SDF-1 ligand and/or its CXC4 receptor may be effective for the treatment of FMC, as described for human breast cancer, strengthening the concept that spontaneous feline mammary carcinoma is a suitable model for comparative oncology.

  14. Saxagliptin Attenuates Albuminuria by Inhibiting Podocyte Epithelial- to-Mesenchymal Transition via SDF-1α in Diabetic Nephropathy.

    Science.gov (United States)

    Chang, Yun-Peng; Sun, Bei; Han, Zhe; Han, Fei; Hu, Shao-Lan; Li, Xiao-Yu; Xue, Mei; Yang, Yang; Chen, Li; Li, Chun-Jun; Chen, Li-Ming

    2017-01-01

    The dipeptidyl peptidase-4 (DPP-4) inhibitor saxagliptin has been found to reduce progressive albuminuria, but the exact mechanism of inhibition is unclear. Podocyte epithelial-to-mesenchymal transition (EMT) has emerged as a potential pathway leading to proteinuria in diabetic nephropathy (DN). Stromal cell-derived factor-1α (SDF-1α), one of the substrates of DPP-4, can activate the protein kinase A pathway and subsequently inhibit its downstream effector, transforming growth factor-β1 (TGF-β1), which induces podocyte EMT. Thus, this study was designed to test the hypothesis that saxagliptin reduces progressive albuminuria by preventing podocyte EMT through inhibition of SDF-1α cleavage in DN. The results of a series of assays, including ELISA, western blotting, and immunochemistry/immunofluorescence, showed that saxagliptin treatment obviously ameliorated urinary microalbumin excretion and renal histological changes in high-fat diet/streptozotocin-induced diabetic rats. Furthermore, saxagliptin-treated diabetic rats presented with suppression of DPP-4 activity/protein expression accompanied by restoration of SDF-1α levels, which subsequently hindered NOX2 expression and podocyte EMT. In vitro , we consistently observed that saxagliptin significantly inhibited increased DPP-4 activity/expression, oxidative stress and podocyte EMT. Application of an SDF-1α receptor inhibitor (AMD3100) to cultured podocytes further confirmed the essential role of SDF-1α in podocyte EMT inhibition. In sum, we demonstrated for the first time that saxagliptin treatment plays an essential role in ameliorating progressive DN by preventing podocyte EMT through a SDF-1α-related pathway, suggesting that saxagliptin could offer renoprotection and that SDF-1α might be a potential therapeutic target for DN.

  15. Cloning, expression and identification of an isoform of human stromal cell derived factor-1α

    OpenAIRE

    LIANG, YIN-KU; PING, WEI; BIAN, LIU-JIAO

    2015-01-01

    Human stromal cell derived factor-1α (hSDF-1α), a chemotactic factor of stem cells, regulates inflammation, promotes the mobilization of stem cells and induces angiogenesis following ischemia. Six SDF-1 isoforms, SDF-1α, SDF-1β, SDF-1γ, SDF-1δ, SDF-1ε and SDF-1ϕ, which all contain a signal peptide at the N-terminus, have been reported. In the present study a special isoform of hSDF-1α is described that does not contain the N-terminal signal peptide sequence. The hSDF-1α gene was cloned with t...

  16. Inhibition of SDF-1α/CXCR4 Signalling in Subchondral Bone Attenuates Post-Traumatic Osteoarthritis

    Directory of Open Access Journals (Sweden)

    Yonghui Dong

    2016-06-01

    Full Text Available Previous studies showed that SDF-1α is a catabolic factor that can infiltrate cartilage, decrease proteoglycan content, and increase MMP-13 activity. Inhibiting the SDF-1α/CXCR4 signalling pathway can attenuate the pathogenesis of osteoarthritis (OA. Recent studies have also shown that SDF-1α enhances chondrocyte proliferation and maturation. These results appear to be contradictory. In the current study, we used a destabilisation OA animal model to investigate the effects of SDF-1α/CXCR4 signalling in the tibial subchondral bone and the OA pathological process. Post-traumatic osteoarthritis (PTOA mice models were prepared by transecting the anterior cruciate ligament (ACLT, or a sham surgery was performed, in a total of 30 mice. Mice were treated with phosphate buffer saline (PBS or AMD3100 (an inhibitor of CXCR4 and sacrificed at 30 days post ACLT or sham surgery. Tibial subchondral bone status was quantified by micro-computed tomography (μCT. Knee-joint histology was analysed to examine the articular cartilage and joint degeneration. The levels of SDF-1α and collagen type I c-telopeptidefragments (CTX-I were quantified by ELISA. Bone marrow mononuclear cells (BMMCs were used to clarify the effects of SDF-1α on osteoclast formation and activity in vivo. μCT analysis revealed significant loss of trabecular bone from tibial subchondral bone post-ACLT, which was effectively prevented by AMD3100. AMD3100 could partially prevent bone loss and articular cartilage degeneration. Serum biomarkers revealed an increase in SDF-1α and bone resorption, which were also reduced by AMD3100. SDF-1α can promote osteoclast formation and the expression oftartrate resistant acid phosphatase (TRAP, cathepsin K (CK, and matrix metalloproteinase (MMP-9 in osteoclasts by activating the MAPK pathway, including ERK and p38, but not JNK. In conclusion, inhibition of SDF-1α/CXCR4signalling was able to prevent trabecular bone loss and attenuated cartilage

  17. SDF-1α/CXCR4 Signaling in Lipid Rafts Induces Platelet Aggregation via PI3 Kinase-Dependent Akt Phosphorylation.

    Science.gov (United States)

    Ohtsuka, Hiroko; Iguchi, Tomohiro; Hayashi, Moyuru; Kaneda, Mizuho; Iida, Kazuko; Shimonaka, Motoyuki; Hara, Takahiko; Arai, Morio; Koike, Yuichi; Yamamoto, Naomasa; Kasahara, Kohji

    2017-01-01

    Stromal cell-derived factor-1α (SDF-1α)-induced platelet aggregation is mediated through its G protein-coupled receptor CXCR4 and phosphatidylinositol 3 kinase (PI3K). Here, we demonstrate that SDF-1α induces phosphorylation of Akt at Thr308 and Ser473 in human platelets. SDF-1α-induced platelet aggregation and Akt phosphorylation are inhibited by pretreatment with the CXCR4 antagonist AMD3100 or the PI3K inhibitor LY294002. SDF-1α also induces the phosphorylation of PDK1 at Ser241 (an upstream activator of Akt), GSK3β at Ser9 (a downstream substrate of Akt), and myosin light chain at Ser19 (a downstream element of the Akt signaling pathway). SDF-1α-induced platelet aggregation is inhibited by pretreatment with the Akt inhibitor MK-2206 in a dose-dependent manner. Furthermore, SDF-1α-induced platelet aggregation and Akt phosphorylation are inhibited by pretreatment with the raft-disrupting agent methyl-β-cyclodextrin. Sucrose density gradient analysis shows that 35% of CXCR4, 93% of the heterotrimeric G proteins Gαi-1, 91% of Gαi-2, 50% of Gβ and 4.0% of PI3Kβ, and 4.5% of Akt2 are localized in the detergent-resistant membrane raft fraction. These findings suggest that SDF-1α/CXCR4 signaling in lipid rafts induces platelet aggregation via PI3K-dependent Akt phosphorylation.

  18. SDF-1/CXCR4 Axis Regulates Cell Cycle Progression and Epithelial-Mesenchymal Transition via Up-regulation of Survivin in Glioblastoma.

    Science.gov (United States)

    Liao, Anyan; Shi, Ranran; Jiang, Yuliang; Tian, Suqing; Li, Panpan; Song, Fuxi; Qu, Yalan; Li, Jinna; Yun, Haiqin; Yang, Xiangshan

    2016-01-01

    Stromal cell-derived factor 1 (SDF-1)/CXCR4 ligand-receptor axis is widely recommended as an attractive target for cancer therapy. Meanwhile, epithelial-mesenchymal transition (EMT) process is linked to disease pathophysiology. As one of inhibitors of apoptosis proteins, survivin is implicated in the onset and development of cancer. In the present study, we tried to determine the cause-effect associations between SDF-1/CXCR4 axis and survivin expression in glioblastoma U-251 cell line. Survivin activation and inhibition were induced with exogenous SDF-1 and survivin small interfering RNA (survivin siRNA), respectively. Western blot was used to detect relevant proteins in SDF-1/CXCR4 axis. Western blot analysis revealed that survivin expression in U-251 increased in a dose- and time-dependent manner in response to SDF-1 treatment. However, the interference with MEK/ERK and PI3K/AKT pathway prohibited SDF-1-induced survivin up-regulation. Importantly, survivin knockdown abrogated cell cycle progression and the expression of snail and N-cadherin, compared with non-transfectants. In conclusion, the present study shows that SDF-1 up-regulates survivin via MEK/ERK and PI3K/AKT pathway, leading to cell cycle progression and EMT occurrence dependent on survivin. The blockade of survivin will allow for the treatment of glioblastoma.

  19. Overexpression of SDF-1 activates the NF-κB pathway to induce epithelial to mesenchymal transition and cancer stem cell-like phenotypes of breast cancer cells.

    Science.gov (United States)

    Kong, Lingxin; Guo, Sufen; Liu, Chunfeng; Zhao, Yiling; Feng, Chong; Liu, Yunshuang; Wang, Tao; Li, Caijuan

    2016-03-01

    The formation of EMT and EMT-induced CSC-like phenotype is crucial for the metastasis of tumor cells. The stromal cell-derived factor-1 (SDF-1) is upregulated in various human carcinomas, which is closely associated with proliferation, migration, invasion and prognosis of malignancies. However, limited attention has been directed towards the effect of SDF-1 on epithelial to mesenchymal transition (EMT) or cancer stem cell (CSC)-like phenotype formation in breast cancer cells and the related mechanism. In the present study, we screened MCF-7 cells with low SDF-1 expression level for the purpose of evaluating whether SDF-1 is involved in EMT and CSC-like phenotype formation in MCF-7 cells. The pEGFP-N1-SDF-1 plasmid was transfected into MCF-7 cells, and the stably overexpressed SDF-1 in MCF-7 cells was confirmed by real-time PCR and western blot analysis. Colony formation assay, MTT, wound healing assay and Transwell invasion assay demonstrated that overexpression of SDF-1 significantly boosted the proliferation, migration and invasion of MCF-7 cells compared with parental (PSDF-1 overexpressing MCF-7 cells (PSDF-1 overexpressed MCF-7 cells in comparison with parental (PSDF-1 induced the activation of NF-κB pathway in MCF-7 cells. Conversely, suppressing or silencing p65 expression by antagonist or RNA interference could remarkably increase the expression of E-cadherin in SDF-1 overexpressed MCF-7 cells (PSDF-1 enhanced EMT by activating the NF-κB pathway of MCF-7 cells and further induced the formation of CSC-like phenotypes, ultimately promoting the proliferation and metastasis of MCF-7 cells. Therefore, SDF-1 may further be assessed as a potential target for gene therapy of breast cancer.

  20. Enhancing the Migration Ability of Mesenchymal Stromal Cells by Targeting the SDF-1/CXCR4 Axis

    Directory of Open Access Journals (Sweden)

    Leah A. Marquez-Curtis

    2013-01-01

    Full Text Available Mesenchymal stromal cells (MSCs are currently being investigated in numerous clinical trials of tissue repair and various immunological disorders based on their ability to secrete trophic factors and to modulate inflammatory responses. MSCs have been shown to migrate to sites of injury and inflammation in response to soluble mediators including the chemokine stromal cell-derived factor-(SDF-1, but during in vitro culture expansion MSCs lose surface expression of key homing receptors particularly of the SDF-1 receptor, CXCR4. Here we review studies on enhancement of SDF-1-directed migration of MSCs with the premise that their improved recruitment could translate to therapeutic benefits. We describe our studies on approaches to increase the CXCR4 expression in in vitro-expanded cord blood-derived MSCs, namely, transfection, using the commercial liposomal reagent IBAfect, chemical treatment with the histone deacetylase inhibitor valproic acid, and exposure to recombinant complement component C1q. These methodologies will be presented in the context of other cell targeting and delivery strategies that exploit pathways involved in MSC migration. Taken together, these findings indicate that MSCs can be manipulated in vitro to enhance their in vivo recruitment and efficacy for tissue repair.

  1. Molecular characterization of sdf1 and cxcr4 in the Mozambique tilapia, Oreochromis mossambicus.

    Science.gov (United States)

    Amat-Fernandez, Jorge; Hammond, Michael J; Liang, Di; Wang, Tianfang; Ventura, Tomer; Elizur, Abigail; Cummins, Scott F

    2017-01-01

    Animal sexual reproduction relies on primordial germ cells (PGCs), the predecessors of the germ cell lineage, giving rise to either spermatogonia or oogonia after the completion of gonadal differentiation. There is limited information on the mechanism of PGC migration leading to the formation of the primordial gonad in Perciform fish. Oreochromis mossambicus, a tilapiine species, was investigated that is a commercially important aquaculture species in many parts of the world while in other areas it has become an invasive pest. Key components involved in PGC migration were identified, including the stromal-cell derived factor 1 (Om-sdf1a, Om-sdf1b) and the CXC receptor 4 (Om-cxcr4): both share conservation with existing model species. The spatial gene expression profiles were determined through transcript and protein analysis and displayed distinct localisation within the region of the developing gonad in larvae and within the adult gonads of certain cell populations. A recombinant Om-sdf1a was produced in Escherichia coli that activates Om-cxcr4 using a BRET-based yeast in vitro assay system, suggesting that it is structurally similar to the native Om-sdf1a and is appropriate for further structural studies. This study has improved understanding of the molecular basis of tilapia reproduction through investigation of gonad development, which may be important in the progression towards reproductive suppression methods to control tilapia populations in the wild. In addition, this research will facilitate developments in germ cell transplantation, an innovative technique that harnesses germ cell migration and allows the uptake of foreign germ cells, which differentiate to produce sperm or ova. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Fabrication and evaluation of SDF-1 loaded galactosylated chitosan nanoparticles for liver targeting

    Science.gov (United States)

    Xue-Hui, Chu; Zhang-Qi, Feng; Qian, Xu; Jiang-Qiang, Xiao; Xian-Wen, Yuan; Xi-Tai, Sun

    2017-03-01

    Objective. SDF-1 loaded galactosylated chitosan (GC) nanoparticles for liver targeting were synthesized by electrospraying technique, and its biocompatibility and liver targeting effect were evaluated. Method. The SDF-1 loaded GC nanoparticles were constructed and its morphology was observed by the scanning electron microscopy (SEM). Hepatocytes were harvested and cocultured with the nanoparticles, and the albumin secretion and urea synthesis were detected by enzyme-linked immunosorbent assay assay, the concentration of lactate dehydrogenase (LDH) and tumor necrosis factor-α (TNF-α) was also measured. Finally, the nanoparticles were injected intravenously through the caudal vein of rat, and its liver targeting effect was evaluated. Result. SEM showed the nanoparticles distributed uniformly, with an average diameter of 100 nm and a regular spherical shape. There was no significant difference in urea synthesis, albumin secretion, concentration of LDH and TNF-α between two groups (p > 0.05). The nanoparticles were significantly accumulated in the liver tissue after its injection, but seldom fluorescence signals were observed in the lung, spleen, heart and kidney. Conclusion. The SDF-1 loaded GC nanoparticles showed uniform distribution, good biocompatibility and liver targeting effect, and suggested its potential application as a liver targeting delivery system.

  3. Transplantation of iPS cell-derived neural progenitors overexpressing SDF-1α increases regeneration and functional recovery after ischemic stroke.

    Science.gov (United States)

    Chau, Monica; Deveau, Todd C; Song, Mingke; Wei, Zheng Z; Gu, Xiaohuan; Yu, Shan Ping; Wei, Ling

    2017-11-14

    Ischemic stroke is a leading cause of human death and disability while clinical treatments are limited. The adult brain possesses endogenous regenerative activities that may benefit tissue repair after stroke. Trophic factors such as stromal cell-derived factor 1 alpha (SDF-1α) are upregulated in the ischemic brain, which promote endogenous regeneration. The regenerative response, however, is normally insufficient. Transplantation of exogenous cells has been explored as regenerative therapies. One promising cell type for transplantation is induced pluripotent stem (iPS) cells which are cells genetically reprogrammed from adult somatic cells. We hypothesized that transplanting neural progenitor cells derived from iPS cells (iPS-NPCs) could provide cell replacement and trophic support. The trophic factor SDF-1α was overexpressed in iPS-NPCs by lentiviral transduction to test if SDF-1α could increase regeneration in the ischemic brain. These SDF-1α-iPS-NPCs were differentiated in vitro to express mature neuronal and synaptic markers. Differentiated cells expressed functional Na + and K + channels, and fired action potentials. In the oxygen glucose deprivation (OGD) test, SDF-1α-iPS-NPCs survived significantly better compared to control iPS-NPCs. In mice subjected to focal cerebral ischemia in the sensorimotor cortex, iPS-NPCs and SDF-1α-iPS-NPCs were intracranially transplanted into the ischemic cortex 7 days after stroke. Neuronal differentiation of transplanted cells was identified using NeuN 14 days after transplantation. Mice that received SDF-1α-iPS-NPCs had greater numbers of NeuN/BrdU and Glut-1/BrdU co-labeled cells in the peri-infarct area and improved locomotion compared to the control iPS-NPC transplantation. Thus, SDF-1α upregulation in transplanted cells may be a therapeutic strategy to enhance endogenous neurovascular repair after ischemic stroke in adult mice.

  4. PTH/SDF-1α cotherapy induces CD90+CD34− stromal cells migration and promotes tissue regeneration in a rat periodontal defect model

    Science.gov (United States)

    Wang, Fang; Du, Lingqian; Ge, Shaohua

    2016-01-01

    Stromal cell-derived factor-1α (SDF-1α) is a key stem cell homing factor that is crucial for recruitment of stem cells to many diseased organs. However, the therapeutic activity of SDF-1α is potentially limited by N-terminal cleavage at position-2 proline by a cell surface protein CD26/dipeptidyl peptidase-IV (DPP-IV). Parathyroid hormone (PTH) is a DPP-IV inhibitor and has been suggested as a promising agent for periodontal tissue repair. The purpose of this study was to explore the effects of a cell-free system comprising SDF-1α and scaffold plus PTH systemic application on periodontal tissue regeneration in vivo. The results showed that PTH/SDF-1α cotherapy improved the quantity of regenerated bone and resulted in better organization of ligament interface. We further investigated the possible mechanisms, and found that PTH/SDF-1α cotherapy enhanced CD90+CD34− stromal cells migration in vivo, increased the number of CXCR4 + cells in periodontal defects, induced early bone osteoclastogenesis and enhanced the expression of runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP) and collagen I (Col I) in newly formed bone tissue. In conclusion, this cell-free tissue engineering system with local administration of SDF-1α and systemic application of PTH could be employed to induce CD90+CD34− stromal cells recruitment and promote periodontal tissue regeneration. PMID:27480134

  5. Injection of SDF-1 loaded nanoparticles following traumatic brain injury stimulates neural stem cell recruitment.

    Science.gov (United States)

    Zamproni, Laura N; Mundim, Mayara V; Porcionatto, Marimelia A; des Rieux, Anne

    2017-03-15

    Recruiting neural stem cell (NSC) at the lesion site is essential for central nervous system repair. This process could be triggered by the local delivery of the chemokine SDF-1. We compared two PLGA formulations for local brain SDF-1 delivery: SDF-1 loaded microspheres (MS) and SDF-1 loaded nanoparticles (NP). Both formulations were able to encapsulate more than 80% of SDF-1 but presented different release profiles, with 100% of SDF-1 released after 6days for the MS and with 25% of SDF-1 released after 2 weeks for NP. SDF-1 bioactivity was demonstrated by a chemotactic assay. When injected in mouse brain after traumatic brain injury, only SDF-1 nanoparticles induced NSC migration to the damage area. More neuroblasts (DCX+ cells) could be visualized around the lesions treated with NP SDF-1 compared to the other conditions. Rostral migratory stream destabilization with massive migration of DCX+ cell toward the perilesional area was observed 2 weeks after NP SDF-1 injection. Local injection of SDF-1-loaded nanoparticles induces recruitment of NSC and could be promising for brain injury lesion. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Ischemic brain extract increases SDF-1 expression in astrocytes through the CXCR2/miR-223/miR-27b pathway.

    Science.gov (United States)

    Shin, Jin Hee; Park, Young Mi; Kim, Dong Hee; Moon, Gyeong Joon; Bang, Oh Young; Ohn, Takbum; Kim, Hyeon Ho

    2014-09-01

    Ischemic cerebral stroke is one of the leading global causes of mortality and morbidity. Ischemic preconditioning (IPC) refers to a sublethal ischemia and resulting in tolerance to subsequent severe ischemic injury. Although several pathways are reportedly involved in IPC-mediated neuroprotection, the functional role of astrocytes is not fully understood. Stromal cell-derived factor-1 (SDF-1), a CXC chemokine produced mainly in astrocytes, is a ligand for chemokine receptor CXCR4. SDF-1 is reported to play a critical role in neuroprotection after stroke by mediating the migration of neuronal progenitor cells. We hypothesized that stimuli derived from ischemic brain were involved in the protective effects of IPC. To investigate this hypothesis, the mechanism in which ischemic brain extract (IBE) induced SDF-1 expression was investigated in C6 astrocytoma cells. IBE treatment of C6 cells increased SDF-1 expression compared to that in untreated or normal brain extract (NBE)-treated cells by downregulating SDF-1 targeting miRNA, miR-27b. MiR-223 was inversely upregulated in IBE-treated cells; overexpression of miR-223 decreased the expression of miR-27b by suppressing IKKα expression. Analysis of cytokine array data revealed an IBE associated enhanced expression of CINC-1 (CXCL1) and LIX1 (CXCL5). Knockdown or inhibition of their receptor, CXCR2, abolished IBE-mediated increased expression of SDF-1. These results were confirmed in primary cultured astrocytes. Taken together, the data demonstrate that IBE-elicited signals increase SDF-1 expression through the CXCR2/miR-223/miR-27b pathway in C6 astrocytoma cells and primary astrocytes, supporting the view that increased expression of SDF-1 by ischemic insults is a possible mechanism underlying therapeutic application of IPC. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. SDF-1/CXCR4 axis induces human dental pulp stem cell migration through FAK/PI3K/Akt and GSK3β/β-catenin pathways

    Science.gov (United States)

    Li, Mingwei; Sun, Xuefei; Ma, Liang; Jin, Lu; Zhang, Wenfei; Xiao, Min; Yu, Qing

    2017-01-01

    SDF-1 (stromal cell derived factor-1) has been found to be widely expressed during dental pulp inflammation, while hDPSCs (human dental pulp stem cells) contribute to the repair of dental pulp. We showed that the migration of hDPSCs was induced by SDF-1 in a concentration-dependent manner and could be inhibited with siCXCR4 (C-X-C chemokine receptor type 4) and siCDC42 (cell division control protein 42), as well as drug inhibitors such as AMD3100 (antagonist of CXCR4), LY294002 (inhibitor of PI3K) and PF573228 (inhibitor of FAK). It was also confirmed that SDF-1 regulated the phosphorylation of FAK (focal adhesion kinases) on cell membranes and the translocation of β-catenin into the cell nucleus. Subsequent experiments confirmed that the expression of CXCR4 and β-catenin and the phosphorylation of FAK, PI3K (phosphoinositide 3-kinase), Akt and GSK3β (glycogen synthase kinase-3β) were altered significantly with SDF-1 stimulation. FAK and PI3K worked in coordination during this process. Our findings provide direct evidence that SDF-1/CXCR4 axis induces hDPSCs migration through FAK/PI3K/Akt and GSK3β/β-catenin pathways, implicating a novel mechanism of dental pulp repair and a possible application of SDF-1 for the treatment of pulpitis. PMID:28067275

  8. SDF-1/CXCR4 axis induces human dental pulp stem cell migration through FAK/PI3K/Akt and GSK3β/β-catenin pathways.

    Science.gov (United States)

    Li, Mingwei; Sun, Xuefei; Ma, Liang; Jin, Lu; Zhang, Wenfei; Xiao, Min; Yu, Qing

    2017-01-09

    SDF-1 (stromal cell derived factor-1) has been found to be widely expressed during dental pulp inflammation, while hDPSCs (human dental pulp stem cells) contribute to the repair of dental pulp. We showed that the migration of hDPSCs was induced by SDF-1 in a concentration-dependent manner and could be inhibited with siCXCR4 (C-X-C chemokine receptor type 4) and siCDC42 (cell division control protein 42), as well as drug inhibitors such as AMD3100 (antagonist of CXCR4), LY294002 (inhibitor of PI3K) and PF573228 (inhibitor of FAK). It was also confirmed that SDF-1 regulated the phosphorylation of FAK (focal adhesion kinases) on cell membranes and the translocation of β-catenin into the cell nucleus. Subsequent experiments confirmed that the expression of CXCR4 and β-catenin and the phosphorylation of FAK, PI3K (phosphoinositide 3-kinase), Akt and GSK3β (glycogen synthase kinase-3β) were altered significantly with SDF-1 stimulation. FAK and PI3K worked in coordination during this process. Our findings provide direct evidence that SDF-1/CXCR4 axis induces hDPSCs migration through FAK/PI3K/Akt and GSK3β/β-catenin pathways, implicating a novel mechanism of dental pulp repair and a possible application of SDF-1 for the treatment of pulpitis.

  9. Role of SDF1/CXCR4 Interaction in Experimental Hemiplegic Models with Neural Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Noboru Suzuki

    2012-02-01

    Full Text Available Much attention has been focused on neural cell transplantation because of its promising clinical applications. We have reported that embryonic stem (ES cell derived neural stem/progenitor cell transplantation significantly improved motor functions in a hemiplegic mouse model. It is important to understand the molecular mechanisms governing neural regeneration of the damaged motor cortex after the transplantation. Recent investigations disclosed that chemokines participated in the regulation of migration and maturation of neural cell grafts. In this review, we summarize the involvement of inflammatory chemokines including stromal cell derived factor 1 (SDF1 in neural regeneration after ES cell derived neural stem/progenitor cell transplantation in mouse stroke models.

  10. Osteoprotegerin regulates cancer cell migration through SDF-1/CXCR4 axis and promotes tumour development by increasing neovascularization.

    Science.gov (United States)

    Benslimane-Ahmim, Zahia; Pereira, Jessica; Lokajczyk, Anna; Dizier, Blandine; Galy-Fauroux, Isabelle; Fischer, Anne-Marie; Heymann, Dominique; Boisson-Vidal, Catherine

    2017-06-01

    We previously reported that OPG is involved in ischemic tissue neovascularization through the secretion of SDF-1 by pretreated-OPG endothelial colony-forming cells (ECFCs). As the vascularization is one of the key factor influencing the tumour growth and cancer cell dissemination, we investigated whether OPG was able to modulate the invasion of human MNNG-HOS osteosarcoma and DU145 prostate cancer cell lines in vitro and in vivo. Cell motility was analysed in vitro by using Boyden chambers. Human GFP-labelled MMNG-HOS cells were inoculated in immunodeficient mice and the tumour nodules formed were then injected with OPG and/or FGF-2, AMD3100 or 0.9% NaCl (control group). Tumour growth was manually followed and angiogenesis was assessed by immunohistochemistry. In vitro, SDF-1 released by OPG-pretreated ECFCs markedly attracted both MNNG-HOS and DU145 cells and induced spontaneous migration of cancer cells. In vivo, tumour volumes were significantly increased in OPG-treated group compared to the control group and OPG potentiated the effect of FGF-2. Concomitantly, OPG alone or combined with FGF-2 increased the number of new vasculature compared to the control group. Interestingly AMD3100, an inhibitor of SDF-1, prevented the in vivo effects of OPG induced by SDF-1 This study provides experimental evidence that OPG promotes tumour development trough SDF-1/CXCR4 axis. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Testosterone and Voluntary Exercise Promote Angiogenesis in Hearts of Rats with Diabetes by Enhancing Expression of VEGF-A and SDF-1a.

    Science.gov (United States)

    Chodari, Leila; Mohammadi, Mustafa; Ghorbanzadeh, Vajiheh; Dariushnejad, Hassan; Mohaddes, Gisou

    2016-10-01

    Impaired angiogenesis in cardiac tissue is a major complication of diabetes. This study was aimed to evaluate the effects of testosterone and voluntary exercise on vascular endothelial growth factor-A (VEGF-A), stromal cell-derived factor 1a (SDF-1a) and myocardial capillary density in heart of rats with diabetes. Type 1 diabetes was induced by intraperitoneal injection of 55 mg/kg of streptozotocin in 80 male Wistar rats. After 42 days of treatment with testosterone (2 mg/kg/day) or voluntary exercise alone or in combination, angiogenesis was determined in the hearts by immunostaining for PECAM-1/CD31. The expressions of VEGF-A and SDF-1a levels in heart were also determined by the ELISA method. Our results showed that capillary density, VEGF-A and SDF-1a levels in the heart were significantly decreased in castrated rats with diabetes, whereas these effects were reversed by testosterone and exercise. Furthermore, simultaneous treatment of castrated rats with diabetes with testosterone and exercise had a synergistic effect on capillary density, VEGF-A and SDF-1a levels in the heart. In the group with diabetes, either testosterone or exercise increased capillary density, VEGF-A and SDF-1a protein levels in heart tissue. However, the effects of combination therapy in rats with diabetes with testosterone and exercise on capillary density, VEGF-A and SDF-1a levels in the heart was synergistic. Our findings suggest that testosterone and exercise can promote neoangiogenesis in rats with diabetes and in castrated rats with diabetes. The proangiogenesis effect of testosterone and exercise is associated with the enhanced expression of VEGF-A and SDF-1a in heart tissue. Copyright © 2016 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

  12. Resveratrol pretreatment enhanced homing of SDF-1α-preconditioned bone marrow-derived mesenchymal stem cells in a rat model of liver cirrhosis.

    Science.gov (United States)

    Hajinejad, Mehrdad; Pasbakhsh, Parichehr; Omidi, Ameneh; Mortezaee, Keywan; Nekoonam, Saied; Mahmoudi, Reza; Kashani, Iraj Ragerdi

    2018-03-01

    Stromal cell-derived factor-1α (SDF-1α) has been known to implicate in homing of MSCs, and resveratrol has been reported to have a positive influence on SDF-1 level in the site of injury. In this study, a combined strategy was applied to evaluate bone marrow-derived MSCs (BMSCs) homing to the rat model of liver cirrhosis induced by common bile duct ligation (CBDL): (1) pretreatment delivery of resveratrol into the cirrhotic liver, and (2) transplantation of ex vivo BMSC preconditioning with SDF-1α. BMSCs were preconditioned with 10 ng/µL SDF-1α for 1 h and then labeled with the CM-Dil. Cirrhosis was induced by CBDL. Animals received intraperitoneal injection of resveratrol for 7 days, started on day 28 of CBDL post-operative. On day 36 post-operative, 1 × 10 6 of SDF-1α-preconditioned BMSCs was injected via caudal vein. Animals were sacrificed at 72 h post-cell transplantation. Immunofluorescence and flow cytometry assessments showed that the BMSC+SDF+RV group had an increased rate of homing into the liver, but it had a decreased rate of homing into the lung and spleen, as compared with the other groups (P SDF+RV group showed high protein expression of SIRT1, but low protein expression of p53 in the liver (P SDF-1α-preconditioned BMSCs in vitro, and that AKTs and CXCL12 expressed in injured liver undergoing resveratrol injection. Our findings suggest that reseveratrol pretreatment prior to SDF-1α preconditioning could be a promising strategy for designing cell-based therapies for liver cirrhosis. © 2017 Wiley Periodicals, Inc.

  13. Angiogenic Capacity of Dental Pulp Stem Cell Regulated by SDF-1α-CXCR4 Axis

    Science.gov (United States)

    Nam, Hyun; Kim, Gee-Hye; Bae, Yoon-Kyung; Jeong, Da-Eun

    2017-01-01

    Previously, the perivascular characteristics of dental pulp stem cells (DPSCs) were reported, which suggested the potential application of DPSCs as perivascular cell source. In this study, we investigated whether DPSCs had angiogenic capacity by coinjection with human umbilical vein endothelial cells (HUVECs) in vivo; in addition, we determined the role of stromal cell-derived factor 1-α (SDF-1α) and C-X-C chemokine receptor type 4 (CXCR4) axis in the mutual interaction between DPSCs and HUVECs. Primarily isolated DPSCs showed mesenchymal stem cell- (MSC-) like characteristics. Moreover, DPSCs expressed perivascular markers such as NG2, α-smooth muscle actin (α-SMA), platelet-derived growth factor receptor β (PDGFRβ), and CD146. In vivo angiogenic capacity of DPSCs was demonstrated by in vivo Matrigel plug assay. We could observe microvessel-like structures in the coinjection of DPSCs and HUVECs at 7 days postinjection. To block SDF-1α and CXCR4 axis between DPSCs and HUVECs, AMD3100, a CXCR4 antagonist, was added into Matrigel plug. No significant microvessel-like structures were observed at 7 days postinjection. In conclusion, DPSCs have perivascular characteristics that contribute to in vivo angiogenesis. The findings of this study have potential applications in neovascularization of engineered tissues and vascular diseases. PMID:28588623

  14. Angiogenic Capacity of Dental Pulp Stem Cell Regulated by SDF-1α-CXCR4 Axis

    Directory of Open Access Journals (Sweden)

    Hyun Nam

    2017-01-01

    Full Text Available Previously, the perivascular characteristics of dental pulp stem cells (DPSCs were reported, which suggested the potential application of DPSCs as perivascular cell source. In this study, we investigated whether DPSCs had angiogenic capacity by coinjection with human umbilical vein endothelial cells (HUVECs in vivo; in addition, we determined the role of stromal cell-derived factor 1-α (SDF-1α and C-X-C chemokine receptor type 4 (CXCR4 axis in the mutual interaction between DPSCs and HUVECs. Primarily isolated DPSCs showed mesenchymal stem cell- (MSC- like characteristics. Moreover, DPSCs expressed perivascular markers such as NG2, α-smooth muscle actin (α-SMA, platelet-derived growth factor receptor β (PDGFRβ, and CD146. In vivo angiogenic capacity of DPSCs was demonstrated by in vivo Matrigel plug assay. We could observe microvessel-like structures in the coinjection of DPSCs and HUVECs at 7 days postinjection. To block SDF-1α and CXCR4 axis between DPSCs and HUVECs, AMD3100, a CXCR4 antagonist, was added into Matrigel plug. No significant microvessel-like structures were observed at 7 days postinjection. In conclusion, DPSCs have perivascular characteristics that contribute to in vivo angiogenesis. The findings of this study have potential applications in neovascularization of engineered tissues and vascular diseases.

  15. Mifepristone inhibits ovarian cancer metastasis by intervening in SDF-1/CXCR4 chemokine axis.

    Science.gov (United States)

    Zheng, Ning; Chen, Jiahang; Liu, Weiqun; Liu, Jian; Li, Tao; Chen, Hongning; Wang, Jichuang; Jia, Lee

    2017-08-29

    SDF-1/CXCR4 signaling axis determines the proliferative potential and site-specific cancer metastasis. Recent studies suggest involvement of the axis and steroidal hormone in ovarian cancer metastasis. Here we hypothesize that mifepristone (RU486), a well-known progesterone-based abortifacient, might interfere this axis and inhibit ovarian cancer metastasis. Mifepristone at concentrations SDF-1. SDF-1 significantly stimulated proliferation of SKOV-3 and IGROV-1 cells with concomitant increases in intracellular phosphorylation of Akt and ERK. SDF-1 activated cell chemotatic migration and actin polymerization, and up-regulated expression of MMP-2, MMP-9, COX-2, VEGF without influencing the adhesion molecules ICAM-1 and integrins β1, α1, α3, α5, and α6. The above-mentioned effects of SDF-1 could be antagonized by mifepristone concentration-dependently, and CXCR4 antagonist AMD3100. Mifepristone suppressed the SDF-1-induced migration, invasion and adhesion of the cancer cells to extracellular matrixes. Three-day pretreatment of nude mice with mifepristone (5 and 20 mg/kg/day) followed by a single intraperitoneal IGROV-1 inoculation, along with repeated SDF-1 and mifepristone administrations in turn every other day for 36 days significantly reduced ascitic fluid, metastatic foci, tumor weight and immunoreactivity of CXCR4 in comparison with the SDF-1-treated control. Our results suggest that mifepristone inhibit SDF-1/CXCR4 signaling axis, may have preventive and therapeutic effects on ovarian cancer metastasis.

  16. SDF-1α in Glycan Nanoparticles Exhibits Full Activity and Reduces Pulmonary Hypertension in Rats

    Science.gov (United States)

    Yin, Tao; Bader, Andrew R.; Hou, Tim K.; Maron, Bradley A.; Kao, Derrick D.; Qian, Ray; Kohane, Daniel S.; Handy, Diane E.; Loscalzo, Joseph; Zhang, Ying-Yi

    2013-01-01

    In order to establish a homing signal in the lung to recruit circulating stem cells for tissue repair, we formulated a nanoparticle, SDF-1α NP, by complexing SDF-1α with dextran sulfate and chitosan. The data show that SDF-1α was barely released from the nanoparticles over an extended period of time in vitro (3% in 7 days at 37°C); however, incorporated SDF-1α exhibited full chemotactic activity and receptor activation compared to its free form. The nanoparticles were not endocytosed after incubation with Jurkat cells. When aerosolized into the lungs of rats, SDF-1α NP displayed a greater retention time compared to free SDF-1α (64% vs. 2% remaining at 16 hr). In a rat model of monocrotaline-induced lung injury, SDF-1α NP, but not free form SDF-1α, was found to reduce pulmonary hypertension. These data suggest that the nanoparticle formulation protected SDF-1α from rapid clearance in the lung and sustained its biological function in vivo. PMID:24059347

  17. DIPEPTIDYL PEPTIDASE-4 REGULATION OF SDF-1/CXCR4 AXIS: IMPLICATIONS FOR CARDIOVASCULAR DISEASE

    Directory of Open Access Journals (Sweden)

    Jixin eZhong

    2015-09-01

    Full Text Available Dipeptidyl peptidase-4 (DPP4 is a ubiquitously expressed protease that regulates a diverse number of physiologic functions. As a dipeptidase it exerts its catalytic effects on proteins/peptides with proline, alanine or serine in the penultimate (P1 amino acid residue from the amino terminus. The evidence to date supports an important effect of DPP4 in catalytic cleavage of incretin peptides and this perhaps represents the main mechanism by which DPP4 inhibition improves glycemic control. DPP4 also plays an important role in the degradation of multiple chemokines of which such as stromal-cell-derived factor-1 (SDF-1, also known as CXCL12 is perhaps an increasingly recognized target, given its importance in processes such as hematopoiesis, angiogenesis and stem cell homing. In the current review, we will summarize the importance of DPP4-mediated enzymatic processing of cytokines/chemokines with an emphasis on SDF-1 and resultant implications for cardiovascular physiology and disease.

  18. Mesenchymal stem cell expression of SDF-1β synergizes with BMP-2 to augment cell-mediated healing of critical-sized mouse calvarial defects.

    Science.gov (United States)

    Herberg, Samuel; Aguilar-Perez, Alexandra; Howie, R Nicole; Kondrikova, Galina; Periyasamy-Thandavan, Sudharsan; Elsalanty, Mohammed E; Shi, Xingming; Hill, William D; Cray, James J

    2017-06-01

    Bone has the potential for spontaneous healing. This process, however, often fails in patients with comorbidities. Tissue engineering combining functional cells, biomaterials and osteoinductive cues may provide alternative treatment strategies. We have recently demonstrated that stromal cell-derived factor-1β (SDF-1β) works in concert with bone morphogenetic protein-2 (BMP-2) to potentiate osteogenic differentiation of bone marrow-derived mesenchymal stem/stromal cells (BMSCs). Here, we test the hypothesis that SDF-1β overexpressed in Tet-Off-SDF-1β BMSCs, delivered on acellular dermal matrix (ADM), synergistically augments BMP-2-induced healing of critical-sized mouse calvarial defects. BMSC therapies alone showed limited bone healing, which was increased with co-delivery of BMP-2. This was further enhanced in Tet-Off-SDF-1β BMSCs + BMP-2. Only limited BMSC retention on ADM constructs was observed after 4 weeks in vivo, which was increased with BMP-2 co-delivery. In vitro cell proliferation studies showed that supplementing BMP-2 to Tet-Off BMSCs significantly increased the cell number during the first 24 h. Consequently, the increased cell numbers decreased the detectable BMP-2 levels in the medium, but increased cell-associated BMP-2. The data suggest that SDF-1β provides synergistic effects supporting BMP-2-induced, BMSC-mediated bone formation and appears suitable for optimization of bone augmentation in combination therapy protocols. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

  19. Development of a non-toxic and non-denaturing formulation process for encapsulation of SDF-1α into PLGA/PEG-PLGA nanoparticles to achieve sustained release.

    Science.gov (United States)

    Haji Mansor, Muhammad; Najberg, Mathie; Contini, Aurélien; Alvarez-Lorenzo, Carmen; Garcion, Emmanuel; Jérôme, Christine; Boury, Frank

    2018-04-01

    Chemokines are known to stimulate directed migration of cancer cells. Therefore, the strategy involving gradual chemokine release from polymeric vehicles for trapping cancer cells is of interest. In this work, the chemokine stromal cell-derived factor-1α (SDF-1α) was encapsulated into nanoparticles composed of poly-(lactic-co-glycolic acid) (PLGA) and a polyethylene glycol (PEG)-PLGA co-polymer to achieve sustained release. SDF-1α, and lysozyme as a model protein, were firstly precipitated to promote their stability upon encapsulation. A novel phase separation method utilising a non-toxic solvent in the form of isosorbide dimethyl ether was developed for the individual encapsulation of SDF-1α and lysozyme precipitates. Uniform nanoparticles of 200-250 nm in size with spherical morphologies were successfully synthesised under mild formulation conditions and conveniently freeze-dried in the presence of hydroxypropyl-β-cyclodextrin as a stabiliser. The effect of PLGA carboxylic acid terminal capping on protein encapsulation efficiency and release rate was also explored. Following optimisation, sustained release of SDF-1α was achieved over a period of 72 h. Importantly, the novel encapsulation process was found to induce negligible protein denaturation. The obtained SDF-1α nanocarriers may be subsequently incorporated within a hydrogel or other scaffolds to establish a chemokine concentration gradient for the trapping of glioblastoma cells. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Critical role of SDF-1/CXCR4 signaling pathway in stem cell homing in the deafened rat cochlea after acoustic trauma.

    Science.gov (United States)

    Peyvandi, Ali Asghar; Roozbahany, Navid Ahmady; Peyvandi, Hassan; Abbaszadeh, Hojjat-Allah; Majdinasab, Niloofar; Faridan, Mohammad; Niknazar, Somayeh

    2018-01-01

    Previous animal studies have shown that stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor-4 (CXCR4) signaling pathway plays an important role in the targeted migration of bone marrow-derived mesenchymal stem cells (BMSCs) to the injured area. In the present study, we aimed to investigate the potential role of chemotactic SDF-1/CXCR4 signaling pathway in the homing of transplanted BMSCs to the injured cochlea after noise-induced hearing loss (NIHL) in a rat model. White noise exposure (110 dB) paradigm was used for hearing loss induction in male rats for 6 hours in 5 days. Distortion-product otoacoustic emission (DPOAE) responses were recorded before the experiment and post noise exposure. Hoechst 33342-labeled BMSCs and CXCR4 antagonist (AMD3100)-treated BMSCs were injected into the rat cochlea through the round window. SDF-1 protein expression in the cochlear tissue was assayed using western blot assay. The number of labeled BMSCs reaching the endolymph was determined after 24 hours. SDF-1 was significantly increased in the cochlear tissue of rats in the noise exposure group than in the control group. The number of Hoechst 33342-labeled BMSCs reaching the endolymph of the cochlea was significantly smaller in the AMD3100-treated BMSCs group than in the normal BMSCs group. Our present findings suggest that the SDF-1/CXCR4 signaling pathway has a critical role in BMSCs migration to the injured cochlea in a rat model of noise-induced hearing loss.

  1. Role of SDF-1 (CXCL12) in regulating hematopoietic stem and progenitor cells traffic into the liver during extramedullary hematopoiesis induced by G-CSF, AMD3100 and PHZ.

    Science.gov (United States)

    Mendt, Mayela; Cardier, Jose E

    2015-12-01

    The stromal cell derived factor 1 (SDF-1/CXCL12) plays an essential role in the homing of hematopoietic stem and progenitor cells (HSPCs) to bone marrow (BM). It is not known whether SDF-1 may also regulate the homing of HSPCs to the liver during extramedullary hematopoiesis (EMH). Here, we investigated the possible role of SDF-1 in attracting HSPCs to the liver during experimental EMH induced by the hematopoietic mobilizers G-CSF, AMD3100 and phenylhydrazine (PHZ). Mice treated with G-CSF, AMD3100 and PHZ showed a significant increase in the expression of SDF-1 in the liver sinusoidal endothelial cells (LSECs) microenvironments. Liver from mice treated with the hematopoietic mobilizers showed HSPCs located adjacent to the LSEC microenvironments, expressing high levels of SDF-1. An inverse relationship was found between the hepatic SDF-1 levels and those in the BM. In vitro, LSEC monolayers induced the migration of HSPCs, and this effect was significantly reduced by AMD3100. In conclusion, our results provide the first evidence showing that SDF-1 expressed by LSEC can be a major player in the recruitment of HSPCs to the liver during EMH induced by hematopoietic mobilizers. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. CXCL12/SDF-1 over-expression in human insulinomas and its biological relevance

    DEFF Research Database (Denmark)

    Ilhan, Aysegul; Nabokikh, Anastasiya; Maj, Magdalena

    2009-01-01

    This study was performed on the basis of previously obtained investigative gene array data concerning the over-expression of CXCL12/SDF-1 in human insulinomas versus human pancreatic islet preparations. The presence of CXCL12/SDF-1 was studied by RT-qPCR in human insulinomas (n=8) versus pancreatic...

  3. SDF-1/CXCR4 expression in head and neck cancer and outcome after postoperative radiochemotherapy

    Directory of Open Access Journals (Sweden)

    Chiara De-Colle

    2017-08-01

    Conclusions: Our exploratory data support the hypothesis that overexpression of intracellular SDF-1 is an independent negative prognostic biomarker for LRC after postoperative RT-CT in high-risk HNSCC. Prospective validation is warranted and further exploration of SDF-1/CXCR4 as a potential therapeutic target to overcome treatment resistance in HNSCC appears promising.

  4. The SDF-1α/CXCR4 Axis is Required for Proliferation and Maturation of Human Fetal Pancreatic Endocrine Progenitor Cells

    Science.gov (United States)

    Kayali, Ayse G.; Lopez, Ana D.; Hao, Ergeng; Hinton, Andrew; Hayek, Alberto; King, Charles C.

    2012-01-01

    The chemokine receptor CXCR4 and ligand SDF-1α are expressed in fetal and adult mouse islets. Neutralization of CXCR4 has previously been shown to diminish ductal cell proliferation and increase apoptosis in the IFNγ transgenic mouse model in which the adult mouse pancreas displays islet regeneration. Here, we demonstrate that CXCR4 and SDF-1α are expressed in the human fetal pancreas and that during early gestation, CXCR4 colocalizes with neurogenin 3 (ngn3), a key transcription factor for endocrine specification in the pancreas. Treatment of islet like clusters (ICCs) derived from human fetal pancreas with SDF-1α resulted in increased proliferation of epithelial cells in ICCs without a concomitant increase in total insulin expression. Exposure of ICCs in vitro to AMD3100, a pharmacological inhibitor of CXCR4, did not alter expression of endocrine hormones insulin and glucagon, or the pancreatic endocrine transcription factors PDX1, Nkx6.1, Ngn3 and PAX4. However, a strong inhibition of β cell genesis was observed when in vitro AMD3100 treatment of ICCs was followed by two weeks of in vivo treatment with AMD3100 after ICC transplantation into mice. Analysis of the grafts for human C-peptide found that inhibition of CXCR4 activity profoundly inhibits islet development. Subsequently, a model pancreatic epithelial cell system (CFPAC-1) was employed to study the signals that regulate proliferation and apoptosis by the SDF-1α/CXCR4 axis. From a selected panel of inhibitors tested, both the PI 3-kinase and MAPK pathways were identified as critical regulators of CFPAC-1 proliferation. SDF-1α stimulated Akt phosphorylation, but failed to increase phosphorylation of Erk above the high basal levels observed. Taken together, these results indicate that SDF-1α/CXCR4 axis plays a critical regulatory role in the genesis of human islets. PMID:22761699

  5. Association of platelet-SDF-1 with hemodynamic function and infarct size using cardiac MR in patients with AMI

    International Nuclear Information System (INIS)

    Geisler, Tobias; Fekecs, Lisa; Wurster, Thomas; Chiribiri, Amedeo; Schuster, Andreas; Nagel, Eike; Miller, Stephan; Gawaz, Meinrad; Stellos, Konstantinos; Bigalke, Boris

    2012-01-01

    Purpose: Platelet-derived stromal-cell-derived factor-1 (SDF-1) plays an important role in trafficking hematopoetic progenitor cells for tissue regeneration and neovascularisation. The aim was to evaluate platelet-SDF-1 and CD34 + progenitor cells in patients with acute myocardial infarction (AMI) compared with hemodynamic function and infarct size using late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) imaging. Materials and methods: We consecutively evaluated 40 patients with AMI, who received coronary angiography for primary coronary intervention. Blood was sampled for flow cytometry to determine mean fluorescence intensity (MFI) of platelet-SDF-1 and for isolation of CD34 + progenitor cells. 48 h and three months after coronary stenting, all patients underwent 1.5 T CMR for volumetric assessment and LGE. Results: Patients with enhanced platelet-SDF-1 expression (median ≥ 68.5 MFI) showed a significant amelioration of left ventricular ejection fraction (LVEF) (baseline vs. follow-up mean ± SD: 45 ± 6% vs. 56 ± 6%; P = 0.018) and of stroke volume (73.1 ± 19.1 mL vs. 89.9 ± 21.3 mL; P = 0.032) at three-month follow-up in contrast to patients with a decreased platelet-SDF-1 expression level (LVEF: 53 ± 8% vs. 56 ± 10%; P = 0.267; stroke volume: 85.6 ± 23.1 mL vs. 87.4 ± 23.2 mL; P = 0.803). Inversely, LGE infarct size showed significantly reduced in patients with enhanced platelet-SDF-1 expression at three months (18.9 ± 12 mL vs. 6.3 ± 5.1 mL; P = 0.002) compared to patients with decreased platelet-SDF-1 (12.7 ± 12.7 mL vs. 7.6 ± 8.4 mL; P = 0.156). Time-dependent autocorrelation coefficients shifted for both SV (lag 1: r = −0.368; P = 0.001) and the number of CD34 + cells (lag 1: r = 0.633; P = 0.001) to a positive autocorrelation (SV; lag 2: r = 0.295; P = 0.001; CD34 + cells; lag 2: r = 0.287; P = 0.001). Patients with increased number of CD34 + cells (median ≥ 420 cells/hpf) showed a significant amelioration of stroke volume

  6. Injectable hydrogel delivery plus preconditioning of mesenchymal stem cells: exploitation of SDF-1/CXCR4 axis toward enhancing the efficacy of stem cells' homing.

    Science.gov (United States)

    Naderi-Meshkin, Hojjat; Matin, Maryam M; Heirani-Tabasi, Asieh; Mirahmadi, Mahdi; Irfan-Maqsood, Muhammad; Edalatmanesh, Mohmmad Amin; Shahriyari, Mina; Ahmadiankia, Naghmeh; Moussavi, Nasser Sanjar; Bidkhori, Hamid Reza; Bahrami, Ahmad Reza

    2016-07-01

    Clinical applications of mesenchymal stem cells (MSCs) rely on their capacity to home and engraft in the appropriate target injury tissues for the long term. However, their homing efficiency has been observed to be very poor because of the lack or modifications of homing factors SDF-1α and CXCR4 receptors. Hence, this study was designed to investigate the homing and retention of pretreated human adipose tissue-derived MSCs (hASCs) from three different delivery routes in response to SDF-1α, released from chitosan-based injectable hydrogels. After stimulation of ASCs with a hypoxia mimicking agent, the expression level and functionality of CXCR4 were analyzed by flowcytometric analysis (FACS), transwell migration assay and qPCR. Then, the homing/retention of pretreated DiI-labeled hASCs were compared through three different in vivo delivery routes, 2 weeks after transplantation in Wistar rats. The cells were tracked histologically by fluorescent microscope and by PCR for human-specific CXCR4 gene. Results showed CXCR4 has dynamic expression pattern and pretreatment of hASCs significantly up-regulates CXCR4, leading to an increase in migration capacity toward 100 ng/mL SDF-1α in vitro and homing into the subcutaneously implanted hydrogel releasing SDF-1α in vivo. Furthermore, it seems that SDF-1α is particularly important in the retention of ASCs, in addition to its chemoattraction role. In summary, the delivery route in which the ASCs were mixed with the hydrogel rather than systemic delivery and local injection and preconditioning undertaken to increase CXCR4 expression concomitant with SDF-1α delivery by the injectable hydrogel, allowed for further homing/retention of ASCs. This might be a promising way to get better therapeutic outcomes in stem cell therapy. © 2015 International Federation for Cell Biology.

  7. A new method of wound treatment: targeted therapy of skin wounds with reactive oxygen species-responsive nanoparticles containing SDF-1α

    Science.gov (United States)

    Tang, Tao; Jiang, Hao; Yu, Yuan; He, Fang; Ji, Shi-zhao; Liu, Ying-ying; Wang, Zhong-shan; Xiao, Shi-chu; Tang, Cui; Wang, Guang-Yi; Xia, Zhao-Fan

    2015-01-01

    Objective To accelerate wound healing through promoting vascularization by using reactive oxygen species (ROS)-responsive nanoparticles loaded with stromal cell-derived factor-1α(SDF-1α). Methods The ROS-reactive nanomaterial poly-(1,4-phenyleneacetone dimethylene thioketal) was synthesized, and its physical and chemical properties were characterized. ROS-responsive nanoparticles containing SDF-1α were prepared through a multiple emulsion solvent evaporation method. The loading capacity, stability, activity of the encapsulated protein, toxicity, and in vivo distribution of these nanoparticles were determined. These nanoparticles were administered by intravenous infusion to mice with full-thickness skin defects to study their effects on the directed chemotaxis of bone marrow mesenchymal stem cells, wound vascularization, and wound healing. Results The synthesized ROS-reactive organic polymer poly-(1,4-phenyleneacetone dimethylene thioketal) possessed a molecular weight of approximately 11.5 kDa with a dispersity of 1.97. ROS-responsive nanoparticles containing SDF-1α were prepared with an average diameter of 110 nm and a drug loading capacity of 1.8%. The encapsulation process showed minimal effects on the activity of SDF-1α, and it could be effectively released from the nanoparticles in the presence of ROS. Encapsulated SDF-1α could exist for a long time in blood. In mice with full-thickness skin defects, SDF-1α was effectively released and targeted to the wounds, thus promoting the chemotaxis of bone marrow mesenchymal stem cells toward the wound and its periphery, inducing wound vascularization, and accelerating wound healing. PMID:26527874

  8. SDF-1α/CXCR4 Axis Mediates The Migration of Mesenchymal Stem Cells to The Hypoxic-Ischemic Brain Lesion in A Rat Model.

    Science.gov (United States)

    Yu, Qin; Liu, Lizhen; Lin, Jie; Wang, Yan; Xuan, Xiaobo; Guo, Ying; Hu, Shaojun

    2015-01-01

    Transplantation of mesenchymal stem cells (MSCs) can promote functional recovery of the brain after hypoxic-ischemic brain damage (HIBD). However, the mechanism regulating MSC migration to a hypoxic-ischemic lesion is poorly understood. Interaction between stromal cell-derived factor-1α (SDF-1α) and its cognate receptor CXC chemokine receptor 4 (CXCR4) is crucial for homing and migration of multiple stem cell types. In this study, we investigate the potential role of SDF-1α/CXCR4 axis in mediating MSC migration in an HIBD model. In this experimental study, we first established the animal model of HIBD using the neonatal rat. Bone marrow MSCs were cultured and labeled with 5-bromo-21-deoxyuridine (BrdU) after which 6×10(6) cells were intravenously injected into the rat. BrdU positive MSCs in the hippocampus were detected by immunohistochemical analyses. The expression of hypoxia-inducible factor-1α (HIF-1α) and SDF-1α in the hippocampus of hypoxic-ischemic rats was detected by Western blotting. To investigate the role of hypoxia and SDF-1α on migration of MSCs in vitro, MSCs isolated from normal rats were cultured in a hypoxic environment (PO2=1%). Migration of MSCs was detected by the transwell assay. The expression of CXCR4 was tested using Western blotting and flow cytometry. BrdU-labeled MSCs were found in the rat brain, which suggested that transplanted MSCs migrated to the site of the hypoxic-ischemic brain tissue. HIF-1α and SDF-1α significantly increased in the hippocampal formations of HIBD rats in a time-dependent manner. They peaked on day 7 and were stably expressed until day 21. Migration of MSCs in vitro was promoted by SDF-1α under hypoxia and inhibited by the CXCR4 inhibitor AMD3100. The expression of CXCR4 on MSCs was elevated by hypoxia stimulation as well as microdosage treatment of SDF-1α. This observation illustrates that SDF-1α/CXCR4 axis mediate the migration of MSCs to a hypoxic-ischemic brain lesion in a rat model.

  9. Caloric restriction and the adipokine leptin alter the SDF-1 signaling axis in bone marrow and in bone marrow derived mesenchymal stem cells.

    Science.gov (United States)

    Periyasamy-Thandavan, Sudharsan; Herberg, Samuel; Arounleut, Phonepasong; Upadhyay, Sunil; Dukes, Amy; Davis, Colleen; Johnson, Maribeth; McGee-Lawrence, Meghan; Hamrick, Mark W; Isales, Carlos M; Hill, William D

    2015-07-15

    Growing evidence suggests that the chemokine stromal cell-derived factor-1 (SDF-1) is essential in regulating bone marrow (BM) derived mesenchymal stromal/stem cell (BMSC) survival, and differentiation to either a pro-osteogenic or pro-adipogenic fate. This study investigates the effects of caloric restriction (CR) and leptin on the SDF-1/CXCR4 axis in bone and BM tissues in the context of age-associated bone loss. For in vivo studies, we collected bone, BM cells and BM interstitial fluid from 12 and 20 month-old C57Bl6 mice fed ad-libitum (AL), and 20-month-old mice on long-term CR with, or without, intraperitoneal injection of leptin for 10 days (10 mg/kg). To mimic conditions of CR in vitro, 18 month murine BMSCs were treated with (1) control (Ctrl): normal proliferation medium, (2) nutrient restriction (NR): low glucose, low serum medium, or (3) NR + leptin: NR medium + 100 ng/ml leptin for 6-48 h. In BMSCs both protein and mRNA expression of SDF-1 and CXCR4 were increased by CR and CR + leptin. In contrast, the alternate SDF-1 receptor CXCR7 was decreased, suggesting a nutrient signaling mediated change in SDF-1 axis signaling in BMSCs. However, in bone SDF-1, CXCR4 and 7 gene expression increase with age and this is reversed with CR, while addition of leptin returns this to the "aged" level. Histologically bone formation was lower in the calorically restricted mice and BM adipogenesis increased, both effects were reversed with the 10 day leptin treatment. This suggests that in bone CR and leptin alter the nutrient signaling pathways in different ways to affect the local action of the osteogenic cytokine SDF-1. Studies focusing on the molecular interaction between nutrient signaling by CR, leptin and SDF-1 axis may help to address age-related musculoskeletal changes. Published by Elsevier Ireland Ltd.

  10. A Novel Mechanism by Which SDF-1β Protects Cardiac Cells From Palmitate-Induced Endoplasmic Reticulum Stress and Apoptosis via CXCR7 and AMPK/p38 MAPK-Mediated Interleukin-6 Generation

    Science.gov (United States)

    Zhao, Yuguang; Tan, Yi; Xi, Shugang; Li, Yunqian; Li, Cai; Cui, Jiuwei; Yan, Xiaoqing; Li, Xiaokun; Wang, Guanjun; Li, Wei; Cai, Lu

    2013-01-01

    We studied the protective effect of stromal cell-derived factor-1β (SDF-1β) on cardiac cells from lipotoxicity in vitro and diabetes in vivo. Exposure of cardiac cells to palmitate increased apoptosis by activating NADPH oxidase (NOX)–associated nitrosative stress and endoplasmic reticulum (ER) stress, which was abolished by pretreatment with SDF-1β via upregulation of AMP-activated protein kinase (AMPK)–mediated p38 mitogen-activated protein kinase (MAPK) phosphorylation and interleukin-6 (IL-6) production. The SDF-1β cardiac protection could be abolished by inhibition of AMPK, p38 MAPK, or IL-6. Activation of AMPK or addition of recombinant IL-6 recaptured a similar cardiac protection. SDF-1β receptor C-X-C chemokine receptor type 4 (CXCR4) antagonist AMD3100 or CXCR4 small interfering RNA could not, but CXCR7 small interfering RNA completely abolished SDF-1β’s protection from palmitate-induced apoptosis and activation of AMPK and p38 MAPK. Administration of SDF-1β to diabetic rats, induced by feeding a high-fat diet, followed by a small dose of streptozotocin, could significantly reduce cardiac apoptosis and increase AMPK phosphorylation along with prevention of diabetes-induced cardiac oxidative damage, inflammation, hypertrophy, and remodeling. These results showed that SDF-1β protects against palmitate-induced cardiac apoptosis, which is mediated by NOX-activated nitrosative damage and ER stress, via CXCR7, to activate AMPK/p38 MAPK–mediated IL-6 generation. The cardiac protection by SDF-1β from diabetes-induced oxidative damage, cell death, and remodeling was also associated with AMPK activation. PMID:23423573

  11. Stichopus japonicus Polysaccharide, Fucoidan, or Heparin Enhanced the SDF-1α/CXCR4 Axis and Promoted NSC Migration via Activation of the PI3K/Akt/FOXO3a Signaling Pathway.

    Science.gov (United States)

    Cui, Chao; Wang, Peng; Cui, Ningshan; Song, Shuliang; Liang, Hao; Ji, Aiguo

    2016-11-01

    Stichopus japonicus Polysaccharide (SJP) is a sulfated polysaccharide from the body wall of the sea cucumber, Stichopus japonicus. Fucoidan is a heparinoid compound that belongs to a family of sulfated polyfucose polysaccharides. Heparin is a glycosaminoglycan. SJP, fucoidan, and heparin profoundly promoted stromal cell-derived factor 1 alpha (SDF-1α)-induced neural stem cell (NSC) migration in a concentration-dependent manner. In addition, the basal migration capacity of cells was significantly promoted after incubation with SJP, fucoidan, or heparin. Interaction of SJP, fucoidan, or heparin with SDF-1α efficiently showed additive effects on the promotion of cell migration from the neurosphere. SJP, fucoidan, or heparin interaction with SDF-1α treatment could increase Nestin expression. SDF-1α modulated by SJP, fucoidan, or heparin activated the CXCR4 receptor and directed cellular migration via the activation of the PI3K/Akt/FOXO3a signaling pathway. Moreover, interaction of SJP, fucoidan, or heparin with SDF-1α effectively promoted NSC migration and induced SDF-1α and CXCR4 expressions. Results suggested that SJP, fucoidan, and heparin might be good candidates for alleviating injury-initiated signals to which NSCs respond.

  12. Inkjet-based biopatterning of SDF-1β augments BMP-2-induced repair of critical size calvarial bone defects in mice.

    Science.gov (United States)

    Herberg, Samuel; Kondrikova, Galina; Periyasamy-Thandavan, Sudharsan; Howie, R Nicole; Elsalanty, Mohammed E; Weiss, Lee; Campbell, Phil; Hill, William D; Cray, James J

    2014-10-01

    A major problem in craniofacial surgery is non-healing bone defects. Autologous reconstruction remains the standard of care for these cases. Bone morphogenetic protein-2 (BMP-2) therapy has proven its clinical utility, although non-targeted adverse events occur due to the high milligram-level doses used. Ongoing efforts explore the use of different growth factors, cytokines, or chemokines, as well as co-therapy to augment healing. Here we utilize inkjet-based biopatterning to load acellular DermaMatrix delivery matrices with nanogram-level doses of BMP-2, stromal cell-derived factor-1β (SDF-1β), transforming growth factor-β1 (TGF-β1), or co-therapies thereof. We tested the hypothesis that bioprinted SDF-1β co-delivery enhances BMP-2 and TGF-β1-driven osteogenesis both in-vitro and in-vivo using a mouse calvarial critical size defect (CSD) model. Our data showed that BMP-2 bioprinted in low-doses induced significant new bone formation by four weeks post-operation. TGF-β1 was less effective compared to BMP-2, and SDF-1β therapy did not enhance osteogenesis above control levels. However, co-delivery of BMP-2+SDF-1β was shown to augment BMP-2-induced bone formation compared to BMP-2 alone. In contrast, co-delivery of TGF-β1+SDF-1β decreased bone healing compared to TGF-β1 alone. This was further confirmed in vitro by osteogenic differentiation studies using MC3T3-E1 pre-osteoblasts. Our data indicates that sustained release delivery of a low-dose growth factor therapy using biopatterning technology can aid in healing CSD injuries. SDF-1β augments the ability for BMP-2 to drive healing, a result confirmed in vivo and in vitro; however, because SDF-1β is detrimental to TGF-β1-driven osteogenesis, its effect on osteogenesis is not universal. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. In-situ tissue regeneration through SDF-1α driven cell recruitment and stiffness-mediated bone regeneration in a critical-sized segmental femoral defect.

    Science.gov (United States)

    Cipitria, Amaia; Boettcher, Kathrin; Schoenhals, Sophia; Garske, Daniela S; Schmidt-Bleek, Katharina; Ellinghaus, Agnes; Dienelt, Anke; Peters, Anja; Mehta, Manav; Madl, Christopher M; Huebsch, Nathaniel; Mooney, David J; Duda, Georg N

    2017-09-15

    In-situ tissue regeneration aims to utilize the body's endogenous healing capacity through the recruitment of host stem or progenitor cells to an injury site. Stromal cell-derived factor-1α (SDF-1α) is widely discussed as a potent chemoattractant. Here we use a cell-free biomaterial-based approach to (i) deliver SDF-1α for the recruitment of endogenous bone marrow-derived stromal cells (BMSC) into a critical-sized segmental femoral defect in rats and to (ii) induce hydrogel stiffness-mediated osteogenic differentiation in-vivo. Ionically crosslinked alginate hydrogels with a stiffness optimized for osteogenic differentiation were used. Fast-degrading porogens were incorporated to impart a macroporous architecture that facilitates host cell invasion. Endogenous cell recruitment to the defect site was successfully triggered through the controlled release of SDF-1α. A trend for increased bone volume fraction (BV/TV) and a significantly higher bone mineral density (BMD) were observed for gels loaded with SDF-1α, compared to empty gels at two weeks. A trend was also observed, albeit not statistically significant, towards matrix stiffness influencing BV/TV and BMD at two weeks. However, over a six week time-frame, these effects were insufficient for bone bridging of a segmental femoral defect. While mechanical cues combined with ex-vivo cell encapsulation have been shown to have an effect in the regeneration of less demanding in-vivo models, such as cranial defects of nude rats, they are not sufficient for a SDF-1α mediated in-situ regeneration approach in segmental femoral defects of immunocompetent rats, suggesting that additional osteogenic cues may also be required. Stromal cell-derived factor-1α (SDF-1α) is a chemoattractant used to recruit host cells for tissue regeneration. The concept that matrix stiffness can direct mesenchymal stromal cell (MSC) differentiation into various lineages was described a decade ago using in-vitro experiments. Recently

  14. Association of SDF-1 with Metastasis in Breast Cancer Patient at Sanglah Hospital, Bali

    Directory of Open Access Journals (Sweden)

    Kristanto Yuli Yarso

    2016-10-01

    Full Text Available Objectives: More than 24% breast cancer patients came to Sanglah Teaching Hospital with distant metastasis which cause 90% of cancer related death. Distant metastasis is complex process of interaction between tumor cells and its micro environment involving a chemoattractant cytokines which lead circulating tumor cells toward target organs. One of the most common cytokines involved in metastasis of multiple tumor is SDF-1, produces by target organ or tumor cells itselves. However, only few stucy ever evaluate the relationship between its concentrations in tumor tissue with metastasis. Method: A cross sectional analysis study was conducted involving clinical data and paraffin blocks from 46 patients. Samples were grouped into metastasis and non-metastasis group and level of tumor tissue SDF-1 was evaluated by immunohistochemistry method. Numerical conversion was done using modified “Mirisola” technique and statistical analysis was conducted using SPSS 16 software. Results: The overall median expression of SDF-1 was 4.83 in which the median is 4.08±2.25 in non-metastatic group and 5.71±2.61 in metastatic group (p=0.012. In addition, parenchymal carcinoma cell had significantly higher expression of SDF-1 compared with microenvironmental cell both in metastatic group (carcinoma cell vs microenvironment; 4,57+1,91 vs 3,68 +2,06; p=0,004 and non-metastatic group (3,19 +2,29 vs 2,16+1,11; p=0.011. Finally, logistic regression analysis of SDF-1 expression also gave significant result that MBC had significantly higher expression of SDF-1 (p=0.039.  Conclusions: There was significant association between of SDF-1 expression and distant metastasis in breast cancer and majority of SDF was produced by cancer cells

  15. Genotyping of CCR5 gene, CCR2b and SDF1 variants related to HIV-1 infection in Gabonese subjects.

    Science.gov (United States)

    Mombo, Landry Erik; Bisseye, Cyrille; Mickala, Patrick; Ossari, Simon; Makuwa, Maria

    2015-01-01

    Given the magnitude of the HIV epidemic infection, many viral and human factors were analyzed, and the most decisive was the variant CCR5-Δ32. The presence of a low HIV prevalence (1.8%) in Gabon in the 1990s, compared to neighboring countries, represents a paradox that led us to search for viral and human genetic variants in this country. In this study, only variants of coreceptors and chemokines were investigated. Variants of the coding region of the CCR5 gene were analyzed by denaturing gradient gel electrophoresis, and then variants of SDF1 and CCR2b were determined by polymerase chain reaction-restriction fragment length polymorphism. Four rare variants of the CCR5 coreceptor were found, while CCR5-Δ32 and CCR5m303 variants were not found. No association with CCR2b-V64I (17%) and SDF1-3'A (2%) variants was determined in relation to HIV-1 infection in Gabonese patients. The paradox of HIV seroprevalence in Gabon, which ended in the 2000s, was not caused by human genetic variants but rather by environmental factors. © 2015 S. Karger AG, Basel.

  16. SDF-1/CXCR4 expression in head and neck cancer and outcome after postoperative radiochemotherapy.

    Science.gov (United States)

    De-Colle, Chiara; Mönnich, David; Welz, Stefan; Boeke, Simon; Sipos, Bence; Fend, Falko; Mauz, Paul-Stefan; Tinhofer, Inge; Budach, Volker; Jawad, Jehad Abu; Stuschke, Martin; Balermpas, Panagiotis; Rödel, Claus; Grosu, Anca-Ligia; Abdollahi, Amir; Debus, Jürgen; Bayer, Christine; Belka, Claus; Pigorsch, Steffi; Combs, Stephanie E; Lohaus, Fabian; Linge, Annett; Krause, Mechthild; Baumann, Michael; Zips, Daniel; Menegakis, Apostolos

    2017-08-01

    Outcome after postoperative radiochemotherapy (RT-CT) for patients with advanced head and neck squamous cell carcinomas (HNSCC) remains unsatisfactory, especially among those with HPV negative tumours. Therefore, new biomarkers are needed to further define subgroups for individualised therapeutic approaches. Preclinical and first clinical observations showed that the chemokine receptor CXCR4 and its ligand SDF-1 (CXCL12) play an important role in tumour cell proliferation, survival, cancer progression, metastasis and treatment resistance. However, the data on the prognostic value of SDF-1/CXCR4 expression for HNSCC are conflicting. The aim of our hypothesis-generating study was to retrospectively explore the prognostic potential of SDF-1/CXCR4 in a well-defined cohort of HNSCC patients collected within the multicenter biomarker study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG). Patients with stage III and IVA HNSCC of the oral cavity, oropharynx and hypopharynx were treated with resection and adjuvant radiotherapy (RT) with ≥60 Gy and concurrent cisplatin-based chemotherapy (CT). Tissue micro-arrays (TMAs) from a total of 221 patients were generated from surgical specimens, 201 evaluated for the SDF-1 and CXCR4 expression by immunofluorescence and correlated with clinico-pathological and outcome data. In univariate and multivariate analyses intracellular SDF-1 expression was associated with lower loco-regional control (LRC) in the entire patient group as well as in the HPV16 DNA negative subgroup. CXCR4 expression showed a trend for lower LRC in the univariate analysis which was not confirmed in the multivariate analysis. Neither for SDF-1 nor CXCR4 expression associations with distant metastasis free or overall survival were found. Our exploratory data support the hypothesis that overexpression of intracellular SDF-1 is an independent negative prognostic biomarker for LRC after postoperative RT-CT in high-risk HNSCC. Prospective

  17. CXCR4+ CD45- Cells are Niche Forming for Osteoclastogenesis via the SDF-1, CXCL7, and CX3CL1 Signaling Pathways in Bone Marrow.

    Science.gov (United States)

    Goto, Yoh; Aoyama, Mineyoshi; Sekiya, Takeo; Kakita, Hiroki; Waguri-Nagaya, Yuko; Miyazawa, Ken; Asai, Kiyofumi; Goto, Shigemi

    2016-11-01

    Bone homeostasis comprises the balance between bone-forming osteoblasts and bone-resorbing osteoclasts (OCs), with an acceleration of osteoclastic bone resorption leading to osteoporosis. OCs can be generated from bone marrow cells (BMCs) under the tightly regulated local bone environment. However, it remained difficult to identify the critical cells responsible for providing an osteoclastogenesis niche. In this study, we used a fluorescence-activated cell sorting technique to determine the cell populations important for forming an appropriate microenvironment for osteoclastogenesis and to verify the associated interactions between osteoclast precursor cells and non-OCs. We isolated and removed a small cell population specific for osteoclastogenesis (CXCR4 + CD45 - ) from mouse BMCs and cultured the remaining cells with receptor activator of nuclear factor-kappa B ligand (RANKL) and macrophage-colony stimulating factor. The resulting cultures showed significantly less large osteoclast formation. Quantitative RT-PCR analysis revealed that these CXCR4 + CD45 - cells expressed low levels of RANK and RANKL, but high levels of critical chemokines including stromal cell derived factor 1 (SDF-1), chemokine (C-X-C motif) ligand 7 (CXCL7), and chemokine (C-X3-C motif) ligand 1 (CX3CL1). Furthermore, an SDF-1-specific antibody strongly suppressed OC formation in RAW264.7 cells and antibodies against SDF-1, CXCL7, and CX3CL1 suppressed OC formation in BMCs. These results suggest that isolated CXCR4 + CD45 - cells support an appropriate microenvironment for osteoclastogenesis with a direct effect on the cells expressing SDF-1, CXCL7, and CX3CL1 receptors. The regulation of CXCR4 + CD45 - cell function might therefore inform therapeutic strategies for diseases involving loss of bone homeostasis. Stem Cells 2016;34:2733-2743. © 2016 AlphaMed Press.

  18. SDF-1alpha concentration dependent modulation of RhoA and Rac1 modifies breast cancer and stromal cells interaction.

    Science.gov (United States)

    Pasquier, Jennifer; Abu-Kaoud, Nadine; Abdesselem, Houari; Madani, Aisha; Hoarau-Véchot, Jessica; Thawadi, Hamda Al; Vidal, Fabien; Couderc, Bettina; Favre, Gilles; Rafii, Arash

    2015-08-01

    The interaction of SDF-1alpha with its receptor CXCR4 plays a role in the occurrence of distant metastasis in many solid tumors. This interaction increases migration from primary sites as well as homing at distant sites. Here we investigated how SDF-1α could modulate both migration and adhesion of cancer cells through the modulation of RhoGTPases. We show that different concentrations of SDF-1α modulate the balance of adhesion and migration in cancer cells. Increased migration was obtained at 50 and 100 ng/ml of SDF-1α; however migration was reduced at 200 ng/ml. The adhesion between breast cancer cells and BMHC was significantly increased by SDF-1α treatment at 200 ng/ml and reduced using a blocking monoclonal antibody against CXCR4. We showed that at low SDF-1α concentration, RhoA was activated and overexpressed, while at high concentration Rac1 was promoting SDF-1α mediating-cell adhesion. We conclude that SDF-1α concentration modulates migration and adhesion of breast cancer cells, by controlling expression and activation of RhoGTPases.

  19. SDF-1/CXCL12 modulates mitochondrial respiration of immature blood cells in a bi-phasic manner.

    Science.gov (United States)

    Messina-Graham, Steven; Broxmeyer, Hal

    2016-05-01

    SDF-1/CXCL12 is a potent chemokine required for the homing and engraftment of hematopoietic stem and progenitor cells. Previous data from our group has shown that in an SDF-1/CXCL12 transgenic mouse model, lineage(-) Sca-1(+) c-Kit(+) (LSK) bone marrow cells have reduced mitochondrial membrane potential versus wild-type. These results suggested that SDF-1/CXCL12 may function to keep mitochondrial respiration low in immature blood cells in the bone marrow. Low mitochondrial metabolism helps to maintain low levels of reactive oxygen species (ROS), which can influence differentiation. To test whether SDF-1/CXCL12 regulates mitochondrial metabolism, we employed the human leukemia cell line HL-60, that expresses high levels of the SDF-1/CXCL12 receptor, CXCR4, as a model of hematopoietic progenitor cells in vitro. We treated HL-60 cells with SDF-1/CXCL12 for 2 and 24h. Oxygen consumption rates (OCR), mitochondrial-associated ATP production, mitochondrial mass, and mitochondrial membrane potential of HL-60 cells were significantly reduced at 2h and increased at 24h as compared to untreated control cells. These biphasic effects of SDF-1/CXCL12 were reproduced with lineage negative primary mouse bone marrow cells, suggesting a novel function of SDF-1/CXCL12 in modulating mitochondrial respiration by regulating mitochondrial oxidative phosphorylation, ATP production and mitochondrial content. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Hyaluronic acid-laminin hydrogels increase neural stem cell transplant retention and migratory response to SDF-1α.

    Science.gov (United States)

    Addington, C P; Dharmawaj, S; Heffernan, J M; Sirianni, R W; Stabenfeldt, S E

    2017-07-01

    The chemokine SDF-1α plays a critical role in mediating stem cell response to injury and disease and has specifically been shown to mobilize neural progenitor/stem cells (NPSCs) towards sites of neural injury. Current neural transplant paradigms within the brain suffer from low rates of retention and engraftment after injury. Therefore, increasing transplant sensitivity to injury-induced SDF-1α represents a method for increasing neural transplant efficacy. Previously, we have reported on a hyaluronic acid-laminin based hydrogel (HA-Lm gel) that increases NPSC expression of SDF-1α receptor, CXCR4, and subsequently, NPSC chemotactic migration towards a source of SDF-1α in vitro. The study presented here investigates the capacity of the HA-Lm gel to promote NPSC response to exogenous SDF-1α in vivo. We observed the HA-Lm gel to significantly increase NPSC transplant retention and migration in response to SDF-1α in a manner critically dependent on signaling via the SDF-1α-CXCR4 axis. This work lays the foundation for development of a more effective cell therapy for neural injury, but also has broader implications in the fields of tissue engineering and regenerative medicine given the essential roles of SDF-1α across injury and disease states. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. SDF-1alpha concentration dependent modulation of RhoA and Rac1 modifies breast cancer and stromal cells interaction

    International Nuclear Information System (INIS)

    Pasquier, Jennifer; Abu-Kaoud, Nadine; Abdesselem, Houari; Madani, Aisha; Hoarau-Véchot, Jessica; Thawadi, Hamda Al.; Vidal, Fabien; Couderc, Bettina; Favre, Gilles; Rafii, Arash

    2015-01-01

    The interaction of SDF-1alpha with its receptor CXCR4 plays a role in the occurrence of distant metastasis in many solid tumors. This interaction increases migration from primary sites as well as homing at distant sites. Here we investigated how SDF-1α could modulate both migration and adhesion of cancer cells through the modulation of RhoGTPases. We show that different concentrations of SDF-1α modulate the balance of adhesion and migration in cancer cells. Increased migration was obtained at 50 and 100 ng/ml of SDF-1α; however migration was reduced at 200 ng/ml. The adhesion between breast cancer cells and BMHC was significantly increased by SDF-1α treatment at 200 ng/ml and reduced using a blocking monoclonal antibody against CXCR4. We showed that at low SDF-1α concentration, RhoA was activated and overexpressed, while at high concentration Rac1 was promoting SDF-1α mediating-cell adhesion. We conclude that SDF-1α concentration modulates migration and adhesion of breast cancer cells, by controlling expression and activation of RhoGTPases. The online version of this article (doi:10.1186/s12885-015-1556-7) contains supplementary material, which is available to authorized users

  2. Analysis of CCR5 and SDF-1 genetic variants and HIV infection in Indian population.

    Science.gov (United States)

    Gupta, A; Padh, Harish

    2015-08-01

    HIV-1 infection and progression exhibits interindividual variation. The polymorphism in the chemokine receptors CCR5 and CXCR4, the principal coreceptors for HIV-1 and their ligands like SDF-1 have a profound effect in altering the HIV-1 disease progression rate. A single nucleotide polymorphism designated SDF1-3'UTR-801G-A has been associated with resistance to HIV-1 infection or delayed progression to AIDS. In this study, the SDF1-3'A polymorphism, CCR5∆32 polymorphism and CCR5 promoter polymorphism at positions 58934 G/T, 59029 G/A, 59353 T/C, 59356 C/T, 59402 A/G and 59653 C/T were analysed in Indian population. The polymorphisms in HIV-1 patients and healthy individuals were evaluated by conventional PCR, RFLP-PCR and direct sequencing techniques. The CCR5∆32 mutant allele was found to be almost absent in Indian population. The analysis of the CCR5-59356C/T polymorphism revealed a trend towards an association of the C allele with an increased risk of HIV-1 infection. The frequency of allele CCR5-59356C was higher in HIV-1 patients (100%) as compared to healthy control subjects (89%, P = 0.003). The correlation of SDF1-3'A and CCR5 promoter CCR5-58934G/T, CCR5-59029G/A, CCR5-59353T/C, CCR5-59402 A/G and CCR5-59653C/T polymorphisms and protection to HIV-1 infection and progression to AIDS was found to be nonsignificant. Nine haplotypes with more than 1% frequency were detected but were not significant in their protective role against HIV. Comparative analysis with global populations showed a noteworthy difference in CCR5 and SDF-1 polymorphisms' frequency distribution, indicating the ethnic variability of Indians. Although susceptibility to infections cannot be completely dependent on one or few genetic variants, it is important to remember that SDF-1 and CCR5 variants have been correlated globally with HIV-1 infection and disease progression. In the light of that, higher frequency of SDF-1 variants in the Indian population is noteworthy. © 2015 John

  3. The Polyketide MPBD Initiates the SDF-1 Signaling Cascade That Coordinates Terminal Differentiation in Dictyostelium ▿ †

    Science.gov (United States)

    Anjard, Christophe; Su, Yongxuan; Loomis, William F.

    2011-01-01

    Dictyostelium uses a wide array of chemical signals to coordinate differentiation as it switches from a unicellular to a multicellular organism. MPBD, the product of the polyketide synthase encoded by stlA, regulates stalk and spore differentiation by rapidly stimulating the release of the phosphopeptide SDF-1. By analyzing specific mutants affected in MPBD or SDF-1 production, we delineated a signal transduction cascade through the membrane receptor CrlA coupled to Gα1, leading to the inhibition of GskA so that the precursor of SDF-1 is released. It is then processed by the extracellular protease of TagB on prestalk cells. SDF-1 apparently acts through the adenylyl cyclase ACG to activate the cyclic AMP (cAMP)-dependent protein kinase A (PKA) and trigger the production of more SDF-1. This signaling cascade shows similarities to the SDF-2 signaling pathway, which acts later to induce rapid spore encapsulation. PMID:21602484

  4. The effect of delivering the chemokine SDF-1α in a matrix-bound manner on myogenesis

    Science.gov (United States)

    Sadir, Rabia; Almodovar, Jorge; Mertani, Hichem C.; Bruckert, Franz; Albiges-Rizo, Corinne; Weidenhaupt, Marianne; Lortat-Jacob, Hugues; Picart, Catherine

    2014-01-01

    Several chemokines are important in muscle myogenesis and in the recruitment of muscle precursors during muscle regeneration. Among these, the SDF-1α chemokine (CXCL12) is a potent chemoattractant known to be involved in muscle repair. SDF-1α was loaded in polyelectrolyte multilayer films made of poly(l-lysine) and hyaluronan to be delivered locally to myoblast cells in a matrix-bound manner. The adsorbed amounts of SDF-1α were tuned over a large range from 100 ng/cm2 to 5 μg/cm2, depending on the initial concentration of SDF-1α in solution, its pH, and on the film crosslinking extent. Matrix-bound SDF-1α induced a striking increase in myoblast spreading, which was revealed when it was delivered from weakly crosslinked films. It also significantly enhanced cell migration in a dose-dependent manner, which again depended on its presentation by the biopolymeric film. The low-crosslinked film was the most efficient in boosting cell migration. Furthermore, matrix-bound SDF-1α also increased the expression of myogenic markers but the fusion index decreased in a dose-dependent manner with the adsorbed amount of SDF-1α. At high adsorbed amounts of SDF-1α, a large number of Troponin T-positive cells had only one nucleus. Overall, this work reveals the importance of the presentation mode of SDF-1α to emphasize its effect on myogenic processes. These films may be further used to provide insight into the role of SDF-1α presented by a biomaterial in physiological or pathological processes. PMID:24612919

  5. SDF-1/CXCR4/CXCR7 is pivotal for vascular smooth muscle cell proliferation and chronic allograft vasculopathy.

    Science.gov (United States)

    Thomas, Michael N; Kalnins, Aivars; Andrassy, Martin; Wagner, Anne; Klussmann, Sven; Rentsch, Markus; Habicht, Antje; Pratschke, Sebastian; Stangl, Manfred; Bazhin, Alexandr V; Meiser, Bruno; Fischereder, Michael; Werner, Jens; Guba, Markus; Andrassy, Joachim

    2015-12-01

    Chronic rejection remains a major obstacle in transplant medicine. Recent studies suggest a crucial role of the chemokine SDF-1 on neointima formation after injury. Here, we investigate the potential therapeutic effect of inhibiting the SDF-1/CXCR4/CXCR7 axis with an anti-SDF-1 Spiegelmer (NOX-A12) on the development of chronic allograft vasculopathy. Heterotopic heart transplants from H-2bm12 to B6 mice and aortic transplants from Balb/c to B6 were performed. Mice were treated with NOX-A12. Control animals received a nonfunctional Spiegelmer (revNOX-A12). Samples were retrieved at different time points and analysed by histology, RT-PCR and proliferation assay. Blockade of SDF-1 caused a significant decrease in neointima formation as measured by intima/media ratio (1.0 ± 0.1 vs. 1.8 ± 0.1, P SDF-1 inhibition (3.42 ± 0.37 vs. 1.67 ± 0.33, P SDF-1/CXCR4/CXCR7 plays a critical role in the development of chronic allograft vasculopathy (CAV). Therefore, pharmacological inhibition of SDF-1 with NOX-A12 may represent a therapeutic option to ameliorate chronic rejection changes. © 2015 Steunstichting ESOT.

  6. Soro urêmico inibe a expressão in vitro da quimiocina SDF-1: possível impacto da toxicidade urêmica na lesão endotelial

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    Vanessa Ribeiro

    2014-04-01

    Full Text Available Introdução: A disfunção endotelial é importante na patogênese da doença cardiovascular (DCV relacionada à doença renal crônica (DRC. Stromal cell-derived factor-1 (SDF-1 é uma quimiocina que mobiliza células endoteliais progenitoras (EPC e em conjunto com a interleucina-8 (IL-8 podem ser usadas como marcadores de reparo e lesão tecidual. Objetivo: Neste trabalho, foi investigado o efeito do meio urêmico na expressão de SDF-1 e IL-8 in vivo e in vitro. Métodos: A inflamação sistêmica foi avaliada por meio da proteína C-reativa (PCR e interleucina-6 (IL-6. IL-8 e SDF-1 foram avaliados por ELISA como marcadores de disfunção endotelial e reparo tecidual, respectivamente. Os estudos in vitro foram realizados em células endoteliais umbilicais humanas (HUVEC expostas ao meio urêmico ou saudável. Resultados: Foram incluídos nesse estudo 26 pacientes em hemodiálise (HD (17 ± 3 meses em diálise, 52 ± 2 anos, 38% homens e 11% diabéticos. As concentrações séricas de PCR, IL-6, SDF-1 e IL-8 foram 4,9 ± 4,8 mg/ml, 6,7 ± 8,1 pg/ml, 2625,9 ± 1288,6 pg/ml e 128,2 ± 206,2 pg/ml, respectivamente. Houve correlação positiva entre PCR e IL-6 (ρ = 0,57; p < 0,005 e entre SDF-1 e IL-8 (ρ = 0,45; p < 0,05. Os resultados in vitro demonstraram que a expressão de SDF-1 pelas HUVEC após 6 horas de tratamento com meio urêmico é menor comparada ao tratamento com meio saudável (p < 0,05. Após 12 horas de tratamento, ocorreu aumento de IL-8 quando as HUVECs foram expostas ao meio urêmico (p < 0,005. Conclusão: Sugerimos que SDF-1 e IL-8 nos pacientes em HD podem ser usados para mensurar a extensão do dano e consequente ativação vascular na uremia.

  7. Soluble factors from stellate cells induce pancreatic cancer cell proliferation via Nrf2-activated metabolic reprogramming and ROS detoxification.

    Science.gov (United States)

    Wu, Yuan Seng; Looi, Chung Yeng; Subramaniam, Kavita S; Masamune, Atsushi; Chung, Ivy

    2016-06-14

    Pancreatic stellate cells (PSC), a prominent stromal cell, contribute to the progression of pancreatic ductal adenocarcinoma (PDAC). We aim to investigate the mechanisms by which PSC promote cell proliferation in PDAC cell lines, BxPC-3 and AsPC-1. PSC-conditioned media (PSC-CM) induced proliferation of these cells in a dose- and time-dependent manner. Nrf2 protein was upregulated and subsequently, its transcriptional activity was increased with greater DNA binding activity and transcription of target genes. Downregulation of Nrf2 led to suppression of PSC-CM activity in BxPC-3, but not in AsPC-1 cells. However, overexpression of Nrf2 alone resulted in increased cell proliferation in both cell lines, and treatment with PSC-CM further enhanced this effect. Activation of Nrf2 pathway resulted in upregulation of metabolic genes involved in pentose phosphate pathway, glutaminolysis and glutathione biosynthesis. Downregulation and inhibition of glucose-6-phosphate-dehydrogenase with siRNA and chemical approaches reduced PSC-mediated cell proliferation. Among the cytokines present in PSC-CM, stromal-derived factor-1 alpha (SDF-1α) and interleukin-6 (IL-6) activated Nrf2 pathway to induce cell proliferation in both cells, as shown with neutralization antibodies, recombinant proteins and signaling inhibitors. Taken together, SDF-1α and IL-6 secreted from PSC induced PDAC cell proliferation via Nrf2-activated metabolic reprogramming and ROS detoxification.

  8. Migration towards SDF-1 selects angiogenin-expressing bone marrow monocytes endowed with cardiac reparative activity in patients with previous myocardial infarction.

    Science.gov (United States)

    Ascione, Raimondo; Rowlinson, Jonathan; Avolio, Elisa; Katare, Rajesh; Meloni, Marco; Spencer, Helen L; Mangialardi, Giuseppe; Norris, Caroline; Kränkel, Nicolle; Spinetti, Gaia; Emanueli, Costanza; Madeddu, Paolo

    2015-04-11

    Chemokine-directed migration is crucial for homing of regenerative cells to the infarcted heart and correlates with outcomes of cell therapy trials. Hence, transplantation of chemokine-responsive bone marrow cells may be ideal for treatment of myocardial ischemia. To verify the therapeutic activity of bone marrow mononuclear cells (BM-MNCs) selected by in vitro migration towards the chemokine stromal cell-derived factor-1 (SDF-1) in a mouse model of myocardial infarction (MI), we used BM-MNCs from patients with previous large MI recruited in the TransACT-1&2 cell therapy trials. Unfractioned BM-MNCs, SDF-1-responsive, and SDF-1-nonresponsive BM-MNCs isolated by patients recruited in the TransACT-1&2 cell therapy trials were tested in Matrigel assay to evaluate angiogenic potential. Secretome and antigenic profile were characterized by flow cytometry. Angiogenin expression was measured by RT-PCR. Cells groups were also intramyocardially injected in an in vivo model of MI (8-week-old immune deficient CD1-FOXN1(nu/nu) mice). Echocardiography and hemodynamic measurements were performed before and at 14 days post-MI. Arterioles and capillaries density, infiltration of inflammatory cells, interstitial fibrosis, and cardiomyocyte proliferation and apoptosis were assessed by immunohistochemistry. In vitro migration enriched for monocytes, while CD34(+) and CD133(+) cells and T lymphocytes remained mainly confined in the non-migrated fraction. Unfractioned total BM-MNCs promoted angiogenesis on Matrigel more efficiently than migrated or non-migrated cells. In mice with induced MI, intramyocardial injection of unfractionated or migrated BM-MNCs was more effective in preserving cardiac contractility and pressure indexes than vehicle or non-migrated BM-MNCs. Moreover, unfractioned BM-MNCs enhanced neovascularization, whereas the migrated fraction was unique in reducing the infarct size and interstitial fibrosis. In vitro studies on isolated cardiomyocytes suggest participation

  9. Cyclophosphamide-induced cystitis increases bladder CXCR4 expression and CXCR4-macrophage migration inhibitory factor association.

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    Pedro L Vera

    Full Text Available BACKGROUND: Macrophage migration inhibitory factor (MIF is a pro-inflammatory cytokine involved in cystitis and a non-cognate ligand of the chemokine receptor CXCR4 in vitro. We studied whether CXCR4-MIF associations occur in rat bladder and the effect of experimental cystitis. METHODS AND FINDINGS: Twenty male rats received saline or cyclophosphamide (40 mg/kg; i.p.; every 3(rd day to induce persistent cystitis. After eight days, urine was collected and bladders excised under anesthesia. Bladder CXCR4 and CXCR4-MIF co-localization were examined with immunhistochemistry. ELISA determined MIF and stromal derived factor-1 (SDF-1; cognate ligand for CXCR4 levels. Bladder CXCR4 expression (real-time RTC-PCR and protein levels (Western blotting were examined. Co-immunoprecipitations studied MIF-CXCR4 associations.Urothelial basal and intermediate (but not superficial cells in saline-treated rats contained CXCR4, co-localized with MIF. Cyclophosphamide treatment caused: 1 significant redistribution of CXCR4 immunostaining to all urothelial layers (especially apical surface of superficial cells and increased bladder CXCR4 expression; 2 increased urine MIF with decreased bladder MIF; 3 increased bladder SDF-1; 4 increased CXCR4-MIF associations. CONCLUSIONS: These data demonstrate CXCR4-MIF associations occur in vivo in rat bladder and increase in experimental cystitis. Thus, CXCR4 represents an alternative pathway for MIF-mediated signal transduction during bladder inflammation. In the bladder, MIF may compete with SDF-1 (cognate ligand to activate signal transduction mediated by CXCR4.

  10. SDF1-3'A polymorphism is associated with increased risk of hematological malignancy: a meta-analysis

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    Zhang X

    2017-03-01

    Full Text Available Xiaowen Zhang, Yang Fan, Zhijie Li Medical Research Center, Shengjing Hospital of China Medical University, Shenyang, China Abstract: CXCL12 (also named SDF1, a member of the chemokine family, has been demonstrated to play an important role in the progression of multiple types of hematological malignancy. Several recent studies have shown that SDF1-3'A polymorphism (rs1801157 is associated with susceptibility to hematological malignancy, but published studies’ results are disputed. Therefore, we performed a meta-analysis to evaluate the relationship between SDF1-3'A polymorphism and the risk of hematological malignancy based on the existing literature. We carried out a comprehensive literature search using the Web of Science, PubMed, Cochrane Library, Chinese Wan Fang, and Chinese National Knowledge Infrastructure databases. And the raw data were extracted and calculated in standard steps of meta-analysis. Overall, nine qualified studies containing 1,576 cases and 1,674 controls were included in the ultimate meta-analysis. The pooled results displayed that AA genotype significantly increased the risk of hematological malignancy. The result of subgroup analysis further indicated that SDF1-3'A polymorphism was significantly associated with increased risk of chronic myeloid leukemia, Hodgkin’s lymphoma and multiple myeloma, but was not associated with increased risk of acute myeloid leukemia and non-Hodgkin’s lymphoma. In addition, SDF1-3'A polymorphism was associated with increased risk of hematological malignancy in Africans and Asians, but not in Caucasians. In conclusion, our meta-analysis firstly demonstrated that SDF1-3'A polymorphism may be associated with increased risk of hematological malignancy, especially for chronic myeloid leukemia, Hodgkin’s lymphoma, multiple myeloma and the non-Caucasian population. Nevertheless, these conclusions should be reconfirmed by more evidence from large sample sized studies. Keywords: SDF1

  11. Gene polymorphisms in CCR5, CCR2, SDF1 and RANTES among Chinese Han population with HIV-1 infection.

    Science.gov (United States)

    Li, Hui; Liu, Ting-Jun; Hong, Ze-Hui

    2014-06-01

    Chemokines and chemokine receptors are crucial for immune response in HIV-1 infection. Although many studies have been done to investigate the relationship between chemokines and chemokine receptor gene polymorphisms and host's susceptibility to HIV-1 infection, the conclusions are under debate. In the present study, a cohort of 287 HIV-1 seropositive patients, 388 ethnically age-matched healthy controls and 49 intravenous drug users (IDUs) HIV-1 exposed seronegative individuals (HESN) from Chinese Han population were enrolled in order to determine the influence of host genetic factors on HIV-1 infection. Seven polymorphisms on four known chemokines/chemokine receptor genes (CCR5Δ32, CCR5 m303, CCR5 59029A/G, CCR2 64I, RANTES -403A/G, RANTES -28C/G and SDF1 3'-A) were screened. CCR5Δ32 and CCR5 m303 were absent or infrequent in Chinese Han population, which may not be hosts' genetic protective factors for HIV-1 infection. Our results showed the CCR5 59029A/G, CCR2 64I and SDF1 3'-A were not associated with host's resistance to HIV-1 infection. The frequency of RANTES -403A allele was significantly lower in HIV-1 patients than in healthy blood donors (p=0.0005) and HESN group (p=0.035), which implied the association between A allele and reduced HIV-1 infection risk. Different genetic models were assessed to investigate this association (AA vs. GG+AG, OR=0.38 95% CI, 0.22-0.65 p=0.0004; A vs. G, OR=0.66 95% CI, 0.52-0.84 p=0.0006), which supported this association, either. The genotype and allele distribution of RANTES -28 between HIV-1 patients and healthy controls (genotype profile: p=0.072; allele profile: p=0.027) or HIV-1 seronegative group (genotype profile: p=0.036; allele profile: p=0.383) were both at the marginal level of significance, which were not observed after Bonferroni correction. All these results suggest the RANTES -403A may be associated with reduced susceptibility to HIV-1 infection, while the RANTES -28 locus not. By lack of the patients

  12. Prolyl-hydroxylase inhibition induces SDF-1 associated with increased CXCR4+/CD11b+ subpopulations and cardiac repair.

    Science.gov (United States)

    Ghadge, Santhosh Kumar; Messner, Moritz; Van Pham, Thi; Doppelhammer, Maximilian; Petry, Andreas; Görlach, Agnes; Husse, Britta; Franz, Wolfgang-Michael; Zaruba, Marc-Michael

    2017-08-01

    SDF-1/CXCR4 activation facilitates myocardial repair. Therefore, we aimed to activate the HIF-1α target genes SDF-1 and CXCR4 by dimethyloxalylglycine (DMOG)-induced prolyl-hydroxylase (PH) inhibition to augment CXCR4+ cell recruitment and myocardial repair. SDF-1 and CXCR4 expression was analyzed under normoxia and ischemia ± DMOG utilizing SDF-1-EGFP and CXCR4-EGFP reporter mice. In bone marrow and heart, CXCR4-EGFP was predominantly expressed in CD45+/CD11b+ leukocytes which significantly increased after myocardial ischemia. PH inhibition with 500 μM DMOG induced upregulation of SDF-1 mRNA in human microvascular endothelial cells (HMEC-1) and aortic vascular smooth muscle cells (HAVSMC). CXCR4 was highly elevated in HMEC-1 but almost no detectable in HAVSMC. In vivo, systemic administration of the PH inhibitor DMOG without pretreatment upregulated nuclear HIF-1α and SDF-1 in the ischemic mouse heart associated with increased recruitment of CD45+/CXCR4-EGFP+/CD11b+ cell subsets. Enhanced PH inhibition significantly upregulated reparative M2 like CXCR4-EGFP+ CD11b+/CD206+ cells compared to inflammatory M2-like CXCR4-EGFP+ CD11b+/CD86+ cells associated with reduced apoptotic cell death, increased neovascularization, reduced scar size, and an improved heart function after MI. In summary, our data suggest increased PH inhibition as a promising tool for a customized upregulation of SDF-1 and CXCR4 expression to attract CXCR4+/CD11b+ cells to the ischemic heart associated with increased cardiac repair. DMOG-induced prolyl-hydroxylase inhibition upregulates SDF-1 and CXCR4 in human endothelial cells. Systemic application of DMOG upregulates nuclear HIF-1α and SDF-1 in vivo. Enhanced prolyl-hydroxylase inhibition increases mainly CXCR4+/CD11b+ cells. DMOG increased reparative M2-like CD11b+/CD206+ cells compared to M1-like cells after MI. Enhanced prolyl-hydroxylase inhibition improved cardiac repair and heart function.

  13. [The mechanism of polypeptide derived from viral macrophage inflammatory protein II modulates SDF-1α/CXCR4-induced migration].

    Science.gov (United States)

    Yang, Qing-ling; Ding, Yong-xing; Chen, Chang-jie; Yang, Zhi-feng; Gao, Yan-jun

    2012-02-01

    To assess whether NT21MP, the synthetic antagonist 21-mer peptide derived from viral macrophage inflammatory protein II inhibits human SKBR3 cells migration by interfering with SDF-1α/CXCR4 signaling. The levels of CXCR4 were detected in breast cancer cells SKBR3 and MCF-7 by RT-PCR and immunohistochemistry. The effect of SDF-1α-induced SKBR3 migration (chemotaxis) in the presence and absence of NT21MP was determined using the Boyden chamber migration assay. Intracellular Ca(2+); concentration was measured by fluorometric analysis. Western blot analyses were performed to quantify phosphorylated ERK1/2 and FAK expression levels. The expression of CXCR4 was higher in SKBR3 than MCF-7 cells; SKBR3 migration increased in SDF-1α-treated cells. In contrast, AMD3100, an inhibitor of CXCR4 effectively inhibited SKBR3 migration. SKBR3 migration was decreased when the cells were exposed to NT21MPdose dependently(PSKBR3 migration. In addition, NT21MP significantly decreased SDF-1α-induced SKBR3 migration and downregulated SDF-1α-induced express of phospho-ERK1/2 and phospho-FAK(PSKBR3 migration. The plausible mechanism of action could be upstream blockage of Ca(2+); influx and the downstream reduction of ERK1/2 and FAK signals.

  14. Cardiogenic induction of pluripotent stem cells streamlined through a conserved SDF-1/VEGF/BMP2 integrated network.

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    Anca Chiriac

    Full Text Available BACKGROUND: Pluripotent stem cells produce tissue-specific lineages through programmed acquisition of sequential gene expression patterns that function as a blueprint for organ formation. As embryonic stem cells respond concomitantly to diverse signaling pathways during differentiation, extraction of a pro-cardiogenic network would offer a roadmap to streamline cardiac progenitor output. METHODS AND RESULTS: To resolve gene ontology priorities within precursor transcriptomes, cardiogenic subpopulations were here generated according to either growth factor guidance or stage-specific biomarker sorting. Innate expression profiles were independently delineated through unbiased systems biology mapping, and cross-referenced to filter transcriptional noise unmasking a conserved progenitor motif (55 up- and 233 down-regulated genes. The streamlined pool of 288 genes organized into a core biological network that prioritized the "Cardiovascular Development" function. Recursive in silico deconvolution of the cardiogenic neighborhood and associated canonical signaling pathways identified a combination of integrated axes, CXCR4/SDF-1, Flk-1/VEGF and BMP2r/BMP2, predicted to synchronize cardiac specification. In vitro targeting of the resolved triad in embryoid bodies accelerated expression of Nkx2.5, Mef2C and cardiac-MHC, enhanced beating activity, and augmented cardiogenic yield. CONCLUSIONS: Transcriptome-wide dissection of a conserved progenitor profile thus revealed functional highways that coordinate cardiogenic maturation from a pluripotent ground state. Validating the bioinformatics algorithm established a strategy to rationally modulate cell fate, and optimize stem cell-derived cardiogenesis.

  15. The SDF-1/CXCR4 axis promotes recovery after spinal cord injury by mediating bone marrow-derived from mesenchymal stem cells.

    Science.gov (United States)

    Wang, Guo-Dong; Liu, Yi-Xun; Wang, Xiao; Zhang, Yong-Le; Zhang, Ya-Dong; Xue, Feng

    2017-02-14

    This study aims to explore the role of the SDF-1/CXCR4 axis in mediating BMSCs and SCI recovery. BMSCs were collected and SCI rat models were established. Wistar rats were assigned into the blank control, sham, SCI, SCI + BMSCs, SCI + BMSCs + SDF-1, SCI + BMSCs + AMD3100 (an inhibitor of SDF-1/CXCR4 axis) and SCI + BMSCs + SDF-1 + AMD3100 groups. Hind limb motor function was measured 7, 14, 21 and 28 days after operation. qRT-PCR, western blotting and ELISA was performed to determine the expressions of SDF-1, CXCR4, NGF, BDNF, GFAP and GAP-43, TNF-α, IL-1β, L-6 and IFN-γ. Hind limb motor function scores 7 days after the operation were reduced in the SCI rats of the blank control and sham groups. Hind limb function was found to be better in the SCI + BMSCs and SCI + BMSCs + SDF-1 groups than in the SCI, SCI + BMSCs + AMD3100 and SCI + BMSCs + SDF-1 + AMD3100 groups 14, 21 and 28 days after operation. Furthermore, the SCI group had lower SDF-1, CXCR4, NGF, BDNF and GAP-43 expressions but higher GFAP, TNF-α, IL-1β, IL-6 and IFN-γ than the blank control and sham groups 28 days after operation. While, the SCI + BMSCs, SCI + BMSCs + SDF-1 and SCI + BMSCs + SDF-1 + AMD3100 groups displayed opposite trends to the SCI and SCI + BMSCs + AMD3100 groups. In conclusion, SDF-1/CXCR4 axis promotes recovery after SCI by mediating BMSCs.

  16. Baicalin attenuates chronic hypoxia-induced pulmonary hypertension via adenosine A2A receptor-induced SDF-1/CXCR4/PI3K/AKT signaling.

    Science.gov (United States)

    Huang, Xiaoying; Wu, Peiliang; Huang, Feifei; Xu, Min; Chen, Mayun; Huang, Kate; Li, Guo-Ping; Xu, Manhuan; Yao, Dan; Wang, Liangxing

    2017-08-03

    Baicalin, an important flavonoid in Scutellaria baicalensis Georgi extracts, exerts a variety of pharmacological effects. In this study, we explored the effects of baicalin on chronic hypoxia-induced pulmonary arterial hypertension (PAH) and investigated the mechanism underlying these effects. Moreover, we examined whether the inflammatory response was mediated by the A 2A receptor (A 2A R) and stromal cell-derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4)-induced phosphatidyl inositol-3-kinase (PI3K) signaling in vivo. We established a hypoxia-induced pulmonary hypertension (HPH) mouse model by subjecting wild-type (WT) and A 2A R knockout (A 2A R -/- ) animals to chronic hypoxia, and we examined the effects of a 4-week treatment with baicalin or the A 2A R agonist CGS21680 in these animals. Invasive hemodynamic parameters, the right ventricular hypertrophy index, pulmonary congestion, the pulmonary arterial remodeling index, blood gas parameters, A 2A R expression, and the expression of SDF-1/CXCR4/PI3K/protein kinase B (PKB; AKT) signaling components were measured. Compared with WT mice, A 2A R -/- mice exhibited increased right ventricular systolic pressure (RVSP), right ventricle-to-left ventricle plus septum [RV/(LV + S)] ratio, RV weight-to-body weight (RV/BW) ratio, and lung wet weight-to-body weight (Lung/BW) ratio in the absence of an altered mean carotid arterial pressure (mCAP). These changes were accompanied by increases in pulmonary artery wall area and thickness and reductions in arterial oxygen pressure (P a O 2 ) and hydrogen ion concentration (pH). In the HPH model, A 2A R -/- mice displayed increased CXCR4, SDF-1, phospho-PI3K, and phospho-AKT expression compared with WT mice. Treating WT and A 2A R -/- HPH mice with baicalin or CGS21680 attenuated the hypoxia-induced increases in RVSP, RV/(LV + S) and Lung/BW, as well as pulmonary arterial remodeling. Additionally, baicalin or CGS21680 alone could reverse the hypoxia

  17. Identification of hepatic niche harboring human acute lymphoblastic leukemic cells via the SDF-1/CXCR4 axis.

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    Itaru Kato

    Full Text Available In acute lymphoblastic leukemia (ALL patients, the bone marrow niche is widely known to be an important element of treatment response and relapse. Furthermore, a characteristic liver pathology observed in ALL patients implies that the hepatic microenvironment provides an extramedullary niche for leukemic cells. However, it remains unclear whether the liver actually provides a specific niche. The mechanism underlying this pathology is also poorly understood. Here, to answer these questions, we reconstituted the histopathology of leukemic liver by using patients-derived primary ALL cells into NOD/SCID/Yc (null mice. The liver pathology in this model was similar to that observed in the patients. By using this model, we clearly demonstrated that bile duct epithelial cells form a hepatic niche that supports infiltration and proliferation of ALL cells in the liver. Furthermore, we showed that functions of the niche are maintained by the SDF-1/CXCR4 axis, proposing a novel therapeutic approach targeting the extramedullary niche by inhibition of the SDF-1/CXCR4 axis. In conclusion, we demonstrated that the liver dissemination of leukemia is not due to nonselective infiltration, but rather systematic invasion and proliferation of leukemic cells in hepatic niche. Although the contribution of SDF-1/CXCR4 axis is reported in some cancer cells or leukemic niches such as bone marrow, we demonstrated that this axis works even in the extramedullary niche of leukemic cells. Our findings form the basis for therapeutic approaches that target the extramedullary niche by inhibiting the SDF-1/CXCR4 axis.

  18. Haematopoietic stem cell migration to the ischemic damaged kidney is not altered by manipulating the SDF-1/CXCR4-axis

    NARCIS (Netherlands)

    Stroo, Ingrid; Stokman, Geurt; Teske, Gwendoline J. D.; Florquin, Sandrine; Leemans, Jaklien C.

    2009-01-01

    Methods. HSC were isolated from mouse bone marrow and labelled with a cell tracker. Acceptor mice were subjected to unilateral ischemia and received HSC intravenously directly after reperfusion. In addition, in separate groups of acceptor mice, endogenous SDF-1 or HSC-associated CXCR4 was blocked or

  19. Expression of Wnt-Inhibitors and SDF-1 in Whole Bone Marrow Biopsies in Association to the Osteolytic Bone Disease of Multiple Myeloma

    DEFF Research Database (Denmark)

    Kristensen, Ida Bruun; Christensen, Jacob Haaber; Lyng, Maria Bibi

    Expression of Wnt-Inhibitors and SDF-1 in Whole Bone Marrow Biopsies in Association to the Osteolytic Bone Disease of Multiple Myeloma......Expression of Wnt-Inhibitors and SDF-1 in Whole Bone Marrow Biopsies in Association to the Osteolytic Bone Disease of Multiple Myeloma...

  20. Evidence of an interaction between TGF-β1 and the SDF-1/CXCR4/CXCR7 axis in human platelets.

    Science.gov (United States)

    Rath, Dominik; Chatterjee, Madhumita; Holtkamp, Annabell; Tekath, Nina; Borst, Oliver; Vogel, Sebastian; Müller, Karin; Gawaz, Meinrad; Geisler, Tobias

    2016-08-01

    TGF-β1, SDF-1 and its cognate receptors CXCR4 and CXCR7 are expressed on the surface of human platelets and their expression levels are differently regulated in symptomatic coronary artery disease (CAD). All these proteins and receptors influence outcome in patients with symptomatic CAD. There might be a crosstalk between TGF-β1 and the SDF-1/CXCR4/CXCR7 axis. Interrelations in CAD, especially in the context of platelets, are poorly understood. Therefore, we aimed to provide clinical and experimental evidence of interactions between TGF-β1 and the SDF-1/CXCR4/CXCR7 axis in human platelets. Blood samples of the complete cohort (n=284) were analysed for platelet surface expression levels of TGF-β1, SDF-1, CXCR4 and CXCR7 by flow cytometry. For stimulation assays platelet rich plasma was treated with TGF-β1 or SDF-1 and then analysed by flow cytometry. Multiple regression analyses were run to show independent associations of TGF-β1 with SDF-1, CXCR4, CXCR7 and clinical cofactors. Both, CXCR4 and CXCR7 significantly predicted TGF-β1 (pSDF-1, surface expression of TGF-β1 increased significantly when compared to resting platelets [mean TGF-β1 MFI 19.01 vs. mean TGF-β1 MFI 14.01, pSDF-1 on TGF-β1 surface expression was significantly blunted. Stimulation with TGF-β1 did not alter SDF-1, CXCR4 or CXCR7 expression significantly. We provide first clinical and experimental data suggesting a cross-talk between TGF-β and the SDF-1/CXCR4/CXCR7 axis in platelets which does not involve transcriptional modulation as shown previously for other cellular systems. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Co-transplantation with mesenchymal stem cells expressing a SDF-1/HOXB4 fusion protein markedly improves hematopoietic stem cell engraftment and hematogenesis in irradiated mice.

    Science.gov (United States)

    Chen, Tingting; Zhang, Pei; Fan, Wenxia; Qian, Fenghua; Pei, Li; Xu, Shuangnian; Zou, Zhongmin; Ni, Bing; Zhang, Yong

    2014-01-01

    Mesenchymal stem cells (MSCs) contribute to the engraftment of transplanted hematopoietic stem cells (HSCs). MSCs also accelerate hematological recovery by secreting SDF-1 and enabling HSCs to enter the bone marrow (BM) via the SDF-1/CXCR4 axis. HOXB4 has been shown to stimulate HSC self-renewal. In this study, we examined whether SDF-1 and HOXB4 expression in MSCs co-transplanted with HSCs could synergistically improve hematopoietic recovery in irradiated mice. Using recombinant adenoviruses, we generated genetically modified BM-MSCs that expressed SDF-1, HOXB4, and an SDF-1/HOXB4 fusion gene. We then co-transplanted these modified MSCs with HSCs and investigated blood cell counts, BM cellularity, degree of human HSC engraftment, and survival rate in irradiated mice. We found that co-culturing the SDF-1/HOXB4 fusion gene-modified MSCs (SDF-1/HOXB4-MSCs) and human umbilical cord blood CD34(+) cells significantly improved HSC cell expansion in vitro. More importantly, co-transplantation of CD34(+) cells and SDF-1/HOXB4-MSCs markedly increased the hematopoietic potential of irradiated mice as evidenced by the rapid recovery of WBC, PLT and HGB levels in peripheral blood and of BM cellularity. Co-transplantation also markedly improved engraftment of human CD45(+) cells in mouse BM. Our study demonstrates that SDF-1/HOXB4-MSCs markedly accelerate hematopoietic recovery and significantly improve survival among mice treated with a lethal dose of irradiation. Therefore, SDF-1/HOXB4-MSCs could have therapeutic value by improving the efficacy of clinical transplantations in patients with defective hematopoiesis.

  2. Chronic cadmium exposure stimulates SDF-1 expression in an ERα dependent manner.

    Directory of Open Access Journals (Sweden)

    Esmeralda Ponce

    Full Text Available Cadmium is an omnipotent environmental contaminant associated with the development of breast cancer. Studies suggest that cadmium functions as an endocrine disruptor, mimicking the actions of estrogen in breast cancer cells and activating the receptor to promote cell growth. Although acute cadmium exposure is known to promote estrogen receptor-mediated gene expression associated with growth, the consequence of chronic cadmium exposure is unclear. Since heavy metals are known to bioaccumulate, it is necessary to understand the effects of prolonged cadmium exposure. This study aims to investigate the effects of chronic cadmium exposure on breast cancer progression. A MCF7 breast cancer cell line chronically exposed to 10(-7 M CdCl2 serves as our model system. Data suggest that prolonged cadmium exposures result in the development of more aggressive cancer phenotypes - increased cell growth, migration and invasion. The results from this study show for the first time that chronic cadmium exposure stimulates the expression of SDF-1 by altering the molecular interactions between ERα, c-jun and c-fos. This study provides a mechanistic link between chronic cadmium exposure and ERα and demonstrates that prolonged, low-level cadmium exposure contributes to breast cancer progression.

  3. 17-AAG, a Hsp90 inhibitor, attenuates the hypoxia-induced expression of SDF-1alpha and ILK in mouse RPE cells.

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    Wang, Ye Qing; Zhang, Xiao Mei; Wang, Xiao Dan; Wang, Bin Jie; Wang, Wei

    2010-03-01

    The aim of this study was to investigate the changes of SDF-1alpha and ILK expression in mouse retinal pigment epithelium (RPE) cells in response to hypoxia, and the effect of 17-Allylamino-17-demethoxygeldanamycin (17-AAG), a heat shock protein 90 (Hsp90) inhibitor, on the hypoxia-induced expression of SDF-1alpha and ILK. RPE cells were cultured with 200 micromol/L cobalt chloride (CoCl(2)) for different times (1, 3, 6, 12, 24, 72 h) to imitate chemical hypoxia. Pretreatment of 17-AAG was 1 h prior to hypoxic insult. Cellular viability after 17-AAG treatment was assessed by MTT assay, and the changes of SDF-1alpha and ILK expression were examined by RT-PCR and Western blot. Up-regulation of SDF-1alpha and ILK expression in response to hypoxia was observed. One hour pretreatment of 17-AAG could remarkably decreased the hypoxia-induced SDF-1alpha and ILK expression in vitro. Our results indicated that SDF-1alpha and ILK involved in the hypoxic response of RPE cells, and 1 h pretreatment of 17-AAG had an inhibitive effect on the hypoxia-induced SDF-1alpha and ILK expression.

  4. Distribution of CCR5-Delta32, CCR5 promoter 59029 A/G, CCR2-64I and SDF1-3'A genetic polymorphisms in HIV-1 infected and uninfected patients in the west region of Cameroon.

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    Nkenfou, Céline Nguefeu; Mekue, Linda Chapdeleine Mouafo; Nana, Christelle Tafou; Kuiate, Jules Roger

    2013-07-23

    Genetic variants of the genes encoding human immunodeficiency virus-1 (HIV-1) co-receptors and their ligands, like CC-chemokine receptor 5 delta 32 mutation (CCR5-Delta32), CCR5 promoter A/G (Adenine/Guanine), CC-chemokine receptor 2 mutation 64 isoleucine (CCR2-64I) and the stromal cell-derived factor 3'A mutation (SDF1-3'A), are involved in the susceptibility to HIV-1 infection and progression. The prevalence of these mutations varies by region. However, little is known about their distribution in the population of Dschang, located in the west region of Cameroon. The prevalence of HIV in the west region of Cameroon is lower than elsewhere in Cameroon. The objectives of this study were to determine the distribution of four AIDS Related Gene (ARG) variants in HIV-infected and non-infected population of Cameroon especially in the west region and to estimate the contribution of these variants to the susceptibility or resistance to HIV infection. We also aimed to evaluate the effectiveness of genotyping using dried blood spot (DBS) samples. A total of 179 participants were recruited from two hospitals in Dschang in the west region of Cameroon. Their genotypes for CCR5-Delta32, CCR5 promoter 59029A/G, CCR2-64I and SDF1-3'A were analyzed using polymerase chain reaction (PCR) and restriction fragment length polymorphisms. A total of 179 participants were enrolled in the study. Among them, 32 (17.9%) were HIV positive and 147 (82.1%) were HIV negative. The allelic frequencies of these genes were: 0%, 49.72%, 17.6% and 100% respectively for CCR5-Delta32, CCR5 promoter 59029A/G, CCR2-64I and SDF1-3'A. No individual was found to carry the CCR5-Delta 32 mutation. All participants recruited were heterozygous for the SDF1-3'A allele. Our data suggest that the CCR5-Delta32 cannot account for the protection as it was completely absent in our population. SDF1-3'A variants, may be in association with other polymorphisms, may account for the overall protection from HIV-1 infection

  5. A novel combination of factors, termed SPIE, which promotes dopaminergic neuron differentiation from human embryonic stem cells.

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    Tandis Vazin

    Full Text Available BACKGROUND: Stromal-Derived Inducing Activity (SDIA is one of the most efficient methods of generating dopaminergic (DA neurons from embryonic stem cells (ESC. DA neuron induction can be achieved by co-culturing ESC with the mouse stromal cell lines PA6 or MS5. The molecular nature of this effect, which has been termed "SDIA" is so far unknown. Recently, we found that factors secreted by PA6 cells provided lineage-specific instructions to induce DA differentiation of human ESC (hESC. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we compared PA6 cells to various cell lines lacking the SDIA effect, and employed genome expression analysis to identify differentially-expressed signaling molecules. Among the factors highly expressed by PA6 cells, and known to be associated with CNS development, were stromal cell-derived factor 1 (SDF-1/CXCL12, pleiotrophin (PTN, insulin-like growth factor 2 (IGF2, and ephrin B1 (EFNB1. When these four factors, the combination of which was termed SPIE, were applied to hESC, they induced differentiation to TH-positive neurons in vitro. RT-PCR and western blot analysis confirmed the expression of midbrain specific markers, including engrailed 1, Nurr1, Pitx3, and dopamine transporter (DAT in cultures influenced by these four molecules. Electrophysiological recordings showed that treatment of hESC with SPIE induced differentiation of neurons that were capable of generating action potentials and forming functional synaptic connections. CONCLUSIONS/SIGNIFICANCE: The combination of SDF-1, PTN, IGF2, and EFNB1 mimics the DA phenotype-inducing property of SDIA and was sufficient to promote differentiation of hESC to functional midbrain DA neurons. These findings provide a method for differentiating hESC to form DA neurons, without a requirement for the use of animal-derived cell lines or products.

  6. Ultrasound-Targeted Microbubble Destruction Improves the Migration and Homing of Mesenchymal Stem Cells after Myocardial Infarction by Upregulating SDF-1/CXCR4: A Pilot Study

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    Lu Li

    2015-01-01

    Full Text Available Mesenchymal stem cell (MSC therapy shows considerable promise for the treatment of myocardial infarction (MI. However, the inefficient migration and homing of MSCs after systemic infusion have limited their therapeutic applications. Ultrasound-targeted microbubble destruction (UTMD has proven to be promising to improve the homing of MSCs to the ischemic myocardium, but the concrete mechanism remains unclear. We hypothesize that UTMD promotes MSC homing by upregulating SDF-1/CXCR4, and this study was aimed at exploring this potential mechanism. We analyzed SDF-1/CXCR4 expression after UTMD treatment in vitro and in vivo and counted the number of homing MSCs in MI areas. The in vitro results demonstrated that UTMD not only led to elevated secretion of SDF-1 but also resulted in an increased proportion of MSCs that expressed surface CXCR4. The in vivo findings show an increase in the number of homing MSCs and higher expression of SDF-1/CXCR4 in the UTMD combined with MSCs infusion group compared to other groups. In conclusion, UTMD can increase SDF-1 expression in the ischemic myocardium and upregulate the expression of surface CXCR4 on MSCs, which provides a molecular mechanism for the homing of MSCs assisted by UTMD via SDF-1/CXCR4 axis.

  7. SDF-1/CXCR4 expression is an independent negative prognostic biomarker in patients with head and neck cancer after primary radiochemotherapy.

    Science.gov (United States)

    De-Colle, Chiara; Menegakis, Apostolos; Mönnich, David; Welz, Stefan; Boeke, Simon; Sipos, Bence; Fend, Falko; Mauz, Paul-Stefan; Tinhofer, Inge; Budach, Volker; Abu Jawad, Jehad; Stuschke, Martin; Balermpas, Panagiotis; Rödel, Claus; Grosu, Anca-Ligia; Abdollahi, Amir; Debus, Jürgen; Belka, Claus; Ganswindt, Ute; Pigorsch, Steffi; Combs, Stephanie E; Lohaus, Fabian; Linge, Annett; Krause, Mechthild; Baumann, Michael; Zips, Daniel

    2018-01-01

    Preclinical and clinical data suggest that the chemokine pathway governed by SDF-1 and CXCR4 contributes to a resistant phenotype. This retrospective biomarker study aims to explore the specific prognostic value of SDF-1 and CXCR4 expression in locally advanced head and neck squamous cell carcinomas (HNSCC) treated with primary radiochemotherapy (RT-CT). Biopsies from 141 HNSCC tumours of the oral cavity, oropharynx and hypopharynx were evaluated for SDF-1 and CXCR4 expression by immunofluorescence. SDF-1 and CXCR4 expression was correlated with clinico-pathological characteristics and outcome after RT-CT. Patients with tumours exhibiting overexpression of intracellular SDF-1 and CXCR4 have a higher risk for loco-regional relapse and a worse overall survival after RT-CT (multivariate analysis, hazard ratio 2.33, CI [1.18-4.62], p = 0.02 and hazard ratio 2.02, CI [1.13-3.59], p = 0.02, respectively). Similar results were observed when only the subgroup of HPV DNA negative patients were analysed (hazard ratio 2.23 and 2.16, p = 0.02 and p = 0.01, respectively). Our data support the importance of SDF-1 and CXCR4 expression for loco-regional control and overall survival in HNSCC after primary radiochemotherapy. Prospective multivariate validation and further studies into CXCR4 inhibition to overcome radiation resistance are warranted. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Hypoxic Preconditioning Combined with Microbubble-Mediated Ultrasound Effect on MSCs Promote SDF-1/CXCR4 Expression and its Migration Ability: An In Vitro Study.

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    Li, Lu; Wu, Shengzheng; Li, Peijing; Zhuo, Lisha; Gao, Yunhua; Xu, Yali

    2015-12-01

    Our objective is to investigate the promoting effect of hypoxic preconditioning combined with microbubble (MB)-mediated ultrasound (US) on the SDF-1/CXCR4 expression and the migration ability of mesenchymal stem cells (MSCs). Based on the uniform design, the parameters of MB-mediated US, such as the total treatment time (T), acoustic intensity (Q), and the dosage of MBs, were optimized firstly. The results were assessed by regression analysis. Using the optimum irradiation parameters, the concentration of SDF-1 in the supernatant, the expression levels of membrane CXCR4, and the cell viability of hypoxic MSCs or normoxic MSCs were compared. The in vitro transwell migration assay was performed as well. The best combination of parameters for more SDF-1 secretion and less MSCs death was T = 30 s, A = 0.6 W/cm(2), and MB = 10(6)/ml. After 24 h of hypoxic preconditioning, the expression of SDF-1 and surface CXCR4 was increased in the hypoxic MSC group as compared to the normoxic MSC group (P SDF-1/CXCR4 with the optimum parameters (P SDF-1/CXCR4 expression and improve the migration ability in MSCs.

  9. Expression and function of the SDF-1 chemokine receptors CXCR4 and CXCR7 during mouse limb muscle development and regeneration.

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    Hunger, Conny; Ödemis, Veysel; Engele, Jürgen

    2012-10-15

    The chemokine, SDF-1/CXCL12, and its receptor, CXCR4, have been implied to play major roles during limb myogenesis. This concept was recently challenged by the identification of CXCR7 as an alternative SDF-1 receptor, which can either act as a scavenger receptor, a modulator of CXCR4, or an active chemokine receptor. We have now re-examined this issue by determining whether SDF-1 would signal to C2C12 myoblasts and subsequently influence their differentiation via CXCR4 and/or CXCR7. In addition, we have analyzed CXCR7, CXCR4, and SDF-1 expression in developing and injured mouse limb muscles. We demonstrate that in undifferentiated C2C12 cells, SDF-1-dependent cell signaling and resulting inhibitory effects on myogenic differentiation are entirely mediated by CXCR4. We further demonstrate that CXCR7 expression increases in differentiating C2C12 cells, which in turn abrogates CXCR4 signaling. Moreover, consistent with the view that CXCR4 and CXCR7 control limb myogenesis in vivo by similar mechanisms, we found that CXCR4 expression is the highest in late embryonic hindlimb muscles and drops shortly after birth when secondary muscle growth terminates. Vice versa, CXCR7 expression increased perinatally and persisted into adult life. Finally, underscoring the role of the SDF-1 system in muscle regeneration, we observed that SDF-1 is continuously expressed by endomysial cells of postnatal and adult muscle fibers. Analysis of dystrophin-deficient mdx mice additionally revealed that muscle regeneration is associated with muscular re-expression of CXCR4. The apparent tight control of limb muscle development and regeneration by CXCR4 and CXCR7 points to these chemokine receptors as promising therapeutic targets for certain muscle disorders. Copyright © 2012 Elsevier Inc. All rights reserved.

  10. Activation of A2aR attenuates bleomycin-induced pulmonary fibrosis via the SDF-1/CXCR4 axis-related pathway.

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    Chen, Yanfan; Yu, Xiaoming; He, Yicheng; Zhang, Lin; Huang, Xiaoying; Xu, Xiaomei; Chen, Mayun; Chen, Xiang; Wang, Liangxing

    2017-01-01

    Previous studies in our lab have demonstrated that Adenosine A2a receptor (A 2a R) gene-knockout mice were vulnerable to pulmonary fibrosis induced by bleomycin (BLM). Inhibition of the SDF-1/CXCR4 axis has been reported to protect the lungs from fibrogenesis in BLM-exposed mice. Little is yet known about the relationships between A 2a R and the SDF-1/CXCR4 axis in idiopathic pulmonary fibrosis (IPF). This study probes the role of A 2a R in the fibrotic process and explores the relationship between A 2a R and the SDF-1/CXCR4 axis in BLM-induced pulmonary fibrosis in mice. In the study, A 2a R-/- and A 2a R+/+ BALB/c mice were exposed to BLM by intratracheal instillation, and CGS-21680 (CGS), an A 2a R agonist, was administered daily for 28 days to the A 2a R+/+ mice in the BLM-induced fibrosis group. Activation of A 2a R produced an anti-fibrotic effect as indicated by the evaluations of the lung architecture, microstructure and ultrastructure. The quantitative analysis indicated that treatment with CGS significantly reduced the collagen content in lungs. To explore the potential mechanisms, the expression levels of A 2a R, SDF-1, and CXCR4 were subsequently determined using ELISA, in situ hybridization (ISH), immunohistochemical staining and western blotting techniques. Administration of CGS markedly suppressed the elevated expression levels of SDF-1 and CXCR4. Moreover, the A 2a R-/- mice developed more severe pulmonary fibrosis than the normal mice when exposed to BLM. Furthermore, the SDF-1/CXCR4 axis was aberrantly uninhibited in the knockout mice. Together, these findings indicated that A 2a R alleviated BLM-induced lung fibrosis, at least partially via the SDF-1/CXCR4 pathway, which could be a potential therapeutic target for the treatment of IPF.

  11. Biomaterial-enabled delivery of SDF-1α at the ventral side of breast cancer cells reveals a crosstalk between cell receptors to promote the invasive phenotype.

    Science.gov (United States)

    Liu, Xi Qiu; Fourel, Laure; Dalonneau, Fabien; Sadir, Rabia; Leal, Salome; Lortat-Jacob, Hugues; Weidenhaupt, Marianne; Albiges-Rizo, Corinne; Picart, Catherine

    2017-05-01

    The SDF-1α chemokine (CXCL12) is a potent bioactive chemoattractant known to be involved in hematopoietic stem cell homing and cancer progression. The associated SDF-1α/CXCR4 receptor signaling is a hallmark of aggressive tumors, which can metastasize to distant sites such as lymph nodes, lung and bone. Here, we engineered a biomimetic tumoral niche made of a thin and soft polyelectrolyte film that can retain SDF-1α to present it, in a spatially-controlled manner, at the ventral side of the breast cancer cells. Matrix-bound SDF-1α but not soluble SDF-1α induced a striking increase in cell spreading and migration in a serum-containing medium, which was associated with the formation of lamellipodia and filopodia in MDA-MB231 cells and specifically mediated by CXCR4. Other Knockdown and inhibition experiments revealed that CD44, the major hyaluronan receptor, acted in concert, via a spatial coincidence, to drive a specific matrix-bound SDFα-induced cell response associated with ERK signaling. In contrast, the β1 integrin adhesion receptor played only a minor role on cell polarity. The CXCR4/CD44 mediated cellular response to matrix-bound SDF-1α involved the Rac1 RhoGTPase and was sustained solely in the presence of matrix-bound SDFα, in contrast with the transient signaling observed in response to soluble SDF-1α. Our results highlight that a biomimetic tumoral niche enables to reveal potent cellular effects and so far hidden molecular mechanisms underlying the breast cancer response to chemokines. These results open new insights for the design of future innovative therapies in metastatic cancers, by inhibiting CXCR4-mediated signaling in the tumoral niche via dual targeting of receptors (CXCR4 and CD44) or of associated signaling molecules (CXCR4 and Rac1). Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Stromal cell-derived factor-1β potentiates bone morphogenetic protein-2-stimulated osteoinduction of genetically engineered bone marrow-derived mesenchymal stem cells in vitro.

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    Herberg, Samuel; Fulzele, Sadanand; Yang, Nianlan; Shi, Xingming; Hess, Matthew; Periyasamy-Thandavan, Sudharsan; Hamrick, Mark W; Isales, Carlos M; Hill, William D

    2013-01-01

    Skeletal injuries are among the most prevalent clinical problems and bone marrow-derived mesenchymal stem/stromal cells (BMSCs) have successfully been used for the treatment thereof. Stromal cell-derived factor-1 (SDF-1; CXCL12) is a member of the CXC chemokine family with multiple splice variants. The two most abundant variants, SDF-1α and SDF-1β, share identical amino acid sequences, except for four additional amino acids at the C-terminus of SDF-1β, which may mediate surface stabilization via glycosaminoglycans and protect SDF-1β from proteolytic cleavage, rendering it twice as potent as SDF-1α. Increasing evidence suggests that SDF-1 is involved in bone formation through regulation of recruitment, engraftment, proliferation, and differentiation of stem/progenitor cells. The underlying molecular mechanisms, however, have not yet been fully elucidated. In this study, we tested the hypothesis that SDF-1β can potentiate bone morphogenetic protein-2 (BMP-2)-stimulated osteogenic differentiation and chemotaxis of BMSCs in vitro. Utilizing retrovirus-mediated gene transfer to generate novel Tet-Off-SDF-1β BMSCs, we found that conditional SDF-1β expression is tightly regulated by doxycycline in a dose-dependent and temporal fashion, leading to significantly increased SDF-1β mRNA and protein levels. In addition, SDF-1β was found to enhance BMP-2-stimulated mineralization, mRNA and protein expression of key osteogenic markers, and regulate BMP-2 signal transduction via extracellular signal-regulated kinases 1/2 (Erk1/2) phosphorylation in genetically engineered BMSCs in vitro. We also showed that SDF-1β promotes the migratory response of CXC chemokine receptor 4 (CXCR4)-expressing BMSCs in vitro. Taken together, these data support that SDF-1β can play an important role in BMP-2-stimulated osteogenic differentiation of BMSCs and may exert its biological activity in both an autocrine and paracrine fashion.

  13. The Role of Vascular Endothelial Growth Factor Receptor-1 Signaling in the Recovery from Ischemia.

    Science.gov (United States)

    Amano, Hideki; Kato, Shintaro; Ito, Yoshiya; Eshima, Koji; Ogawa, Fumihiro; Takahashi, Ryo; Sekiguchi, Kazuki; Tamaki, Hideaki; Sakagami, Hiroyuki; Shibuya, Masabumi; Majima, Masataka

    2015-01-01

    Vascular endothelial growth factor (VEGF) is one of the most potent angiogenesis stimulators. VEGF binds to VEGF receptor 1 (VEGFR1), inducing angiogenesis through the receptor's tyrosine kinase domain (TK), but the mechanism is not well understood. We investigated the role of VEGFR1 tyrosine kinase signaling in angiogenesis using the ischemic hind limb model. Relative to control mice, blood flow recovery was significantly impaired in mice treated with VEGFA-neutralizing antibody. VEGFR1 tyrosine kinase knockout mice (TK-/-) had delayed blood flow recovery from ischemia and impaired angiogenesis, and this phenotype was unaffected by treatment with a VEGFR2 inhibitor. Compared to wild type mice (WT), TK-/- mice had no change in the plasma level of VEGF, but the plasma levels of stromal-derived cell factor 1 (SDF-1) and stem cell factor, as well as the bone marrow (BM) level of pro-matrix metalloproteinase-9 (pro-MMP-9), were significantly reduced. The recruitment of cells expressing VEGFR1 and C-X-C chemokine receptor type 4 (CXCR4) into peripheral blood and ischemic muscles was also suppressed. Furthermore, WT transplanted with TK-/- BM significantly impaired blood flow recovery more than WT transplanted with WT BM. These results suggest that VEGFR1-TK signaling facilitates angiogenesis by recruiting CXCR4+VEGFR1+ cells from BM.

  14. The peculiarities of the SDF-1/CXCL12 system: in some cells, CXCR4 and CXCR7 sing solos, in others, they sing duets.

    Science.gov (United States)

    Puchert, Malte; Engele, Jürgen

    2014-02-01

    The chemokine SDF-1/CXCL12 induces and modulates major steps of ontogenesis, regeneration and tumorigenesis. Depending on the organ or tissue, CXCL12 serves as a proliferation or cell survival factor, influences differentiation, induces adhesion and/or regulates cell migration. These functions are mediated by the two chemokine receptors, CXCR4 and CXCR7. Whereas CXCR4 is still viewed as the sole G-protein-activating and, hence, signaling receptor for CXCL12, CXCR7 is regarded as a non-classic scavenging or decoy receptor that modulates the function of CXCR4. However, this view might be too limited, since evidence has accumulated favoring a cell-type-specific mode of CXCL12 signaling. In addition to the "classic" CXCL12 signaling mode via CXCR4, CXCR4 and CXCR7 have to form a receptor unit for successful CXCL12 signaling in some cells. Moreover, examples exist whereby CXCL12 receptors split functions or switch roles, such that CXCR7 (instead of CXCR4) mediates signal transduction. The obvious lack of a universal mode of CXCL12 signaling urges a re-evaluation of the role of this chemokine in development, health and disease. This review depicts the exceptional characteristics of CXCL12-induced signal transduction in various cells and organs, points out remaining controversies and mentions consequences for therapeutic interventions.

  15. Inhibition of angiogenesis, fibrosis and thrombosis by tetramethylpyrazine: mechanisms contributing to the SDF-1/CXCR4 axis.

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    Xiaoxiao Cai

    Full Text Available BACKGROUND: Tetramethylpyrazine (TMP is one of the active ingredients extracted from the Chinese herb Chuanxiong, which has been used to treat cerebrovascular and cardiovascular diseases, pulmonary diseases and cancer. However, the molecular mechanisms underlying the actions of TMP have not been fully elucidated. In a previous study we showed that TMP-mediated glioma suppression and neural protection involves the inhibition of CXCR4 expression. The SDF-1/CXCR4 axis plays a fundamental role in many physiological and pathological processes. In this study, we further investigated whether the regulation of the SDF-1/CXCR4 pathway is also involved in the TMP-mediated inhibition of neovascularization or fibrosis and improvement of microcirculation. METHODOLOGY/PRINCIPAL FINDINGS: Using a scratch-wound assay, we demonstrated that TMP significantly suppressed the migration and tubule formation of the human umbilical vein endothelial cell line ECV304 in vitro. The expression of CXCR4 in ECV304 cells is notably down-regulated after TMP treatment. In addition, TMP significantly suppresses corneal neovascularization in a rat model of corneal alkali burn injury. The expression of CXCR4 on days 1, 3 and 7 post-injury was determined through RT-PCR analysis. Consistent with our hypotheses, the expression of CXCR4 in the rat cornea is significantly increased with alkali burn and dramatically down-regulated with TMP treatment. Moreover, TMP treatment significantly attenuates bleomycin-induced rat pulmonary fibrosis, while immunofluorescence shows a notably decreased amount of CXCR4-positive cells in the TMP-treated group. Furthermore, TMP significantly down-regulates the expression of CXCR4 in platelets, lymphocytes and red blood cells. Whole-blood viscosity and platelet aggregation in rats are significantly decreased by TMP treatment. CONCLUSIONS: These results show that TMP exerts potent effects in inhibiting neovascularization, fibrosis and thrombosis under

  16. Causal pathways of the effects of age and the CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles on AIDS development

    NARCIS (Netherlands)

    Geskus, Ronald B.; Meyer, Laurence; Hubert, Jean-Baptiste; Schuitemaker, Hanneke; Berkhout, Ben; Rouzioux, Christine; Theodorou, Ioannis D.; Delfraissy, Jean-François; Prins, Maria; Coutinho, Roel A.

    2005-01-01

    OBJECTIVE: To investigate the causal pathways by which age and the CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles influence progression to AIDS. DESIGN: Analysis of follow-up data from 2 cohort studies among homosexual men (n=400), having >10 years of follow-up. METHODS: The effects of the 4

  17. Hesperidin suppresses the migration and invasion of non-small cell lung cancer cells by inhibiting the SDF-1/CXCR-4 pathway.

    Science.gov (United States)

    Xia, Rongmu; Xu, Gang; Huang, Yue; Sheng, Xin; Xu, Xianlin; Lu, Hongling

    2018-03-28

    The present study aimed to investigate the ability of hesperidin to suppress the migration and invasion of A549 cells, and to investigate the role of the SDF-1/CXCR-4 cascade in this suppression. We performed a Transwell migration assay to measure the migratory capability of A549 cells treated with 0.5% DMSO, SDF-1α, AMD3100 or hesperidin. The SDF-1 level in the culture medium was determined by an enzyme-linked immunosorbent assay (ELISA) to detect whether different concentrations of hesperidin affected SDF-1 secretion. A wound-healing assay was performed to determine the effects of different concentrations of hesperidin on the migration inhibition of A549, H460 and H1975 cells. Additionally, the effect of various hesperidin concentrations on the rate of A549 cell invasion and migration was examined with and without Matrigel in Transwell assays, respectively. Western blot analysis was used to evaluate the protein levels of CXCR-4, MMP-9, CK-19, Vimentin, p65, p-p65, p-IκB, IκB, p-Akt and Akt. RT-qPCR was used to detect the mRNA levels of CXCR-4, MMP-9, CK-19, Vimentin, p65, IκB, SDF-1 and Akt. The Transwell migration assay indicated that SDF-1α promoted A549 cell migration, while AMD3100 and hesperidin significantly inhibited the migratory capability. The wound-healing assay demonstrated that hesperidin treatment significantly reduced the rate of wound closure compared with the control group in a dose-dependent manner. Similarly, the migration and invasive abilities of A549 cells, H460 and H1975 cells treated with hesperidin were significantly decreased compared with the control group. The ELISA data suggested that hesperidin attenuated the secretion of SDF-1 from A549 cells in a dose-dependent manner. Furthermore, western blot analysis indicated that SDF-1α treatment significantly increased the levels of CXCR-4, p-p65, p-IκB and p-Akt in A549 cells. In contrast, AMD3100 or hesperidin reversed the effect induced by SDF-1α through decreasing the expression

  18. Stromal Cell-Derived Factor-1 Promotes Cell Migration, Tumor Growth of Colorectal Metastasis

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    Otto Kollmar

    2007-10-01

    Full Text Available In a mouse model of established extrahepatic colorectal metastasis, we analyzed whether stromal cellderived factor (SDF 1 stimulates tumor cell migration in vitro, angiogenesis, tumor growth in vivo. METHODS: Using chemotaxis chambers, CT26.WT colorectal tumor cell migration was studied under stimulation with different concentrations of SDF-1. To evaluate angiogenesis, tumor growth in vivo, green fluorescent protein-transfected CT26.WT cells were implanted in dorsal skinfold chambers of syngeneic BALB/c mice. After 5 days, tumors were locally exposed to SDF-1. Cell proliferation, tumor microvascularization, growth were studied during a further 9-day period using intravital fluorescence microscopy, histology, immunohistochemistry. Tumors exposed to PBS only served as controls. RESULTS:In vitro, > 30% of unstimulated CT26.WT cells showed expression of the SDF-1 receptor CXCR4. On chemotaxis assay, SDF-1 provoked a dose-dependent increase in cell migration. In vivo, SDF-1 accelerated neovascularization, induced a significant increase in tumor growth. Capillaries of SDF-1-treated tumors showed significant dilation. Of interest, SDF-1 treatment was associated with a significantly increased expression of proliferating cell nuclear antigen, a downregulation of cleaved caspase-3. CONCLUSION: Our study indicates that the CXC chemokine SDF-1 promotes tumor cell migration in vitro, tumor growth of established extrahepatic metastasis in vivo due to angiogenesis-dependent induction of tumor cell proliferation, inhibition of apoptotic cell death.

  19. [Cancer-associated-fibroblasts regulate the chemoresistance of lung cancer cell line A549 via SDF-1 secretion].

    Science.gov (United States)

    Zou, F; Zhang, Z H; Zhang, Y T; Zhao, J Q; Zhang, X L; Wen, C L; Song, X Y; Zhou, W M

    2017-05-23

    Objective: To investigate whether cancer-associated- fibroblasts (CAF), the key component of tumor microenvironment, regulate the chemoresistant capacity of lung cancer cell line A549 through SDF-1 secretion. Methods: Primary cell isolation techniques was used to isolate cancer-associated-fibroblasts from lung cancer patients. MTT assay was applied to determine the proliferation and chemoresistance of A549 cells. Quantative PCR was used to detect the mRNA changes of Bcl-xL. Western blotting was used to detect the protein expression of Bcl-xL. ELISA was applied to detect the SDF-1 secretion from normal fibroblasts (NF) and CAF. Results: CAF promoted the proliferation of A549 cells, while NF had no significant effect on them. After 72 hrs incubation, the absorbance value of A549+ CAF medium group was 0.814±0.006, significantly different from the 0.753±0.006 of the A549+ NF medium group ( P A549 group, A549+ NF medium group and A549+ CAF medium group were 1.00±0.11, 1.10±0.09 and 3.50±0.30, respectively, showing a significant difference between the A549+ NF medium group and A549+ CAF medium group ( P A549 group, A549+ NF medium group and A549+ CAF medium group were 1.00±0.08, 1.10±0.12 and 3.10±0.25, respectively, with a significant difference between the A549+ NF medium group and A549+ CAF medium group ( P A549+ NF medium group and A549+ CAF medium group were 3.23±0.02 and 9.53±0.10, respectively, significantly different from each other ( P A549 group, A549+ AMD3100 group, A549+ NF medium group, A549+ NF medium+ AMD3100 group, A549+ CAF medium and A549+ CA Fmedium+ AMD3100 group were 0.43±0.03, 0.25±0.02, 0.48±0.03, 0.31±0.03, 0.72±0.06 and 0.45±0.03, respectively. The data of A549+ NF medium group was significantly different from that of A549+ CAF medium group ( P A549 cells through SDF-1 secretion, upregulating the expression level of Bcl-xL through interaction with CXCR4. Our study not only illustrates that tumor microenvironment is able to enhance

  20. The Significance of SDF-1α-CXCR4 Axis in in vivo Angiogenic Ability of Human Periodontal Ligament Stem Cells.

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    Bae, Yoon-Kyung; Kim, Gee-Hye; Lee, Jae Cheoun; Seo, Byoung-Moo; Joo, Kyeung-Min; Lee, Gene; Nam, Hyun

    2017-06-30

    Periodontal ligament stem cells (PDLSCs) are multipotent stem cells derived from periodontium and have mesenchymal stem cell (MSC)-like characteristics. Recently, the perivascular region was recognized as the developmental origin of MSCs, which suggests the in vivo angiogenic potential of PDLSCs. In this study, we investigated whether PDLSCs could be a potential source of perivascular cells, which could contribute to in vivo angiogenesis. PDLSCs exhibited typical MSC-like characteristics such as the expression pattern of surface markers (CD29, CD44, CD73, and CD105) and differentiation potentials (osteogenic and adipogenic differentiation). Moreover, PDLSCs expressed perivascular cell markers such as NG2, αsmooth muscle actin, platelet-derived growth factor receptor β, and CD146. We conducted an in vivo Matrigel plug assay to confirm the in vivo angiogenic potential of PDLSCs. We could not observe significant vessel-like structures with PDLSCs alone or human umbilical vein endothelial cells (HU-VECs) alone at day 7 after injection. However, when PDLSCs and HUVECs were co-injected, there were vessel-like structures containing red blood cells in the lumens, which suggested that anastomosis occurred between newly formed vessels and host circulatory system. To block the SDF-1α and CXCR4 axis between PDLSCs and HUVECs, AMD3100, a CXCR4 antagonist, was added into the Matrigel plug. After day 3 and day 7 after injection, there were no significant vessel-like structures. In conclusion, we demonstrated the peri-vascular characteristics of PDLSCs and their contribution to in vivo angiogenesis, which might imply potential application of PDLSCs into the neovascularization of tissue engineering and vascular diseases.

  1. Association of gene polymorphism of SDF1(CXCR12 with susceptibility to HIV-1 infection and AIDS disease progression: A meta-analysis.

    Directory of Open Access Journals (Sweden)

    Jiwei Ding

    Full Text Available Genetic polymorphism of viral receptors is relevant to risks of HIV-1 infection, while it is still under debated whether the polymorphism of SDF1, a unique ligand for HIV-1 coreceptor CXCR4, is associated with HIV susceptibility and AIDS disease progression. Therefore, we provided an updated quantitative assessment by meta-analysis from 16 case-control and 7 cohort studies.Articles reporting the relationship between SDF1 polymorphism and HIV susceptibility or AIDS progression were retrieved from PubMed, Embase and Ovid electronic databases up to Apr 2017. Data were pooled by odds ratios (ORs for HIV-1 infection with 95% confidence intervals (CIs and summary relative hazards (RHs for AIDS progression with 95% CIs using 1987 Center for Disease Control (CDC case definition of AIDS (CDC87 and 1993 Center for Disease Control (CDC case definition of AIDS (CDC93 and death as endpoints.As a result, 16 studies regarding susceptibility to HIV-1 infection with 2803 HIV-infected patients and 3697 healthy individuals and 7 studies regarding disease progression with 4239 subjects were included in the meta-analysis. For risks of infection, no evidences indicated SDF1 polymorphism was associated with the risk of HIV-1 infection in all genetic models (recessive model: OR = 0.94, 95% Cl: 0.75-1.17; homozygous model: OR = 0.89, 95% Cl: 0.70-1.15; heterozygous model: OR = 1.06, 95% Cl: 0.83-1.35; allele model: OR = 0.95, 95% Cl: 0.79-1.13, Furthermore, we failed to find an delayed AIDS progression except in some specific cohorts including MACS cohorts (RH = 0.38, 95% Cl: 0.17-0.59 for time to AIDS; RH = 0.27, 95% Cl: 0.07-0.46 for time to death at the study entry.Overall, no significant association was found between SDF1 polymorphism and HIV susceptibility. A protective effect of SDF1 on AIDS progression and death was seen especially in two studies based on the same cohorts. In conclusion, SDF1 polymorphism exerts a moderate protective effect against AIDS disease

  2. Comparison of chemokines (CCL-5 and SDF-1), chemokine receptors (CCR-5 and CXCR-4) and IL-6 levels in patients with different severities of depression.

    Science.gov (United States)

    Ogłodek, Ewa A; Szota, Anna; Just, Marek J; Moś, Danuta; Araszkiewicz, Aleksander

    2014-10-01

    Depression can be perceived as a psychoneuroimmunological disorder in which cytokines affecting the body's neurochemical and neuroendocrine functions play an important role. Among cytokines, chemokines participating in activation of the inflammatory response are considered to be crucial. 160 men and women were enrolled in the study. 120 of them were diagnosed with various types of depression. The mean age was 45.2 ± 4.5 years (range: 19-47 years). The control group consisted of 40 healthy individuals. The average age in this group was 42.4 ± 4.1 years. Plasma levels of chemokines and their receptors (CCL-5 - RANTES and CXCR-5, SDF-1 and CXCR-4), as well as of IL-6, were assessed by ELISA. There was an increase in SDF-1 and CCL-5 levels in women and men with different severities of depression, versus the control group. Also, an increase in the IL-6 levels, CXCR4 and CCR-5 receptors was observed in both women and men with all types of depression. Levels of SDF-1 and CCL-5 chemokines, as well as of CCR-5 and CXCR4 chemokine receptors, were higher in women than in men. The results of this study indicate the need for assessment of CCL-5 and SDF-1 chemokines levels, as they are likely markers of developing depression. Early measurement of these chemokines levels may be helpful in choosing the best pharmacotherapy. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  3. Chemokine stromal cell-derived factor 1alpha activates basophils by means of CXCR4

    DEFF Research Database (Denmark)

    Jinquan, T; Jacobi, H H; Jing, C

    2000-01-01

    The CXC chemokine receptor 4 (CXCR4) is predominantly expressed on inactivated naive T lymphocytes, B lymphocytes, dendritic cells, and endothelial cells. CXC chemokine stromal cell-derived factor 1alpha (SDF-1alpha) is the only known ligand for CXCR4. To date, the CXCR4 expression and function...... of SDF-1alpha in basophils are unknown....

  4. Stromal cell derived factor-1: its influence on invasiveness and migration of breast cancer cells in vitro, and its association with prognosis and survival in human breast cancer

    International Nuclear Information System (INIS)

    Kang, Hua; Watkins, Gareth; Parr, Christian; Douglas-Jones, Anthony; Mansel, Robert E; Jiang, Wen G

    2005-01-01

    Stromal cell-derived factor (SDF)-1 (CXC chemokine ligand-12) is a member of the CXC subfamily of chemokines, which, through its cognate receptor (CXC chemokine receptor [CXCR]4), plays an important role in chemotaxis of cancer cells and in tumour metastasis. We conducted the present study to evaluate the effect of SDF-1 on the invasiveness and migration of breast cancer cells, and we analyzed the expression of SDF-1 and its relation to clinicopathological features and clinical outcomes in human breast cancer. Expression of SDF-1 mRNA in breast cancer, endothelial (HECV) and fibroblast (MRC5) cell lines and in human breast tissues were studied using RT-PCR. MDA-MB-231 cells were transfected with a SDF-1 expression vector, and their invasiveness and migration was tested in vitro. In addition, the expression of SDF-1 was investigated using immunohistochemistry and quantitative RT-PCR in samples of normal human mammary tissue (n = 32) and mammary tumour (n = 120). SDF-1 expression was identified in MRC5, MDA-MB-435s and MDA-MB-436 cell lines, but CXCR4 expression was detected in all cell lines and breast tissues. An autocrine loop was created following transfection of MDA-MB-231 (which was CXCR4 positive and SDF-1 negative) with a mammalian expression cassette encoding SDF-1 (MDA-MB-231SDF1 +/+ ) or with control plasmid pcDNA4/GFP (MDA-MB-231 +/- ). MDA-MB-231SDF1 +/+ cells exhibited significantly greater invasion and migration potential (in transfected cells versus in wild type and empty MDA-MB-231 +/- ; P < 0.01). In mammary tissues SDF-1 staining was primarily seen in stromal cells and weakly in mammary epithelial cells. Significantly higher levels of SDF-1 were seen in node-positive than in node-negative tumours (P = 0.05), in tumours that metastasized (P = 0.05), and tumours from patients who died (P = 0.03) than in tumours from patients who were disease free. It was most notable that levels of SDF-1 correlated significantly with overall survival (P = 0.001) and

  5. MicroRNA-381 Favors Repair of Nerve Injury Through Regulation of the SDF-1/CXCR4 Signaling Pathway via LRRC4 in Acute Cerebral Ischemia after Cerebral Lymphatic Blockage

    Directory of Open Access Journals (Sweden)

    Jian-Min Piao

    2018-04-01

    Full Text Available Background/Aims: Acute cerebral ischemia is a manifestation of cerebral vascular insufficiency and has a high mortality. However, the therapy for acute cerebral ischemia is still limited. This study aimed to investigate the effect of microRNA-381 (miR-381 on the repair of nerve injury in rats with acute cerebral ischemia after cerebral lymphatic blockage (CLB by targeting leucine-rich repeat C4 protein (LRRC4 through the Stromal cell-derived factor-1/CXC chemokine receptor-4 signaling pathway. Methods: Rat models of CLB and middle cerebral artery occlusion (MCAO were established, and 56 Wistar rats were divided into sham, MCAO, CLB + MCAO, CLB + MCAO + miR-381 inhibitor, CLB + MCAO + miR-381 mimic, CLB + MCAO + AMD3100 and CLB + MCAO + miR-381 mimic + AMD3100 groups. Modified neurological severity score (mNSS was used to determine nerve injury, TTC staining to measure infarction volume, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL staining and flow cytometry to evaluate cell apoptosis, immunofluorescence to measure BrdU-positive cell number, enzyme-linked immunosorbent assay (ELISA to determine contents of tumor necrosis factor-α (TNF-α, interleukin-1β (IL-1β, interleukin-6 (IL-6, interleukin-10 (IL-10, nerve growth factor (NGF and neurite outgrowth inhibitor -A (Nogo-A, Reverse transcription quantitative polymerase chain reaction (RT-qPCR and Western blotting to evaluate expression of miR-381, LRRC4, SDF-1, CXCR4, pERK, Slit2 and vascular endothelial growth factor (VEGF. Results: LRRC4 was a target gene of miR-381. Compared with the results in the CLB + MCAO group, mNSS, infarction volume, apoptosis rate and TNF-α, IL-1β, IL-6 and Nogo-A contents as well as LRRC4 expression in the CLB + MCAO + miR-381 inhibitor and CLB + MCAO + AMD3100 groups were increased (those in the CLB + MCAO + AMD3100 group > those in the CLB + MCAO + miR-381 mimic + AMD3100 group, while BrdU-positive cell number, contents of NGF and

  6. LPS Promotes Pre-osteoclast Activity by Up-regulating CXCR4 via TLR-4

    NARCIS (Netherlands)

    Xing, Q.; de Vos, P.; Faas, M. M.; Ye, Q.; Ren, Y.

    Lipopolysaccharide (LPS) has been shown to be a prominent pathogenic factor in inflammatory bone loss. However, knowledge of the mechanisms involved is limited. The role of the SDF-1/CXCR4 (Stromal-derived factor-1 and its unique chemokine receptor) axis in LPS-induced bone loss has not been

  7. The role of CXCL12-CXCR4 signaling pathway in pancreatic development

    DEFF Research Database (Denmark)

    Katsumoto, Keiichi; Kume, Shoen

    2013-01-01

    Chemokine (C-X-C motif) receptor 4 (CXCR4) is the receptor for chemokine (C-X-C motif) ligand 12 (CXCL12, also known as stromal derived factor-1, Sdf1). CXCR4, a protein consisting 352 amino acids, is known to transduce various signals such as cell differentiation, cell survival, cell proliferation...

  8. Stanniocalcin-1 regulates endothelial gene expression and modulates trans-endothelial migration of leukocytes

    Science.gov (United States)

    The mammalian counterpart of the fish calcium-regulating hormone stanniocalcin-1 (STC1) inhibits monocyte chemotactic protein-1- and stromal-derived factor-1alpha (SDF-1alpha)-mediated chemotaxis and diminishes chemokinesis in macrophage-like RAW264.7 and U937 cells in a manner that may involve atte...

  9. Stromal Cell-Derived Factor 1 Gene Polymorphism Is Associated with Susceptibility to Adverse Long-Term Allograft Outcomes in Non-Diabetic Kidney Transplant Recipients

    Directory of Open Access Journals (Sweden)

    Chung-Jieh Wang

    2014-07-01

    Full Text Available Although the genetic polymorphism of Stromal Cell-Derived Factor 1 (SDF-1 is associated with higher mortality of liver allograft recipients, the role of SDF-1 in the modulation of renal allograft outcomes is unclear. Between March 2000 and January 2008, we recruited 252 non-diabetic renal transplant recipients (RTRs. Baseline characteristics and blood chemistry were recorded. Genomic DNA extraction with polymerase chain reaction-restriction fragment length polymorphism was utilized to analyze the genetic polymorphisms of SDF-1 (rs1801157. The influence of SDF-1 on an adverse renal allograft outcome, defined as either a doubling of serum creatinine, graft failure, or patient death was evaluated. Sixteen patients with the SDF-1 AA/AG genotype and nine with the SDF-1 GG genotype reached an adverse outcome. According to Kaplan-Meier analysis, patients carrying the SDF-1 AA/AG genotype or A allele showed a significantly higher risk of reaching an adverse outcome than those carrying the SDF-1 GG genotype or G allele (p = 0.041; p = 0.0051, respectively; log rank test. Stepwise multivariate Cox proportional regression analysis revealed that patients carrying the SDF-1 AA/AG genotype and A allele had a 2.742-fold (95% CI. 1.106–6.799, p = 0.03 and 2.306-fold (95% CI. 1.254–4.24, p = 0.008 risk of experiencing an adverse outcome. The SDF-1 AA/AG genotype and A allele have a detrimental impact on the long-term outcome of RTRs.

  10. Effects of CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles on HIV-1 disease progression

    DEFF Research Database (Denmark)

    Ioannidis, J P; Rosenberg, P S; Goedert, J J

    2001-01-01

    seroconversion. Data were combined with fixed-effects and random-effects models. RESULTS: Both the CCR5-Delta32 and CCR2-64I alleles were associated with a decreased risk for progression to AIDS (relative hazard among seroconverters, 0.74 and 0.76, respectively; P = 0.01 for both), a decreased risk for death...... (relative hazard among seroconverters, 0.64 and 0.74; P CCR5-Delta32 or CCR2-64I allele had no clear protective effect on the risk for death.......00), or death after development of AIDS (relative hazard, 0.81 and 0.97; P > 0.5 for all). CONCLUSIONS: The CCR5-Delta32 and CCR2-64I alleles had a strong protective effect on progression of HIV-1 infection, but SDF-1 3'A homozygosity carried no such protection....

  11. Distribution of CCR5-Delta32, CCR5 promoter 59029 A/G, CCR2-64I and SDF1-3’A genetic polymorphisms in HIV-1 infected and uninfected patients in the West Region of Cameroon

    Science.gov (United States)

    2013-01-01

    Background Genetic variants of the genes encoding Human Immunodeficiency Virus-1 (HIV-1) co-receptors and their ligands, like CC-Chemokine Receptor 5 delta 32 mutation (CCR5-Delta32), CCR5 promoter A/G (Adenine/Guanine), CC-Chemokine Receptor 2 mutation 64 isoleucine (CCR2-64I) and the Stromal cell-derived Factor 3’A mutation (SDF1-3’A), are involved in the susceptibility to HIV-1 infection and progression. The prevalence of these mutations varies by Region. However, little is known about their distribution in the population of Dschang, located in the West Region of Cameroon. The prevalence of HIV in the West Region of Cameroon is lower than elsewhere in Cameroon. The objectives of this study were to determine the distribution of four AIDS Related Gene (ARG) variants in HIV-infected and non-infected population of Cameroon especially in the West Region and to estimate the contribution of these variants to the susceptibility or resistance to HIV infection. We also aimed to evaluate the effectiveness of genotyping using dried blood spot (DBS) samples. Methods A total of 179 participants were recruited from two hospitals in Dschang in the West Region of Cameroon. Their genotypes for CCR5-Delta32, CCR5 promoter 59029A/G, CCR2-64I and SDF1-3’A were analyzed using polymerase chain reaction (PCR) and restriction fragment length polymorphisms. Results A total of 179 participants were enrolled in the study. Among them, 32 (17.9%) were HIV positive and 147 (82.1%) were HIV negative. The allelic frequencies of these genes were: 0%, 49.72%, 17.6% and 100% respectively for CCR5-Delta32, CCR5 promoter 59029A/G, CCR2-64I and SDF1-3’A. No individual was found to carry the CCR5-Delta 32 mutation. All participants recruited were heterozygous for the SDF1-3’A allele. Conclusion Our data suggest that the CCR5-Delta32 cannot account for the protection as it was completely absent in our population. SDF1-3’A variants, may be in association with other polymorphisms, may account

  12. Stroma cell-derived factor-1α signaling enhances calcium transients and beating frequency in rat neonatal cardiomyocytes.

    Directory of Open Access Journals (Sweden)

    Ielham Hadad

    Full Text Available Stroma cell-derived factor-1α (SDF-1α is a cardioprotective chemokine, acting through its G-protein coupled receptor CXCR4. In experimental acute myocardial infarction, administration of SDF-1α induces an early improvement of systolic function which is difficult to explain solely by an anti-apoptotic and angiogenic effect. We wondered whether SDF-1α signaling might have direct effects on calcium transients and beating frequency.Primary rat neonatal cardiomyocytes were culture-expanded and characterized by immunofluorescence staining. Calcium sparks were studied by fluorescence microscopy after calcium loading with the Fluo-4 acetoxymethyl ester sensor. The cardiomyocyte enriched cellular suspension expressed troponin I and CXCR4 but was vimentin negative. Addition of SDF-1α in the medium increased cytoplasmic calcium release. The calcium response was completely abolished by using a neutralizing anti-CXCR4 antibody and partially suppressed and delayed by preincubation with an inositol triphosphate receptor (IP3R blocker, but not with a ryanodine receptor (RyR antagonist. Calcium fluxes induced by caffeine, a RyR agonist, were decreased by an IP3R blocker. Treatment with forskolin or SDF-1α increased cardiomyocyte beating frequency and their effects were additive. In vivo, treatment with SDF-1α increased left ventricular dP/dtmax.These results suggest that in rat neonatal cardiomyocytes, the SDF-1α/CXCR4 signaling increases calcium transients in an IP3-gated fashion leading to a positive chronotropic and inotropic effect.

  13. Inhibition of SDF-1-induced migration of oncogene-driven myeloid leukemia by the L-RNA aptamer (Spiegelmer), NOX-A12, and potentiation of tyrosine kinase inhibition.

    Science.gov (United States)

    Weisberg, Ellen L; Sattler, Martin; Azab, Abdel Kareem; Eulberg, Dirk; Kruschinski, Anna; Manley, Paul W; Stone, Richard; Griffin, James D

    2017-12-15

    Resistance to targeted tyrosine kinase inhibitors (TKI) remains a challenge for the treatment of myeloid leukemias. Following treatment with TKIs, the bone marrow microenvironment has been found to harbor a small pool of surviving leukemic CD34+ progenitor cells. The long-term survival of these leukemic cells has been attributed, at least in part, to the protective effects of bone marrow stroma. We found that the NOX-A12 'Spiegelmer', an L-enantiomeric RNA oligonucleotide that inhibits SDF-1α, showed in vitro and in vivo activity against BCR-ABL- and FLT3-ITD-dependent leukemia cells. NOX-A12 was sufficient to suppress SDF-1-induced migration in vitro . The combination of NOX-A12 with TKIs reduced cell migration in the same in vitro model of SDF-1-induced chemotaxis to a greater extent than either drug alone, suggesting positive cooperativity as a result of the SDF-1 blocking function of NOX-A12 and cytotoxicity resulting from targeted oncogenic kinase inhibition. These results are consistent with our in vivo findings using a functional pre-clinical mouse model of chronic myeloid leukemia (CML), whereby we demonstrated the ability of NOX-A12, combined with the ABL kinase inhibitor, nilotinib, to reduce the leukemia burden in mice to a greater extent than either agent alone. Overall, the data support the idea of using SDF-1 inhibition in combination with targeted kinase inhibition to override drug resistance in oncogene-driven leukemia to significantly diminish or eradicate residual leukemic disease.

  14. RhoA and RhoC are involved in stromal cell-derived factor-1-induced cell migration by regulating F-actin redistribution and assembly.

    Science.gov (United States)

    Luo, Jixian; Li, Dingyun; Wei, Dan; Wang, Xiaoguang; Wang, Lan; Zeng, Xianlu

    2017-12-01

    Stromal cell-derived factor-1 (SDF-1) signaling is important to the maintenance and progression of T-cell acute lymphoblastic leukemia by inducing chemotaxis migration. To identify the mechanism of SDF-1 signaling in the migration of T-ALL, Jurkat acute lymphoblastic leukemia cells were used. Results showed that SDF-1 induces Jurkat cell migration by F-actin redistribution and assembly, which is dependent on Rho activity. SDF-1 induced RhoA and RhoC activation, as well as reactive oxygen species (ROS) production, which was inhibited by Rho inhibitor. The Rho-dependent ROS production led to subsequent cytoskeleton redistribution and assembly in the process of migration. Additionally, RhoA and RhoC were involved in SDF-1-induced Jurkat cell migration. Taken together, we found a SDF-1/CXCR4-RhoA and RhoC-ROS-cytoskeleton pathway that regulates Jurkat cell migration in response to SDF-1. This work will contribute to a clearer insight into the migration mechanism of acute lymphoblastic leukemia.

  15. 舌扁平上皮癌におけるSDF-1/CXCR4 発現と臨床病理的因子との関連について

    OpenAIRE

    中津川, 周生; 獨協医科大学口腔外科学

    2012-01-01

    ケモカインSDF-1 とその受容体であるCXCR4 による ケモカインシステムは,癌の転移ならびに細胞増殖に関与すると報告されており,多臓器において研究がなされているが,その発現と臨床的意義については,一定の見解が得られていない.今回われわれは,舌扁平上皮癌におけるSDF-1/CXCR4 の発現と臨床病理学的因子(年齢,性別, pT, pN, pStage, 分化度, Y-K 分類,5 年累積生存率)との関係について検討をしたので報告する.対象は,当科にて手術療法を施行した舌扁平上皮癌一次症例53 例で,未治療生検組織を用い,リアルタイムRT-PCR による遺伝子発現および免疫組織化学染色法を用い発現検索を行った.その結果,SDF-1遺伝子発現例に頸部リンパ節転移が有意に多く, 5 年累積生存率においては,SDF-1 ならびにCXCR4 遺伝子が両者共に発現した症例は,SDF-1 とCXCR4 遺伝子両者共に発現しなかった症例と比べ,有意に生存率が不良であった.しかしながら,それ以外の因子では,遺伝子検索ならびに免疫組織化学染色による検討のいずれにおいても,SDF-1 とCXCR...

  16. Linker-free covalent immobilization of heparin, SDF-1α, and CD47 on PTFE surface for antithrombogenicity, endothelialization and anti-inflammation.

    Science.gov (United States)

    Gao, Ang; Hang, Ruiqiang; Li, Wan; Zhang, Wei; Li, Penghui; Wang, Guomin; Bai, Long; Yu, Xue-Feng; Wang, Huaiyu; Tong, Liping; Chu, Paul K

    2017-09-01

    Small-diameter vascular grafts made of biomedical polytetrafluoroethylene (PTFE) suffer from the poor long-term patency rate originating from thrombosis and intimal hyperplasia, which can be ascribed to the insufficient endothelialization and chronic inflammation of the materials. Hence, bio-functionalization of PTFE grafts is highly desirable to circumvent these disadvantages. In this study, a versatile "implantation-incubation" approach in which the biomedical PTFE is initially modified by plasma immersion ion implantation (PIII) is described. After the N 2 PIII treatment, the surface of biomedical PTFE is roughened with nanostructures and more importantly, the abundant free radicals generated underneath the surface continuously migrate to the surface and react with environmental molecules. Taking advantage of this mechanism, various biomolecules with different functions can be steadily immobilized on the surface of PTFE by simple solution immersion. As examples, three typical biomolecules, heparin, SDF-1α, and CD47, are covalently grafted onto the PTFE. In addition to retaining the bioactivity, the surface-functionalized PTFE exhibits reduced thrombogenicity, facilitates the recruitment of endothelial progenitor cells, and even alleviates the inflammatory immune responses of monocytes-macrophages and is thus promising to the development of small-diameter prosthetic vascular grafts with good long-term patency. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Low-Dose Bone Morphogenetic Protein-2/Stromal Cell-Derived Factor-1β Cotherapy Induces Bone Regeneration in Critical-Size Rat Calvarial Defects

    Science.gov (United States)

    Herberg, Samuel; Susin, Cristiano; Pelaez, Manuel; Howie, R. Nicole; Moreno de Freitas, Rubens; Lee, Jaebum; Cray, James J.; Johnson, Maribeth H.; Elsalanty, Mohammed E.; Hamrick, Mark W.; Isales, Carlos M.; Wikesjö, Ulf M.E.

    2014-01-01

    Increasing evidence suggests that stromal cell-derived factor-1 (SDF-1/CXCL12) is involved in bone formation, though underlying molecular mechanisms remain to be fully elucidated. Also, contributions of SDF-1β, the second most abundant splice variant, as an osteogenic mediator remain obscure. We have shown that SDF-1β enhances osteogenesis by regulating bone morphogenetic protein-2 (BMP-2) signaling in vitro. Here we investigate the dose-dependent contribution of SDF-1β to suboptimal BMP-2-induced local bone formation; that is, a dose that alone would be too low to significantly induce bone formation. We utilized a critical-size rat calvarial defect model and tested the hypotheses that SDF-1β potentiates BMP-2 osteoinduction and that blocking SDF-1 signaling reduces the osteogenic potential of BMP-2 in vivo. In preliminary studies, radiographic analysis at 4 weeks postsurgery revealed a dose-dependent relationship in BMP-2-induced new bone formation. We then found that codelivery of SDF-1β potentiates suboptimal BMP-2 (0.5 μg) osteoinduction in a dose-dependent order, reaching comparable levels to the optimal BMP-2 dose (5.0 μg) without apparent adverse effects. Blocking the CXC chemokine receptor 4 (CXCR4)/SDF-1 signaling axis using AMD3100 attenuated the osteoinductive potential of the optimal BMP-2 dose, confirmed by qualitative histologic analysis. In conclusion, SDF-1β provides potent synergistic effects that support BMP-induced local bone formation and thus appears a suitable candidate for optimization of bone augmentation using significantly lower amounts of BMP-2 in spine, orthopedic, and craniofacial settings. PMID:24341891

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

    Science.gov (United States)

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

    2018-04-01

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

  19. The SDF1-CXCR4 Axis Functions through p38-MAPK Signaling to Drive Breast Cancer Progression and Metastasis

    Science.gov (United States)

    2008-09-01

    hormone-independent, endocrine therapy resistant and metastatic phenotype. Our preliminary evidence demonstrates that over expression of CXCR4 in... AER signal pathway, growth factor mediated signaling, and other kinase networks could be responsible for this resistance. It has been shown that...and PI3K/AKT have been implicated in development of endocrine therapy resistance in breast carcinoma. More recently, our lab became interested in

  20. Combination of Vessel-Targeting Agents and Fractionated Radiation Therapy: The Role of the SDF-1/CXCR4 Pathway

    International Nuclear Information System (INIS)

    Chen, Fang-Hsin; Fu, Sheng-Yung; Yang, Ying-Chieh; Wang, Chun-Chieh; Chiang, Chi-Shiun; Hong, Ji-Hong

    2013-01-01

    Purpose: To investigate vascular responses during fractionated radiation therapy (F-RT) and the effects of targeting pericytes or bone marrow-derived cells (BMDCs) on the efficacy of F-RT. Methods and Materials: Murine prostate TRAMP-C1 tumors were grown in control mice or mice transplanted with green fluorescent protein-tagged bone marrow (GFP-BM), and irradiated with 60 Gy in 15 fractions. Mice were also treated with gefitinib (an epidermal growth factor receptor inhibitor) or AMD3100 (a CXCR4 antagonist) to examine the effects of combination treatment. The responses of tumor vasculatures to these treatments and changes of tumor microenvironment were assessed. Results: After F-RT, the tumor microvascular density (MVD) was reduced; however, the surviving vessels were dilated, incorporated with GFP-positive cells, tightly adhered to pericytes, and well perfused with Hoechst 33342, suggesting a more mature structure formed primarily via vasculogenesis. Although the gefitinib+F-RT combination affected the vascular structure by dissociating pericytes from the vascular wall, it did not further delay tumor growth. These tumors had higher MVD and better vascular perfusion function, leading to less hypoxia and tumor necrosis. By contrast, the AMD3100+F-RT combination significantly enhanced tumor growth delay more than F-RT alone, and these tumors had lower MVD and poorer vascular perfusion function, resulting in increased hypoxia. These tumor vessels were rarely covered by pericytes and free of GFP-positive cells. Conclusions: Vasculogenesis is a major mechanism for tumor vessel survival during F-RT. Complex interactions occur between vessel-targeting agents and F-RT, and a synergistic effect may not always exist. To enhance F-RT, using CXCR4 inhibitor to block BM cell influx and the vasculogenesis process is a better strategy than targeting pericytes by epidermal growth factor receptor inhibitor

  1. Stem cells from human exfoliated deciduous tooth exhibit stromal-derived inducing activity and lead to generation of neural crest cells from human embryonic stem cells.

    Science.gov (United States)

    Karbalaie, Khadijeh; Tanhaei, Somayyeh; Rabiei, Farzaneh; Kiani-Esfahani, Abbas; Masoudi, Najmeh Sadat; Nasr-Esfahani, Mohammad Hossein; Baharvand, Hossein

    2015-01-01

    The neural crest is a transient structure of early vertebrate embryos that generates neural crest cells (NCCs). These cells can migrate throughout the body and produce a diverse array of mature tissue types. Due to the ethical and technical problems surrounding the isolation of these early human embryo cells, researchers have focused on in vitro studies to produce NCCs and increase their knowledge of neural crest development. In this experimental study, we cultured human embryonic stem cells (hESCs) on stromal stem cells from human exfoliated deciduous teeth (SHED) for a two-week period. We used different approaches to characterize these differentiated cells as neural precursor cells (NPCs) and NCCs. In the first co-culture week, hESCs appeared as crater-like structures with marginal rosettes. NPCs derived from these structures expressed the early neural crest marker p75 in addition to numerous other genes associated with neural crest induction such as SNAIL, SLUG, PTX3 and SOX9. Flow cytometry analysis showed 70% of the cells were AP2/P75 positive. Moreover, the cells were able to self-renew, sustain multipotent differentiation potential, and readily form neurospheres in suspension culture. SHED, as an adult stem cell with a neural crest origin, has stromal-derived inducing activity (SDIA) and can be used as an NCC inducer from hESCs. These cells provide an invaluable resource to study neural crest differentiation in both normal and disordered human neural crest development.

  2. Platelet expression of stromal cell-derived factor-1 is associated with the degree of valvular aortic stenosis.

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    Thomas Wurster

    Full Text Available BACKGROUND AND PURPOSE: Platelet surface expression of stromal-cell-derived factor-1 (SDF-1 is increased during platelet activation and constitutes an important factor in hematopoetic progenitor cell trafficking at sites of vascular injury and ischemia. Enhanced platelet SDF-1 expression has been reported previously in patients suffering from acute coronary syndrome (ACS. We hypothesized that expression of platelet associated SDF-1 may also be influenced by calcified valvular aortic stenosis (AS. METHODS: We consecutively evaluated 941 patients, who were admitted to the emergency department with dyspnea and chest pain. Platelet surface expression of SDF-1 was determined by flow cytometry, AS was assessed using echocardiography and hemodynamic assessment by heart catheterization. A 1∶1 propensity score matching was implemented to match 218 cases with 109 pairs adjusting for age, sex, cardiovascular risk factors, and medication including ACE inhibitors, angiotensin receptor blockers, beta blockers, statins, aspirin, clopidogrel, GPIIb/IIIa antagonists, and vitamin K antagonists. RESULTS: Patients with valvular AS showed enhanced platelet SDF-1 expression compared to patients without AS (non-valvular disease, NV independent of ACS and stable coronary artery disease (SAP [mean fluorescence intensity (MFI for ACS (AS vs. NV: 75±40.4 vs. 39.5±23.3; P = 0.002; for SAP (AS vs. NV: 54.9±44.6 vs. 24.3±11.2; P = 0.008]. Moreover, the degree of AS significantly correlated with SDF-1 platelet surface expression (r = 0.462; P = 0.002. CONCLUSIONS: Valvular AS is associated with enhanced platelet-SDF-1 expression; moreover the degree of valvular AS correlates with SDF-1 platelet surface expression. These findings may have clinical implications in the future.

  3. Platelet expression of stromal cell-derived factor-1 is associated with the degree of valvular aortic stenosis.

    Science.gov (United States)

    Wurster, Thomas; Tegtmeyer, Roland; Borst, Oliver; Rath, Dominik; Geisler, Tobias; Gawaz, Meinrad; Bigalke, Boris

    2014-01-01

    Platelet surface expression of stromal-cell-derived factor-1 (SDF-1) is increased during platelet activation and constitutes an important factor in hematopoetic progenitor cell trafficking at sites of vascular injury and ischemia. Enhanced platelet SDF-1 expression has been reported previously in patients suffering from acute coronary syndrome (ACS). We hypothesized that expression of platelet associated SDF-1 may also be influenced by calcified valvular aortic stenosis (AS). We consecutively evaluated 941 patients, who were admitted to the emergency department with dyspnea and chest pain. Platelet surface expression of SDF-1 was determined by flow cytometry, AS was assessed using echocardiography and hemodynamic assessment by heart catheterization. A 1∶1 propensity score matching was implemented to match 218 cases with 109 pairs adjusting for age, sex, cardiovascular risk factors, and medication including ACE inhibitors, angiotensin receptor blockers, beta blockers, statins, aspirin, clopidogrel, GPIIb/IIIa antagonists, and vitamin K antagonists. Patients with valvular AS showed enhanced platelet SDF-1 expression compared to patients without AS (non-valvular disease, NV) independent of ACS and stable coronary artery disease (SAP) [mean fluorescence intensity (MFI) for ACS (AS vs. NV): 75±40.4 vs. 39.5±23.3; P = 0.002; for SAP (AS vs. NV): 54.9±44.6 vs. 24.3±11.2; P = 0.008]. Moreover, the degree of AS significantly correlated with SDF-1 platelet surface expression (r = 0.462; P = 0.002). Valvular AS is associated with enhanced platelet-SDF-1 expression; moreover the degree of valvular AS correlates with SDF-1 platelet surface expression. These findings may have clinical implications in the future.

  4. Epigenetic regulation of cardiac progenitor cells marker c-kit by stromal cell derived factor-1α.

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    Zhongpu Chen

    Full Text Available BACKGROUND: Cardiac progenitor cells (CPCs have been proven suitable for stem cell therapy after myocardial infarction, especially c-kit(+CPCs. CPCs marker c-kit and its ligand, the stem cell factor (SCF, are linked as c-kit/SCF axis, which is associated with the functions of proliferation and differentiation. In our previous study, we found that stromal cell-derived factor-1α (SDF-1α could enhance the expression of c-kit. However, the mechanism is unknown. METHODS AND RESULTS: CPCs were isolated from adult mouse hearts, c-kit(+ and c-kit(- CPCs were separated by magnetic beads. The cells were cultured with SDF-1α and CXCR4-selective antagonist AMD3100, and c-kit expression was measured by qPCR and Western blotting. Results showed that SDF-1α could enhance c-kit expression of c-kit(+CPCs, made c-kit(-CPCs expressing c-kit, and AMD3100 could inhibit the function of SDF-1α. After the intervention of SDF-1α and AMD3100, proliferation and migration of CPCs were measured by CCK-8 and transwell assay. Results showed that SDF-1α could enhance the proliferation and migration of both c-kit(+ and c-kit(- CPCs, and AMD3100 could inhibit these functions. DNA methyltransferase (DNMT mRNA were measured by qPCR, DNMT activity was measured using the DNMT activity assay kit, and DNA methylation was analyzed using Sequenom's MassARRAY platform, after the CPCs were cultured with SDF-1α. The results showed that SDF-1α stimulation inhibited the expression of DNMT1 and DNMT3β, which are critical for the maintenance of regional DNA methylation. Global DNMT activity was also inhibited by SDF-1α. Lastly, SDF-1α treatment led to significant demethylation in both c-kit(+ and c-kit(- CPCs. CONCLUSIONS: SDF-1α combined with CXCR4 could up-regulate c-kit expression of c-kit(+CPCs and make c-kit(-CPCs expressing c-kit, which result in the CPCs proliferation and migration ability improvement, through the inhibition of DNMT1 and DNMT3β expression and global DNMT

  5. Expression of platelet-bound stromal cell-derived factor-1 in patients with non-valvular atrial fibrillation and ischemic heart disease.

    Science.gov (United States)

    Stellos, Konstantinos; Rahmann, A; Kilias, A; Ruf, M; Sopova, K; Stamatelopoulos, K; Jorbenadze, R; Weretka, S; Geisler, T; Gawaz, M; Weig, H-J; Bigalke, B

    2012-01-01

    Blood cell infiltration and inflammation are involved in atrial remodelling during atrial fibrillation (AF) although the exact mechanisms of inflammatory cell recruitment remain poorly understood. Platelet-bound stromal cell-derived factor-1 (SDF-1) is increased in cases of ischemic myocardium and regulates recruitment of CXCR4(+) cells on the vascular wall. Whether platelet-bound SDF-1 expression is differentially influenced by non-valvular paroxysmal or permanent atrial fibrillation (AF) in patients with stable angina pectoris (SAP) or acute coronary syndrome (ACS) has not been reported so far. A total of 1291 consecutive patients with coronary artery disease (CAD) undergoing coronary angiography were recruited. Among the patients with SAP, platelet-bound-SDF-1 is increased in patients with paroxysmal AF compared with SR or to persistent/permanent AF (P disease. Further in vivo studies are required to elucidate the role of SDF-1 in atrial remodeling and the atrial fibrillation course.

  6. Stromal cell derived factor-1α (SDF-1α) directed chemoattraction of transiently CXCR4 overexpressing mesenchymal stem cells into functionalized three-dimensional biomimetic scaffolds

    DEFF Research Database (Denmark)

    Thieme, S; Ryser, Martin; Gentsch, Marcus

    2009-01-01

    Three-dimensional (3D) bone substitute material should not only serve as scaffold in large bone defects but also attract mesenchymal stem cells, a subset of bone marrow stromal cells (BMSCs) that are able to form new bone tissue. An additional crucial step is to attract BMSCs from the surface int...

  7. Early in-situ cellularization of a supramolecular vascular graft is modified by synthetic stromal cell-derived factor-1α derived peptides.

    Science.gov (United States)

    Muylaert, Dimitri E P; van Almen, Geert C; Talacua, Hanna; Fledderus, Joost O; Kluin, Jolanda; Hendrikse, Simone I S; van Dongen, Joost L J; Sijbesma, Eline; Bosman, Anton W; Mes, Tristan; Thakkar, Shraddha H; Smits, Anthal I P M; Bouten, Carlijn V C; Dankers, Patricia Y W; Verhaar, Marianne C

    2016-01-01

    In an in-situ approach towards tissue engineered cardiovascular replacement grafts, cell-free scaffolds are implanted that engage in endogenous tissue formation. Bioactive molecules can be incorporated into such grafts to facilitate cellular recruitment. Stromal cell derived factor 1α (SDF1α) is a powerful chemoattractant of lymphocytes, monocytes and progenitor cells and plays an important role in cellular signaling and tissue repair. Short SDF1α-peptides derived from its receptor-activating domain are capable of activating the SDF1α-specific receptor CXCR4. Here, we show that SDF1α-derived peptides can be chemically modified with a supramolecular four-fold hydrogen bonding ureido-pyrimidinone (UPy) moiety, that allows for the convenient incorporation of the UPy-SDF1α-derived peptides into a UPy-modified polymer scaffold. We hypothesized that a UPy-modified material bioactivated with these UPy-SDF1α-derived peptides can retain and stimulate circulating cells in an anti-inflammatory, pro-tissue formation signaling environment. First, the early recruitment of human peripheral blood mononuclear cells to the scaffolds was analyzed in vitro in a custom-made mesofluidic device applying physiological pulsatile fluid flow. Preferential adhesion of lymphocytes with reduced expression of inflammatory factors TNFα, MCP1 and lymphocyte activation marker CD25 was found in the bioactivated scaffolds, indicating a reduction in inflammatory signaling. As a proof of concept, in-vivo implantation of the bioactivated scaffolds as rat abdominal aorta interposition grafts showed increased cellularity by CD68+ cells after 7 days. These results indicate that a completely synthetic, cell-free biomaterial can attract and stimulate specific leukocyte populations through supramolecular incorporation of short bioactive SDF1α derived peptides. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Frequencies of CCR5-D32, CCR2-64I and SDF1-3’A mutations in Human Immunodeficiency Virus (HIV seropositive subjects and seronegative individuals from the state of Pará in Brazilian Amazonia

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    Fernanda Andreza de Pinho Lott Carvalhaes

    2005-12-01

    Full Text Available The distribution of genetic polymorphisms of chemokine receptors CCR5-delta32, CCR2-64I and chemokine (SDF1-3’A mutations were studied in 110 Human Immunodeficiency Virus type 1 (HIV-1 seropositive individuals (seropositive group and 139 seronegative individuals (seronegative group from the population of the northern Brazilian city of Belém which is the capital of the state of Pará in the Brazilian Amazon. The CCR5-delta32 mutation was found in the two groups at similar frequencies, i.e. 2.2% for the seronegative group and 2.7% for the seropositive group. The frequencies of the SDF1-3’A mutation were 21.0% for the seronegative group and 15.4% for the seropositive group, and the CCR2-64I allele was found at frequencies of 12.5% for the seronegative group and 5.4% for the seropositive group. Genotype distributions were consistent with Hardy-Weinberg expectations in both groups, suggesting that none of the three mutations has a detectable selective effect. Difference in the allelic and genotypic frequencies was statistically significant for the CCR2 locus, the frequency in the seronegative group being twice that found in the seropositive group. This finding may indicate a protective effect of the CCR2-64I mutation in relation to HIV transmission. However, considering that the CCR2-64I mutation has been more strongly associated with a decreased risk for progression for AIDS than to the resistance to the HIV infection, this could reflect an aspect of population structure or a Type I error.

  9. Signalling mechanisms of SDF-induced endothelial cell proliferation and migration

    International Nuclear Information System (INIS)

    Kuhlmann, Christoph Ruediger Wolfram; Schaefer, Christian Alexander; Reinhold, Lars; Tillmanns, Harald; Erdogan, Ali

    2005-01-01

    The aim of our study was to investigate the effect of stromal-derived factor-1-α (SDF-1-α) on endothelial angiogenic effects. SDF-1-α (50 ng/ml) increased the number of cultured endothelial cells from 33,653 ± 1183 to 55,398 ± 2741, which significantly reduced by adding the BK Ca -inhibitor iberiotoxin, or the endothelial nitric oxide synthase-blocker, L-NMMA (n = 24, p Ca open-state probability (NPo) was analysed using the patch-clamp technique and NPo was increased from 0.003 (control) to 0.052 (SDF-1-α; n = 10, p Ca and an increased production of NO

  10. Spatio-temporal changes of SDF1 and its CXCR4 receptor in the dorsal root ganglia following unilateral sciatic nerve injury as a model of neuropathic pain

    Czech Academy of Sciences Publication Activity Database

    Dubový, P.; Klusáková, I.; Svíženská, I.; Brázda, Václav

    2010-01-01

    Roč. 133, č. 3 (2010), s. 323-337 ISSN 0948-6143 Grant - others:GA ČR(CZ) GA309/07/0121 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : chemokine * satellite glial cells * chronic constriction injury Subject RIV: BO - Biophysics Impact factor: 4.727, year: 2010

  11. Platelet-derived stromal cell-derived factor-1 is required for the transformation of circulating monocytes into multipotential cells.

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    Noriyuki Seta

    Full Text Available BACKGROUND: We previously described a primitive cell population derived from human circulating CD14(+ monocytes, named monocyte-derived multipotential cells (MOMCs, which are capable of differentiating into mesenchymal and endothelial lineages. To generate MOMCs in vitro, monocytes are required to bind to fibronectin and be exposed to soluble factor(s derived from circulating CD14(- cells. The present study was conducted to identify factors that induce MOMC differentiation. METHODS: We cultured CD14(+ monocytes on fibronectin in the presence or absence of platelets, CD14(- peripheral blood mononuclear cells, platelet-conditioned medium, or candidate MOMC differentiation factors. The transformation of monocytes into MOMCs was assessed by the presence of spindle-shaped adherent cells, CD34 expression, and the potential to differentiate in vitro into mesenchymal and endothelial lineages. RESULTS: The presence of platelets or platelet-conditioned medium was required to generate MOMCs from monocytes. A screening of candidate platelet-derived soluble factors identified stromal cell-derived factor (SDF-1 as a requirement for generating MOMCs. Blocking an interaction between SDF-1 and its receptor CXCR4 inhibited MOMC generation, further confirming SDF-1's critical role in this process. Finally, circulating MOMC precursors were found to reside in the CD14(+CXCR4(high cell population. CONCLUSION: The interaction of SDF-1 with CXCR4 is essential for the transformation of circulating monocytes into MOMCs.

  12. Overexpression of CXCR4 on human CD34+ progenitors increases their proliferation, migration, and NOD/SCID repopulation.

    Science.gov (United States)

    Kahn, Joy; Byk, Tamara; Jansson-Sjostrand, Lottie; Petit, Isabelle; Shivtiel, Shoham; Nagler, Arnon; Hardan, Izhar; Deutsch, Varda; Gazit, Zulma; Gazit, Dan; Karlsson, Stefan; Lapidot, Tsvee

    2004-04-15

    A major limitation to clinical stem cell-mediated gene therapy protocols is the low levels of engraftment by transduced progenitors. We report that CXCR4 overexpression on human CD34+ progenitors using a lentiviral gene transfer technique helped navigate these cells to the murine bone marrow and spleen in response to stromal-derived factor 1 (SDF-1) signaling. Cells overexpressing CXCR4 exhibited significant increases in SDF-1-mediated chemotaxis and actin polymerization compared with control cells. A major advantage of CXCR4 overexpression was demonstrated by the ability of transduced CD34+ cells to respond to lower, physiologic levels of SDF-1 when compared to control cells, leading to improved SDF-1-induced migration and proliferation/survival, and finally resulting in significantly higher levels of in vivo repopulation of nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice including primitive CD34+/CD38(-/low) cells. Importantly, no cellular transformation was observed following transduction with the CXCR4 vector. Unexpectedly, we documented lack of receptor internalization in response to high levels of SDF-1, which can also contribute to increased migration and proliferation by the transduced CD34+ cells. Our results suggest CXCR4 overexpression for improved definitive human stem cell motility, retention, and multilineage repopulation, which could be beneficial for in vivo navigation and expansion of hematopoietic progenitors.

  13. Perspectives on testicular sex cord-stromal tumors and those composed of both germ cells and sex cord-stromal derivatives with a comparison to corresponding ovarian neoplasms.

    Science.gov (United States)

    Roth, Lawrence M; Lyu, Bingjian; Cheng, Liang

    2017-07-01

    Sex cord-stromal tumors (SCSTs) are the second most frequent category of testicular neoplasms, accounting for approximately 2% to 5% of cases. Both genetic and epigenetic factors account for the differences in frequency and histologic composition between testicular and ovarian SCSTs. For example, large cell calcifying Sertoli cell tumor and intratubular large cell hyalinizing Sertoli cell neoplasia occur in the testis but have not been described in the ovary. In this article, we discuss recently described diagnostic entities as well as inconsistencies in nomenclature used in the recent World Health Organization classifications of SCSTs in the testis and ovary. We also thoroughly review the topic of neoplasms composed of both germ cells and sex cord derivatives with an emphasis on controversial aspects. These include "dissecting gonadoblastoma" and testicular mixed germ cell-sex cord stromal tumor (MGC-SCST). The former is a recently described variant of gonadoblastoma that sometimes is an immediate precursor of germinoma in the dysgenetic gonads of patients with a disorder of sex development. Although the relationship of dissecting gonadoblastoma to the previously described undifferentiated gonadal tissue is complex and not entirely resolved, we believe that it is preferable to continue to use the term undifferentiated gonadal tissue for those cases that are not neoplastic and are considered to be the precursor of classical gonadoblastoma. Although the existence of testicular MGC-SCST has been challenged, the most recent evidence supports its existence; however, testicular MGC-SCST differs significantly from ovarian examples due to both genetic and epigenetic factors. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Progestins inhibit estradiol-induced vascular endothelial growth factor and stromal cell-derived factor 1 in human endometrial stromal cells.

    Science.gov (United States)

    Okada, Hidetaka; Okamoto, Rika; Tsuzuki, Tomoko; Tsuji, Shoko; Yasuda, Katsuhiko; Kanzaki, Hideharu

    2011-09-01

    To investigate whether 17β-estradiol (E(2)) and progestins exert direct effects on vascular endothelial growth factor (VEGF) and stromal cell-derived factor 1 (SDF-1/CXCL12) in human endometrial stromal cells (ESCs) and thereby to clarify the regulatory function of these local angiogenic factors in the endometrium. In vitro experiment. Research laboratory at Kansai Medical University. Fourteen patients undergoing hysterectomy for benign reasons. ESCs were cultured with E(2) and/or various clinically relevant progestins (medroxyprogesterone acetate [MPA], norethisterone [NET], levonorgestrel [LNG], dienogest [DNG], and progesterone [P]). The mRNA levels and production of VEGF and SDF-1 were assessed by real-time reverse-transcription polymerase chain reaction and ELISA, respectively. E(2) significantly induced the mRNA levels and protein production of VEGF and SDF-1 in ESCs. MPA could antagonize the E(2)-stimulated effects in a time- and dose-dependent manner, and this effect could be reversed by RU-486 (P receptor antagonist). All of the progestins (MPA, NET, LNG, and DNG; 10(-9) to 10(-7) mol/L) attenuated E(2)-induced VEGF and SDF-1 production, whereas P showed these inhibitory effects only when present in a high concentration (10(-7) mol/L). Progestins have inhibitory effects on E(2)-induced VEGF and SDF-1 in ESCs. These results may indicate a potential mechanism for action of the female sex steroids in the human endometrium that can be helpful for various clinical applications. Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  15. Early in-situ cellularization of a supramolecular vascular graft is modified by synthetic stromal cell-derived factor-1α derived peptides

    NARCIS (Netherlands)

    Muylaert, Dimitri E. P.; van Almen, Geert C.; Talacua, Hanna; Fledderus, Joost O.; Kluin, Jolanda; Hendrikse, Simone I. S.; van Dongen, Joost L. J.; Sijbesma, Eline; Bosman, Anton W.; Mes, Tristan; Thakkar, Shraddha H.; Smits, Anthal I. P. M.; Bouten, Carlijn V. C.; Dankers, Patricia Y. W.; Verhaar, Marianne C.

    2016-01-01

    In an in-situ approach towards tissue engineered cardiovascular replacement grafts, cell-free scaffolds are implanted that engage in endogenous tissue formation. Bioactive molecules can be incorporated into such grafts to facilitate cellular recruitment. Stromal cell derived factor 1α (SDF1α) is a

  16. Early in-situ cellularization of a supramolecular vascular graft is modified by synthetic stromal cell-derived factor-1α derived peptides

    NARCIS (Netherlands)

    Muylaert, Dimitri E P; van Almen, Geert C; Talacua, Hanna; Fledderus, Joost O; Kluin, Jolanda; Hendrikse, Simone I S; van Dongen, Joost L J; Sijbesma, Eline; Bosman, Anton W; Mes, Tristan; Thakkar, Shraddha H; Smits, Anthal I P M; Bouten, Carlijn V C; Dankers, Patricia Y W; Verhaar, Marianne C

    In an in-situ approach towards tissue engineered cardiovascular replacement grafts, cell-free scaffolds are implanted that engage in endogenous tissue formation. Bioactive molecules can be incorporated into such grafts to facilitate cellular recruitment. Stromal cell derived factor 1α (SDF1α) is a

  17. Bone Marrow Suppression by c-Kit Blockade Enhances Tumor Growth of Colorectal Metastases through the Action of Stromal Cell-Derived Factor-1

    Directory of Open Access Journals (Sweden)

    Kathrin Rupertus

    2012-01-01

    Full Text Available Background. Mobilization of c-Kit+ hematopoietic cells (HCs contributes to tumor vascularization. Whereas survival and proliferation of HCs are regulated by binding of the stem cell factor to its receptor c-Kit, migration of HCs is directed by stromal cell-derived factor (SDF-1. Therefore, targeting migration of HCs provides a promising new strategy of anti-tumor therapy. Methods. BALB/c mice (=16 were pretreated with an anti-c-Kit antibody followed by implantation of CT26.WT-GFP colorectal cancer cells into dorsal skinfold chambers. Animals (=8 additionally received a neutralizing anti-SDF-1 antibody. Animals (=8 treated with a control antibody served as controls. Investigations were performed using intravital fluorescence microscopy, immunohistochemistry, flow cytometry and western blot analysis. Results. Blockade of c-Kit significantly enhanced tumor cell engraftment compared to controls due to stimulation of tumor cell proliferation and invasion without markedly affecting tumor vascularization. C-Kit blockade significantly increased VEGF and CXCR4 expression within the growing tumors. Neutralization of SDF-1 completely antagonized this anti-c-Kit-associated tumor growth by suppression of tumor neovascularization, inhibition of tumor cell proliferation and reduction of muscular infiltration. Conclusion. Our study indicates that bone marrow suppression via anti-c-Kit pretreatment enhances tumor cell engraftment of colorectal metastases due to interaction with the SDF-1/CXCR4 pathway which is involved in HC-mediated tumor angiogenesis.

  18. Hypoxic stress simultaneously stimulates vascular endothelial growth factor via hypoxia-inducible factor-1α and inhibits stromal cell-derived factor-1 in human endometrial stromal cells.

    Science.gov (United States)

    Tsuzuki, Tomoko; Okada, Hidetaka; Cho, Hisayuu; Tsuji, Shoko; Nishigaki, Akemi; Yasuda, Katsuhiko; Kanzaki, Hideharu

    2012-02-01

    Hypoxia of the human endometrium is a physiologic event occurring during the perimenstrual period and the local stimulus for angiogenesis. The aim of this study was to investigate the effects of hypoxic stress on the regulation of vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1 (SDF-1/CXCL12), and the potential role of hypoxia-inducible factor-1α (HIF-1α) in the endometrium. Human endometrial stromal cells (ESCs, n= 22 samples) were studied in vitro. ESCs were cultured under hypoxic and normoxic conditions and treated with cobalt chloride (CoCl₂; a hypoxia-mimicking agent) and/or echinomycin, a small-molecule inhibitor of HIF-1α activity. The mRNA levels and production of VEGF and SDF-1 were assessed by real-time PCR and ELISA, respectively. The HIF-1α protein levels were measured using western blot analysis. Hypoxia simultaneously induced the expression of mRNA and production of VEGF and attenuated the expression and production of SDF-1 from ESCs in a time-dependent manner. Similar changes were observed in the ESCs after stimulation with CoCl₂ in a dose-dependent manner. CoCl₂ significantly induced the expression of HIF-1α protein, and its highest expression was observed at 6 h. Echinomycin inhibited hypoxia-induced VEGF production without affecting the HIF-1α protein level and cell toxicity and had no effect on SDF-1 secretion (P hypoxic conditions that could influence angiogenesis in the human endometrium.

  19. Ultrasound-targeted stromal cell-derived factor-1-loaded microbubble destruction promotes mesenchymal stem cell homing to kidneys in diabetic nephropathy rats

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    Wu S

    2014-12-01

    Full Text Available Shengzheng Wu,1 Lu Li,1 Gong Wang,1 Weiwei Shen,2 Yali Xu,1 Zheng Liu,1 Zhongxiong Zhuo,1 Hongmei Xia,1 Yunhua Gao,1 Kaibin Tan1 1Department of Ultrasound, 2Department of Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing, People’s Republic of China Abstract: Mesenchymal stem cell (MSC therapy has been considered a promising strategy to cure diabetic nephropathy (DN. However, insufficient MSCs can settle in injured kidneys, which constitute one of the major barriers to the effective implementation of MSC therapy. Stromal cell-derived factor-1 (SDF-1 plays a vital role in MSC migration and involves activation, mobilization, homing, and retention, which are presumably related to the poor homing in DN therapy. Ultrasound-targeted microbubble destruction has become one of the most promising strategies for the targeted delivery of drugs and genes. To improve MSC homing to DN kidneys, we present a strategy to increase SDF-1 via ultrasound-targeted microbubble destruction. In this study, we developed SDF-1-loaded microbubbles (MBSDF-1 via covalent conjugation. The characterization and bioactivity of MBSDF-1 were assessed in vitro. Target release in the targeted kidneys was triggered with diagnostic ultrasound in combination with MBSDF-1. The related bioeffects were also elucidated. Early DN was induced in rats with streptozotocin. Green fluorescent protein-labeled MSCs were transplanted intravenously following the target release of SDF-1 in the kidneys of normal and DN rats. The homing efficacy was assessed by detecting the implanted exogenous MSCs at 24 hours. The in vitro results showed an impressive SDF-1 loading efficacy of 79% and a loading content of 15.8 µg/mL. MBSDF-1 remained bioactive as a chemoattractant. In the in vivo study, SDF-1 was successfully released in the targeted kidneys. The homing efficacy of MSCs to DN kidneys after the target release of SDF-1 was remarkably ameliorated at 24 hours compared with

  20. Intravenous administration of mesenchymal stem cells exerts therapeutic effects on parkinsonian model of rats: Focusing on neuroprotective effects of stromal cell-derived factor-1α

    Directory of Open Access Journals (Sweden)

    Tayra Judith

    2010-04-01

    Full Text Available Abstract Background Mesenchymal stem cells (MSCs are pluripotent stem cells derived from bone marrow with secretory functions of various neurotrophic factors. Stromal cell-derived factor-1α (SDF-1α is also reported as one of chemokines released from MSCs. In this research, the therapeutic effects of MSCs through SDF-1α were explored. 6-hydroxydopamine (6-OHDA, 20 μg was injected into the right striatum of female SD rats with subsequent administration of GFP-labeled MSCs, fibroblasts, (i.v., 1 × 107 cells, respectively or PBS at 2 hours after 6-OHDA injection. All rats were evaluated behaviorally with cylinder test and amphetamine-induced rotation test for 1 month with consequent euthanasia for immunohistochemical evaluations. Additionally, to explore the underlying mechanisms, neuroprotective effects of SDF-1α were explored using 6-OHDA-exposed PC12 cells by using dopamine (DA assay and TdT-mediated dUTP-biotin nick-end labeling (TUNEL staining. Results Rats receiving MSC transplantation significantly ameliorated behaviorally both in cylinder test and amphetamine-induced rotation test compared with the control groups. Correspondingly, rats with MSCs displayed significant preservation in the density of tyrosine hydroxylase (TH-positive fibers in the striatum and the number of TH-positive neurons in the substantia nigra pars compacta (SNc compared to that of control rats. In the in vitro study, SDF-1α treatment increased DA release and suppressed cell death induced by 6-OHDA administration compared with the control groups. Conclusions Consequently, MSC transplantation might exert neuroprotection on 6-OHDA-exposed dopaminergic neurons at least partly through anti-apoptotic effects of SDF-1α. The results demonstrate the potentials of intravenous MSC administration for clinical applications, although further explorations are required.

  1. A Novel Autologous Cell Based Therapy to Promote Diabetic Wound Healing

    Science.gov (United States)

    Castilla, Diego M.; Liu, Zhao-Jun; Tian, Runxia; Li, Yan; Livingstone, Alan S.; Velazquez, Omaida C.

    2012-01-01

    Objectives We have previously shown that stromal-derived-factor-1 α(SDF-1α) is down-regulated within diabetic cutaneous wounds, and that direct application of recombinant SDF-1α increases wound closure rates, neovascularization and endothelial progenitor cell(s)(EPC) recruitment. However, increased wound levels of exogenous SDF-1α results in elevated systemic levels of this pro-angiogenic chemokine that raises concerns for tumorgenesis and inflammation. We now seek to test the efficacy of a novel, safer cell-based therapy (CBT) employing ex-vivo primed bone marrow stem cells (BMDSC) with SDF-1 α. We also elucidate the mechanism of action of this new approach for accelerating diabetic wound healing. Methods Unfractionated BMDSC from diabetic Leprdb/db mice were incubated for 20h with SDF-1α(100ng/mL) or BSA(control). Pre-treated-BMDSC (1×106) were injected subcutaneously into full-thickness skin wounds in Leprdb/db mice (n=8/group). Wound closure rates, capillary density and recruitment of EPC were assessed with serial photography, DiI-perfusion, confocal microscopy and immunohistochemistry. Expression of molecular targets, which may mediate pro-healing/pro-angiogenic effects of SDF-1α-primed-BMDSC was evaluated by PCRArray and immunoblotting assay. The biological function of a potential mediator was tested in a mouse wound healing model. Serum SDF-1α levels were measured with ELISA. Results SDF-1α-primed-BMDSC significantly promote wound healing (p<.0001), neovascularization (p=.0028) and EPC recruitment(p=.0059). Gene/ protein expression studies demonstrate up-regulation of EphRB4 and Plasminogen as downstream targets potentially mediating the pro-healing and pro-angiogenic responses. Ex-vivo BMDSC activation and subsequent inoculation of cells into wounds does not increase systemic SDF-1α levels. Conclusion We report a novel CBT that is highly effective in promoting healing and neovascularization in a murine model of Type 2 Diabetes. Furthermore, we

  2. Expression of osteoprotegerin, receptor activator of nuclear factor kappa-B ligand, tumor necrosis factor-related apoptosis-inducing ligand, stromal cell-derived factor-1 and their receptors in epithelial metastatic breast cancer cell lines

    Directory of Open Access Journals (Sweden)

    Labovsky Vivian

    2012-06-01

    Full Text Available Abstract Background While breast cancer (BC is the major cause of death among women worldwide, there is no guarantee of better patient survival because many of these patients develop primarily metastases, despite efforts to detect it in its early stages. Bone metastasis is a common complication that occurs in 65-80 % of patients with disseminated disease, but the molecular basis underlying dormancy, dissemination and establishment of metastasis is not understood. Our objective has been to evaluate simultaneously osteoprotegerin (OPG, receptor activator of nuclear factor kappa B ligand (RANKL, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, stromal cell-derived factor-1 (SDF-1, and their receptors (R in 2 human BC cell lines, MDA-MB-231 and MCF-7. Methods OPG, RANKL, TRAIL and SDF-1 expression and release, in addition to the expression of their receptors has been investigated using immunofluorescence, immunocytochemistry and ELISA analyses. Results MCF-7 cells released higher levels of OPG in conditioned media (CM than MDA-MB-231 cells; 100 % of both types of cell expressed OPG, RANKL, TRAIL and SDF-1. Moreover, 100 % in both lines expressed membrane RANKL and RANK, whereas only 50 % expressed CXCR4. Furthermore, 100 % expressed TRAIL-R1 and R4, 30-50 % TRAIL-R2, and 40-55 % TRAIL-R3. Conclusions MCF-7 and MDA-MB-231 cells not only released OPG, but expressed RANKL, TRAIL and SDF-1. The majority of the cells also expressed RANK, CXCR4 and TRAIL-R. Since these ligands and their receptors are implicated in the regulation of proliferation, survival, migration and future bone metastasis during breast tumor progression, assessment of these molecules in tumor biopsies of BC patients could be useful in identifying patients with more aggressive tumors that are also at risk of bone metastasis, which may thus improve the available options for therapeutic intervention.

  3. Genetic factors associated with slow progression of HIV among perinatally-infected Indian children.

    Science.gov (United States)

    Chaudhuri, Riya Pal; Neogi, Ujjwal; Rao, Shwetha D; Shet, Anita

    2014-10-01

    To study the association between common AIDS restriction genes and slow disease progression among perinatally-infected children in India. ART-naïve children were identified and selected host factors including CCR5-∆32, SDF1-3'A, CCR5-59029G, HLA-B*27, B*57 were studied using allele-specific PCR-RFLP and SSPGo HLA typing kits. Among 165 children, 10 (6%) long-term non-progressors and 8 (5%) slow progressors were identified. For comparison, 12 children with normal progression of HIV were included. The frequencies of CCR5-∆32 deletion, SDF1-3'A and CCR5-59029G did not differ significantly. HLA-B*27 and B*57 were observed only in long-term non-progressors or slow progressors, who also harbored either SDF1-3'A and/or CCR5-59029G. There is an association between host genetic factors and slow disease progression in this population.

  4. 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

  5. A DC-81-indole conjugate agent suppresses melanoma A375 cell migration partially via interrupting VEGF production and stromal cell-derived factor-1α-mediated signaling

    International Nuclear Information System (INIS)

    Hsieh, Ming-Chu; Hu, Wan-Ping; Yu, Hsin-Su; Wu, Wen-Chuan; Chang, Long-Sen; Kao, Ying-Hsien; Wang, Jeh-Jeng

    2011-01-01

    Pyrrolo[2,1-c][1,4]benzodiazepine (PBD) chemicals are antitumor antibiotics inhibiting nucleic acid synthesis. An indole carboxylate-PBD hybrid with six-carbon spacer structure (IN6CPBD) has been previously demonstrated to induce melanoma cell apoptosis and reduce metastasis in mouse lungs. This study aimed at investigating the efficacy of the other hybrid compound with four-carbon spacer (IN4CPBD) and elucidating its anti-metastatic mechanism. Human melanoma A375 cells with IN4CPBD treatment underwent cytotoxicity and apoptosis-associated assays. Transwell migration assay, Western blotting, and ELISA were used for mechanistic study. IN4CPBD exhibited potent melanoma cytotoxicity through interrupting G1/S cell cycle progression, increasing DNA fragmentation and hypodipoidic DNA contents, and reducing mitochondrial membrane potential. Caspase activity elevation suggested that both intrinsic and extrinsic pathways were involved in IN4CPBD-induced melanoma apoptosis. IN4CPBD up-regulated p53 and p21, thereby concomitantly derailing the equilibrium between Bcl-2 and Bax levels. Transwell migration assay demonstrated that stromal cell-derived factor-1α (SDF-1α) stimulated A375 cell motility, while kinase inhibitors treatment confirmed that Rho/ROCK, Akt, ERK1/2, and p38 MAPK pathways were involved in SDF-1α-enhanced melanoma migration. IN4CPBD not only abolished the SDF-1α-enhanced chemotactic motility but also suppressed constitutive MMP-9 and VEGF expression. Mechanistically, IN4CPBD down-regulated Akt, ERK1/2, and p38 MAPK total proteins and MYPT1 phosphorylation. In conclusion, beyond the fact that IN4CPBD induces melanoma cell apoptosis at cytotoxic dose, the interruption in the VEGF expression and the SDF-1α-related signaling at cytostatic dose may partially constitute the rationale for its in vivo anti-metastatic potency. - Research highlights: → A novel carboxylate-PBD hybrid as anti-melanoma drug. → IN4CPBD interrupts melanoma cell cycle progression

  6. Recruitment of bone marrow-derived cells to the periodontal ligament via the stromal cell-derived factor-1/C-X-C chemokine receptor type 4 axis.

    Science.gov (United States)

    Kaku, M; Kitami, M; Rosales Rocabado, J M; Ida, T; Akiba, Y; Uoshima, K

    2017-08-01

    The periodontal ligament (PDL) is a non-mineralized connective tissue that exists between the alveolar bone and root surface cementum and plays important roles in tooth function. The PDL harbors a remarkable reserve of multipotent stem cells, which maintain various types of cells. However, the sources of these stem cells, other than their developmental origin, are not well understood. To elucidate the recruitment of bone marrow (BM)-derived stem cells in the PDL, green fluorescent protein (GFP)-expressing BM-derived cells were transplanted into the femoral BM of immunodeficient rats, and the distribution and expression of stem cell markers in the PDL were analyzed in vivo. To evaluate the functional significance of BM-derived cells to the PDL, tooth replantation was performed and the expression of stromal cell-derived factor (SDF)-1, a critical chemotactic signal for mesenchymal stem cell recruitment, was analyzed. To confirm the SDF-1-dependency of BM-derived cell migration to the PDL, PDL-conditioned medium (CM) was prepared, and BM-derived cell migration was analyzed using a transwell culture system. Four weeks after cell transplantation, GFP-positive cells were detected in the PDL, and some of them were also positive for stem cell markers (i.e., CD29, SSEA4, and αSMA). Seven days after tooth replantation, the number of GFP- and SDF-1-positive cells significantly increased in PDL. Concurrently, the concentration of SDF-1 and the number of colony-forming units of fibroblasts in peripheral blood were increased. BM-derived cell migration increased in PDL-CM and was inhibited by an inhibitor of C-X-C chemokine receptor type 4 (CXCR4), an SDF-1 receptor. These results indicate that stem cells and their progeny in PDL are not only derived from their developmental origin but are also supplied from the BM via the blood as the need arises. Moreover, this BM-derived cell recruitment appears to be regulated, at least partially, by the SDF-1/CXCR4 axis. © 2017 John Wiley

  7. Treatment of femoral head necrosis with transplantation of stromal cell-derived factor-1: an experimental study

    International Nuclear Information System (INIS)

    Meng Wei; Cao Haili; Bai Bin; Zheng Shangfei; Xu Wei

    2009-01-01

    Objective: To discuss the therapeutic mechanism and efficacy of stromal cell-derived factor-1 (SDF-1) in the treatment of femoral head necrosis. Methods: Experimental models of hydrocortisoneinduced femoral head necrosis were established in 30 Japanese rabbits, which were randomly and equally divided into three groups. Group A was regarded as control group, group B received marrow core decompression and saline injection treatment and group C underwent marrow core decompression and SDF-1 transplantation. Eight weeks after the procedure all the survival rabbits (n = 27) were sacrificed, and the specimens were sent for the measuring of bone mineral density and for histopathologic examination. Results Eight weeks after the treatment, the bone mineral density of rabbits in group C was significantly increased. Pathologically, in SDF-1 treated rabbits the amounts of the blood vessels and osteoblast cells were obviously increased while the empty bone lacunae were markedly decreased. Conclusion: Transplantation of stromal cell-derived factor-1 together with marrow core decompression is very effective for the treatment of femoral head necrosis and this technique has showed a vast and bright prospect in clinical practice. (authors)

  8. Adrenaline administration promotes the efficiency of granulocyte colony stimulating factor-mediated hematopoietic stem and progenitor cell mobilization in mice.

    Science.gov (United States)

    Chen, Chong; Cao, Jiang; Song, Xuguang; Zeng, Lingyu; Li, Zhenyu; Li, Yong; Xu, Kailin

    2013-01-01

    A high dose of granulocyte colony stimulating factor (G-CSF) is widely used to mobilize hematopoietic stem and progenitor cells (HSPC), but G-CSF is relatively inefficient and may cause adverse effects. Recently, adrenaline has been found to play important roles in HSPC mobilization. In this study, we explored whether adrenaline combined with G-CSF could induce HSPC mobilization in a mouse model. Mice were treated with adrenaline and either a high or low dose of G-CSF alone or in combination. Peripheral blood HSPC counts were evaluated by flow cytometry. Levels of bone marrow SDF-1 were measured by ELISA, the transcription of CXCR4 and SDF-1 was measured by real-time RT-PCR, and CXCR4 protein was detected by Western blot. Our results showed that adrenaline alone fails to mobilize HSPCs into the peripheral blood; however, when G-CSF and adrenaline are combined, the WBC counts and percentages of HSPCs are significantly higher compared to those in mice that received G-CSF alone. The combined use of adrenaline and G-CSF not only accelerated HSPC mobilization, but also enabled the efficient mobilization of HSPCs into the peripheral blood at lower doses of G-CSF. Adrenaline/G-CSF treatment also extensively downregulated levels of SDF-1 and CXCR4 in mouse bone marrow. These results demonstrated that adrenaline combined with G-CSF can induce HSPC mobilization by down-regulating the CXCR4/SDF-1 axis, indicating that the use of adrenaline may enable the use of reduced dosages or durations of G-CSF treatment, minimizing G-CSF-associated complications.

  9. Intra-articular injection of human meniscus stem/progenitor cells promotes meniscus regeneration and ameliorates osteoarthritis through stromal cell-derived factor-1/CXCR4-mediated homing.

    Science.gov (United States)

    Shen, Weiliang; Chen, Jialin; Zhu, Ting; Chen, Longkun; Zhang, Wei; Fang, Zhi; Heng, Boon Chin; Yin, Zi; Chen, Xiao; Ji, Junfeng; Chen, Weishan; Ouyang, Hong-Wei

    2014-03-01

    Meniscus injury is frequently encountered in clinical practice. Current surgical therapy involving partial or complete meniscectomy relieves pain in the short-term but often leads to osteoarthritis (OA) in the long-term. In this study, we report a new strategy of articular cartilage protection by intra-articular injection of novel human meniscus stem/progenitor cells (hMeSPCs). We found that hMeSPCs displayed both mesenchymal stem cell characteristics and high expression levels of collagen II. In the rat meniscus injury model, hMeSPC transplantation not only led to more neo-tissue formation and better-defined shape but also resulted in more rounded cells and matured extracellular matrix. Stromal cell-derived factor-1 (SDF-1) enhanced the migration of hMeSPCs, whereas AMD3100 abolished the chemotactic effects of SDF-1 on hMeSPCs, both in vitro and in vivo. In an experimental OA model, transplantation of hMeSPCs effectively protected articular cartilage, as evidenced by reduced expression of OA markers such as collagen I, collagen X, and hypoxia-inducible factor 2α but increased expression of collagen II. Our study demonstrated for the first time that intra-articular injection of hMeSPCs enhanced meniscus regeneration through the SDF-1/CXCR4 axis. Our study highlights a new strategy of intra-articular injection of hMeSPCs for meniscus regeneration.

  10. Intra-Articular Injection of Human Meniscus Stem/Progenitor Cells Promotes Meniscus Regeneration and Ameliorates Osteoarthritis Through Stromal Cell-Derived Factor-1/CXCR4-Mediated Homing

    Science.gov (United States)

    Shen, Weiliang; Chen, Jialin; Zhu, Ting; Chen, Longkun; Zhang, Wei; Fang, Zhi; Heng, Boon Chin; Yin, Zi; Chen, Xiao; Ji, Junfeng

    2014-01-01

    Meniscus injury is frequently encountered in clinical practice. Current surgical therapy involving partial or complete meniscectomy relieves pain in the short-term but often leads to osteoarthritis (OA) in the long-term. In this study, we report a new strategy of articular cartilage protection by intra-articular injection of novel human meniscus stem/progenitor cells (hMeSPCs). We found that hMeSPCs displayed both mesenchymal stem cell characteristics and high expression levels of collagen II. In the rat meniscus injury model, hMeSPC transplantation not only led to more neo-tissue formation and better-defined shape but also resulted in more rounded cells and matured extracellular matrix. Stromal cell-derived factor-1 (SDF-1) enhanced the migration of hMeSPCs, whereas AMD3100 abolished the chemotactic effects of SDF-1 on hMeSPCs, both in vitro and in vivo. In an experimental OA model, transplantation of hMeSPCs effectively protected articular cartilage, as evidenced by reduced expression of OA markers such as collagen I, collagen X, and hypoxia-inducible factor 2α but increased expression of collagen II. Our study demonstrated for the first time that intra-articular injection of hMeSPCs enhanced meniscus regeneration through the SDF-1/CXCR4 axis. Our study highlights a new strategy of intra-articular injection of hMeSPCs for meniscus regeneration. PMID:24448516

  11. Upregulating CXCR4 in human fetal mesenchymal stem cells enhances engraftment and bone mechanics in a mouse model of osteogenesis imperfecta.

    Science.gov (United States)

    Jones, Gemma N; Moschidou, Dafni; Lay, Kenneth; Abdulrazzak, Hassan; Vanleene, Maximilien; Shefelbine, Sandra J; Polak, Julia; de Coppi, Paolo; Fisk, Nicholas M; Guillot, Pascale V

    2012-01-01

    Stem cells have considerable potential to repair damaged organs and tissues. We previously showed that prenatal transplantation of human first trimester fetal blood mesenchymal stem cells (hfMSCs) in a mouse model of osteogenesis imperfecta (oim mice) led to a phenotypic improvement, with a marked decrease in fracture rate. Donor cells differentiated into mature osteoblasts, producing bone proteins and minerals, including collagen type Iα2, which is absent in nontransplanted mice. This led to modifications of the bone matrix and subsequent decrease of bone brittleness, indicating that grafted cells directly contribute to improvement of bone mechanical properties. Nevertheless, the therapeutic effect was incomplete, attributing to the limited level of engraftment in bone. In this study, we show that although migration of hfMSCs to bone and bone marrow is CXCR4-SDF1 (SDF1 is stromal-derived factor) dependent, only a small number of cells present CXCR4 on the cell surface despite high levels of internal CXCR4. Priming with SDF1, however, upregulates CXCR4 to increase the CXCR4(+) cell fraction, improving chemotaxis in vitro and enhancing engraftment in vivo at least threefold in both oim and wild-type bone and bone marrow. Higher engraftment in oim bones was associated with decreased bone brittleness. This strategy represents a step to improve the therapeutic benefits of fetal cell therapy toward being curative.

  12. A cellular, molecular, and pharmacological basis for appendage regeneration in mice.

    Science.gov (United States)

    Leung, Thomas H; Snyder, Emily R; Liu, Yinghua; Wang, Jing; Kim, Seung K

    2015-10-15

    Regenerative medicine aims to restore normal tissue architecture and function. However, the basis of tissue regeneration in mammalian solid organs remains undefined. Remarkably, mice lacking p21 fully regenerate injured ears without discernable scarring. Here we show that, in wild-type mice following tissue injury, stromal-derived factor-1 (Sdf1) is up-regulated in the wound epidermis and recruits Cxcr4-expressing leukocytes to the injury site. In p21-deficient mice, Sdf1 up-regulation and the subsequent recruitment of Cxcr4-expressing leukocytes are significantly diminished, thereby permitting scarless appendage regeneration. Lineage tracing demonstrates that this regeneration derives from fate-restricted progenitor cells. Pharmacological or genetic disruption of Sdf1-Cxcr4 signaling enhances tissue repair, including full reconstitution of tissue architecture and all cell types. Our findings identify signaling and cellular mechanisms underlying appendage regeneration in mice and suggest new therapeutic approaches for regenerative medicine. © 2015 Leung et al.; Published by Cold Spring Harbor Laboratory Press.

  13. A New Bone Substitute Developed from 3D-Prints of Polylactide (PLA Loaded with Collagen I: An In Vitro Study

    Directory of Open Access Journals (Sweden)

    Ulrike Ritz

    2017-11-01

    Full Text Available Although a lot of research has been performed, large segmental bone defects caused by trauma, infection, bone tumors or revision surgeries still represent big challenges for trauma surgeons. New and innovative bone substitutes are needed. Three-dimensional (3D printing is a novel procedure to create 3D porous scaffolds that can be used for bone tissue engineering. In the present study, solid discs as well as porous cage-like 3D prints made of polylactide (PLA are coated or filled with collagen, respectively, and tested for biocompatibility and endotoxin contamination. Microscopic analyses as well as proliferation assays were performed using various cell types on PLA discs. Stromal-derived factor (SDF-1 release from cages filled with collagen was analyzed and the effect on endothelial cells tested. This study confirms the biocompatibility of PLA and demonstrates an endotoxin contamination clearly below the FDA (Food and Drug Administration limit. Cells of various cell types (osteoblasts, osteoblast-like cells, fibroblasts and endothelial cells grow, spread and proliferate on PLA-printed discs. PLA cages loaded with SDF-1 collagen display a steady SDF-1 release, support cell growth of endothelial cells and induce neo-vessel formation. These results demonstrate the potential for PLA scaffolds printed with an inexpensive desktop printer in medical applications, for example, in bone tissue engineering.

  14. A New Bone Substitute Developed from 3D-Prints of Polylactide (PLA) Loaded with Collagen I: An In Vitro Study.

    Science.gov (United States)

    Ritz, Ulrike; Gerke, Rebekka; Götz, Hermann; Stein, Stefan; Rommens, Pol Maria

    2017-11-29

    Although a lot of research has been performed, large segmental bone defects caused by trauma, infection, bone tumors or revision surgeries still represent big challenges for trauma surgeons. New and innovative bone substitutes are needed. Three-dimensional (3D) printing is a novel procedure to create 3D porous scaffolds that can be used for bone tissue engineering. In the present study, solid discs as well as porous cage-like 3D prints made of polylactide (PLA) are coated or filled with collagen, respectively, and tested for biocompatibility and endotoxin contamination. Microscopic analyses as well as proliferation assays were performed using various cell types on PLA discs. Stromal-derived factor (SDF-1) release from cages filled with collagen was analyzed and the effect on endothelial cells tested. This study confirms the biocompatibility of PLA and demonstrates an endotoxin contamination clearly below the FDA (Food and Drug Administration) limit. Cells of various cell types (osteoblasts, osteoblast-like cells, fibroblasts and endothelial cells) grow, spread and proliferate on PLA-printed discs. PLA cages loaded with SDF-1 collagen display a steady SDF-1 release, support cell growth of endothelial cells and induce neo-vessel formation. These results demonstrate the potential for PLA scaffolds printed with an inexpensive desktop printer in medical applications, for example, in bone tissue engineering.

  15. Chemokines, macrophage inflammatory protein-2 and stromal cell-derived factor-1α, suppress amyloid β-induced neurotoxicity

    International Nuclear Information System (INIS)

    Raman, Dayanidhi; Milatovic, Snjezana-Zaja; Milatovic, Dejan; Splittgerber, Ryan; Fan, Guo-Huang; Richmond, Ann

    2011-01-01

    Alzheimer's disease (AD) is characterized by a progressive cognitive decline and accumulation of neurotoxic oligomeric peptides amyloid-β (Aβ). Although the molecular events are not entirely known, it has become evident that inflammation, environmental and other risk factors may play a causal, disruptive and/or protective role in the development of AD. The present study investigated the ability of the chemokines, macrophage inflammatory protein-2 (MIP-2) and stromal cell-derived factor-1α (SDF-1α), the respective ligands for chemokine receptors CXCR2 and CXCR4, to suppress Aβ-induced neurotoxicity in vitro and in vivo. Pretreatment with MIP-2 or SDF-1α significantly protected neurons from Aβ-induced dendritic regression and apoptosis in vitro through activation of Akt, ERK1/2 and maintenance of metalloproteinase ADAM17 especially with SDF-1α. Intra-cerebroventricular (ICV) injection of Aβ led to reduction in dendritic length and spine density of pyramidal neurons in the CA1 area of the hippocampus and increased oxidative damage 24 h following the exposure. The Aβ-induced morphometric changes of neurons and increase in biomarkers of oxidative damage, F 2 -isoprostanes, were significantly inhibited by pretreatment with the chemokines MIP-2 or SDF-1α. Additionally, MIP-2 or SDF-1α was able to suppress the aberrant mislocalization of p21-activated kinase (PAK), one of the proteins involved in the maintenance of dendritic spines. Furthermore, MIP-2 also protected neurons against Aβ neurotoxicity in CXCR2−/− mice, potentially through observed up regulation of CXCR1 mRNA. Understanding the neuroprotective potential of chemokines is crucial in defining the role for their employment during the early stages of neurodegeneration. -- Research highlights: ► Neuroprotective ability of the chemokines MIP2 and CXCL12 against Aβ toxicity. ► MIP-2 or CXCL12 prevented dendritic regression and apoptosis in vitro. ► Neuroprotection through activation of Akt, ERK

  16. Chemokines, macrophage inflammatory protein-2 and stromal cell-derived factor-1{alpha}, suppress amyloid {beta}-induced neurotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Raman, Dayanidhi; Milatovic, Snjezana-Zaja [Department of Cancer Biology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States); Milatovic, Dejan [Department of Pediatrics/Pediatric Toxicology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States); Splittgerber, Ryan [Department of Cancer Biology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States); Fan, Guo-Huang [Department of Neurobiology and Neurotoxicology, Meharry Medical College, Nashville, TN 37221 (United States); Richmond, Ann, E-mail: ann.richmond@vanderbilt.edu [VA Medical Center, Nashville, TN 37232 (United States); Department of Cancer Biology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States)

    2011-11-15

    Alzheimer's disease (AD) is characterized by a progressive cognitive decline and accumulation of neurotoxic oligomeric peptides amyloid-{beta} (A{beta}). Although the molecular events are not entirely known, it has become evident that inflammation, environmental and other risk factors may play a causal, disruptive and/or protective role in the development of AD. The present study investigated the ability of the chemokines, macrophage inflammatory protein-2 (MIP-2) and stromal cell-derived factor-1{alpha} (SDF-1{alpha}), the respective ligands for chemokine receptors CXCR2 and CXCR4, to suppress A{beta}-induced neurotoxicity in vitro and in vivo. Pretreatment with MIP-2 or SDF-1{alpha} significantly protected neurons from A{beta}-induced dendritic regression and apoptosis in vitro through activation of Akt, ERK1/2 and maintenance of metalloproteinase ADAM17 especially with SDF-1{alpha}. Intra-cerebroventricular (ICV) injection of A{beta} led to reduction in dendritic length and spine density of pyramidal neurons in the CA1 area of the hippocampus and increased oxidative damage 24 h following the exposure. The A{beta}-induced morphometric changes of neurons and increase in biomarkers of oxidative damage, F{sub 2}-isoprostanes, were significantly inhibited by pretreatment with the chemokines MIP-2 or SDF-1{alpha}. Additionally, MIP-2 or SDF-1{alpha} was able to suppress the aberrant mislocalization of p21-activated kinase (PAK), one of the proteins involved in the maintenance of dendritic spines. Furthermore, MIP-2 also protected neurons against A{beta} neurotoxicity in CXCR2-/- mice, potentially through observed up regulation of CXCR1 mRNA. Understanding the neuroprotective potential of chemokines is crucial in defining the role for their employment during the early stages of neurodegeneration. -- Research highlights: Black-Right-Pointing-Pointer Neuroprotective ability of the chemokines MIP2 and CXCL12 against A{beta} toxicity. Black-Right-Pointing-Pointer MIP

  17. Mutation in cpsf6/CFIm68 (Cleavage and Polyadenylation Specificity Factor Subunit 6 causes short 3'UTRs and disturbs gene expression in developing embryos, as revealed by an analysis of primordial germ cell migration using the medaka mutant naruto.

    Directory of Open Access Journals (Sweden)

    Takao Sasado

    Full Text Available Our previous studies analyzing medaka mutants defective in primordial germ cell (PGC migration identified cxcr4b and cxcr7, which are both receptors of the chemokine sdf1/cxcl12, as key regulators of PGC migration. Among PGC migration mutants, naruto (nar is unique in that the mutant phenotype includes gross morphological abnormalities of embryos, suggesting that the mutation affects a broader range of processes. A fine genetic linkage mapping and genome sequencing showed the nar gene encodes Cleavage and Polyadenylation Specificity Factor subunit 6 (CPSF6/CFIm68. CPSF6 is a component of the Cleavage Factor Im complex (CFIm which plays a key role in pre-mRNA 3'-cleavage and polyadenylation. 3'RACE of sdf1a/b and cxcr7 transcripts in the mutant embryos indicated shorter 3'UTRs with poly A additions occurring at more upstream positions than wild-type embryos, suggesting CPSF6 functions to prevent premature 3'UTR cleavage. In addition, expression of the coding region sequences of sdf1a/b in nar mutants was more anteriorly extended in somites than wild-type embryos, accounting for the abnormally extended distribution of PGCs in nar mutants. An expected consequence of shortening 3'UTR is the escape from the degradation mechanism mediated by microRNAs interacting with distal 3'UTR sequence. The abnormal expression pattern of sdf1a coding sequence may be at least partially accounted for by this mechanism. Given the pleiotropic effects of nar mutation, further analysis using the nar mutant will reveal processes in which CPSF6 plays essential regulatory roles in poly A site selection and involvement of 3'UTRs in posttranscriptional gene regulation in various genes in vivo.

  18. SDF-1, DC1/DC2, and Tumor Angiogenesis

    Science.gov (United States)

    2006-04-01

    temperature with anti-CXCL12 antibody (clone K15C, IgG2a, 10 Ag /mL), or control isotype. Antibody binding was detected with biotinylated anti-mouse antibodies...Bronte, V., Serafini, P., Apolloni , E. & Zanovello, P. Tumor- induced immune dysfunctions caused by myeloid suppressor cells. J. Immunother. 24, 431

  19. Cross-talk between the dipeptidyl peptidase-4 and stromal cell-derived factor-1 in stem cell homing and myocardial repair: Potential impact of dipeptidyl peptidase-4 inhibitors.

    Science.gov (United States)

    Anderluh, Marko; Kocic, Gordana; Tomovic, Katarina; Kocic, Radivoj; Deljanin-Ilic, Marina; Smelcerovic, Andrija

    2016-11-01

    Dipeptidyl peptidase-4 (DPP-4), glycyl-prolyl-naphthylamidase, is a serine protease that catalyzes the hydrolysis of various proline-containing polypeptides. It is involved in the inactivation of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), having in this way a profound influence on glucose metabolism. During organ damage, stromal and endothelial cells produce a chemokine known as stromal cell-derived factor-1 (SDF-1), a powerful chemoattractant of stem/progenitor cells. SDF-1 binds to a specific α-chemokine receptor (CXCR4) and can be degraded by proteases, including matrix DPP-4/CD26, presented in the circulation, or activated in injured tissues. DPP-4 inhibition has received considerable attention because of its significant therapeutic benefits in the regulation of insulin secretion and tissue insulin sensitivity, the regulation of tumor growth and metastasis, angiogenesis, tissue repair, especially after myocardial infarction, and regulation of endocrine function. Inhibition of circulating proteases appears to maintain the optimal endogenous SDF-1 concentration and may enhance homing of endothelial progenitor cells. In the present article, we present an overview of some basic facts about the role of DPP-4 in glucose homeostasis, the mechanism of its inhibition, and a brief summary of available DPP-4 inhibitors. Furthermore, since protection against the overactivity of proteases is important for restorating cardiac function and repair after myocardial damage, necrosis and apoptosis, we propose that administration of a DPP-4 inhibitor may also be beneficial following myocardial infarction by the prevention of cleavage of stem cell chemoattractant cytokine SDF-1. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Low current electrical stimulation upregulates cytokine expression in the anal sphincter.

    Science.gov (United States)

    Salcedo, Levilester; Lian, Lei; Jiang, Hai-Hong; Sopko, Nikolai; Penn, Marc; Damaser, Margot; Zutshi, Massarat

    2012-02-01

    Stem cells are an emerging treatment for regeneration of damaged anal sphincter tissues. Homing to the site of injury can be potentiated by stromal derived factor 1 (SDF-1) and monocyte chemotactic protein 3 (MCP-3) expression. The effects of electrical stimulation (ES) on upregulation of these cytokines were investigated. The anal sphincter complex of Sprague Dawley rats was stimulated with current of 0.25 mA, pulse duration of 40 pulses/s, pulse width of 100 μs, and frequency of 100 Hz for 1 or 4 h. Sham was created using the same needle which was inserted into the anal sphincter without electrical stimulation in different groups of animals. The rats were euthanized immediately or 24 h after stimulation. Cytokine analysis was performed using real-time polymerase chain reaction. Statistical analysis was performed. Results are presented as a fold increase compared to sham that was normalized to 1. SDF-1 and MCP-3 immediately after 1 h were 2.5 ± 0.77 and 3.1± 0.93 vs. sham, respectively, showing significant increase. After 1-h stimulation and euthanasia 24 h after, SDF-1 and MCP-3 were 1.49 ± 0.16 and 1.51± 0.14 vs. sham, respectively, showing significant increase. Immediately and 24 h after 4-h stimulation, SDF-1 was 1.21 ± 0.16 and 0.54 ± 0.16 vs. sham, respectively, and was not significantly different. Immediately and 24 h after 4-h stimulation, MCP-3 was 1.29 ± 0.41 and 0.35 ±1.0 vs. sham, respectively, and was not significantly different. SDF-1 and MCP-3 after 1 h were significantly higher than after 4 h of stimulation at both time points. Electrical stimulation for 1 h significantly upregulates SDF-1 and MCP-3 expression that persists for 24 h. Prolonged stimulation reduced chemokine expression, suggesting electrolysis of cells.

  1. Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy

    Science.gov (United States)

    Askari, Arman T.; Unzek, Samuel; Popovic, Zoran B.; Goldman, Corey K.; Forudi, Farhad; Kiedrowski, Matthew; Rovner, Aleksandr; Ellis, Stephen G.; Thomas, James D.; DiCorleto, Paul E.; hide

    2003-01-01

    BACKGROUND: Myocardial regeneration via stem-cell mobilisation at the time of myocardial infarction is known to occur, although the mechanism for stem-cell homing to infarcted tissue subsequently and whether this approach can be used for treatment of ischaemic cardiomyopathy are unknown. We investigated these issues in a Lewis rat model (ligation of the left anterior descending artery) of ischaemic cardiomyopathy. METHODS: We studied the effects of stem-cell mobilisation by use of granulocyte colony-stimulating factor (filgrastim) with or without transplantation of syngeneic cells. Shortening fraction and myocardial strain by tissue doppler imaging were quantified by echocardiography. FINDINGS: Stem-cell mobilisation with filgrastim alone did not lead to engraftment of bone-marrow-derived cells. Stromal-cell-derived factor 1 (SDF-1), required for stem-cell homing to bone marrow, was upregulated immediately after myocardial infarction and downregulated within 7 days. 8 weeks after myocardial infarction, transplantation into the peri-infarct zone of syngeneic cardiac fibroblasts stably transfected to express SDF-1 induced homing of CD117-positive stem cells to injured myocardium after filgrastim administration (control vs SDF-1-expressing cardiac fibroblasts mean 7.2 [SD 3.4] vs 33.2 [6.0] cells/mm2, n=4 per group, pcell homing to injured myocardium and suggest a strategy for directed stem-cell engraftment into injured tissues. Our findings also indicate that therapeutic strategies focused on stem-cell mobilisation for regeneration of myocardial tissue must be initiated within days of myocardial infarction unless signalling for stem-cell homing is re-established.

  2. The role of osteoblasts in regulating hematopoietic stem cell activity and tumor metastasis

    Directory of Open Access Journals (Sweden)

    Neiva K.

    2005-01-01

    Full Text Available Bone marrow stromal cells are critical regulators of hematopoiesis. Osteoblasts are part of the stromal cell support system in bone marrow and may be derived from a common precursor. Several studies suggested that osteoblasts regulate hematopoiesis, yet the entire mechanism is not understood. It is clear, however, that both hematopoietic precursors and osteoblasts interact for the production of osteoclasts and the activation of resorption. We observed that hematopoietic stem cells (HSCs regulate osteoblastic secretion of various growth factors, and that osteoblasts express some soluble factors exclusively in the presence of HSCs. Osteoblasts and hematopoietic cells are closely associated with each other in the bone marrow, suggesting a reciprocal relationship between them to develop the HSC niche. One critical component regulating the niche is stromal-derived factor-1 (SDF-1 and its receptor CXCR4 which regulates stem cell homing and, as we have recently demonstrated, plays a crucial role in facilitating those tumors which metastasize to bone. Osteoblasts produce abundant amounts of SDF-1 and therefore osteoblasts play an important role in metastasis. These findings are discussed in the context of the role of osteoblasts in marrow function in health and disease.

  3. Improving the biological function of decellularized heart valves through integration of protein tethering and three-dimensional cell seeding in a bioreactor.

    Science.gov (United States)

    Namiri, Mehrnaz; Kazemi Ashtiani, Mohammad; Abbasalizadeh, Saeed; Mazidi, Zahra; Mahmoudi, Elena; Nikeghbalian, Saman; Aghdami, Nasser; Baharvand, Hossein

    2017-11-21

    Decellularized xenogeneic heart valves (DHVs) are promising products for valve replacement. However, the widespread clinical application of such products is limited due to the risk of immune reaction, progressive degeneration, inflammation, and calcification. Here, we have developed an optimized decellularization protocol for a xenogeneic heart valve. We improved the biological function of DHVs by protein tethering onto DHV and three-dimensional (3D) cell seeding in a bioreactor. Our results showed that heart valves treated with a Triton X-100 and sodium deoxycholate-based protocol were completely cell-free, with preserved biochemical and biomechanical properties. The immobilization of stromal derived factor-1α (SDF-1α) and basic fibroblast growth factor on DHV significantly improved recellularization with endothelial progenitor cells under the 3D culture condition in the bioreactor compared to static culture conditions. Cell phenotype analysis showed higher fibroblast-like cells and less myofibroblast-like cells in both protein-tethered DHVs. However, SDF-DHV significantly enhanced recellularization both in vitro and in vivo compared to basic fibroblast growth factor DHV and demonstrated less inflammatory cell infiltration. SDF-DHV had less calcification and platelet adhesion. Altogether, integration of SDF-1α immobilization and 3D cell seeding in a bioreactor might provide a novel, promising approach for production of functional heart valves. Copyright © 2017 John Wiley & Sons, Ltd.

  4. Primordial germ cell migration in the yellowtail kingfish (Seriola lalandi) and identification of stromal cell-derived factor 1.

    Science.gov (United States)

    Fernández, J A; Bubner, E J; Takeuchi, Y; Yoshizaki, G; Wang, T; Cummins, S F; Elizur, A

    2015-03-01

    Primordial germ cells (PGCs) are progenitors of the germ cell lineage, giving rise to either spermatogonia or oogonia after the completion of gonadal differentiation. Currently, there is little information on the mechanism of PGCs migration leading to the formation of the primordial gonad in perciform fish. Yellowtail kingfish (Seriola lalandi) (YTK) (order Perciforms) inhabit tropical and temperate waters in the southern hemisphere. Fundamental details into the molecular basis of larval development in this species can be easily studied in Australia, as they are commercially cultured and readily available. In this study, histological analysis of YTK larvae revealed critical time points for the migration of PGCs to the genital ridge, resulting in the subsequent development of the primordial gonad. In YTK larvae at 3, 5, 7 and 10 days post hatch (DPH), PGCs were not yet enclosed by somatic cells, indicating the primordial gonad had not yet started to form. While at 15, 18 and 20 DPH PGCs had already settled at the genital ridge and started to become enclosed by somatic cells indicating the primordial gonad had started to develop. A higher number of PGCs were observed in the larvae at 15 and 18 DPH indicating PGCs proliferation, which corresponds with them becoming enclosed by the somatic cells. Directional migration of PGCs toward the genital ridge is a critical event in the subsequent development of a gonad. In zebrafish, mouse and chicken, stromal-cell derived factor (SDF1) signalling is one of the key molecules for PGC migration. We subsequently isolated from YTK the SDF1 (Slal-SDF1) gene, which encodes for a 98-residue precursor protein with a signal peptide at the N-terminus. There is spatial conservation between fish species of four cysteine residues at positions C9, C11, C34 and C49, expected to form disulphide bonds and stabilize the SDF structure. In YTK, Slal-SDF1 gene expression analyses shows that this gene is expressed in larvae from 1 to 22 DPH and

  5. Function-oriented development of CXCR4 antagonists as selective human immunodeficiency virus (HIV)-1 entry inhibitors.

    Science.gov (United States)

    Wu, Chien-Huang; Wang, Chuan-Jen; Chang, Chun-Ping; Cheng, Yung-Chi; Song, Jen-Shin; Jan, Jiing-Jyh; Chou, Ming-Chen; Ke, Yi-Yu; Ma, Jing; Wong, Ying-Chieh; Hsieh, Tsung-Chih; Tien, Yun-Chen; Gullen, Elizabeth A; Lo, Chen-Fu; Cheng, Chia-Yi; Liu, Yu-Wei; Sadani, Amit A; Tsai, Chia-Hua; Hsieh, Hsin-Pang; Tsou, Lun K; Shia, Kak-Shan

    2015-02-12

    Motivated by the pivotal role of CXCR4 as an HIV entry co-receptor, we herein report a de novo hit-to-lead effort on the identification of subnanomolar purine-based CXCR4 antagonists against HIV-1 infection. Compound 24, with an EC50 of 0.5 nM against HIV-1 entry into host cells and an IC50 of 16.4 nM for inhibition of radioligand stromal-derived factor-1α (SDF-1α) binding to CXCR4, was also found to be highly selective against closely related chemokine receptors. We rationalized that compound 24 complementarily interacted with the critical CXCR4 residues that are essential for binding to HIV-1 gp120 V3 loop and subsequent viral entry. Compound 24 showed a 130-fold increase in anti-HIV activity compared to that of the marketed CXCR4 antagonist, AMD3100 (Plerixafor), whereas both compounds exhibited similar potency in mobilization of CXCR4(+)/CD34(+) stem cells at a high dose. Our study offers insight into the design of anti-HIV therapeutics devoid of major interference with SDF-1α function.

  6. Prostate stromal cells express the progesterone receptor to control cancer cell mobility.

    Directory of Open Access Journals (Sweden)

    Yue Yu

    Full Text Available Reciprocal interactions between epithelium and stroma play vital roles for prostate cancer development and progression. Enhanced secretions of cytokines and growth factors by cancer associated fibroblasts in prostate tumors create a favorable microenvironment for cancer cells to grow and metastasize. Our previous work showed that the progesterone receptor (PR was expressed specifically in prostate stromal fibroblasts and smooth muscle cells. However, the expression levels of PR and its impact to tumor microenvironment in prostate tumors are poorly understood.Immunohistochemistry assays are applied to human prostate tissue biopsies. Cell migration, invasion and proliferation assays are performed using human prostate cells. Real-time PCR and ELISA are applied to measure gene expression at molecular levels.Immunohistochemistry assays showed that PR protein levels were decreased in cancer associated stroma when compared with paired normal prostate stroma. Using in vitro prostate stromal cell models, we showed that conditioned media collected from PR positive stromal cells inhibited prostate cancer cell migration and invasion, but had minor suppressive impacts on cancer cell proliferation. PR suppressed the secretion of stromal derived factor-1 (SDF-1 and interlukin-6 (IL-6 by stromal cells independent to PR ligands. Blocking PR expression by siRNA or supplementation of exogenous SDF-1 or IL-6 to conditioned media from PR positive stromal cells counteracted the inhibitory effects of PR to cancer cell migration and invasion.Decreased expression of the PR in cancer associated stroma may contribute to the elevated SDF-1 and IL-6 levels in prostate tumors and enhance prostate tumor progression.

  7. Dysregulation of neurotrophic and haematopoietic growth factors in Alzheimer's disease: from pathophysiology to novel treatment strategies.

    Science.gov (United States)

    Sopova, Kateryna; Gatsiou, Katerina; Stellos, Konstantinos; Laske, Christoph

    2014-01-01

    Alzheimer's disease (AD) is the leading cause of dementia in the elderly. Growth factors have been demonstrated to act in a synergistic way in angiogenesis and neurogenesis contributing to self-healing powers of the adult human brain. A growing body of evidence demonstrates that levels of many growth factors (neurotrophins and hematopoietins) are altered in cerebrospinal fluid and peripheral blood from AD patients and in animal models of AD. The present review summarizes the role of several neurotrophic growth factors (e.g., BDNF, SCF, NGF, GDNF) and haematopoietic growth factors (e.g., G-CSF, VEGF, SDF-1) in AD. Moreover, we summarize recent studies evaluating the diagnostic and prognostic value of growth factor levels in blood and cerebrospinal fluid in patients with AD and discuss the potential role of these growth factors as a promising new therapeutic approach in AD.

  8. Selective labelling of stromal cell-derived factor 1α with carboxyfluorescein to study receptor internalisation.

    Science.gov (United States)

    Bellmann-Sickert, Kathrin; Baumann, Lars; Beck-Sickinger, Annette G

    2010-10-01

    SDF1α plays an important role in the regeneration of injured tissue after ischemia or stroke by inducing the migration of progenitor cells. In order to study the function of this therapeutically relevant chemokine site-specific protein labelling is of great interest. However, modification of SDF1α is complicated because of its complex tertiary structure. Here, we describe the first site-specific fluorescent modification of SDF1α by EPL. We recombinantly expressed SDF1α (1-49) by intein-mediated protein expression. The C-terminal peptide SDF1α (50-68) was synthesised by SPPS and selectively labelled with carboxyfluorescein at Lys(56). In a cell migration assay, M-[K(56)(CF)]SDF1α showed a clear potency to induce chemotaxis of human T-cell leukaemia cells. Microscopic analysis on HEK293 cells transfected with the CXCR4 revealed specific binding of the fluorescent ligand. Furthermore, receptor-induced internalisation of the ligand could be visualised. These results show that site-specific modification of SDF1α yields in a biologically functional molecule that allows the characterisation of CXCR4 production of cells on a molecular level. © 2010 European Peptide Society and John Wiley & Sons, Ltd.

  9. Cytokines Elevated in HIV Elite Controllers Reduce HIV ReplicationIn Vitroand Modulate HIV Restriction Factor Expression.

    Science.gov (United States)

    Jacobs, Evan S; Keating, Sheila M; Abdel-Mohsen, Mohamed; Gibb, Stuart L; Heitman, John W; Inglis, Heather C; Martin, Jeffrey N; Zhang, Jinbing; Kaidarova, Zhanna; Deng, Xutao; Wu, Shiquan; Anastos, Kathryn; Crystal, Howard; Villacres, Maria C; Young, Mary; Greenblatt, Ruth M; Landay, Alan L; Gange, Stephen J; Deeks, Steven G; Golub, Elizabeth T; Pillai, Satish K; Norris, Philip J

    2017-03-15

    A subset of HIV-infected individuals termed elite controllers (ECs) maintain CD4 + T cell counts and control viral replication in the absence of antiretroviral therapy (ART). Systemic cytokine responses may differentiate ECs from subjects with uncontrolled viral replication or from those who require ART to suppress viral replication. We measured 87 cytokines in four groups of women: 73 ECs, 42 with pharmacologically suppressed viremia (ART), 42 with uncontrolled viral replication (noncontrollers [NCs]), and 48 HIV-uninfected (NEG) subjects. Four cytokines were elevated in ECs but not NCs or ART subjects: CCL14, CCL21, CCL27, and XCL1. In addition, median stromal cell-derived factor-1 (SDF-1) levels were 43% higher in ECs than in NCs. The combination of the five cytokines suppressed R5 and X4 virus replication in resting CD4 + T cells, and individually SDF-1β, CCL14, and CCL27 suppressed R5 virus replication, while SDF-1β, CCL21, and CCL14 suppressed X4 virus replication. Functional studies revealed that the combination of the five cytokines upregulated CD69 and CCR5 and downregulated CXCR4 and CCR7 on CD4 + T cells. The CD69 and CXCR4 effects were driven by SDF-1, while CCL21 downregulated CCR7. The combination of the EC-associated cytokines induced expression of the anti-HIV host restriction factors IFITM1 and IFITM2 and suppressed expression of RNase L and SAMHD1. These results identify a set of cytokines that are elevated in ECs and define their effects on cellular activation, HIV coreceptor expression, and innate restriction factor expression. This cytokine pattern may be a signature characteristic of HIV-1 elite control, potentially important for HIV therapeutic and curative strategies. IMPORTANCE Approximately 1% of people infected with HIV control virus replication without taking antiviral medications. These subjects, termed elite controllers (ECs), are known to have stronger immune responses targeting HIV than the typical HIV-infected subject, but the

  10. The Role of SDF-1 (Alpha) CXCR4/MMP in PC Bone Metastasis

    Science.gov (United States)

    2006-03-01

    metastasis. The IVth International conference on cancer induced bone diseases. San Antonio , TX. December 2003. Role of CXCR4 and MMP-9 in prostate...chemoinvasion of breast cancer cells. Oncogene, 23: 157-167, 2004. 11. Shulby, S. A., Dolloff, N. G., Stearns, M. E., Meucci , O., and Fatatis, A. CX3CR1

  11. The Role of SDF-1alpha and CXCR4 in Metastatic Breast Cancer

    Science.gov (United States)

    2006-08-01

    diagnosis and prevention of this disease is urgently needed. Currently, breast cancer is treated with surgery , chemotherapy, and radiation therapy or...breast cancer cells could be due to alterations in gene expression pro- files that are important for cell growth and induction of apo- ptosis . Thus...Statistical analysis. The statistical significance was determined using Student’s t test, and P < 0.05 was considered significant. Results Cell

  12. Expression of SDF1 receptors in the patients with Hodgkin lymphoma

    Directory of Open Access Journals (Sweden)

    farhad Shahsavar

    2014-09-01

    Conclusion: The results of this study showed that RDC1 could be a marker for diagnosis of Hodgkin lymphoma. However, further studies using larger sample sizes and more accurate techniques are needed to confirm these results.

  13. Protective role of vitamin E preconditioning of human dermal fibroblasts against thermal stress in vitro.

    Science.gov (United States)

    Butt, Hira; Mehmood, Azra; Ali, Muhammad; Tasneem, Saba; Anjum, Muhammad Sohail; Tarar, Moazzam N; Khan, Shaheen N; Riazuddin, Sheikh

    2017-09-01

    Oxidative microenvironment of burnt skin restricts the outcome of cell based therapies of thermal skin injuries. The aim of this study was to precondition human dermal fibroblasts with an antioxidant such as vitamin E to improve their survival and therapeutic abilities in heat induced oxidative in vitro environment. Fibroblasts were treated with 100μM vitamin E for 24h at 37°C followed by heat shock for 10min at 51°C in fresh serum free medium. Preconditioning with vitamin E reduced cell injury as demonstrated by decreased expression of annexin-V, cytochrome p450 (CYP450) mediated oxidative reactions, senescence and release of lactate dehydrogenase (LDH) accomplished by down-regulated expression of pro-apoptotic BAX gene. Vitamin E preconditioned cells exhibited remarkable improvement in cell viability, release of paracrine factors such as epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), stromal derived factor-1alpha (SDF-1α) and also showed significantly up-regulated levels of PCNA, VEGF, BCL-XL, FGF7, FGF23, FLNβ and Col7α genes presumably through activation of phosphatidylinositol 3-kinase (PI3-K)/Akt pathway. The results suggest that pretreatment of fibroblasts with vitamin E prior to transplantation in burnt skin speeds up the wound healing process by improving the antioxidant scavenging responses in oxidative environment of transplanted burn wounds. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. CXCR4 expression on monocytes is up-regulated by dexamethasone and is modulated by autologous CD3+ T cells.

    Science.gov (United States)

    Caulfield, Jason; Fernandez, Maria; Snetkov, Vladimir; Lee, Tak; Hawrylowicz, Catherine

    2002-02-01

    Chemokines and their receptors regulate cell migration to sites of inflammation. The glucocorticoid dexamethasone has potent anti-inflammatory effects, yet paradoxically up-regulates expression of some cytokine receptors. We have examined the effects of dexamethasone on chemokine receptor expression. Using an RNase protection assay, we show that dexamethasone up-regulates human peripheral blood mononuclear cell (PBMC) expression of CXCR4 mRNA. Flow cytometric analysis demonstrated that increased expression of CXCR4, but not CXCR1 and CXCR2, occurred on both monocytes and CD3+ T cells in PBMC mixed cultures. A stromal-derived factor (SDF)-1alpha-mediated calcium influx was detected on monocytes. Basal levels of CXCR4 expression on purified monocytes were lower when compared with monocytes in mixed PBMC cultures. Co-culture of monocytes with purified CD3+ T cells led to enhanced basal expression of CXCR4 on monocytes. The use of transwells to partition CD3+ T cells resulted in increased CXCR4 expression on monocytes, suggesting that CD3+ T-cell derived soluble factors regulate CXCR4 expression.

  15. Prominent Vascularization Capacity of Mesenchymal Stem Cells in Collagen-Gold Nanocomposites.

    Science.gov (United States)

    Hsieh, Shu-Chen; Chen, Hui-Jye; Hsu, Shan-Hui; Yang, Yi-Chin; Tang, Cheng-Ming; Chu, Mei-Yun; Lin, Pei-Ying; Fu, Ru-Huei; Kung, Mei-Lang; Chen, Yun-Wen; Yeh, Bi-Wen; Hung, Huey-Shan

    2016-10-26

    The ideal characteristics of surface modification on the vascular graft for clinical application would be with excellent hemocompatibility, endothelialization capacity, and antirestenosis ability. Here, Fourier transform infrared spectroscopy (FTIR), surface enhanced Raman spectroscopy (SERS), atomic force microscopy (AFM), contact angle (θ) measurement, and thermogravimetric analysis (TGA) were used to evaluate the chemical and mechanical properties of collagen-gold nanocomposites (collagen+Au) with 17.4, 43.5, and 174 ppm of Au and suggested that the collagen+Au with 43.5 ppm of Au had better biomechanical properties and thermal stability than pure collagen. Besides, stromal-derived factor-1α (SDF-1α) at 50 ng/mL promoted the migration of mesenchymal stem cells (MSCs) on collagen+Au material through the α5β3 integrin/endothelial oxide synthase (eNOS)/metalloproteinase (MMP) signaling pathway which can be abolished by the knockdown of vascular endothelial growth factor (VEGF). The potentiality of collagen+Au with MSCs for vascular regeneration was evaluated by our in vivo rat model system. Artery tissues isolated from an implanted collagen+Au-coated catheter with MSCs expressed substantial CD-31 and α-SMA, displayed higher antifibrotic ability, antithrombotic activity, as well as anti-inflammatory response than all other materials. Our results indicated that the implantation of collagen+Au-coated catheters with MSCs could be a promising strategy for vascular regeneration.

  16. CXCR4 (CD184) expression on stem cell harvest and CD34+ cells post-transplant.

    Science.gov (United States)

    Asfour, Inas; Afify, Hanaa; Elkourashy, Shaza; Ayoub, Maryse; Kamal, Gihan; Gamal, Mary; Elgohary, Ghada

    2017-06-01

    CXCR4 is a receptor for stromal-derived factor-1 (SDF-1), a molecule that has a chemotactic activity for lymphocytes and is important in homing of hematopoietic stem cells to their adult marrow. We evaluated the CXCR4 (CD184) expression in the harvest cells and in the post-transplant bone marrow (BM) and its relation to engraftment, as determined by the consensus criteria and chimerism. This is a prospective study which included 30 patients undergoing hematopoietic stem cell transplantation; 15 patients received autograft and 15 patients received allograft on dates between January 2012 and May 2014. We assessed CD184 (CXCR4) using flow cytometry in the harvest cells together with post-transplant BM assessment on Day 28 and Day 90 for complete morphologic, molecular studies, and detection of CD184 expression on CD34 + cells with chimerism studies on total peripheral blood mononuclear cells. Diagnoses of the enrolled patients were as follows: seven (24.1%) with acute myeloid leukemia, eight (27.6%) with multiple myeloma, four (13.8%) with acute lymphoblastic leukemia, three (10.3%) with non-Hodgkin lymphoma, two (6.9%) with myelodysplastic syndromes, two (6.9%) with aplastic anemia, two (6.9%) with chronic myeloid leukemia, one (3.4%) with Hodgkin lymphoma, and one (3.4%) with plasmacytomas. One patient died and was excluded from the study because there were not enough data about engraftment. There was no statistical significance between the level of CD184 in stem cell harvest and the prediction of successful engraftment (p>0.05) as well as in Day 28 BM sample (p>0.05), whereas there was a statistical significance between the level of CD184 in Day 90 BM sample and the occurrence of successful engraftment (p=0.002). SDF-1/CXCR4 axis plays a crucial role in engraftment; however, more studies are warranted to assess their expression post-transplant. Evaluating the ligand (chemokine, SDF-1) or its receptor (CXCR4) may serve as potential surrogate markers for assessment

  17. The role of sialomucin CD164 (MGC-24v or endolyn) in prostate cancer metastasis

    International Nuclear Information System (INIS)

    Havens, AM; Jung, Y; Sun, YX; Wang, J; Shah, RB; Bühring, HJ; Pienta, KJ; Taichman, RS

    2006-01-01

    The chemokine stromal derived factor-1 (SDF-1 or CXCL12) and its receptor CXCR4 have been demonstrated to be crucial for the homing of stem cells and prostate cancers to the marrow. While screening prostate cancers for CXCL12-responsive adhesion molecules, we identified CD164 (MGC-24) as a potential regulator of homing. CD164 is known to function as a receptor that regulates stem cell localization to the bone marrow. Using prostate cancer cell lines, it was demonstrated that CXCL12 induced both the expression of CD164 mRNA and protein. Functional studies demonstrated that blocking CD164 on prostate cancer cell lines reduced the ability of these cells to adhere to human bone marrow endothelial cells, and invade into extracellular matrices. Human tissue microarrays stained for CD164 demonstrated a positive correlation with prostate-specific antigen levels, while its expression was negatively correlated with the expression of androgen receptor. Our findings suggest that CD164 may participate in the localization of prostate cancer cells to the marrow and is further evidence that tumor metastasis and hematopoietic stem cell trafficking may involve similar processes

  18. Prospective identification and skeletal localization of cells capable of multilineage differentiation in vivo.

    Science.gov (United States)

    Taichman, Russell S; Wang, Zhuo; Shiozawa, Yusuke; Jung, Younghun; Song, Junhui; Balduino, Alex; Wang, Jincheng; Patel, Lalit R; Havens, Aaron M; Kucia, Magdalena; Ratajczak, Mariusz Z; Krebsbach, Paul H

    2010-10-01

    A prospective in vivo assay was used to identify cells with potential for multiple lineage differentiation. With this assay, it was first determined that the 5-fluorouracil resistant cells capable of osseous tissue formation in vivo also migrated toward stromal derived factor-1 (SDF-1) in vitro. In parallel, an isolation method based on fluorescence-activated cell sorting was employed to identify a very small cell embryonic-like Lin-/Sca-1+CD45- cell that with as few as 500 cells was capable of forming bone-like structures in vivo. Differential marrow fractionation studies determined that the majority of the Lin-Sca-1+CD45- cells reside in the subendosteal regions of marrow. To determine whether these cells were capable of differentiating into multiple lineages, stromal cells harvested from Col2.3 Delta TK mice were implanted with a gelatin sponge into SCID mice to generate thymidine kinase sensitive ossicles. At 1.5 months, 2,000 green fluorescent protein (GFP)+ Lin-Sca-1+CD45- cells were injected into the ossicles. At harvest, colocalization of GFP-expressing cells with antibodies to the osteoblast-specific marker Runx-2 and the adipocyte marker PPAP gamma were observed. Based on the ability of the noncultured cells to differentiate into multiple mesenchymal lineages in vivo and the ability to generate osseous tissues at low density, we propose that this population fulfills many of the characteristics of mesenchymal stem cells.

  19. Mutation of Asp(171) and Asp(262) of the chemokine receptor CXCR4 impairs its coreceptor function for human immunodeficiency virus-1 entry and abrogates the antagonistic activity of AMD3100

    DEFF Research Database (Denmark)

    Hatse, S; Princen, K; Gerlach, L O

    2001-01-01

    that the antagonistic action of AMD3100 against CXCR4--as assessed by the inhibitory effects of the compound on stromal cell-derived factor (SDF-1) binding to its receptor and on SDF-1-induced intracellular calcium signaling, and by displacement of the CXCR4-specific antibody, clone 12G5--was greatly reduced...

  20. Increased migration of cord blood-derived CD34+ cells, as compared to bone marrow and mobilized peripheral blood CD34+ cells across uncoated or fibronectin-coated filters

    NARCIS (Netherlands)

    Voermans, C.; Gerritsen, W. R.; von dem Borne, A. E.; van der Schoot, C. E.

    1999-01-01

    Hematopoietic progenitor cells (CD34+ cells) migrate to the bone marrow after reinfusion into peripheral veins. Stromal cell-derived factor-1 (SDF-1) is a chemokine produced by bone marrow stromal cells that induces migration of CD34+ cells. In this study we compared spontaneous and SDF-1-induced

  1. Cytokines and growth factors cross-link heparan sulfate

    Science.gov (United States)

    Migliorini, Elisa; Thakar, Dhruv; Kühnle, Jens; Sadir, Rabia; Dyer, Douglas P.; Li, Yong; Sun, Changye; Volkman, Brian F.; Handel, Tracy M.; Coche-Guerente, Liliane; Fernig, David G.; Lortat-Jacob, Hugues; Richter, Ralf P.

    2015-01-01

    The glycosaminoglycan heparan sulfate (HS), present at the surface of most cells and ubiquitous in extracellular matrix, binds many soluble extracellular signalling molecules such as chemokines and growth factors, and regulates their transport and effector functions. It is, however, unknown whether upon binding HS these proteins can affect the long-range structure of HS. To test this idea, we interrogated a supramolecular model system, in which HS chains grafted to streptavidin-functionalized oligoethylene glycol monolayers or supported lipid bilayers mimic the HS-rich pericellular or extracellular matrix, with the biophysical techniques quartz crystal microbalance (QCM-D) and fluorescence recovery after photobleaching (FRAP). We were able to control and characterize the supramolecular presentation of HS chains—their local density, orientation, conformation and lateral mobility—and their interaction with proteins. The chemokine CXCL12α (or SDF-1α) rigidified the HS film, and this effect was due to protein-mediated cross-linking of HS chains. Complementary measurements with CXCL12α mutants and the CXCL12γ isoform provided insight into the molecular mechanism underlying cross-linking. Fibroblast growth factor 2 (FGF-2), which has three HS binding sites, was also found to cross-link HS, but FGF-9, which has just one binding site, did not. Based on these data, we propose that the ability to cross-link HS is a generic feature of many cytokines and growth factors, which depends on the architecture of their HS binding sites. The ability to change matrix organization and physico-chemical properties (e.g. permeability and rigidification) implies that the functions of cytokines and growth factors may not simply be confined to the activation of cognate cellular receptors. PMID:26269427

  2. The SDF1-CXCR4 Axis Functions through p38-MAPK Signaling to Drive Breast Cancer Progression and Metastasis

    Science.gov (United States)

    2007-09-01

    Endocrinol. 2003 May;17(5):792-803. 7. Coser KR, Chesnes J, Hur J, Ray S, Isselbacher KJ, Shioda T. Global analysis of ligand sensitivity of estrogen...Duong, B.N., Melnik, L.I., Schief, L., Collins-Burow, B.M., Pace, D.K., McLachlan, J.A., Burow, M.E. Flavonoid Phytochemicals Regulate Activator

  3. Relationship of PDCD5 expression with apoptosis, inflammatory factors and MMPs/TIMPs expression in degenerated intervertebral disc tissue

    Directory of Open Access Journals (Sweden)

    Xiao-Hua Gu

    2017-11-01

    Full Text Available Objective: To study the relationship of PDCD5 expression with apoptosis, inflammatory factors and MMPs/TIMPs expression in degenerated intervertebral disc tissue. Methods: Patients with lumbar disc herniation who were treated in the Seventh People's Hospital of Shanghai between March 2015 and February 2017 were selected as the LDH group and patients with violent thoracolumbar vertebral fracture were selected as the control group. The intervertebral disc tissue was collected to determine the mRNA expression of PDCD5 as well as the protein levels of apoptosis molecules, inflammatory factors and MMPs/TIMPs molecules. Results: PDCD5 mRNA expression in intervertebral disc tissue of LDH group was significantly higher than that of control group; Caspase-3, Caspase-8, Fas, Caspase-9, Bax, SDF-1, CXCR-4, TNF-α, PGE2, MMP1, MMP2, MMP8 and MMP9 protein levels in intervertebral disc tissue of LDH group were significantly higher than those of control group and positively correlated with PDCD5 mRNA expression while TIMP1 and TIMP2 protein levels were significantly lower than those of control group and negatively correlated with PDCD5 mRNA expression. Conclusion: The high expression of PDCD5 in degenerated intervertebral disc tissue can activate apoptosis and inflammatory response and cause MMPs/ TIMPs imbalance.

  4. Hypoxia-inducible factor-1α perpetuates synovial fibroblast interactions with T cells and B cells in rheumatoid arthritis.

    Science.gov (United States)

    Hu, Fanlei; Liu, Hongjiang; Xu, Liling; Li, Yingni; Liu, Xu; Shi, Lianjie; Su, Yin; Qiu, Xiaoyan; Zhang, Xia; Yang, Yuqin; Zhang, Jian; Li, Zhanguo

    2016-03-01

    Synovial fibroblast hyperplasia, T-cell hyperactivity, B-cell overactivation, and the self-perpetuating interactions among these cell types are major characteristics of rheumatoid arthritis (RA). The inflamed joints of RA patients are hypoxic, with upregulated expression of hypoxia-inducible factor-1α (HIF-1α) in RA synovial fibroblasts (RASFs). It remains unknown whether HIF-1α regulates interactions between RASFs and T cells and B cells. We report here that HIF-1α promotes the expression of inflammatory cytokines IL-6, IL-8, TNF-α, and IL-1β, and cell-cell contact mediators IL-15, vascular cell adhesion molecule (VCAM)-1, thrombospondin (TSP)-1, and stromal cell-derived factor (SDF)-1 in RASFs. Furthermore, HIF-1α perpetuates RASF-mediated inflammatory Th1- and Th17-cell expansion while differentially inhibiting regulatory B10 and innate-like B cells, leading to increased IFN-γ, IL-17, and IgG production and decreased protective natural IgM secretion. Our findings suggest that HIF-1α perpetuates the interactions between RASFs and T cells and B cells to induce inflammatory cytokine and autoantibody production, thus exacerbating the severity of RA. Targeting HIF-1α may provide new therapeutic strategies for overcoming this persistent disease. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Hypoxia precondition promotes adipose-derived mesenchymal stem cells based repair of diabetic erectile dysfunction via augmenting angiogenesis and neuroprotection.

    Directory of Open Access Journals (Sweden)

    XiYou Wang

    Full Text Available The aim of the present study was to examine whether hypoxia preconditioning could improve therapeutic effects of adipose derived mesenchymal stem cells (AMSCs for diabetes induced erectile dysfunction (DED. AMSCs were pretreated with normoxia (20% O2, N-AMSCs or sub-lethal hypoxia (1% O2, H-AMSCs. The hypoxia exposure up-regulated the expression of several angiogenesis and neuroprotection related cytokines in AMSCs, including vascular endothelial growth factor (VEGF and its receptor FIK-1, angiotensin (Ang-1, basic fibroblast growth factor (bFGF, brain-derived neurotrophic factor (BDNF, glial cell-derived neurotrophic factor (GDNF, stromal derived factor-1 (SDF-1 and its CXC chemokine receptor 4 (CXCR4. DED rats were induced via intraperitoneal injection of streptozotocin (60 mg/kg and were randomly divided into three groups-Saline group: intracavernous injection with phosphate buffer saline; N-AMSCs group: N-AMSCs injection; H-AMSCs group: H-AMSCs injection. Ten rats without any treatment were used as normal control. Four weeks after injection, the mean arterial pressure (MAP and intracavernosal pressure (ICP were measured. The contents of endothelial, smooth muscle, dorsal nerve in cavernoursal tissue were assessed. Compared with N-AMSCs and saline, intracavernosum injection of H-AMSCs significantly raised ICP and ICP/MAP (p<0.05. Immunofluorescent staining analysis demonstrated that improved erectile function by MSCs was significantly associated with increased expression of endothelial markers (CD31 and vWF (p<0.01 and smooth muscle markers (α-SMA (p<0.01. Meanwhile, the expression of nNOS was also significantly higher in rats receiving H-AMSCs injection than those receiving N-AMSCs or saline injection. The results suggested that hypoxic preconditioning of MSCs was an effective approach to enhance their therapeutic effect for DED, which may be due to their augmented angiogenesis and neuroprotection.

  6. Specific recruitment of circulating angiogenic cells using biomaterials as filters.

    Science.gov (United States)

    Parlato, Matthew; Molenda, James; Murphy, William L

    2017-07-01

    Endogenous recruitment of circulating angiogenic cells (CACs) is an emerging strategy to induce angiogenesis within a defect site, and multiple recent strategies have deployed soluble protein releasing biomaterials for this purpose. However, the way in which the design of biomaterials affects CAC recruitment and invasion are poorly understood. Here we used an enhanced-throughput cell invasion assay to systematically examine the effects of biomaterial design on CAC recruitment. The screens co-optimized hydrogel presentation of a stromal-derived factor-1α (SDF-1α) gradient, hydrogel degradability, and hydrogel stiffness for maximal CAC invasion. We also examined the specificity of this invasion by assessing dermal fibroblast, mesenchymal stem cell, and lymphocyte invasion individually and in co-culture with CACs to identify hydrogels specific to CAC invasion. These screens suggested a subset of MMP-degradable hydrogels presenting a specific range of SDF-1α gradient slopes that induced specific invasion of CACs, and we posit that the design parameters of this subset of hydrogels may serve as instructive templates for the future design of biomaterials to specifically recruit CACs. We also posit that this design concept may be applied more broadly in that it may be possible to utilize these specific subsets of biomaterials as "filters" to control which types of cell populations invade into and populate the biomaterial. The recruitment of specific cell types for cell-based therapies in vivo is of great interest to the regenerative medicine community. Circulating angiogenic cells (CACs), CD133+ cells derived from the blood stream, are of particular interest for induction of angiogenesis in ischemic tissues, and recent studies utilizing soluble-factor releasing biomaterials to recruit these cells in vivo show great promise. However, these studies are largely "proof of concept" and are not systematic in nature. Thus, little is currently known about how biomaterial design

  7. Human breast adipose-derived stem cells transfected with the stromal cell-derived factor-1 receptor CXCR4 exhibit enhanced viability in human autologous free fat grafts.

    Science.gov (United States)

    Xu, Fang-tian; Li, Hong-mian; Yin, Qing-Shui; Liu, Da-lie; Nan, Hua; Zhao, Pei-ran; Liang, Shuang-wu

    2014-01-01

    The main complication of autologous free fat tissue transplantation is fat resorption and calcification due to the ischemic necrosis of fat. The promotion of transplant neovascularization soon after autologous free fat grafts may reduce these outcomes. In adulthood, stromal cell-derived factor-1 (SDF-1) and its membrane receptor C-X-C chemokine receptor type 4 (CXCR4) are involved in the homing and migration of multiple stem cell types, neovascularization, and cell proliferation. We hypothesized that CXCR4 may improve the long-term survival of free fat tissue transplants by recruiting endothelial progenitor cells (EPCs) and may therefore improve graft revascularization. In this study, we aimed to determine the effect of human breast adipose-derived stem cells (HBASCs) transfected with the CXCR4 gene on the survival rate of human autologous free fat transplants in nude mice. Human breast adipose-derived stem cells (HBASCs) were expanded ex vivo for 3 passages, labeled with green fluorescent protein (GFP) and transfected with CXCR4 or left untransfected. Autologous fat tissues were mixed with the GFP-labeled, CXCR4-transfected HBASCs (group A), GFP-labeled HBASCs (group B), the known vascularization-promoting agent VEGF (group C), or medium (group D) and then injected subcutaneously into 32 nude mice at 4 spots in a random fashion. Six months later, the transplanted tissue volume and histology were evaluated, and neo-vascularization was quantified by counting the capillaries. CXCR4 and SDF-1α mRNA expression in the transplants was determined using real-time quantitative PCR analysis (qPCR). The data revealed that the control (group D) transplant volume survival was 28.3 ± 4.5%. Mixing CXCR4-transfected (group A) and untransfected (group B) HBASCs significantly increased transplant volume survival (79.5 ± 8.3% and 67.2 ± 5.9%, respectively), whereas VEGF-transfected HBASCs (group C) were less effective (41.2 ± 5.1%). Histological analysis revealed that both types

  8. Increased chemokine signaling in a model of HIV1-associated peripheral neuropathy

    Directory of Open Access Journals (Sweden)

    Buchanan David J

    2009-08-01

    Full Text Available Abstract Painful distal sensory polyneuropathy (DSP is the most common neurological complication of HIV1 infection. Although infection with the virus itself is associated with an incidence of DSP, patients are more likely to become symptomatic following initiation of nucleoside reverse transcriptase inhibitor (NRTI treatment. The chemokines monocyte chemoattractant protein-1 (MCP1/CCL2 and stromal derived factor-1 (SDF1/CXCL12 and their respective receptors, CCR2 and CXCR4, have been implicated in HIV1 related neuropathic pain mechanisms including NRTI treatment in rodents. Utilizing a rodent model that incorporates the viral coat protein, gp120, and the NRTI, 2'3'-dideoxycytidine (ddC, we examined the degree to which chemokine receptor signaling via CCR2 and CXCR4 potentially influences the resultant chronic hypernociceptive behavior. We observed that following unilateral gp120 sciatic nerve administration, rats developed profound tactile hypernociception in the hindpaw ipsilateral to gp120 treatment. Behavioral changes were also present in the hindpaw contralateral to the injury, albeit delayed and less robust. Using immunohistochemical studies, we demonstrated that MCP1 and CCR2 were upregulated by primary sensory neurons in lumbar ganglia by post-operative day (POD 14. The functional nature of these observations was confirmed using calcium imaging in acutely dissociated lumbar dorsal root ganglion (DRG derived from gp120 injured rats at POD 14. Tactile hypernociception in gp120 treated animals was reversed following treatment with a CCR2 receptor antagonist at POD 14. Some groups of animals were subjected to gp120 sciatic nerve injury in combination with an injection of ddC at POD 14. This injury paradigm produced pronounced bilateral tactile hypernociception from POD 14–48. More importantly, functional MCP1/CCR2 and SDF1/CXCR4 signaling was present in sensory neurons. In contrast to gp120 treatment alone, the hypernociceptive behavior

  9. Application of stem cell/growth factor system, as a multimodal therapy approach in regenerative medicine to improve cell therapy yields.

    Science.gov (United States)

    Pourrajab, Fatemeh; Babaei Zarch, Mojtaba; Baghi Yazdi, Mohammad; Rahimi Zarchi, Abolfazl; Vakili Zarch, Abbas

    2014-04-15

    Stem cells hold a great promise for regenerative medicine, especially for replacing cells in infarcted organ that hardly have any intrinsic renewal capacity, including heart and brain. Signaling pathways that regulate pluripotency or lineage-specific gene and protein expression have been the major focus of stem cell research. Between them, there are some well known signaling pathways such as GF/GFR systems, SDF-1α/CXC4 ligand receptor interaction and PI3K/Akt signaling, and cytokines may regulate cell fate decisions, and can be utilized to positively influence cell therapy outcomes or accentuate synergistic compliance. For example, contributing factors in the progression of heart failure are both the loss of cardiomyocytes after myocardial infarction, and the absence of an adequate endogenous repair signaling. Combining cell engraftment with therapeutic signaling factor delivery is more exciting in terms of host progenitor/donor stem cell survival and proliferation. Thus stem cell-based therapy, besides triggering signaling pathways through GF/GFR systems can become a realistic option in regenerative processes for replacing lost cells and reconstituting the damaged organ, as before. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  10. A study of chemokines, chemokine receptors and interleukin-6 in patients with panic disorder, personality disorders and their co-morbidity.

    Science.gov (United States)

    Ogłodek, Ewa A; Szota, Anna M; Just, Marek J; Szromek, Adam R; Araszkiewicz, Aleksander

    2016-08-01

    Stress may induce inflammatory changes in the immune system and activate pro-inflammatory cytokines and their receptors by activating the hypothalamic-pituitary-adrenal axis. 460 hospitalized patients with panic disorders (PD) and/or personality disorders (P) were studied. The study group comprised subjects with PD, avoidant personality disorder (APD), borderline personality disorder (BPD), obsessive-compulsive personality disorder (OCPD), and concomitant (PD+APD; PD+BPD; PD+OCPD). Each study group consisted of 60 subjects (30 females and 30 males). The control group included 20 females and 20 males without any history of mental disorder. ELISA was used to assess the levels of chemokines: CCL-5/RANTES (regulated on activation, normal T-cell expressed and secreted), CXCL-12/SDF-1 (stromal derived factor), their receptors CXCR-5 (C-C chemokine receptor type-5), CXCR-4 (chemokine C-X-C motif receptor-4), and IL-6. Statistically significant differences in the levels of CCL-5 and CCR-5 were revealed between all study groups. The greatest differences were found between the groups with PD+OCPD and PD+APD. Moreover, concomitance of PD with P significantly increased the level of chemokines and their receptors in all study groups versus the subjects with P alone. The results of the study show differences between the groups. To be specific, inflammatory markers were more elevated in the study groups than the controls. Therefore, chemokines and chemokine receptors may be used as inflammatory markers in patients with PD co-existent with P to indicate disease severity. PD was found to be a factor in maintaining inflammatory activity in the immune system in patients with P. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  11. Plerixafor (a CXCR4 antagonist following myeloablative allogeneic hematopoietic stem cell transplantation enhances hematopoietic recovery

    Directory of Open Access Journals (Sweden)

    Michael M. B. Green

    2016-08-01

    Full Text Available Abstract Background The binding of CXCR4 with its ligand (stromal-derived factor-1 maintains hematopoietic stem/progenitor cells (HSPCs in a quiescent state. We hypothesized that blocking CXCR4/SDF-1 interaction after hematopoietic stem cell transplantation (HSCT promotes hematopoiesis by inducing HSC proliferation. Methods We conducted a phase I/II trial of plerixafor on hematopoietic cell recovery following myeloablative allogeneic HSCT. Patients with hematologic malignancies receiving myeloablative conditioning were enrolled. Plerixafor 240 μg/kg was administered subcutaneously every other day beginning day +2 until day +21 or until neutrophil recovery. The primary efficacy endpoints of the study were time to absolute neutrophil count >500/μl and platelet count >20,000/μl. The cumulative incidence of neutrophil and platelet engraftment of the study cohort was compared to that of a cohort of 95 allogeneic peripheral blood stem cell transplant recipients treated during the same period of time and who received similar conditioning and graft-versus-host disease prophylaxis. Results Thirty patients received plerixafor following peripheral blood stem cell (n = 28 (PBSC or bone marrow (n = 2 transplantation. Adverse events attributable to plerixafor were mild and indistinguishable from effects of conditioning. The kinetics of neutrophil and platelet engraftment, as demonstrated by cumulative incidence, from the 28 study subjects receiving PBSC showed faster neutrophil (p = 0.04 and platelet recovery >20 K (p = 0.04 compared to the controls. Conclusions Our study demonstrated that plerixafor can be given safely following myeloablative HSCT. It provides proof of principle that blocking CXCR4 after HSCT enhances hematopoietic recovery. Larger, confirmatory studies in other settings are warranted. Trial registration ClinicalTrials.gov NCT01280955

  12. Amniotic liquid derived stem cells as reservoir of secreted angiogenic factors capable of stimulating neo-arteriogenesis in an ischemic model.

    Science.gov (United States)

    Mirabella, Teodelinda; Teodelinda, Mirabella; Cilli, Michele; Michele, Cilli; Carlone, Sebastiano; Sebastiano, Carlone; Cancedda, Ranieri; Ranieri, Cancedda; Gentili, Chiara; Chiara, Gentili

    2011-05-01

    Most urgent health problems are related to a blood vessel formation failure. The use of stem cells from different sources or species for both in vitro and in vivo engineering of endothelium does not necessarily imply their direct commitment towards a vascular phenotype. In the present study, we used human amniotic fluid stem cells (AFSC) to evoke a strong angiogenic response in murine recipients, in terms of host guided-regeneration of new vessels, and we demonstrated that the AFSC secretome is responsible for the vascularising properties of these cells. We indentified in AFSC conditioned media (ACM) pro-angiogenic soluble factors, such as MCP-1, IL-8, SDF-1, VEGF. Our in vitro results suggest that ACM are cytoprotective, pro-differentiative and chemoattractive for endothelial cells. We also tested ACM on a pre-clinical model of hind-limb ischemic mouse, concluding that ACM contain mediators that promote the neo-arteriogenesis, as remodelling of pre-existing collateral arteries to conductance vessels, thus preventing the capillary loss and the tissue necrosis of distal muscles. In line with the current regenerative medicine trend, in the present study we assert the concept that stem cell-secreted mediators can guide the tissue repair by stimulating or recruiting host reparative cells. Copyright © 2011 Elsevier Ltd. All rights reserved.

  13. Study on mechanisms of preferential distribution of the transplanted dermal multipotent stem cells in rats with combined radiation and wound injury

    International Nuclear Information System (INIS)

    Zong Zhaowen; Cheng Tianmin; Ran Xinze; Li Nan; Dong Shiwu; Ai Guoping; Su Yongping

    2006-01-01

    Objective: To explore the mechanisms of preferential distribution of transplanted dermal muhipotent stem cells (dMSCs) to surface of wound in rats with combined radiation and wound injury (CRWI). Methods: The expression of stromal-dereived factor-1 (SDF-1) in wounds of rats and the expression of CXCR4 (the only known receptor of SDF-1) in dMSCs were examined using RT-PCR and immunohistochemistry. The chemotactic effect of SDF-1 on dMSCs was evaluated in Transwell culture system. Results: The expression of SDF-1 in wound of CRWI rats was upregulated significantly compared with the normal rats'skin, dMSCs expressed CXCR4. SDF-1 had a strong chemotactic effect on dMSCs; the chemotactic effect of wound extracts from CRWI rats was significantly reduced (P<0.05) when neutralized antibody to SDF-1 was added. Conclusion: The upregulated expression of SDF-1 played an important role in the preferential distribution of transplanted dMSCs to wound in rats with CRWI. (authors)

  14. Factors involved in the T helper type 1 and type 2 cell commitment and osteoclast regulation in inflammatory apical diseases.

    Science.gov (United States)

    Fukada, S Y; Silva, T A; Garlet, G P; Rosa, A L; da Silva, J S; Cunha, F Q

    2009-02-01

    Periapical chronic lesion formation involves activation of the immune response and alveolar bone resorption around the tooth apex. However, the overall roles of T helper type 1 (Th1), Th2, and T-regulatory cell (Treg) responses and osteoclast regulatory factors in periapical cysts and granulomas have not been fully determined. This study aimed to investigate whether different forms of apical periodontitis, namely cysts and granulomas, show different balances of Th1, Th2 regulators, Treg markers, and factors involved in osteoclast chemotaxis and activation. Gene expression of these factors was assessed using quantitative real-time polymerase chain reaction, in samples obtained from healthy gingiva (n = 8), periapical granulomas (n = 20), and cysts (n = 10). Periapical cysts exhibited a greater expression of GATA-3, while a greater expression of T-bet, Foxp3, and interleukin-10 (IL-10) was seen in granulomas. The expression of interferon-gamma, IL-4, and transforming growth factor-beta was similar in both lesions. Regarding osteoclastic factors, while the expression of SDF-1alpha/CXCL12 and CCR1 was higher in cysts, the expression of RANKL was significantly higher in granulomas. Both lesions exhibited similar expression of CXCR4, CKbeta8/CCL23, and osteoprotegerin, which were significantly higher than in control. Our results showed a predominance of osteoclast activity in granulomas that was correlated with the Th1 response. The concomitant expression of Treg cell markers suggests a possible suppression of the Th1 response in granulomas. On the other hand, in cysts the Th2 activity is augmented. The mechanisms of periradicular lesion development are still not fully understood but the imbalance of immune and osteoclastic cell activity in cysts and granulomas seems to be critically regulated by Treg cells.

  15. CXCR3 expression on CD34(+) hemopoietic progenitors induced by granulocyte-macrophage colony-stimulating factor

    DEFF Research Database (Denmark)

    Jinquan, T; Anting, L; Jacobi, H H

    2001-01-01

    phosphorylation, which leads to induce CXCR3 expression. gamma IP-10 and Mig can induce Syk, Cbl, and Cbl-b phosphorylation in CD34(+) progenitors by means of CXCR3. gamma IP-10 or Mig has induced neither chemotaxis nor adhesion in GM-CSF-stimulated Cbl-b-blocked CD34(+) hemopoietic progenitors, whereas SDF-1...

  16. Vesnarinone downregulates CXCR4 expression via upregulation of Krüppel-like factor 2 in oral cancer cells

    Directory of Open Access Journals (Sweden)

    Uchida Daisuke

    2009-08-01

    Full Text Available Abstract Background We have demonstrated that the stromal cell-derived factor-1 (SDF-1; CXCL12/CXCR4 system is involved in the establishment of lymph node metastasis in oral squamous cell carcinoma (SCC. Chemotherapy is a powerful tool for the treatment of oral cancer, including oral SCC; however, the effects of chemotherapeutic agents on the expression of CXCR4 are unknown. In this study, we examined the expression of CXCR4 associated with the chemotherapeutic agents in oral cancer cells. Results The expression of CXCR4 was examined using 3 different chemotherapeutic agents; 5-fluorouracil, cisplatin, and vesnarinone (3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl-1-piperazinyl]-2-(1H-quinolinone in B88, a line of oral cancer cells that exhibits high levels of CXCR4 and lymph node metastatic potential. Of the 3 chemotherapeutic agents that we examined, only vesnarinone downregulated the expression of CXCR4 at the mRNA as well as the protein level. Vesnarinone significantly inhibited lymph node metastasis in tumor-bearing nude mice. Moreover, vesnarinone markedly inhibited 2.7-kb human CXCR4 promoter activity, and we identified the transcription factor, Krüppel-like factor 2 (KLF2, as a novel vesnarinone-responsive molecule, which was bound to the CXCR4 promoter at positions -300 to -167 relative to the transcription start site. The forced-expression of KLF2 led to the downregulation of CXCR4 mRNA and impaired CXCR4 promoter activity. The use of siRNA against KLF2 led to an upregulation of CXCR4 mRNA. Conclusion These Results indicate that vesnarinone downregulates CXCR4 via the upregulation of KLF2 in oral cancer.

  17. Protein Kinase A (PKA) Type I Interacts with P-Rex1, a Rac Guanine Nucleotide Exchange Factor

    Science.gov (United States)

    Chávez-Vargas, Lydia; Adame-García, Sendi Rafael; Cervantes-Villagrana, Rodolfo Daniel; Castillo-Kauil, Alejandro; Bruystens, Jessica G. H.; Fukuhara, Shigetomo; Taylor, Susan S.; Mochizuki, Naoki; Reyes-Cruz, Guadalupe; Vázquez-Prado, José

    2016-01-01

    Morphology of migrating cells is regulated by Rho GTPases and fine-tuned by protein interactions and phosphorylation. PKA affects cell migration potentially through spatiotemporal interactions with regulators of Rho GTPases. Here we show that the endogenous regulatory (R) subunit of type I PKA interacts with P-Rex1, a Rac guanine nucleotide exchange factor that integrates chemotactic signals. Type I PKA holoenzyme interacts with P-Rex1 PDZ domains via the CNB B domain of RIα, which when expressed by itself facilitates endothelial cell migration. P-Rex1 activation localizes PKA to the cell periphery, whereas stimulation of PKA phosphorylates P-Rex1 and prevents its activation in cells responding to SDF-1 (stromal cell-derived factor 1). The P-Rex1 DEP1 domain is phosphorylated at Ser-436, which inhibits the DH-PH catalytic cassette by direct interaction. In addition, the P-Rex1 C terminus is indirectly targeted by PKA, promoting inhibitory interactions independently of the DEP1-PDZ2 region. A P-Rex1 S436A mutant construct shows increased RacGEF activity and prevents the inhibitory effect of forskolin on sphingosine 1-phosphate-dependent endothelial cell migration. Altogether, these results support the idea that P-Rex1 contributes to the spatiotemporal localization of type I PKA, which tightly regulates this guanine exchange factor by a multistep mechanism, initiated by interaction with the PDZ domains of P-Rex1 followed by direct phosphorylation at the first DEP domain and putatively indirect regulation of the C terminus, thus promoting inhibitory intramolecular interactions. This reciprocal regulation between PKA and P-Rex1 might represent a key node of integration by which chemotactic signaling is fine-tuned by PKA. PMID:26797121

  18. CXC chemokine receptor 4 expression and stromal cell-derived factor-1alpha-induced chemotaxis in CD4+ T lymphocytes are regulated by interleukin-4 and interleukin-10

    DEFF Research Database (Denmark)

    Jinquan, T; Quan, S; Jacobi, H H

    2000-01-01

    We report that interleukin (IL)-4 and IL-10 can significantly up- or down-regulate CXC chemokine receptor 4 (CXCR4) expression on CD4+ T lymphocytes, respectively. Stromal cell-derived factor-1alpha (SDF-1alpha)-induced CD4+ T-lymphocyte chemotaxis was also correspondingly regulated by IL-4 and IL......-10. IL-4 and IL-10 up- or down-regulated CXCR4 mRNA expression in CD4+ T lymphocytes, respectively, as detected by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). Scatchard analysis revealed a type of CXCR4 with affinity (Kd approximately 6.3 nM), and approximately 70....... The regulation of CXCR4 expression in CD4+ T lymphocytes by IL-4 and IL-10 could be blocked by a selective inhibitor of protein kinase (staurosporine) or by a selective inhibitor of cAMP- and cGMP-dependent protein kinase (H-8), indicating that these cytokines regulate CXCR4 on CD4+ T lymphocytes via both c...

  19. Plasma levels of stromal cell-derived factor-1 (CXCL12) and circulating endothelial progenitor cells in women with idiopathic heavy menstrual bleeding.

    Science.gov (United States)

    Elsheikh, E; Andersson, E; Sylvén, C; Ericzon, B-G; Palmblad, J; Mints, M

    2014-01-01

    Do plasma levels of stromal cell-derived factor-1 (CXCL12, sometimes termed SDF-1) and the numbers of circulating endothelial progenitor cells (EPCs), EPC colony-forming units (EPC-CFU) and mature endothelial cells (ECs) differ between women with idiopathic heavy menstrual bleeding of endometrial origin (HMB-E) and controls and are they related to plasma levels of other angiogenic growth factors? Angiogenesis is altered in women with HMB-E, characterized by a reduction in mean plasma levels of CXCL12, a low number of EPCs-CFUs and a high level of circulating ECs. Plasma levels of CXCL12 are significantly higher during the proliferative than the secretory phase of the menstrual cycle in healthy women and exhibit a negative correlation with blood EPC-CFUs. A prospective cohort study in a university hospital setting. Between 2008 and 2009 10 HMB-E patients were recruited from Karolinska University Hospital. Ten healthy women were also included in the analysis. Ten healthy control women and 10 HMB-E patients, all with regular menstrual cycles, provided 4 blood samples during a single menstrual cycle: 2 in the proliferative phase, 1 at ovulation and 1 in the secretory phase. We assessed plasma levels of CXCL12, vascular endothelial growth factor A(165) (VEGFA), basic fibroblast growth factor (bFGF) and granulocyte and granulocyte-macrophage colony-stimulating factors by ELISA. We counted circulating EPC-CFUs by culture, and ECs and EPCs by flow cytometry and immunostaining for cell surface markers. Plasma levels of CXCL12 were significantly lower in HMB-E patients compared with control women (P Market Insurance. The authors have no conflict of interest to declare.

  20. Human progenitor cells rapidly mobilized by AMD3100 repopulate NOD/SCID mice with increased frequency in comparison to cells from the same donor mobilized by granulocyte colony stimulating factor

    DEFF Research Database (Denmark)

    Hess, David A; Bonde, Jesper; Craft, Timothy P

    2007-01-01

    AMD3100 inhibits the interaction between SDF-1 and CXCR4, and rapidly mobilizes hematopoietic progenitors for clinical transplantation. However, the repopulating function of human cells mobilized with AMD3100 has not been characterized in comparison to cells mobilized with granulocyte-colony stim......AMD3100 inhibits the interaction between SDF-1 and CXCR4, and rapidly mobilizes hematopoietic progenitors for clinical transplantation. However, the repopulating function of human cells mobilized with AMD3100 has not been characterized in comparison to cells mobilized with granulocyte...

  1. Protein Kinase A (PKA) Type I Interacts with P-Rex1, a Rac Guanine Nucleotide Exchange Factor: EFFECT ON PKA LOCALIZATION AND P-Rex1 SIGNALING.

    Science.gov (United States)

    Chávez-Vargas, Lydia; Adame-García, Sendi Rafael; Cervantes-Villagrana, Rodolfo Daniel; Castillo-Kauil, Alejandro; Bruystens, Jessica G H; Fukuhara, Shigetomo; Taylor, Susan S; Mochizuki, Naoki; Reyes-Cruz, Guadalupe; Vázquez-Prado, José

    2016-03-18

    Morphology of migrating cells is regulated by Rho GTPases and fine-tuned by protein interactions and phosphorylation. PKA affects cell migration potentially through spatiotemporal interactions with regulators of Rho GTPases. Here we show that the endogenous regulatory (R) subunit of type I PKA interacts with P-Rex1, a Rac guanine nucleotide exchange factor that integrates chemotactic signals. Type I PKA holoenzyme interacts with P-Rex1 PDZ domains via the CNB B domain of RIα, which when expressed by itself facilitates endothelial cell migration. P-Rex1 activation localizes PKA to the cell periphery, whereas stimulation of PKA phosphorylates P-Rex1 and prevents its activation in cells responding to SDF-1 (stromal cell-derived factor 1). The P-Rex1 DEP1 domain is phosphorylated at Ser-436, which inhibits the DH-PH catalytic cassette by direct interaction. In addition, the P-Rex1 C terminus is indirectly targeted by PKA, promoting inhibitory interactions independently of the DEP1-PDZ2 region. A P-Rex1 S436A mutant construct shows increased RacGEF activity and prevents the inhibitory effect of forskolin on sphingosine 1-phosphate-dependent endothelial cell migration. Altogether, these results support the idea that P-Rex1 contributes to the spatiotemporal localization of type I PKA, which tightly regulates this guanine exchange factor by a multistep mechanism, initiated by interaction with the PDZ domains of P-Rex1 followed by direct phosphorylation at the first DEP domain and putatively indirect regulation of the C terminus, thus promoting inhibitory intramolecular interactions. This reciprocal regulation between PKA and P-Rex1 might represent a key node of integration by which chemotactic signaling is fine-tuned by PKA. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  2. A Single Nucleotide Polymorphism in the Stromal Cell-Derived Factor 1 Gene Is Associated with Coronary Heart Disease in Chinese Patients

    Directory of Open Access Journals (Sweden)

    Lei Feng

    2014-06-01

    Full Text Available Coronary heart disease (CHD is highly prevalent globally and a major cause of mortality. Genetic predisposition is a non-modifiable risk factor associated with CHD. Eighty-four Chinese patients with CHD and 253 healthy Chinese controls without CHD were recruited. Major clinical data were collected, and a single nucleotide polymorphism (SNP in the stromal cell-derived factor 1 (SDF-1 gene at position 801 (G to A, rs1801157 in the 3'-untranslated region was identified. The correlation between rs1801157 genotypes and CHD was evaluated by a multivariate logistic regression analysis. The allele frequency in the CHD and control groups was in Hardy-Weinberg equilibrium (HWE (p > 0.05. The frequency of the GG genotype in the CHD group (59.5% was significantly higher than that in the control group (49.8% (p = 0.036. A number of variables, including male sex, age, presence of hypertension, and the levels of low-density lipoprotein cholesterol (LDL-C, high-density lipoprotein cholesterol (HDL-C, triglycerides (TG, uric acid, and total bilirubin, were associated with CHD in a primary univariate analysis. In a multivariable logistic regression analysis, the GG genotype (GG:AA, odds ratio (OR = 2.31, 95% confidence interval (CI = 1.21–5.23, male sex, advanced age (≥60 years, presence of hypertension, LDL-C level ≥ 3.33 mg/dL, HDL-C level < 1.03 mg/dL, and TG level ≥ 1.7 mg/dL were independent risk factors for CHD.

  3. Identification of E-Selectin as a Novel Target for the Regulation of Post-Natal Neovascularization: Implications for Diabetic Wound Healing

    Science.gov (United States)

    Liu, Zhao-Jun; Tian, Runxia; An, Weijun; Zhuge, Ying; Li, Yan; Shao, Hongwei; Habib, Bianca; Livingstone, Alan S.; Velazquez, Omaida C.

    2012-01-01

    Objectives We previously reported that stromal cell-derived factor-1α (SDF-1α, a homing signal for recruiting endothelial progenitor cells (EPC) to areas of neovascularization), is down-regulated in diabetic wounds 1. We now investigate signals whereby mature endothelial cells (EC) and circulating EPC achieve SDF-1α-mediated EPC homing. Methods SDF-1α in diabetic wounds were therapeutically increased by injection of SDF-1α–engineered bone marrow-derived fibroblasts versus control cells (N= 48 (20, NOD), (28, STZ-C57)). PCR-array gene expression differences were validated by Western blotting and immunohistochemistry. The role of adhesion molecule(s) in mediating SDF-1α-induced EPC homing and wound healing was furthered studied using antagonists in vitro and in vivo. Results Increasing wound SDF-1α via cell-base therapy promotes healing in diabetic mice (~20% increase in healing rates by day 3, p=0.006). SDF-1α increased EC-EPC adhesion and specifically upregulated E-selectin expression in human microvascular EC (2.3-fold increase, p<0.01). This effect was also significant in blood vessels of the experimental mice and resulted in increased wound neovascularization. The regulatory effects of SDF-1α on EC-EPC adhesion and EPC homing were specifically mediated by E-selectin, as the application of E-selectin antagonists significantly inhibited SDF-1α-induced EC-EPC adhesion, EPC homing, wound neovascularization, and wound healing. Conclusions SDF-1α–engineered cell-based therapy promotes diabetic wound healing in mice by specifically upregulating E-selectin expression in mature EC leading to increase EC-EPC adhesion, EPC homing and increased wound neovascularization. These findings provide novel insight into the signals underlying the biological effect of SDF-1α on EPC homing and point to E-selectin as a new potential target for therapeutic manipulation of EPC trafficking in diabetic wound healing. PMID:20881769

  4. Study of stem cell homing & self-renewal marker gene profile of ex vivo expanded human CD34+ cells manipulated with a mixture of cytokines & stromal cell-derived factor 1

    Directory of Open Access Journals (Sweden)

    Jyoti Kode

    2017-01-01

    Interpretation & conclusions: Cocktail of cytokines and SDF1 showed good potential to successfully expand HSPC which exhibited enhanced ability to generate multilineage cells in short-term and long-term repopulation assay. This cocktail-mediated stem cell expansion has potential to obviate the need for longer and large volume apheresis procedure making it convenient for donors.

  5. Hematopoietic stem cell cytokines and fibroblast growth factor-2 stimulate human endothelial cell-pericyte tube co-assembly in 3D fibrin matrices under serum-free defined conditions.

    Directory of Open Access Journals (Sweden)

    Annie O Smith

    Full Text Available We describe a novel 3D fibrin matrix model using recombinant hematopoietic stem cell cytokines under serum-free defined conditions which promotes the assembly of human endothelial cell (EC tubes with co-associated pericytes. Individual ECs and pericytes are randomly mixed together and EC tubes form that is accompanied by pericyte recruitment to the EC tube abluminal surface over a 3-5 day period. These morphogenic processes are stimulated by a combination of the hematopoietic stem cell cytokines, stem cell factor, interleukin-3, stromal derived factor-1α, and Flt-3 ligand which are added in conjunction with fibroblast growth factor (FGF-2 into the fibrin matrix. In contrast, this tube morphogenic response does not occur under serum-free defined conditions when VEGF and FGF-2 are added together in the fibrin matrices. We recently demonstrated that VEGF and FGF-2 are able to prime EC tube morphogenic responses (i.e. added overnight prior to the morphogenic assay to hematopoietic stem cell cytokines in collagen matrices and, interestingly, they also prime EC tube morphogenesis in 3D fibrin matrices. EC-pericyte interactions in 3D fibrin matrices leads to marked vascular basement membrane assembly as demonstrated using immunofluorescence and transmission electron microscopy. Furthermore, we show that hematopoietic stem cell cytokines and pericytes stimulate EC sprouting in fibrin matrices in a manner dependent on the α5β1 integrin. This novel co-culture system, under serum-free defined conditions, allows for a molecular analysis of EC tube assembly, pericyte recruitment and maturation events in a critical ECM environment (i.e. fibrin matrices that regulates angiogenic events in postnatal life.

  6. Radiation-Induced Esophagitis In Vivo and In Vitro Reveals That Epidermal Growth Factor Is a Potential Candidate for Therapeutic Intervention Strategy

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Kyung Su [Department of Radiation Oncology, Seoul National University College of Medicine, Seoul (Korea, Republic of); Jeon, Seong-Uk; Lee, Chan-Ju; Kim, Young-Eun; Bok, Seoyeon; Hong, Beom-Ju; Park, Dong-Young [Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk (Korea, Republic of); Ahn, G-One, E-mail: goneahn@postech.ac.kr [Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk (Korea, Republic of); Kim, Hak Jae, E-mail: khjae@snu.ac.kr [Department of Radiation Oncology, Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2016-07-01

    Purpose: To establish and characterize radiation-induced esophagitis (RIE) in vivo and in vitro. Methods and Materials: Fractionated thoracic irradiation at 0, 8, 12, or 15 Gy was given daily for 5 days to Balb/c or C57Bl/6 mice. Changes in body weight gain and daily food intake were assessed. At the end of the study, we removed the esophagus and examined histology by hematoxylin and eosin staining, immune cell infiltration and apoptosis by fluorescence-activated cell sorting, and gene expression changes by quantitative real-time polymerase chain reaction. Het-1A human esophageal epithelial cells were irradiated at 6 Gy, treated with recombinant human growth factors, and examined for gene expression changes, apoptosis, proliferation, and signal transduction pathways. Results: We observed that irradiation at 12 Gy or 15 Gy per fraction produced significant reduction in body weight and decreased food intake in Balb/c mice but not as much in C57Bl/6 mice. Further analyses of Balb/c mice irradiated at 12 Gy/fraction revealed attenuated epithelium, inflamed mucosa, and increased numbers of infiltrating CD4+ helper T cells and apoptotic cells. Moreover, we found that expression of tissue inhibitor for metalloproteinase-1, plasminogen activator inhibitor-1, granulocyte macrophage-colony stimulating factor, vascular endothelial growth factor, and stromal-derived factor-1 were increased, whereas epidermal growth factor (EGF) was decreased. Irradiated Het-1A cells similarly showed a significant decrease in expression of EGF and connective tissue growth factor (CTGF). Treatment of EGF but not CTGF partially protected Het-1A cells from radiation-induced apoptosis and revealed phosphorylation of EGFR, AKT, and ERK signaling pathways. Conclusions: We established a mouse model of RIE in Balb/c mice with 12 Gy × 5 fractions, which showed reduced body weight gain, food intake, and histopathologic features similar to those of human esophagitis. Decreased EGF expression

  7. Cordyceps sinensis protects against renal ischemia/reperfusion injury in rats.

    Science.gov (United States)

    Wang, Hua-Pin; Liu, Ching-Wen; Chang, Hsueh-Wen; Tsai, Jen-Wei; Sung, Ya-Zhu; Chang, Li-Ching

    2013-03-01

    Cordyceps sinensis (CS) is an entomogenous fungus used as a tonic food and Chinese medicine to replenish health. This study investigated the protective effects of CS in rats post-renal ischemia-reperfusion (I/R) sequence by analyzing the influence on stromal cell-derived factor-1α (SDF-1α and chemokine (C-X-C motif) receptor 4 (CXCR4) expressions and senescence during recovery. Chemokine SDF-1 [now called chemokine C-X-C motif ligand 12 (CXCL12)] and its receptor CXCR4 are crucial in kidney repair after ischemic acute renal failure. CS treatment significantly alleviated I/R-induced renal damage assessed by creatinine levels (p < 0.05) and abated renal tubular damages assessed by periodic acid-Schiff with diastase (PASD) staining. CS induced early SDF-1α expression and increased CXCR4 expression 1-6 h post-reperfusion. Histology studies have revealed that CS induced SDF-1α in squamous cells of Bowman's capsule, mesangial cells, distal convoluted tubules (DCT), and proximal convoluted tubules (PCT). CS also improved renal repair in I/R-induced injury by increasing Ki-67 staining. I/R induced renal senescence after 3 and 6 h of reperfusion. However, CS alleviated I/R-induced senescence at early stage (1 and 3 h). We conclude that CS protects against I/R injury via the SDF-1/CXCR4-signaling axis and alleviates senescence.

  8. Cutting edge: bone morphogenetic protein antagonists Drm/Gremlin and Dan interact with Slits and act as negative regulators of monocyte chemotaxis.

    Science.gov (United States)

    Chen, Bo; Blair, Donald G; Plisov, Sergei; Vasiliev, Gennady; Perantoni, Alan O; Chen, Qian; Athanasiou, Meropi; Wu, Jane Y; Oppenheim, Joost J; Yang, De

    2004-11-15

    Drm/Gremlin and Dan, two homologous secreted antagonists of bone morphogenic proteins, have been shown to regulate early development, tumorigenesis, and renal pathophysiology. In this study, we report that Drm and Dan physically and functionally interact with Slit1 and Slit2 proteins. Drm binding to Slits depends on its glycosylation and is not interfered with by bone morphogenic proteins. Importantly, Drm and Dan function as inhibitors for monocyte migration induced by stromal cell-derived factor 1alpha (SDF-1alpha) or fMLP. The inhibition of SDF-1alpha-induced monocyte chemotaxis by Dan is not due to blocking the binding of SDF-1alpha to its receptor. Thus, the results identify that Drm and Dan can interact with Slit proteins and act as inhibitors of monocyte chemotaxis, demonstrating a previously unidentified biological role for these proteins.

  9. Corruption Factors

    OpenAIRE

    Polterovich, Victor

    1998-01-01

    Among the factors that give rise to corruption, it is suggested that three groups be distinguished: fundamental factors rooted in the imperfection of economic institutions and economic policy, organizational factors ("weakness of the government"), and societal factors that depend on the prehistory and are connected with the mass culture and norms of bureaucratic behavior. A model in which corruption equilibrium is supported by non-optimum tax policy or by slow technical progress is compared w...

  10. Distribution of HIV-1 resistance-conferring polymorphic alleles SDF ...

    Indian Academy of Sciences (India)

    Unknown

    2Department of Genetics, Owaisi Medical and Research Centre, Deccan College of Medical Sciences and ... data, are comparable to those from Africa and Southeast Asia, where AIDS is known to be widespread. ... HIV-1 resistance polymorphism; chemokine receptor; stromal-derived factor-1; Andhra Pradesh; AIDS.

  11. Association of -308 TNF-alpha promoter polymorphism with viral ...

    African Journals Online (AJOL)

    2012-06-02

    Jun 2, 2012 ... Genetic restriction of AIDS pathogenesis by an SDF-1 chemokine gene variant. Science. 1998;279(5349):389-393. 10. Bergamini A, Faggioli E, Bolacchi F, et al. Enhanced production of tumor necrosis factor-alpha and interleukin-6 due to prolonged response to lipopolysaccharide in human macrophages ...

  12. Truncation of CXCL12 by CD26 reduces its CXC chemokine receptor 4- and atypical chemokine receptor 3-dependent activity on endothelial cells and lymphocytes

    DEFF Research Database (Denmark)

    Janssens, Rik; Mortier, Anneleen; Boff, Daiane

    2017-01-01

    The chemokine CXCL12 or stromal cell-derived factor 1/SDF-1 attracts hematopoietic progenitor cells and mature leukocytes through the G protein-coupled CXC chemokine receptor 4 (CXCR4). In addition, it interacts with atypical chemokine receptor 3 (ACKR3 or CXCR7) and glycosaminoglycans. CXCL12 ac...

  13. Periarteriolar Glioblastoma Stem Cell Niches Express Bone Marrow Hematopoietic Stem Cell Niche Proteins

    NARCIS (Netherlands)

    Hira, Vashendriya V. V.; Wormer, Jill R.; Kakar, Hala; Breznik, Barbara; van der Swaan, Britt; Hulsbos, Renske; Tigchelaar, Wikky; Tonar, Zbynek; Khurshed, Mohammed; Molenaar, Remco J.; van Noorden, Cornelis J. F.

    2018-01-01

    In glioblastoma, a fraction of malignant cells consists of therapy-resistant glioblastoma stem cells (GSCs) residing in protective niches that recapitulate hematopoietic stem cell (HSC) niches in bone marrow. We have previously shown that HSC niche proteins stromal cell-derived factor-1α (SDF-1α),

  14. El factoring

    Directory of Open Access Journals (Sweden)

    Alberto Rosenthal

    1988-04-01

    Full Text Available RESUMEN El artículo  presenta, una conceptualización general de lo que es el factoring, el origen del mismo, su evolución y hace una clasificación de los distintos tipos de factoring.

  15. Organizational factors

    International Nuclear Information System (INIS)

    Holy, J.

    1999-12-01

    The following organizational factors are considered with respect to the human factor and operating safety of nuclear power plants: external influences; objectives and strategy; positions and ways of management; allocation of resources; working with human resources; operators' training; coordination of work; knowledge of organization and management; proceduralization of the topic; labour organizing culture; self-improvement system; and communication. (P.A.)

  16. Met-Independent Hepatocyte Growth Factor-mediated regulation of cell adhesion in human prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Davis Rodney

    2006-07-01

    Full Text Available Abstract Background Prostate cancer cells communicate reciprocally with the stromal cells surrounding them, inside the prostate, and after metastasis, within the bone. Each tissue secretes factors for interpretation by the other. One stromally-derived factor, Hepatocyte Growth Factor (HGF, was found twenty years ago to regulate invasion and growth of carcinoma cells. Working with the LNCaP prostate cancer progression model, we found that these cells could respond to HGF stimulation, even in the absence of Met, the only known HGF receptor. The new HGF binding partner we find on the cell surface may help to clarify conflicts in the past literature about Met expression and HGF response in cancer cells. Methods We searched for Met or any HGF binding partner on the cells of the PC3 and LNCaP prostate cancer cell models, using HGF immobilized on agarose beads. By using mass spectrometry analyses and sequencing we have identified nucleolin protein as a novel HGF binding partner. Antibodies against nucleolin (or HGF were able to ameliorate the stimulatory effects of HGF on met-negative prostate cancer cells. Western blots, RT-PCR, and immunohistochemistry were used to assess nucleolin levels during prostate cancer progression in both LNCaP and PC3 models. Results We have identified HGF as a major signaling component of prostate stromal-conditioned media (SCM and have implicated the protein nucleolin in HGF signal reception by the LNCaP model prostate cancer cells. Antibodies that silence either HGF (in SCM or nucleolin (on the cell surfaces eliminate the adhesion-stimulatory effects of the SCM. Likewise, addition of purified HGF to control media mimics the action of SCM. C4-2, an LNCaP lineage-derived, androgen-independent human prostate cancer cell line, responds to HGF in a concentration-dependent manner by increasing its adhesion and reducing its migration on laminin substratum. These HGF effects are not due to shifts in the expression levels of

  17. Met-Independent Hepatocyte Growth Factor-mediated regulation of cell adhesion in human prostate cancer cells

    International Nuclear Information System (INIS)

    Tate, Amanda; Isotani, Shuji; Bradley, Michael J; Sikes, Robert A; Davis, Rodney; Chung, Leland WK; Edlund, Magnus

    2006-01-01

    Prostate cancer cells communicate reciprocally with the stromal cells surrounding them, inside the prostate, and after metastasis, within the bone. Each tissue secretes factors for interpretation by the other. One stromally-derived factor, Hepatocyte Growth Factor (HGF), was found twenty years ago to regulate invasion and growth of carcinoma cells. Working with the LNCaP prostate cancer progression model, we found that these cells could respond to HGF stimulation, even in the absence of Met, the only known HGF receptor. The new HGF binding partner we find on the cell surface may help to clarify conflicts in the past literature about Met expression and HGF response in cancer cells. We searched for Met or any HGF binding partner on the cells of the PC3 and LNCaP prostate cancer cell models, using HGF immobilized on agarose beads. By using mass spectrometry analyses and sequencing we have identified nucleolin protein as a novel HGF binding partner. Antibodies against nucleolin (or HGF) were able to ameliorate the stimulatory effects of HGF on met-negative prostate cancer cells. Western blots, RT-PCR, and immunohistochemistry were used to assess nucleolin levels during prostate cancer progression in both LNCaP and PC3 models. We have identified HGF as a major signaling component of prostate stromal-conditioned media (SCM) and have implicated the protein nucleolin in HGF signal reception by the LNCaP model prostate cancer cells. Antibodies that silence either HGF (in SCM) or nucleolin (on the cell surfaces) eliminate the adhesion-stimulatory effects of the SCM. Likewise, addition of purified HGF to control media mimics the action of SCM. C4-2, an LNCaP lineage-derived, androgen-independent human prostate cancer cell line, responds to HGF in a concentration-dependent manner by increasing its adhesion and reducing its migration on laminin substratum. These HGF effects are not due to shifts in the expression levels of laminin-binding integrins, nor can they be linked to

  18. Effects of CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles on HIV-1 disease progression: An international meta-analysis of individual-patient data

    DEFF Research Database (Denmark)

    Ioannidis, J P; Rosenberg, Peter; Goedert, J J

    2001-01-01

    Studies relating certain chemokine and chemokine receptor gene alleles with the outcome of HIV-1 infection have yielded inconsistent results.......Studies relating certain chemokine and chemokine receptor gene alleles with the outcome of HIV-1 infection have yielded inconsistent results....

  19. Circulating cytokines and monocyte subpopulations as biomarkers of outcome and biological activity in sunitinib-treated patients with advanced neuroendocrine tumours.

    Science.gov (United States)

    Zurita, A J; Khajavi, M; Wu, H-K; Tye, L; Huang, X; Kulke, M H; Lenz, H-J; Meropol, N J; Carley, W; DePrimo, S E; Lin, E; Wang, X; Harmon, C S; Heymach, J V

    2015-03-31

    Sunitinib is approved worldwide for treatment of advanced pancreatic neuroendocrine tumours (pNET), but no validated markers exist to predict response. This analysis explored biomarkers associated with sunitinib activity and clinical benefit in patients with pNET and carcinoid tumours in a phase II study. Plasma was assessed for vascular endothelial growth factor (VEGF)-A, soluble VEGF receptor (sVEGFR)-2, sVEGFR-3, interleukin (IL)-8 (n=105), and stromal cell-derived factor (SDF)-1α (n=28). Pre-treatment levels were compared between tumour types and correlated with response, progression-free (PFS), and overall survival (OS). Changes in circulating myelomonocytic and endothelial cells were also analysed. Stromal cell-derived factor-1α and sVEGFR-2 levels were higher in pNET than in carcinoid (P=0.003 and 0.041, respectively). High (above-median) baseline SDF-1α was associated with worse PFS, OS, and response in pNET, and high sVEGFR-2 with longer OS (P⩽0.05). For carcinoid, high IL-8, sVEGFR-3, and SDF-1α were associated with shorter PFS and OS, and high IL-8 and SDF-1α with worse response (P⩽0.05). Among circulating cell types, monocytes showed the largest on-treatment decrease, particularly CD14+ monocytes co-expressing VEGFR-1 or CXCR4. Interleukin-8, sVEGFR-3, and SDF-1α were identified as predictors of sunitinib clinical outcome. Putative pro-tumorigenic CXCR4+ and VEGFR-1+ monocytes represent novel candidate markers and biologically relevant targets explaining the activity of sunitinib.

  20. Competitiveness factors

    OpenAIRE

    Popa Liliana-Viorica

    2012-01-01

    Porter's theory supports the idea that, despite the globalization of production and trade, the competitive advantage is created in a national framework, nations, through their institutional, natural, cultural, economic characteristics ultimately determining the development of certain economic activities. The factors considered by Porter as determinants for the competitive advantage are grouped in four categories, the linkages between them being important as well

  1. Risk factors

    International Nuclear Information System (INIS)

    Dennery, M.; Dupont, M.A.

    2007-01-01

    This article deals with the development of risk management in the gas sector business: why a risk factor legal mention must precede any published financial information? Do gas companies have to face new risks? Is there specific risks bound to gas activities? Why companies want to master their risks? Is it mandatory or just a new habit? Do they expect a real benefit in return? These are the risk management questions that are analyzed in this article which is based on the public communication of 15 gas companies randomly selected over the world. The information comes from their annual reports or from documents available on their web sites. The intention of this document is not to be exhaustive or to make statistics but only to shade light on the risk factors of the gas sector. (J.S.)

  2. Vildagliptin, but not glibenclamide, increases circulating endothelial progenitor cell number: a 12-month randomized controlled trial in patients with type 2 diabetes.

    Science.gov (United States)

    Dei Cas, Alessandra; Spigoni, Valentina; Cito, Monia; Aldigeri, Raffaella; Ridolfi, Valentina; Marchesi, Elisabetta; Marina, Michela; Derlindati, Eleonora; Aloe, Rosalia; Bonadonna, Riccardo C; Zavaroni, Ivana

    2017-02-23

    Fewer circulating endothelial progenitor cells (EPCs) and increased plasma (C-term) stromal cell-derived factor 1α (SDF-1α), a substrate of DPP-4, are biomarkers, and perhaps mediators, of cardiovascular risk and mortality. Short-term/acute treatment with DPP-4 inhibitors improve EPC bioavailability; however, long-term effects of DPP-4i on EPCs bioavailability/plasma (C-term) SDF-1α are unknown. Randomized (2:1) open-label trial to compare the effects of vildagliptin (V) (100 mg/day) vs glibenclamide (G) (2.5 mg bid to a maximal dose of 5 mg bid) on circulating EPC levels at 4 and 12 months of treatment in 64 patients with type 2 diabetes in metformin failure. At baseline, and after 4 and 12 months, main clinical/biohumoral parameters, inflammatory biomarkers, concomitant therapies, EPC number (CD34 + /CD133 + /KDR + /10 6 cytometric events) and plasma (C-term) SDF-1α (R&D system) were assessed. Baseline characteristics were comparable in the two groups. V and G similarly and significantly (p < 0.0001) improved glucose control. At 12 months, V significantly increased EPC number (p < 0.05) and significantly reduced (C-term) SDF-1α plasma levels (p < 0.01) compared to G, with no differences in inflammatory biomarkers. V exerts a long-term favorable effect on EPC and (C-term) SDF-1α levels at glucose equipoise, thereby implying a putative beneficial effect on vascular integrity. Trial registration Clinical Trials number: NCT01822548; name: Effect of Vildagliptin vs. Glibenclamide on Circulating Endothelial Progenitor Cell Number Type 2 Diabetes. Registered 28 March, 2013.

  3. Long-term survival of transplanted allogeneic cells engineered to express a T cell chemorepellent.

    Science.gov (United States)

    Papeta, Natalia; Chen, Tao; Vianello, Fabrizio; Gererty, Lyle; Malik, Ashish; Mok, Ying-Ting; Tharp, William G; Bagley, Jessamyn; Zhao, Guiling; Stevceva, Liljana; Yoon, Victor; Sykes, Megan; Sachs, David; Iacomini, John; Poznansky, Mark C

    2007-01-27

    Alloantigen specific T cells have been shown to be required for allograft rejection. The chemokine, stromal cell derived factor-1 (SDF-1) at high concentration, has been shown to act as a T-cell chemorepellent and abrogate T-cell infiltration into a site of antigen challenge in vivo via a mechanism termed fugetaxis or chemorepulsion. We postulated that this mechanism could be exploited therapeutically and that allogeneic cells engineered to express a chemorepellent protein would not be rejected. Allogeneic murine insulinoma beta-TC3 cells and primary islets from BALB/C mice were engineered to constitutively secrete differential levels of SDF-1 and transplanted into allogeneic diabetic C57BL/6 mice. Rejection was defined as the permanent return of hyperglycemia and was correlated with the level of T-cell infiltration. The migratory response of T-cells to SDF-1 was also analyzed by transwell migration assay and time-lapse videomicroscopy. The cytotoxicity of cytotoxic T cell (CTLs) against beta-TC3 cells expressing high levels of SDF-1 was measured in standard and modified chromium-release assays in order to determine the effect of CTL migration on killing efficacy. Control animals rejected allogeneic cells and remained diabetic. In contrast, high level SDF-1 production by transplanted cells resulted in increased survival of the allograft and a significant reduction in blood glucose levels and T-cell infiltration into the transplanted tissue. This is the first demonstration of a novel approach that exploits T-cell chemorepulsion to induce site specific immune isolation and thereby overcomes allograft rejection without the use of systemic immunosuppression.

  4. Panax Notoginseng Saponins Promote Endothelial Progenitor Cell Mobilization and Attenuate Atherosclerotic Lesions in Apolipoprotein E Knockout Mice

    Directory of Open Access Journals (Sweden)

    Ya Liu

    2013-09-01

    Full Text Available Background: Endothelial progenitor cells (EPCs derived from the bone marrow (BM play a key role in the homeostasis of vascular repair by enhanced reendothelialization. Panax notoginseng saponins (PNS, a highly valued traditional Chinese medicine, has been shown to reduce morbidity and mortality from coronary artery disease. The present research was designed to explore the contribution of progenitor cells to the progression of atherosclerotic plaques and the possible modulatory role of PNS in this process. Methods: PNS (60 or 120 mg/kg via intraperitoneal injection was administered over 8 weeks in apolipoprotein E knockout mice on an atherogenic diet. The sizes and histochemical alteration of atherosclerotic lesions and numbers of EPCs in BM and peripheral blood were analyzed. The expression of chemokine stromal cell-derived factor 1α (SDF-1α and its receptor, CXCR4, was monitored as well. Results: PNS significantly reduced the lesion area and intima-to-media ratio compared to vehicle treatment. PNS also augmented endothelialization and reduced the smooth muscle cell (SMCs content of the lesions. The number of c-kit and sca-1 double-positive progenitor cells and flk-1 and sca-1 double-positive progenitor cells were significantly increased in the BM and the peripheral blood of the PNS-treated groups. PNS treatment increased the plasma levels of SDF-1α and SCF as well as the BM levels of matrix metalloproteinase-9 (MMP-9. Moreover, the mRNA levels of SDF-1α and protein levels of CXCR4 were both increased in the BM of mice treated with PNS, while SDF-1α expression decreased. Conclusion: PNS reduce the size of atherosclerotic plaques, and this effect appears to involve progenitor cell mobilization. SDF-1α-CXCR4 interactions and the possible modulatory role of PNS in this process may contribute to the increased progenitor cell mobilization.

  5. The Role of Megakaryocytes in Breast Cancer Metastasis to Bone

    Science.gov (United States)

    2014-05-01

    vonWillibrand factor+, multinucleated cells were used to determine MK numbers. Blood platelets, serum levels of thrombopoietin ( TPO ) and SDF-1 were measured. In...together produced factor(s) that increase MK differentiation. In the meantime TPO -/- mouse embryos were regenerated and mice were backcrossed to...Balb/c so that metastasis could be determined in MK deficient mice. The TPO -/- mice appear to be more susceptible to metastasis than the wildtype, with

  6. Pro-angiogenic cytokines in systemic sclerosis

    Directory of Open Access Journals (Sweden)

    Ewa Robak

    2014-12-01

    Full Text Available Systemic sclerosis (SSc is a multifactorial connective tissue disease characterized by excessive and progressive fibrosis along with microvasculopathy due to poor vascular formation and repair. Despite a general increase in many potent angiogenic factors, the vasculopathy compensatory angiogenesis and vasculogenesis are impaired. In this review, we discuss the role of proangiogenic factors – VEGF, PlGF, endoglin, PDGF, endothelin-1, angiopoietins, SDF-1, uPAR – and the paradoxical paucity of an inadequate angiogenic response in SSc.

  7. Heart disease - risk factors

    Science.gov (United States)

    ... prevention; CVD - risk factors; Cardiovascular disease - risk factors; Coronary artery disease - risk factors; CAD - risk factors ... do smoke, quit. Controlling your cholesterol through diet, exercise, and medicines . Controlling high blood pressure through diet, ...

  8. Circulating concentrations of stem-cell-mobilizing cytokines are associated with levels of osteoprogenitor cells and aortic calcification severity

    International Nuclear Information System (INIS)

    Pal, S.N.; Clancy, P.; Golledge, J.

    2011-01-01

    The background of this study was to investigate the association between aortic calcification, concentrations of stem-cell-mobilizing cytokines and osteocalcin-positive mononuclear cells in a mouse model and patients with peripheral artery disease. We estimated the concentration of the stem-cell-mobilizing cytokines stromal cell-derived factor α (SDF-1α), granulocyte colony stimulating factor and stem cell factor in a mouse model of aortic calcification developed in osteoprotegerin-deficient (OPG -/- ) mice, as well as in patient plasma samples. Calcification was estimated by a colorimetric assay of extracts of harvested mice aortas and by computed tomographic angiogram images in patients. The cytokine concentrations were assessed for association with the severity of calcification and the percentage of osteocalcin-positive mononuclear cells (OCN + MNC) using non-parametric analysis. The serum concentration of stromal SDF-1α and granulocyte-colony stimulating factor (G-CSF) were significantly greater in OPG -/- compared to control mice. The percentage of circulating OCN + MNC was correlated to the concentration of SDF-1α in OPG -/- mice. These cytokines also correlated with the severity of calcification in OPG -/- mice. Patients with more severe calcification had a higher plasma concentration of the cytokines than those with less marked aortic calcification. The concentrations also correlated with circulating OCN + MNC and aortic calcification volumes. The association between stem cell cytokines, OCN + MNC and calcification suggests a possible role of bone-derived osteoprogenitor cells in the pathogenesis of vascular calcification. (author)

  9. Risk Factors for Scleroderma

    Science.gov (United States)

    ... are here: Home For Patients Risk Factors Risk Factors for Scleroderma The cause of scleroderma is still ... Scientists are working diligently to understand what biological factors contribute to scleroderma pathogenesis. Genetic Risk Scleroderma does ...

  10. Factors and factorizations of graphs proof techniques in factor theory

    CERN Document Server

    Akiyama, Jin

    2011-01-01

    This book chronicles the development of graph factors and factorizations. It pursues a comprehensive approach, addressing most of the important results from hundreds of findings over the last century. One of the main themes is the observation that many theorems can be proved using only a few standard proof techniques. This stands in marked contrast to the seemingly countless, complex proof techniques offered by the extant body of papers and books. In addition to covering the history and development of this area, the book offers conjectures and discusses open problems. It also includes numerous explanatory figures that enable readers to progressively and intuitively understand the most important notions and proofs in the area of factors and factorization.

  11. Lipopolysaccharide Promotes Choroidal Neovascularization by Up-Regulation of CXCR4 and CXCR7 Expression in Choroid Endothelial Cell.

    Directory of Open Access Journals (Sweden)

    Yi-fan Feng

    Full Text Available Stromal cell-derived factor-1 (SDF-1 has been confirmed to participate in the formation of choroidal neovascularization (CNV via its two receptors: CXC chemokine receptors 4 (CXCR4 and CXCR7. Previous studies have indicated that the activation of Toll-like receptors (TLRs by lipopolysaccharide (LPS might elevate CXCR4 and/or CXCR7 expression in tumor cells, enhancing the response to SDF-1 to promote invasion and cell dissemination. However, the impact of LPS on the CXCR4 and CXCR7 expression in endothelial cells and subsequent pathological angiogenesis formation remains to be elucidated. The present study shows that LPS enhanced the CXCR4 and CXCR7 expression via activation of the TLR4 pathway in choroid-retinal endothelial (RF/6A cells. In addition, the transcriptional regulation of CXCR4 and CXCR7 by LPS was found to be mediated by phosphorylation of the extracellular signal-related kinase (ERK 1/2 and activation of nuclear factor kappa B (NF-κB signaling pathways, which were blocked by ERK- or NF-κB-specific inhibitors. Furthermore, the increased CXCR4 and CXCR7 expression resulted in increased SDF-1-induced RF/6A cells proliferation, migration and tube formation. In vivo, LPS-treated rat had significantly higher mRNA levels of CXCR4 and CXCR7 expression and lager laser-induced CNV area than vehicle-treated rat. SDF-1 blockade with a neutralizing antibody attenuated the progression of CNV in LPS-treated rat after a single intravitreal injection. Altogether, these results demonstrated that LPS might influence CNV formation by enhancing CXCR7 and CXCR7 expression in endothelial cells, possibly providing a new perspective for the treatment of CNV-associated diseases.

  12. Early upregulation of myocardial CXCR4 expression is critical for dimethyloxalylglycine-induced cardiac improvement in acute myocardial infarction.

    Science.gov (United States)

    Mayorga, Mari; Kiedrowski, Matthew; Shamhart, Patricia; Forudi, Farhad; Weber, Kristal; Chilian, William M; Penn, Marc S; Dong, Feng

    2016-01-01

    The stromal cell-derived factor-1 (SDF-1):CXCR4 is important in myocardial repair. In this study we tested the hypothesis that early upregulation of cardiomyocyte CXCR4 (CM-CXCR4) at a time of high myocardial SDF-1 expression could be a strategy to engage the SDF-1:CXCR4 axis and improve cardiac repair. The effects of the hypoxia inducible factor (HIF) hydroxylase inhibitor dimethyloxalylglycine (DMOG) on CXCR4 expression was tested on H9c2 cells. In mice a myocardial infarction (MI) was produced in CM-CXCR4 null and wild-type controls. Mice were randomized to receive injection of DMOG (DMOG group) or saline (Saline group) into the border zone after MI. Protein and mRNA expression of CM-CXCR4 were quantified. Echocardiography was used to assess cardiac function. During hypoxia, DMOG treatment increased CXCR4 expression of H9c2 cells by 29 and 42% at 15 and 24 h, respectively. In vivo DMOG treatment increased CM-CXCR4 expression at 15 h post-MI in control mice but not in CM-CXCR4 null mice. DMOG resulted in increased ejection fraction in control mice but not in CM-CXCR4 null mice 21 days after MI. Consistent with greater cardiomyocyte survival with DMOG treatment, we observed a significant increase in cardiac myosin-positive area within the infarct zone after DMOG treatment in control mice, but no increase in CM-CXCR4 null mice. Inhibition of cardiomyocyte death in MI through the stabilization of HIF-1α requires downstream CM-CXCR4 expression. These data suggest that engagement of the SDF-1:CXCR4 axis through the early upregulation of CM-CXCR4 is a strategy for improving cardiac repair after MI. Copyright © 2016 the American Physiological Society.

  13. Amplification factor variable amplifier

    NARCIS (Netherlands)

    Akitsugu, Oshita; Nauta, Bram

    2007-01-01

    PROBLEM TO BE SOLVED: To provide an amplification factor variable amplifier capable of achieving temperature compensation of an amplification factor over a wide variable amplification factor range. ; SOLUTION: A Gilbert type amplification factor variable amplifier 11 amplifies an input signal and

  14. Amplification factor variable amplifier

    NARCIS (Netherlands)

    Akitsugu, Oshita; Nauta, Bram

    2010-01-01

    PROBLEM TO BE SOLVED: To provide an amplification factor variable amplifier capable of achieving temperature compensation of an amplification factor over a wide variable amplification factor range. ;SOLUTION: A Gilbert type amplification factor variable amplifier 11 amplifies an input signal and can

  15. Stochastic Matrix Factorization

    OpenAIRE

    Adams, Christopher

    2016-01-01

    This paper considers a restriction to non-negative matrix factorization in which at least one matrix factor is stochastic. That is, the elements of the matrix factors are non-negative and the columns of one matrix factor sum to 1. This restriction includes topic models, a popular method for analyzing unstructured data. It also includes a method for storing and finding pictures. The paper presents necessary and sufficient conditions on the observed data such that the factorization is unique. I...

  16. ISS Payload Human Factors

    Science.gov (United States)

    Ellenberger, Richard; Duvall, Laura; Dory, Jonathan

    2016-01-01

    The ISS Payload Human Factors Implementation Team (HFIT) is the Payload Developer's resource for Human Factors. HFIT is the interface between Payload Developers and ISS Payload Human Factors requirements in SSP 57000. ? HFIT provides recommendations on how to meet the Human Factors requirements and guidelines early in the design process. HFIT coordinates with the Payload Developer and Astronaut Office to find low cost solutions to Human Factors challenges for hardware operability issues.

  17. Factors affecting construction performance: exploratory factor analysis

    Science.gov (United States)

    Soewin, E.; Chinda, T.

    2018-04-01

    The present work attempts to develop a multidimensional performance evaluation framework for a construction company by considering all relevant measures of performance. Based on the previous studies, this study hypothesizes nine key factors, with a total of 57 associated items. The hypothesized factors, with their associated items, are then used to develop questionnaire survey to gather data. The exploratory factor analysis (EFA) was applied to the collected data which gave rise 10 factors with 57 items affecting construction performance. The findings further reveal that the items constituting ten key performance factors (KPIs) namely; 1) Time, 2) Cost, 3) Quality, 4) Safety & Health, 5) Internal Stakeholder, 6) External Stakeholder, 7) Client Satisfaction, 8) Financial Performance, 9) Environment, and 10) Information, Technology & Innovation. The analysis helps to develop multi-dimensional performance evaluation framework for an effective measurement of the construction performance. The 10 key performance factors can be broadly categorized into economic aspect, social aspect, environmental aspect, and technology aspects. It is important to understand a multi-dimension performance evaluation framework by including all key factors affecting the construction performance of a company, so that the management level can effectively plan to implement an effective performance development plan to match with the mission and vision of the company.

  18. Factorization of the Ising model form factors

    International Nuclear Information System (INIS)

    Assis, M; McCoy, B M; Maillard, J-M

    2011-01-01

    We present a general method for analytically factorizing the n-fold form factor integrals f (n) N,N (t) for the correlation functions of the Ising model on the diagonal in terms of the hypergeometric functions 2 F 1 ([1/2, N + 1/2]; [N + 1]; t) which appear in the form factor f (1) N,N (t). New quadratic recursion and quartic identities are obtained for the form factors for n = 2, 3. For n = 2, 3, 4 explicit results are given for the form factors. These factorizations are proved for all N for n = 2, 3. These results yield the emergence of palindromic polynomials canonically associated with elliptic curves. As a consequence, understanding the form factors amounts to describing and understanding an infinite set of palindromic polynomials, canonically associated with elliptic curves. From an analytical viewpoint the relation of these palindromic polynomials with hypergeometric functions associated with elliptic curves is made very explicitly, and from a differential algebra viewpoint this corresponds to the emergence of direct sums of differential operators homomorphic to symmetric powers of a second order operator associated with elliptic curve.

  19. Long-term functional impairment of hemopoietic progenitor cells engineered to express the S1 catalytic subunit of pertussis toxin.

    Science.gov (United States)

    Bonig, Halvard; Rohmer, Laurence; Papayannopoulou, Thalia

    2005-06-01

    A large body of data suggests that pertussis toxin (PTX)-sensitive G protein signals in mature and immature hemopoietic cells control their migration patterns in vitro and in vivo. These effects were derived after treatment of cells or animals with PTX. To circumvent several inherent problems of PTX holotoxin treatment, we expressed the S1 catalytic activity of PTX, thus blocking Gi protein signaling, in 32D murine myeloid progenitor cells and in primary human CD34+ cells, and studied its functional consequences. S1 was expressed using viral vectors. Effects of Gi protein blockade on proliferation, migration, adhesion, and gene expression were tested in vitro. S1 expression was nontoxic for the cells; expression and function were stable long-term and not overridden by compensatory mechanisms. S1-transduced 32D cells and primary CD34+ cells migrated poorly and did not contract their cytoskeleton upon treatment with the chemoattractant stromal cell-derived factor -1 (SDF-1), similar to the phenotype induced by PTX treatment. Gene expression studies comparing S1-transduced and control 32D cells uncovered four genes, expression of which was regulated by Gi protein blockade. Of interest, although SDF-1 signaling was inhibited, comparison between SDF-1-treated and untreated cells suggests that SDF-1 stimulation does not depend on de novo gene expression in these cells. Furthermore, when injected into nonobese diabetic/severe combined immunodeficient mice, seeding of S1-expressing 32D cells to bone marrow was largely blocked. Expression of S1 is an effective approach for studying long-term functional consequences of Gi protein blockade in hemopoietic cells in vitro and in vivo.

  20. Bayesian Exploratory Factor Analysis

    DEFF Research Database (Denmark)

    Conti, Gabriella; Frühwirth-Schnatter, Sylvia; Heckman, James J.

    2014-01-01

    This paper develops and applies a Bayesian approach to Exploratory Factor Analysis that improves on ad hoc classical approaches. Our framework relies on dedicated factor models and simultaneously determines the number of factors, the allocation of each measurement to a unique factor, and the corr......This paper develops and applies a Bayesian approach to Exploratory Factor Analysis that improves on ad hoc classical approaches. Our framework relies on dedicated factor models and simultaneously determines the number of factors, the allocation of each measurement to a unique factor......, and the corresponding factor loadings. Classical identification criteria are applied and integrated into our Bayesian procedure to generate models that are stable and clearly interpretable. A Monte Carlo study confirms the validity of the approach. The method is used to produce interpretable low dimensional aggregates...

  1. CXCR4 antagonist AMD3100 reverses the neurogenesis promoted by enriched environment and suppresses long-term seizure activity in adult rats of temporal lobe epilepsy.

    Science.gov (United States)

    Zhou, Zhike; Liu, Tingting; Sun, Xiaoyu; Mu, Xiaopeng; Zhu, Gang; Xiao, Ting; Zhao, Mei; Zhao, Chuansheng

    2017-03-30

    It has been showed that enriched environment (EE) enhances the hippocampal neurogenesis and improves the cognitive impairments, accompanied by the increased expressions of stromal cell-derived factor-1 (SDF-1) in adult rats of temporal lobe epilepsy (TLE). We examined whether the enhanced neurogenesis and improved cognitive functions induced by EE following seizures were mediated by SDF-1/CXCR4 pathway. Therefore, we investigated the effects of the EE combined with CXCR4 antagonist AMD3100 on neurogenesis, cognitive functions and the long-term seizure activity in the TLE model. Adult rats were randomly assigned as control rats, rats treated with EE, rats subjected to status epilepticus (SE), post-SE rats treated with EE, AMD3100 or EE combined with AMD3100 respectively. We used immunofluorescence staining to analyze the hippocampal neurogenesis and Nissl staining to evaluate hippocampal damage. Electroencephalography was used to measure the frequency and mean duration of spontaneous seizures. Cognitive function was evaluated by Morris water maze test. EE treatment significantly, as well as improved cognitive impairments and decreased long-term seizure activity, and that these effects might be mediated through SDF-1/CXCR4 pathway during the chronic stage of TLE. Although AMD3100 reversed the effect of EE on neurogenesis, it did not abolish the cognitive improvement induced by EE following seizures. More importantly, EE combined with AMD3100 treatment significantly suppressed long-term seizure activity, which provided promising evidences to treat TLE. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Adipose tissue-derived stem cells promote pancreatic cancer cell proliferation and invasion

    International Nuclear Information System (INIS)

    Ji, S.Q.; Cao, J.; Zhang, Q.Y.; Li, Y.Y.; Yan, Y.Q.; Yu, F.X.

    2013-01-01

    To explore the effects of adipose tissue-derived stem cells (ADSCs) on the proliferation and invasion of pancreatic cancer cells in vitro and the possible mechanism involved, ADSCs were cocultured with pancreatic cancer cells, and a cell counting kit (CCK-8) was used to detect the proliferation of pancreatic cancer cells. ELISA was used to determine the concentration of stromal cell-derived factor-1 (SDF-1) in the supernatants. RT-PCR was performed to detect the expression of the chemokine receptor CXCR4 in pancreatic cancer cells and ADSCs. An in vitro invasion assay was used to measure invasion of pancreatic cancer cells. SDF-1 was detected in the supernatants of ADSCs, but not in pancreatic cancer cells. Higher CXCR4 mRNA levels were detected in the pancreatic cancer cell lines compared with ADSCs (109.3±10.7 and 97.6±7.6 vs 18.3±1.7, respectively; P<0.01). In addition, conditioned medium from ADSCs promoted the proliferation and invasion of pancreatic cancer cells, and AMD3100, a CXCR4 antagonist, significantly downregulated these growth-promoting effects. We conclude that ADSCs can promote the proliferation and invasion of pancreatic cancer cells, which may involve the SDF-1/CXCR4 axis

  3. Adipose tissue-derived stem cells promote pancreatic cancer cell proliferation and invasion

    Energy Technology Data Exchange (ETDEWEB)

    Ji, S.Q.; Cao, J. [Department of Liver Surgery I, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai (China); Zhang, Q.Y.; Li, Y.Y. [Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Wenzhou Medical College, Wenzhou (China); Yan, Y.Q. [Department of Liver Surgery I, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai (China); Yu, F.X. [Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Wenzhou Medical College, Wenzhou (China)

    2013-09-27

    To explore the effects of adipose tissue-derived stem cells (ADSCs) on the proliferation and invasion of pancreatic cancer cells in vitro and the possible mechanism involved, ADSCs were cocultured with pancreatic cancer cells, and a cell counting kit (CCK-8) was used to detect the proliferation of pancreatic cancer cells. ELISA was used to determine the concentration of stromal cell-derived factor-1 (SDF-1) in the supernatants. RT-PCR was performed to detect the expression of the chemokine receptor CXCR4 in pancreatic cancer cells and ADSCs. An in vitro invasion assay was used to measure invasion of pancreatic cancer cells. SDF-1 was detected in the supernatants of ADSCs, but not in pancreatic cancer cells. Higher CXCR4 mRNA levels were detected in the pancreatic cancer cell lines compared with ADSCs (109.3±10.7 and 97.6±7.6 vs 18.3±1.7, respectively; P<0.01). In addition, conditioned medium from ADSCs promoted the proliferation and invasion of pancreatic cancer cells, and AMD3100, a CXCR4 antagonist, significantly downregulated these growth-promoting effects. We conclude that ADSCs can promote the proliferation and invasion of pancreatic cancer cells, which may involve the SDF-1/CXCR4 axis.

  4. Heart Disease Risk Factors

    Science.gov (United States)

    ... risk factors are unique to women. These include: Menopause Use of hormonal birth control (certain types of combination pills, patches, ... risk factors are unique to women. These include: Menopause Use of hormonal birth control (certain types of combination pills, patches, ...

  5. Stroke - risk factors

    Science.gov (United States)

    ... Brain cells can die, causing lasting damage. Risk factors are things that increase your chance of getting ... disease or condition. This article discusses the risk factors for stroke and things you can do to ...

  6. Annual Adjustment Factors

    Data.gov (United States)

    Department of Housing and Urban Development — The Department of Housing and Urban Development establishes the rent adjustment factors - called Annual Adjustment Factors (AAFs) - on the basis of Consumer Price...

  7. Human factors in training

    International Nuclear Information System (INIS)

    Dutton, J.W.; Brown, W.R.

    1981-01-01

    The Human Factors concept is a focused effort directed at those activities which require human involvement. Training is, by its nature, an activity totally dependent on the Human Factor. This paper identifies several concerns significant to training situations and discusses how Human Factor awareness can increase the quality of learning. Psychology in the training arena is applied Human Factors. Training is a method of communication represented by sender, medium, and receiver. Two-thirds of this communications model involves the human element directly

  8. Mesonic Form Factors

    International Nuclear Information System (INIS)

    Bonnet, Frederic D.R.; Edwards, Robert G.; Felming, George T.; Randal Lewis; David Richards

    2003-01-01

    We have started a program to compute the electromagnetic form factors of mesons. We discuss the techniques used to compute the pion form factor and present preliminary results computed with domain wall valence fermions on MILC asqtad lattices, as well as Wilson fermions on quenched lattices. These methods can easily be extended to rho-to-gamma-pi transition form factors

  9. Bayesian Exploratory Factor Analysis

    Science.gov (United States)

    Conti, Gabriella; Frühwirth-Schnatter, Sylvia; Heckman, James J.; Piatek, Rémi

    2014-01-01

    This paper develops and applies a Bayesian approach to Exploratory Factor Analysis that improves on ad hoc classical approaches. Our framework relies on dedicated factor models and simultaneously determines the number of factors, the allocation of each measurement to a unique factor, and the corresponding factor loadings. Classical identification criteria are applied and integrated into our Bayesian procedure to generate models that are stable and clearly interpretable. A Monte Carlo study confirms the validity of the approach. The method is used to produce interpretable low dimensional aggregates from a high dimensional set of psychological measurements. PMID:25431517

  10. demographic factors associated factors associated with malaria ...

    African Journals Online (AJOL)

    userpc

    .8%) than those in other nce of 35.4% which was actors can predispose alence of malaria in a study were significantly eveloping guidelines and more effective disease endemic areas (Bashar et therefore attempts to rmation on possible demographic factors d out in four selected geria; Major Ibrahim B. Hospital Zaria, Hajiya.

  11. Sparse Exploratory Factor Analysis.

    Science.gov (United States)

    Trendafilov, Nickolay T; Fontanella, Sara; Adachi, Kohei

    2017-07-13

    Sparse principal component analysis is a very active research area in the last decade. It produces component loadings with many zero entries which facilitates their interpretation and helps avoid redundant variables. The classic factor analysis is another popular dimension reduction technique which shares similar interpretation problems and could greatly benefit from sparse solutions. Unfortunately, there are very few works considering sparse versions of the classic factor analysis. Our goal is to contribute further in this direction. We revisit the most popular procedures for exploratory factor analysis, maximum likelihood and least squares. Sparse factor loadings are obtained for them by, first, adopting a special reparameterization and, second, by introducing additional [Formula: see text]-norm penalties into the standard factor analysis problems. As a result, we propose sparse versions of the major factor analysis procedures. We illustrate the developed algorithms on well-known psychometric problems. Our sparse solutions are critically compared to ones obtained by other existing methods.

  12. New thrombopoietic growth factors

    OpenAIRE

    Kuter, David J.

    2007-01-01

    Although development of first-generation thrombopoietic growth factors (recombinant human thrombopoietin [TPO] and pegylated recombinant human megakaryocyte growth and development factor [PEG-rHuMGDF]) was stopped due to development of antibodies to PEG-rHuMGDF, nonimmunogenic second-generation thrombopoietic growth factors with unique pharmacologic properties have been developed. TPO peptide mimetics contain TPO receptor-activating peptides inserted into complementarity-determining regions o...

  13. Interleukin-3 enhances the migration of human mesenchymal stem cells by regulating expression of CXCR4.

    Science.gov (United States)

    Barhanpurkar-Naik, Amruta; Mhaske, Suhas T; Pote, Satish T; Singh, Kanupriya; Wani, Mohan R

    2017-07-14

    Mesenchymal stem cells (MSCs) represent an important source for cell therapy in regenerative medicine. MSCs have shown promising results for repair of damaged tissues in various degenerative diseases in animal models and also in human clinical trials. However, little is known about the factors that could enhance the migration and tissue-specific engraftment of exogenously infused MSCs for successful regenerative cell therapy. Previously, we have reported that interleukin-3 (IL-3) prevents bone and cartilage damage in animal models of rheumatoid arthritis and osteoarthritis. Also, IL-3 promotes the differentiation of human MSCs into functional osteoblasts and increases their in-vivo bone regenerative potential in immunocompromised mice. However, the role of IL-3 in migration of MSCs is not yet known. In the present study, we investigated the role of IL-3 in migration of human MSCs under both in-vitro and in-vivo conditions. MSCs isolated from human bone marrow, adipose and gingival tissues were used for in-vitro cell migration, motility and wound healing assays in the presence or absence of IL-3. The effect of IL-3 preconditioning on expression of chemokine receptors and integrins was examined by flow cytometry and real-time PCR. The in-vivo migration of IL-3-preconditioned MSCs was investigated using a subcutaneous matrigel-releasing stromal cell-derived factor-1 alpha (SDF-1α) model in immunocompromised mice. We observed that human MSCs isolated from all three sources express IL-3 receptor-α (IL-3Rα) both at gene and protein levels. IL-3 significantly enhances in-vitro migration, motility and wound healing abilities of MSCs. Moreover, IL-3 preconditioning upregulates expression of chemokine (C-X-C motif) receptor 4 (CXCR4) on MSCs, which leads to increased migration of cells towards SDF-1α. Furthermore, CXCR4 antagonist AMD3100 decreases the migration of IL-3-treated MSCs towards SDF-1α. Importantly, IL-3 also induces in-vivo migration of MSCs towards

  14. The Transcription Factor Encyclopedia

    NARCIS (Netherlands)

    Yusuf, Dimas; Butland, Stefanie L.; Swanson, Magdalena I.; Bolotin, Eugene; Ticoll, Amy; Cheung, Warren A.; Zhang, Xiao Yu Cindy; Dickman, Christopher T. D.; Fulton, Debra L.; Lim, Jonathan S.; Schnabl, Jake M.; Ramos, Oscar H. P.; Vasseur-Cognet, Mireille; de Leeuw, Charles N.; Simpson, Elizabeth M.; Ryffel, Gerhart U.; Lam, Eric W.-F.; Kist, Ralf; Wilson, Miranda S. C.; Marco-Ferreres, Raquel; Brosens, Jan J.; Beccari, Leonardo L.; Bovolenta, Paola; Benayoun, Bérénice A.; Monteiro, Lara J.; Schwenen, Helma D. C.; Grontved, Lars; Wederell, Elizabeth; Mandrup, Susanne; Veitia, Reiner A.; Chakravarthy, Harini; Hoodless, Pamela A.; Mancarelli, M. Michela; Torbett, Bruce E.; Banham, Alison H.; Reddy, Sekhar P.; Cullum, Rebecca L.; Liedtke, Michaela; Tschan, Mario P.; Vaz, Michelle; Rizzino, Angie; Zannini, Mariastella; Frietze, Seth; Farnham, Peggy J.; Eijkelenboom, Astrid; Brown, Philip J.; Laperrière, David; Leprince, Dominique; de Cristofaro, Tiziana; Prince, Kelly L.; Putker, Marrit; del Peso, Luis; Camenisch, Gieri; Wenger, Roland H.; Mikula, Michal; Rozendaal, Marieke; Mader, Sylvie; Ostrowski, Jerzy; Rhodes, Simon J.; van Rechem, Capucine; Boulay, Gaylor; Olechnowicz, Sam W. Z.; Breslin, Mary B.; Lan, Michael S.; Nanan, Kyster K.; Wegner, Michael; Hou, Juan; Mullen, Rachel D.; Colvin, Stephanie C.; Noy, Peter John; Webb, Carol F.; Witek, Matthew E.; Ferrell, Scott; Daniel, Juliet M.; Park, Jason; Waldman, Scott A.; Peet, Daniel J.; Taggart, Michael; Jayaraman, Padma-Sheela; Karrich, Julien J.; Blom, Bianca; Vesuna, Farhad; O'Geen, Henriette; Sun, Yunfu; Gronostajski, Richard M.; Woodcroft, Mark W.; Hough, Margaret R.; Chen, Edwin; Europe-Finner, G. Nicholas; Karolczak-Bayatti, Magdalena; Bailey, Jarrod; Hankinson, Oliver; Raman, Venu; Lebrun, David P.; Biswal, Shyam; Harvey, Christopher J.; Debruyne, Jason P.; Hogenesch, John B.; Hevner, Robert F.; Héligon, Christophe; Luo, Xin M.; Blank, Marissa Cathleen; Millen, Kathleen Joyce; Sharlin, David S.; Forrest, Douglas; Dahlman-Wright, Karin; Zhao, Chunyan; Mishima, Yuriko; Sinha, Satrajit; Chakrabarti, Rumela; Portales-Casamar, Elodie; Sladek, Frances M.; Bradley, Philip H.; Wasserman, Wyeth W.

    2012-01-01

    Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review

  15. Factors affecting nuclear development

    International Nuclear Information System (INIS)

    Stevens, G.H.; Girouard, P.

    1995-01-01

    Among the factors affecting nuclear development, some depend more or less on public authorities, but many are out of public authorities control (foreign policies, market and deregulation, socials and environmental impacts, public opinion). As far as possible, the following study tries to identify those factors. (D.L.). 2 photos

  16. [Vulnerability factors to depression].

    Science.gov (United States)

    Bugán, Antal; Margitics, Ferenc; Pauwlik, Zsuzsa

    2006-01-01

    The objective of this study is to reveal in their complexity the biological and cognitive vulnerability factors, as well as the environmental and socialisation predisposing factors playing a role in the development of depression in non-clinical sample of subjects (college students). Biological vulnerability was examined through temperament and character features, cognitive vulnerability was examined through dysfunctional attitudes, attributional style and coping strategies, and environmental, socialization predisposing factors were observed through certain family socialisation effects (type of family atmosphere, educational objectives, educational and rearing attitudes and style) and parental rearing behaviour. 681 college students were involved in this study (465 females, 216 males). Students were assigned to the study group if they fell in the fourth quartile of the sample based on the results obtained by the Beck's Depression Inventory: 170 persons (128 females, 42 males). Students who fell in the first quartile of the sample on the basis of their results obtained by the mentioned Inventory formed the control group: 204 persons (118 females, 86 males). The results of our study have demonstrated that in a sub-clinical sample the lack of parental care was observed to be a socialization predisposing factor in the development of depression, while certain dysfunctional attitudes and pessimistic interpretation styles were detected to be cognitive vulnerability factors, and harm avoidance proved to be a biological vulnerability factor. We also managed to reveal the effects of certain background factors, which produce their influence indirectly through mediating factors.

  17. Rh Factor Blood Test

    Science.gov (United States)

    Rh factor blood test Overview Rhesus (Rh) factor is an inherited protein found on the surface of red blood cells. If your ... Rh negative, you might need to have another blood test — an antibody screen — during your first trimester and ...

  18. Respirator field performance factors

    International Nuclear Information System (INIS)

    Skaggs, B.J.; DeField, J.D.; Strandberg, S.W.; Sutcliffe, C.R.

    1985-01-01

    The Industrial Hygiene Group assisted OSHA and the NRC in measurements of respirator performance under field conditions. They reviewed problems associated with sampling aerosols within the respirator in order to determine fit factors (FFs) or field performance factor (FPF). In addition, they designed an environmental chamber study to determine the effects of temperature and humidity on a respirator wearer

  19. Exploratory Bi-Factor Analysis

    Science.gov (United States)

    Jennrich, Robert I.; Bentler, Peter M.

    2011-01-01

    Bi-factor analysis is a form of confirmatory factor analysis originally introduced by Holzinger. The bi-factor model has a general factor and a number of group factors. The purpose of this article is to introduce an exploratory form of bi-factor analysis. An advantage of using exploratory bi-factor analysis is that one need not provide a specific…

  20. Factor V Leiden thrombophilia.

    Science.gov (United States)

    Kujovich, Jody Lynn

    2011-01-01

    Factor V Leiden is a genetic disorder characterized by a poor anticoagulant response to activated Protein C and an increased risk for venous thromboembolism. Deep venous thrombosis and pulmonary embolism are the most common manifestations, but thrombosis in unusual locations also occurs. The current evidence suggests that the mutation has at most a modest effect on recurrence risk after initial treatment of a first venous thromboembolism. Factor V Leiden is also associated with a 2- to 3-fold increased relative risk for pregnancy loss and possibly other obstetric complications, although the probability of a successful pregnancy outcome is high. The clinical expression of Factor V Leiden is influenced by the number of Factor V Leiden alleles, coexisting genetic and acquired thrombophilic disorders, and circumstantial risk factors. Diagnosis requires the activated Protein C resistance assay (a coagulation screening test) or DNA analysis of the F5 gene, which encodes the Factor V protein. The first acute thrombosis is treated according to standard guidelines. Decisions regarding the optimal duration of anticoagulation are based on an individualized assessment of the risks for venous thromboembolism recurrence and anticoagulant-related bleeding. In the absence of a history of thrombosis, long-term anticoagulation is not routinely recommended for asymptomatic Factor V Leiden heterozygotes, although prophylactic anticoagulation may be considered in high-risk clinical settings. In the absence of evidence that early diagnosis reduces morbidity or mortality, decisions regarding testing at-risk family members should be made on an individual basis.

  1. Recombinant clotting factors.

    Science.gov (United States)

    Pipe, Steven W

    2008-05-01

    The recombinant era for haemophilia began in the early 1980s with the cloning and subsequent expression of functional proteins for both factors VIII and IX. Efficient production of recombinant clotting factors in mammalian cell culture systems required overcoming significant challenges due to the complex post-translational modifications that were integral to their pro-coagulant function. The quick development and commercialization of recombinant clotting factors was, in part, facilitated by the catastrophic impact of viral contamination of plasma-derived clotting factor concentrates at the time. Since their transition into the clinic, the recombinant versions of both factor VIII and IX have proven to be remarkable facsimiles of their plasma-derived counterparts. The broad adoption of recombinant therapy throughout the developed world has significantly increased the supply of clotting factor concentrates and helped advance aggressive therapeutic interventions such as prophylaxis. The development of recombinant VIIa was a further advance bringing a recombinant option to haemophilia patients with inhibitors. Recombinant DNA technology remains the platform to address ongoing challenges in haemophilia care such as reducing the costs of therapy, increasing the availability to the developing world, and improving the functional properties of these proteins. In turn, the ongoing development of new recombinant clotting factor concentrates is providing alternatives for patients with other inherited bleeding disorders.

  2. Factorized Graph Matching.

    Science.gov (United States)

    Zhou, Feng; de la Torre, Fernando

    2015-11-19

    Graph matching (GM) is a fundamental problem in computer science, and it plays a central role to solve correspondence problems in computer vision. GM problems that incorporate pairwise constraints can be formulated as a quadratic assignment problem (QAP). Although widely used, solving the correspondence problem through GM has two main limitations: (1) the QAP is NP-hard and difficult to approximate; (2) GM algorithms do not incorporate geometric constraints between nodes that are natural in computer vision problems. To address aforementioned problems, this paper proposes factorized graph matching (FGM). FGM factorizes the large pairwise affinity matrix into smaller matrices that encode the local structure of each graph and the pairwise affinity between edges. Four are the benefits that follow from this factorization: (1) There is no need to compute the costly (in space and time) pairwise affinity matrix; (2) The factorization allows the use of a path-following optimization algorithm, that leads to improved optimization strategies and matching performance; (3) Given the factorization, it becomes straight-forward to incorporate geometric transformations (rigid and non-rigid) to the GM problem. (4) Using a matrix formulation for the GM problem and the factorization, it is easy to reveal commonalities and differences between different GM methods. The factorization also provides a clean connection with other matching algorithms such as iterative closest point; Experimental results on synthetic and real databases illustrate how FGM outperforms state-of-the-art algorithms for GM. The code is available at http://humansensing.cs.cmu.edu/fgm.

  3. [Human factors in medicine].

    Science.gov (United States)

    Lazarovici, M; Trentzsch, H; Prückner, S

    2017-01-01

    The concept of human factors is commonly used in the context of patient safety and medical errors, all too often ambiguously. In actual fact, the term comprises a wide range of meanings from human-machine interfaces through human performance and limitations up to the point of working process design; however, human factors prevail as a substantial cause of error in complex systems. This article presents the full range of the term human factors from the (emergency) medical perspective. Based on the so-called Swiss cheese model by Reason, we explain the different types of error, what promotes their emergence and on which level of the model error prevention can be initiated.

  4. Two-factor authentication

    CERN Document Server

    Stanislav, Mark

    2015-01-01

    During the book, readers will learn about the various technical methods by which two-factor authentication is implemented, security concerns with each type of implementation, and contextual details to frame why and when these technologies should be used. Readers will also be provided with insight about the reasons that two-factor authentication is a critical security control, events in history that have been important to prove why organization and individual would want to use two factor, and core milestones in the progress of growing the market.

  5. Rh Factor Blood Test

    Science.gov (United States)

    ... June 3, 2015. Rh factor blood test About Advertisement Mayo Clinic does not endorse companies or products. ... a Job Site Map About This Site Twitter Facebook Google YouTube Pinterest Mayo Clinic is a not- ...

  6. Shell Buckling Knockdown Factors

    Data.gov (United States)

    National Aeronautics and Space Administration — The Shell Buckling Knockdown Factor (SBKF) Project, NASA Engineering and Safety Center (NESC) Assessment #: 07-010-E, was established in March of 2007 by the NESC in...

  7. Risk factors for neoplasms

    International Nuclear Information System (INIS)

    Brachner, A.; Grosche, B.

    1991-06-01

    A broad survey is given of risk factors for neoplasms. The main carcinogenic substances (including also ionizing radiation and air pollution) are listed, and are correlated with the risk factors for various cancers most frequently explained and discussed in the literature. The study is intended to serve as a basis for a general assessment of the incidence of neoplasms in children, and of cancer mortality in the entire population of Bavaria in the years 1983-1989, or 1979-1988, respectively, with the principal idea of drawing up an environment-related health survey. The study therefore takes into account not only ionizing radiation as a main risk factor, but also other risk factors detectable within the ecologic context, as e.g. industrial installations and their effects, refuse incineration plants or waste dumps, or the social status. (orig./MG) [de

  8. [Risk factors of schizophrenia].

    Science.gov (United States)

    Suvisaari, Jaana

    2010-01-01

    Schizophrenia is a multifactorial, neurodevelopmental disorder caused by a combination of genetic and environmental risk factors. Disturbances of brain development begin prenatally, while different environmental insults further affect postnatal brain maturation during childhood and adolescence. Genome-wide association studies (GWAS) have succeeded in identifying hundreds of new risk variants for common, multifactorial diseases. In schizophrenia research, GWAS have found several rare copy number variants that considerably increase the risk of schizophrenia, and have shown an association between schizophrenia and the major histocompatibility complex. Research on environmental risk factors in recent years has provided new information particularly on risk factors related to pregnancy and childhood rearing environment. Gene-environment interactions have become a central research topic. There is evidence that genetically susceptible children are more vulnerable to the effects of unstable childhood rearing environment and other environmental risk factors.

  9. Human Factors Laboratory

    Data.gov (United States)

    Federal Laboratory Consortium — Purpose: The purpose of the Human Factors Laboratory is to further the understanding of highway user needs so that those needs can be incorporated in roadway design,...

  10. Trespass event risk factors.

    Science.gov (United States)

    2014-11-12

    The Volpe Center has used three sources of datathe Federal Railroad Administrations required accident reports, locomotive video, and U.S. Census datato investigate common risk factors for railroad trespassing incidents, the leading cause of ...

  11. Human factors in aviation

    National Research Council Canada - National Science Library

    Salas, Eduardo; Maurino, Daniel E

    2010-01-01

    .... HFA offers a comprehensive overview of the topic, taking readers from the general to the specific, first covering broad issues, then the more specific topics of pilot performance, human factors...

  12. Factors Affecting Wound Healing

    Science.gov (United States)

    Guo, S.; DiPietro, L.A.

    2010-01-01

    Wound healing, as a normal biological process in the human body, is achieved through four precisely and highly programmed phases: hemostasis, inflammation, proliferation, and remodeling. For a wound to heal successfully, all four phases must occur in the proper sequence and time frame. Many factors can interfere with one or more phases of this process, thus causing improper or impaired wound healing. This article reviews the recent literature on the most significant factors that affect cutaneous wound healing and the potential cellular and/or molecular mechanisms involved. The factors discussed include oxygenation, infection, age and sex hormones, stress, diabetes, obesity, medications, alcoholism, smoking, and nutrition. A better understanding of the influence of these factors on repair may lead to therapeutics that improve wound healing and resolve impaired wounds. PMID:20139336

  13. Business Intelligence Success Factors

    DEFF Research Database (Denmark)

    Gaardboe, Rikke; Jonasen, Tanja Svarre

    2018-01-01

    Business intelligence (BI) is a strategically important practice in many organizations. Several studies have investigated the factors that contribute to BI success; however, an overview of the critical success factors (CSFs) involved is lacking in the extant literature. We have integrated...... culture. In addition, we contribute to the extant research by extending the framework of information system success and identifying gaps in the extant literature. Furthermore, we contribute to practical implementation through an enhanced understanding of the CSFs related to BI success....

  14. Factors Affecting Wound Healing

    OpenAIRE

    Guo, S.; DiPietro, L.A.

    2010-01-01

    Wound healing, as a normal biological process in the human body, is achieved through four precisely and highly programmed phases: hemostasis, inflammation, proliferation, and remodeling. For a wound to heal successfully, all four phases must occur in the proper sequence and time frame. Many factors can interfere with one or more phases of this process, thus causing improper or impaired wound healing. This article reviews the recent literature on the most significant factors that affect cutane...

  15. Brain derived neurotrophic factor

    DEFF Research Database (Denmark)

    Mitchelmore, Cathy; Gede, Lene

    2014-01-01

    Brain Derived Neurotrophic Factor (BDNF) is a neurotrophin with important functions in neuronal development and neuroplasticity. Accumulating evidence suggests that alterations in BDNF expression levels underlie a variety of psychiatric and neurological disorders. Indeed, BDNF therapies are curre......Brain Derived Neurotrophic Factor (BDNF) is a neurotrophin with important functions in neuronal development and neuroplasticity. Accumulating evidence suggests that alterations in BDNF expression levels underlie a variety of psychiatric and neurological disorders. Indeed, BDNF therapies...

  16. Impact factor distribution revisited

    Science.gov (United States)

    Huang, Ding-wei

    2017-09-01

    We explore the consistency of a new type of frequency distribution, where the corresponding rank distribution is Lavalette distribution. Empirical data of journal impact factors can be well described. This distribution is distinct from Poisson distribution and negative binomial distribution, which were suggested by previous study. By a log transformation, we obtain a bell-shaped distribution, which is then compared to Gaussian and catenary curves. Possible mechanisms behind the shape of impact factor distribution are suggested.

  17. Los factores de riesgo

    Directory of Open Access Journals (Sweden)

    Justo Senado Dumoy

    1999-01-01

    Full Text Available Sobre el fundamento filosófico de los conceptos de la Dialéctica Materialista, se presenta un análisis en relación con el concepto e interpretación de los Factores de Riesgo.A analysis on the concept and interpretation of risk factors is presented based on the philosophical foundation of the concepts of materialist dialectics.

  18. FGF growth factor analogs

    Energy Technology Data Exchange (ETDEWEB)

    Zamora, Paul O [Gaithersburg, MD; Pena, Louis A [Poquott, NY; Lin, Xinhua [Plainview, NY; Takahashi, Kazuyuki [Germantown, MD

    2012-07-24

    The present invention provides a fibroblast growth factor heparin-binding analog of the formula: ##STR00001## where R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, X, Y and Z are as defined, pharmaceutical compositions, coating compositions and medical devices including the fibroblast growth factor heparin-binding analog of the foregoing formula, and methods and uses thereof.

  19. The stem factor challenge

    International Nuclear Information System (INIS)

    Russell, M.J.; Steele, R. Jr.; DeWall, K.G.; Watkins, J.C.; Bramwell, D.

    1994-01-01

    One of the most important challenges that still needs to be met in the effort to understand the operation of motor-operated, rising-stem valves is the ability to determine stem factor throughout the valve's load range. The stem factor represents the conversion of operator torque to stem thrust. Determining the stem factor is important because some motor-operated valves (MOVs) cannot be tested in the plant at design basis conditions. The ability of these valves to perform their design basis function (typically, to operate against specified flow and pressure loads) must be ensured by analytical methods or by extrapolating from the results of tests conducted at lower loads. Because the stem factor tends to vary in response to friction and lubrication phenomena that occur during loading and wedging, analytical methods and extrapolation methods have been difficult to develop and implement. Early investigations into variability in the stem factor tended to look only at the tip of the iceberg; they focused on what was happening at torque switch trip, which usually occurs at full wedging. In most stems, the stem factor is better (lower) in the wedging transient than before wedging, so working with torque switch trip data alone led many early researchers to false conclusions about the relationship between stem factor and load. However, research at the Idaho National Engineering Laboratory (INEL) has taken a closer look at what happens during the running portion of the closing stroke along with the wedging portion. This shift in focus is important, because functional failure of a valve typically consists of a failure to isolate flow, not a failure to achieve full wedging. Thus, the stem factor that must be determined for a valve's design basis closing requirements is the one that corresponds with the running load before wedging

  20. [Pathological gambling: risk factors].

    Science.gov (United States)

    Bouju, G; Grall-Bronnec, M; Landreat-Guillou, M; Venisse, J-L

    2011-09-01

    In France, consumption of gambling games increased by 148% between 1960 and 2005. In 2004, gamblers lost approximately 0.9% of household income, compared to 0.4% in 1960. This represents approximately 134 Euros per year and per head. In spite of this important increase, the level remains lower than the European average (1%). However, gambling practices may continue to escalate in France in the next few years, particularly with the recent announce of the legalisation of online games and sports betting. With the spread of legalised gambling, pathological gambling rates may increase in France in the next years, in response to more widely available and more attractive gambling opportunities. In this context, there is a need for better understanding of the risk factors that are implicated in the development and maintenance of pathological gambling. This paper briefly describes the major risk factors for pathological gambling by examining the recent published literature available during the first quarter of 2008. This documentary basis was collected by Inserm for the collective expert report procedure on Gambling (contexts and addictions). Seventy-two articles focusing on risk factors for pathological gambling were considered in this review. Only 47 of them were taken into account for analysis. The selection of these 47 publications was based on the guide on literature analysis established by the French National Agency for Accreditation and Assessment in Health (ANAES, 2000). Some publications from more recent literature have also been added, mostly about Internet gambling. We identify three major types of risk factors implicated in gambling problems: some of them are related to the subject (individual factors), others are related to the object of the addiction, here the gambling activity by itself (structural factors), and the last are related to environment (contextual or situational factors). Thus, the development and maintenance of pathological gambling seems to be

  1. Building-transmission factors

    International Nuclear Information System (INIS)

    Woolson, W.A.; Marcum, J.; Scott, W.H.; Staggs, V.E.

    1982-01-01

    Parametric representations (called the nine-parameter formula) of the measurements of the radiation transmission through Japanese house models at the BREN reactor and 60 Co experiments are used to correct the free-in-air (FIA) T65 dose values for buildings shielding in the built-up residential areas at Hiroshima and Nagasaki. The accuracy of transmission factors derived from the nine-parameter formula impact the accuracy of the final-exposure dose estimates in the same manner as the accuracy of weapon yield and FIA radiation transport. A preliminary investigation of the accuracy of these transmission factors, sponsored by the Defense Nuclear Agency, has focused primarily on the adequacy of the Bare Reactor Experiment, Nevada (BREN) radiation environments for producing transmission factor data relevant to the situations at Hiroshima and Nagasaki. In addition, the radiation equivalency of house models used at BREN to Japanese house models and the physical basis for the nine-parameter formula have been studied. This investigation has concluded that the average gamma-ray transmission factors based on the nine-parameter formula are probably too high by about a factor of 2. The large discrepancy between the nine-parameter formula and recent estimates results from the apparent failure to properly account for the large gamma-ray dose component caused by capture gamma rays produced in the house walls by the large neutron flux present at BREN

  2. Risk Factors for Dementia

    Directory of Open Access Journals (Sweden)

    Jen-Hau Chen

    2009-10-01

    Full Text Available Dementia is a complex human disease. The incidence of dementia among the elderly population is rising rapidly worldwide. In the United States, Alzheimer's disease (AD is the leading type of dementia and was the fifth and eighth leading cause of death in women and men aged ≥ 65 years, respectively, in 2003. In Taiwan and many other counties, dementia is a hidden health issue because of its underestimation in the elderly population. In Western countries, the prevalence of AD increases from 1–3% among people aged 60–64 years to 35% among those aged > 85 years. In Taiwan, the prevalence of dementia for people aged ≥ 65 years was 2–4% by 2000. Therefore, it is important to identify protective and risk factors for dementia to prevent this disease at an early stage. Several factors are related to dementia, e.g. age, ethnicity, sex, genetic factors, physical activity, smoking, drug use, education level, alcohol consumption, body mass index, comorbidity, and environmental factors. In this review, we focus on studies that have evaluated the association between these factors and the risk of dementia, especially AD and vascular dementia. We also suggest future research directions for researchers in dementia-related fields.

  3. CATTELL AND EYSENCK FACTOR SCORES RELATED TO COMREY PERSONALITY FACTORS.

    Science.gov (United States)

    Comrey, A L; Duffy, K E

    1968-10-01

    The Eysenck Personality Inventory, the Cattell 16 PF Inventory, and the Comrey Personality Inventory were administered to 272 volunteers. Eysenck and Cattell factor scores were correlated with scores over homogeneous item groups (FHIDs) which define the Comrey test factors. This matrix was factor analyzed to relate the Eysenck and Cattell factor scores to the factor structure underlying the Comrey test. The Eysenck Neuroticism, Comrey Neuroticism, and Cattell second-order Anxiety factors appeared to match. The Eysenck Introversion and the Comrey Shyness factors also matched. The 16 Cattell primary factors overlapped but did not match with the Comrey factors.

  4. Business Intelligence Success Factors

    DEFF Research Database (Denmark)

    Gaardboe, Rikke; Jonasen, Tanja Svarre

    2018-01-01

    Business intelligence (BI) is a strategically important practice in many organizations. Several studies have investi-gated the factors that contribute to BI success; however, an overview of the critical success factors (CSFs) involved is lacking in the extant literature. We have integrated...... the findings of 43 studies after conducting a building block search strategy, refer-ence and citation search, and critical assessment of the identified papers. A framework of information system success was used to identify the CSFs and analyze how researchers identify information system success. We discovered...... 34 CSFs related to BI success. The distinct CSFs identified in the extant literature relate to project management skills (13 papers), management support (20 papers), and user involvement (11 papers). In the articles with operationalized BI success, we found several dis-tinct factors: system quality...

  5. Amblyopia risk factor prevalence.

    Science.gov (United States)

    Arnold, Robert W

    2013-01-01

    In 2003, the American Association for Pediatric Ophthalmology and Strabismus (AAPOS) published a set of risk factors for amblyopia. The intent was to promote uniformity of reporting and development in screening. Because this prevalence is not yet known, this meta-analysis is an attempt to estimate it. Major community preschool eye examination studies were reviewed and AAPOS cut-offs estimated. The approximate prevalence of anisometropia is 1.2%, hyperopia is 6%, astigmatism is 15%, myopia is 0.6%, strabismus is 2.5%, and visual acuity less than 20/40 is 6%. The mean combined prevalence is 21% ± 2% compared to a prevalence of amblyopia 20/40 and worse of 2.5%. Knowing risk factor prevalence simplifies validation efforts. Amblyopia screening with a risk factor sensitivity less than 100% is expected and desirable. Copyright 2013, SLACK Incorporated.

  6. factores psicosociales asociados

    Directory of Open Access Journals (Sweden)

    María Teresa Varela Arévalo

    2007-01-01

    Full Text Available El objetivo de este trabajo fue describir el consumo de sustancias psicoactivas [SPA] ilegales en jóvenes y los factores psicosociales de riesgo y de protección asociados. Participaron 763 estudiantes (46,5% hombres y 52,4% mujeres de una universidad privada de Cali, quienes diligenciaron el cuestionario de factores de riesgo y protección para el consumo de drogas. Los resultados muestran que la marihuana fue la droga de mayor consumo; y que existe una fuerte asociación entre el consumo de las cuatro SPA ilegales (marihuana, opiáceos, cocaína y éxtasis y los factores psicosociales de riesgo y/o protección, principalmente, las habilidades de autocontrol, los preconceptos y valoración de las SPA, la relación con personas consumidoras y los comportamientos perturbadores.

  7. Human factors guides

    International Nuclear Information System (INIS)

    Penington, J.

    1995-10-01

    This document presents human factors guides, which have been developed in order to provide licensees of the AECB with advice as to how to address human factors issues within the design and assessment process. This documents presents the results of a three part study undertaken to develop three guides which are enclosed in this document as Parts B, C and D. As part of the study human factors standards, guidelines, handbooks and other texts were researched, to define those which would be most useful to the users of the guides and for the production of the guides themselves. Detailed specifications were then produced to outline the proposed contents and format of the three guides. (author). 100 refs., 3 tabs., 11 figs

  8. Multi-factor authentication

    Science.gov (United States)

    Hamlet, Jason R; Pierson, Lyndon G

    2014-10-21

    Detection and deterrence of spoofing of user authentication may be achieved by including a cryptographic fingerprint unit within a hardware device for authenticating a user of the hardware device. The cryptographic fingerprint unit includes an internal physically unclonable function ("PUF") circuit disposed in or on the hardware device, which generates a PUF value. Combining logic is coupled to receive the PUF value, combines the PUF value with one or more other authentication factors to generate a multi-factor authentication value. A key generator is coupled to generate a private key and a public key based on the multi-factor authentication value while a decryptor is coupled to receive an authentication challenge posed to the hardware device and encrypted with the public key and coupled to output a response to the authentication challenge decrypted with the private key.

  9. Model Correction Factor Method

    DEFF Research Database (Denmark)

    Christensen, Claus; Randrup-Thomsen, Søren; Morsing Johannesen, Johannes

    1997-01-01

    The model correction factor method is proposed as an alternative to traditional polynomial based response surface techniques in structural reliability considering a computationally time consuming limit state procedure as a 'black box'. The class of polynomial functions is replaced by a limit...... statebased on an idealized mechanical model to be adapted to the original limit state by the model correction factor. Reliable approximations are obtained by iterative use of gradient information on the original limit state function analogously to previous response surface approaches. However, the strength...... of the model correction factor method, is that in simpler form not using gradient information on the original limit state function or only using this information once, a drastic reduction of the number of limit state evaluation is obtained together with good approximations on the reliability. Methods...

  10. Geothermal Plant Capacity Factors

    Energy Technology Data Exchange (ETDEWEB)

    Greg Mines; Jay Nathwani; Christopher Richard; Hillary Hanson; Rachel Wood

    2015-01-01

    The capacity factors recently provided by the Energy Information Administration (EIA) indicated this plant performance metric had declined for geothermal power plants since 2008. Though capacity factor is a term commonly used by geothermal stakeholders to express the ability of a plant to produce power, it is a term frequently misunderstood and in some instances incorrectly used. In this paper we discuss how this capacity factor is defined and utilized by the EIA, including discussion on the information that the EIA requests from operations in their 923 and 860 forms that are submitted both monthly and annually by geothermal operators. A discussion is also provided regarding the entities utilizing the information in the EIA reports, and how those entities can misinterpret the data being supplied by the operators. The intent of the paper is to inform the facility operators as the importance of the accuracy of the data that they provide, and the implications of not providing the correct information.

  11. Factor XI deficiency

    Directory of Open Access Journals (Sweden)

    Jayme Diamant

    2004-06-01

    Full Text Available We describe a patient with a prolonged aPTT who was diagnosedas having factor XI deficiency after a rather large hematoma wasformed after angiography. Factor XI deficiency affects 1 in 1 millionpeople, but it is more common in Ashkenazim with a gene frequencyof 5% to 11%, being 0.3% homozygotes. These individuals usuallydo not present hemorrhagic events, except in cases of trauma orsurgery. These patients should be identified by routine coagulationscreening; bleeding could be prevented by use of fresh humanplasma or plasma concentrates.

  12. The Transcription Factor Encyclopedia

    DEFF Research Database (Denmark)

    Yusuf, Dimas; Butland, Stefanie L; Swanson, Magdalena I

    2012-01-01

    mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written......ABSTRACT: Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130...... and vetted by experts in the field. TFe is available at http://www.cisreg.ca/tfe....

  13. Factores de riesgo : prevalencia

    OpenAIRE

    Banegas, José Ramón

    2005-01-01

    Casi la mitad de la población adulta española presenta al menos un factor de riesgo cardiovascular importante: hipertensión, tabaquismo, colesterol alto, sobrepeso, sedentarismo o diabetes, y muchos de estos individuos no lo saben, o no están tratados o no están bien controlados. Por lo tanto, mejorar el grado de conocimiento, tratamiento y control de estos factores de riesgo podría contribuir sustancialmente a reducir la magnitud de la enfermedad cardiovascular como problema de salud pública...

  14. The transcription factor encyclopedia.

    Science.gov (United States)

    Yusuf, Dimas; Butland, Stefanie L; Swanson, Magdalena I; Bolotin, Eugene; Ticoll, Amy; Cheung, Warren A; Zhang, Xiao Yu Cindy; Dickman, Christopher T D; Fulton, Debra L; Lim, Jonathan S; Schnabl, Jake M; Ramos, Oscar H P; Vasseur-Cognet, Mireille; de Leeuw, Charles N; Simpson, Elizabeth M; Ryffel, Gerhart U; Lam, Eric W-F; Kist, Ralf; Wilson, Miranda S C; Marco-Ferreres, Raquel; Brosens, Jan J; Beccari, Leonardo L; Bovolenta, Paola; Benayoun, Bérénice A; Monteiro, Lara J; Schwenen, Helma D C; Grontved, Lars; Wederell, Elizabeth; Mandrup, Susanne; Veitia, Reiner A; Chakravarthy, Harini; Hoodless, Pamela A; Mancarelli, M Michela; Torbett, Bruce E; Banham, Alison H; Reddy, Sekhar P; Cullum, Rebecca L; Liedtke, Michaela; Tschan, Mario P; Vaz, Michelle; Rizzino, Angie; Zannini, Mariastella; Frietze, Seth; Farnham, Peggy J; Eijkelenboom, Astrid; Brown, Philip J; Laperrière, David; Leprince, Dominique; de Cristofaro, Tiziana; Prince, Kelly L; Putker, Marrit; del Peso, Luis; Camenisch, Gieri; Wenger, Roland H; Mikula, Michal; Rozendaal, Marieke; Mader, Sylvie; Ostrowski, Jerzy; Rhodes, Simon J; Van Rechem, Capucine; Boulay, Gaylor; Olechnowicz, Sam W Z; Breslin, Mary B; Lan, Michael S; Nanan, Kyster K; Wegner, Michael; Hou, Juan; Mullen, Rachel D; Colvin, Stephanie C; Noy, Peter John; Webb, Carol F; Witek, Matthew E; Ferrell, Scott; Daniel, Juliet M; Park, Jason; Waldman, Scott A; Peet, Daniel J; Taggart, Michael; Jayaraman, Padma-Sheela; Karrich, Julien J; Blom, Bianca; Vesuna, Farhad; O'Geen, Henriette; Sun, Yunfu; Gronostajski, Richard M; Woodcroft, Mark W; Hough, Margaret R; Chen, Edwin; Europe-Finner, G Nicholas; Karolczak-Bayatti, Magdalena; Bailey, Jarrod; Hankinson, Oliver; Raman, Venu; LeBrun, David P; Biswal, Shyam; Harvey, Christopher J; DeBruyne, Jason P; Hogenesch, John B; Hevner, Robert F; Héligon, Christophe; Luo, Xin M; Blank, Marissa Cathleen; Millen, Kathleen Joyce; Sharlin, David S; Forrest, Douglas; Dahlman-Wright, Karin; Zhao, Chunyan; Mishima, Yuriko; Sinha, Satrajit; Chakrabarti, Rumela; Portales-Casamar, Elodie; Sladek, Frances M; Bradley, Philip H; Wasserman, Wyeth W

    2012-01-01

    Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field. TFe is available at http://www.cisreg.ca/tfe.

  15. Graph factors modulo k

    DEFF Research Database (Denmark)

    Thomassen, Carsten

    2014-01-01

    We prove a general result on graph factors modulo k . A special case says that, for each natural number k , every (12k−7)-edge-connected graph with an even number of vertices contains a spanning subgraph in which each vertex has degree congruent to k modulo 2k.......We prove a general result on graph factors modulo k . A special case says that, for each natural number k , every (12k−7)-edge-connected graph with an even number of vertices contains a spanning subgraph in which each vertex has degree congruent to k modulo 2k....

  16. Factoring humans into procedures

    International Nuclear Information System (INIS)

    Luna, S.F.; Sturdivant, M.H.; McKay, R.C.

    1988-01-01

    INPO statistics on reported events in nuclear power plants rank deficient procedures as the largest single cause of human performance errors. Human factors principles used to improve the effectiveness of the control room operator can also improve the usability of written procedures. This human factors approach treats each page or complement of pages as a display. Four techniques for applying this approach are reviewed in this paper: (1) presenting information in small blocks (or fields), (2) presenting information consistently, (3) using the mental templates of the performer, and (4) matching the physical features of the plant. A final section offers examples in which combinations of these techniques are used

  17. Factor analysis and scintigraphy

    International Nuclear Information System (INIS)

    Di Paola, R.; Penel, C.; Bazin, J.P.; Berche, C.

    1976-01-01

    The goal of factor analysis is usually to achieve reduction of a large set of data, extracting essential features without previous hypothesis. Due to the development of computerized systems, the use of largest sampling, the possibility of sequential data acquisition and the increase of dynamic studies, the problem of data compression can be encountered now in routine. Thus, results obtained for compression of scintigraphic images were first presented. Then possibilities given by factor analysis for scan processing were discussed. At last, use of this analysis for multidimensional studies and specially dynamic studies were considered for compression and processing [fr

  18. STEREOTYPICAL FACTORS IN TOURISM

    Directory of Open Access Journals (Sweden)

    Cristina-Elena ALBU

    2013-06-01

    Full Text Available International tourism has grown rapidly nowdays, contributing to the growth of the global economy. The purpose of this essay is to identify and analyze stereotypical factors in the development of strategies concerning the offer for the tourism industry: the image of a tourist destination, brand, country of origin and customer behaviour. Documentary study was the research method used: representative articles were analysed, as recent as possible, to determine the factors mentioned above. Professionals in the industry of tourism need to understand cultural differences between tourists, as well as those of the host country, to be able to create tourist reception offers that live up to the standards expected by clients.

  19. Factors stimulating content marketing

    Directory of Open Access Journals (Sweden)

    Naser Azad

    2016-02-01

    Full Text Available This paper presents an empirical investigation to determine factors influencing on content marketing in banking industry. The study designs a questionnaire consists of 40 questions in Likert scale and distributes it among 550 randomly selected regular customers of Bank Mellat in city of Tehran, Iran and 400 properly filled questionnaires are collected. Cronbach alphas for all components of the survey are well above desirable level. Using principle component analysis with Varimax rotation, the study has determined six factors influencing the most on content marketing including organization, details, having new ideas, quality, sensitivity and power while the last component contains only two subcomponents and is removed from the study.

  20. Factores sociales del emprendimiento

    OpenAIRE

    Torres Martín, Francisco José

    2017-01-01

    Podemos definir el emprendimiento social como todo aquel emprendimiento que se ha creado con un fin social, con el objetivo prioritario de crear un impacto positivo en la sociedad, mediante una actividad económica. Es importante analizar los aspectos sociales que llevan a la persona adentrase al mundo empresarial, así como las consecuencias que estos les ocasionan. En el trabajo vamos estudiar en profundidad los factores sociales más importantes a la hora de emprender. Los factores sociale...

  1. Risk factors for hypospadias.

    NARCIS (Netherlands)

    Brouwers, M.M.; Feitz, W.F.J.; Roelofs, L.A.J.; Kiemeney, L.A.L.M.; Gier, R.P.E. de; Roeleveld, N.

    2007-01-01

    Despite being one of the most common congenital defects in boys, the etiology of hypospadias remains largely unknown. In this case-referent study, we evaluated a wide spectrum of potential risk factors for hypospadias. Cases were identified from the hospital information system, and referents were

  2. Human factors information system

    International Nuclear Information System (INIS)

    Goodman, P.C.; DiPalo, C.A.

    1991-01-01

    Nuclear power plant safety is dependent upon human performance related to plant operations. To provide improvements in human performance, data collection and assessment play key roles. This paper reports on the Human factors Information System (HFIS) which is designed to meet the needs of the human factors specialists of the United States Nuclear Regulatory Commission. These specialists identify personnel errors and provide guidance designed to prevent such errors. HFIS is a simple and modular system designed for use on a personal computer. It is designed to contain four separate modules that provide information indicative of program or function effectiveness as well as safety-related human performance based on programmatic and performance data. These modules include the Human Factors Status module; the Regulatory Programs module; the Licensee Event Report module; and the Operator Requalification Performance module. Information form these modules can either be used separately or can be combined due to the integrated nature of the system. HFIS has the capability, therefore, to provide insights into those areas of human factors that can reduce the probability of events caused by personnel error at nuclear power plants and promote the health and safety of the public. This information system concept can be applied to other industries as well as the nuclear industry

  3. Fano factor estimation

    Czech Academy of Sciences Publication Activity Database

    Rajdl, Kamil; Lánský, Petr

    2014-01-01

    Roč. 11, č. 1 (2014), s. 105-123 ISSN 1547-1063 R&D Projects: GA ČR(CZ) GAP103/11/0282; GA ČR(CZ) GBP304/12/G069 Institutional support: RVO:67985823 Keywords : variability * neuronal activity * information Subject RIV: JD - Computer Applications, Robotics Impact factor: 0.840, year: 2014

  4. A Formula for Factoring.

    Science.gov (United States)

    Roebuck, Kay I. Meeks

    1997-01-01

    Suggests use of the quadratic formula to build understanding that connections between factors and solutions to equations work both ways. Making use of natural connections among concepts allows students to work more efficiently. Presents four sample problems showing the roots of equations. Messy quadratic equations with rational roots can be solved…

  5. Factoring Fermat Numbers

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 1; Issue 1. Factoring Fermat Numbers. C E Veni Madhavan. Research News Volume 1 Issue 1 January 1996 pp 108-108. Fulltext. Click here to view fulltext PDF. Permanent link: http://www.ias.ac.in/article/fulltext/reso/001/01/0108-0108. Author Affiliations.

  6. Factors affecting mining costs

    International Nuclear Information System (INIS)

    Lowell, A.F.

    1977-01-01

    The subject is discussed under the following headings: investment decision-making, unit cost factors (declining ore grade, low-price contracts, ore grade/output relationship, above average cost increases). Economic, environmental, sociological and political aspects are considered. (U.K.)

  7. Introduction to human factors

    International Nuclear Information System (INIS)

    Winters, J.M.

    1988-03-01

    Some background is given on the field of human factors. The nature of problems with current human/computer interfaces is discussed, some costs are identified, ideal attributes of graceful system interfaces are outlined, and some reasons are indicated why it's not easy to fix the problems

  8. Irrational factor races

    Indian Academy of Sciences (India)

    We investigate the behavior of the sum of the irrational factor function over arithmetic progressions. We first establish a general asymptotic formula for such a sum, and then obtain some further results in the case of arithmetic progressions 3 ± 1.

  9. Factors Impacting Knowledge Sharing

    DEFF Research Database (Denmark)

    Schulzmann, David; Slepniov, Dmitrij

    The purpose of this paper is to examine various factors affecting knowledge sharing at the R&D center of a Western MNE in China. The paper employs qualitative methodology and is based on the action research and case study research techniques. The findings of the paper advance our understanding ab...

  10. Factoring Fermat Numbers

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 1; Issue 1. Factoring Fermat Numbers. C E Veni Madhavan. Research News Volume 1 Issue 1 January 1996 pp 108-108. Fulltext. Click here to view fulltext PDF. Permanent link: https://www.ias.ac.in/article/fulltext/reso/001/01/0108-0108 ...

  11. Assessment of Human Factors

    Science.gov (United States)

    Mount, Frances; Foley, Tico

    1999-01-01

    Human Factors Engineering, often referred to as Ergonomics, is a science that applies a detailed understanding of human characteristics, capabilities, and limitations to the design, evaluation, and operation of environments, tools, and systems for work and daily living. Human Factors is the investigation, design, and evaluation of equipment, techniques, procedures, facilities, and human interfaces, and encompasses all aspects of human activity from manual labor to mental processing and leisure time enjoyments. In spaceflight applications, human factors engineering seeks to: (1) ensure that a task can be accomplished, (2) maintain productivity during spaceflight, and (3) ensure the habitability of the pressurized living areas. DSO 904 served as a vehicle for the verification and elucidation of human factors principles and tools in the microgravity environment. Over six flights, twelve topics were investigated. This study documented the strengths and limitations of human operators in a complex, multifaceted, and unique environment. By focusing on the man-machine interface in space flight activities, it was determined which designs allow astronauts to be optimally productive during valuable and costly space flights. Among the most promising areas of inquiry were procedures, tools, habitat, environmental conditions, tasking, work load, flexibility, and individual control over work.

  12. PATTERNS AND FACTORS INVOLVED

    African Journals Online (AJOL)

    Between 1*' of July 1996 and 30'h of June 2000 a total of 3583 patients were registered at the accident and emergency unit of Nnamdi. Azikiwe ... The case files of these were reviewed with a view to ascertaining the causes and factors involved in the deaths of these patients. The .... H.I.V/AIDS related complications 23 6.8.

  13. Functional Maximum Autocorrelation Factors

    DEFF Research Database (Denmark)

    Larsen, Rasmus; Nielsen, Allan Aasbjerg

    2005-01-01

    \\verb+~+\\$\\backslash\\$cite{ramsay97} to functional maximum autocorrelation factors (MAF)\\verb+~+\\$\\backslash\\$cite{switzer85,larsen2001d}. We apply the method to biological shapes as well as reflectance spectra. {\\$\\backslash\\$bf Methods}. MAF seeks linear combination of the original variables that maximize autocorrelation between...

  14. Human factors in network security

    OpenAIRE

    Jones, Francis B.

    1991-01-01

    Human factors, such as ethics and education, are important factors in network information security. This thesis determines which human factors have significant influence on network security. Those factors are examined in relation to current security devices and procedures. Methods are introduced to evaluate security effectiveness by incorporating the appropriate human factors into network security controls

  15. Factors in Agile Methods Adoption

    Directory of Open Access Journals (Sweden)

    Samia Abdalhamid

    2017-05-01

    Full Text Available There are many factors that can affect the process of adopting Agile methods during software developing. This paper illustrates the critical factors in Agile methods adoption in software organizations. To present the success and failure factors, an exploratory study is carried out among the critical factors of success and failure from existing studies. Dimensions and Factors are introduced utilizing success and failure dimensions. The mind map was used to clarify these factors.

  16. On braid monodromy factorizations

    Energy Technology Data Exchange (ETDEWEB)

    Kharlamov, V M [Institut de Recherche Matematique Avanee Universite Louis Pasteur et CNRS 7 rue Rene Descartes (France); Kulikov, Vik S [Steklov Mathematical Institute, Russian Academy of Sciences (Russian Federation)

    2003-06-30

    We introduce and develop a language of semigroups over the braid groups to study the braid monodromy factorizations (bmf's) of plane algebraic curves and other related objects. As an application, we give a new proof of Orevkov's theorem on the realization of bmf's over a disc by algebraic curves and show that the complexity of such a realization cannot be bounded in terms of the types of factors of the bmf. We also prove that the type of a bmf distinguishes Hurwitz curves with singularities of inseparable type up to H-isotopy and J-holomorphic cuspidal curves in CP{sup 2} up to symplectic isotopy.

  17. Molecular factors in migraine

    OpenAIRE

    Kowalska, Marta; Prendecki, Micha?; Kozubski, Wojciech; Lianeri, Margarita; Dorszewska, Jolanta

    2016-01-01

    Migraine is a common neurological disorder that affects 11% of adults worldwide. This disease most likely has a neurovascular origin. Migraine with aura (MA) and more common form - migraine without aura (MO) ? are the two main clinical subtypes of disease. The exact pathomechanism of migraine is still unknown, but it is thought that both genetic and environmental factors are involved in this pathological process. The first genetic studies of migraine were focused on the rare subtype of MA: fa...

  18. Factors Influencing Army Maintenance

    Science.gov (United States)

    1989-01-01

    Harz (1981), reports the results of questioning largc- numbers of Subject Matter Experts (SMEs) involved in the maintenance process. The second type of...identified maintenance problems (e.g., Kokenes, 1987; Harz , 1981). The second step was the identificatl i of demand factors that affect the actual...Kokenes, 1987; Harz , 1981). Second, if any of the data on which allocations are based are faulty, or budgetary decisions require a cutback in

  19. Power factor controllers

    International Nuclear Information System (INIS)

    1982-01-01

    The power factor controller (PFC) is a solid state electronic device that reduces excessive energy waste in ac induction motors. The significance of the PFC lies in the fact that nearly a billion induction motors are used daily. The PFC is applicable to both single phase and three phase induction motors. Since it is connected to the power lines of the motor and requires no modification to the motor itself, it may be applied to existing motors as well as to new installations

  20. Factors of academic procrastination

    OpenAIRE

    Kranjec, Eva; Košir, Katja; Komidar, Luka

    2017-01-01

    This study investigated dimensions of perfectionism, anxiety, and depression as factors of academic procrastination. Our main research interest was to examine the role of specific dimensions of perfectionism as moderators in the relationship between anxiety and depression and academic procrastination. Four scales were administered on the sample of 403 students: perfectionism scale FMPS, academic procrastination scale APS-SI, depression scale CESD and anxiety scale STAI-X2. The results showed ...

  1. Bayesian Factor Analysis.

    Science.gov (United States)

    1985-03-23

    Fundamantal Factors of Comprehension in...8217’"" . " *. . . . • * • "• "". . . . " . . . . • . . # • • • . .° - -.... . ... .. . . . . . . . . ................. 1 ,,.,..,*, University of Iowa/Novick 8 March 1985 Dr. James McBride Program Manager for Manpower, Psychological...Princeton, NJ 08541 Dr. Vern W. Urry Dr. Peter Stoloff Personnel R&D Center Center for Naval Analysis Office of Personnel Management 200 North

  2. Prognostic factors for medulloblastoma

    International Nuclear Information System (INIS)

    Jenkin, Derek; Al Shabanah, Mohamed; Al Shail, Essam; Gray, Alan; Hassounah, Maher; Khafaga, Yasser; Kofide, Amani; Mustafa, Mahmoud; Schultz, Henrik

    2000-01-01

    Purpose: To evaluate prognostic factors for medulloblastoma. Methods and Materials: One hundred and seventy-three consecutive patients with medulloblastoma, treated at King Faisal Specialist Hospital (KFSH) from 1988-1997, were reviewed. Eighty-four percent were children less than 15 years old. From 1988-1994, treatment was at the discretion of the investigator. From 1994-1998, patients entered a single-arm best practice protocol in which, in staged patients, the surgical intent was total resection, standard radiation treatment was defined, and adjuvant chemotherapy was given to a 'high-risk' subset. Results: For 150 patients who completed surgical and radiation treatment, the 5-year survival rate was 58%, compared with 0% for 16 patients who were unable to start or complete radiation treatment. For staged patients, the 5-year survival was M0 + M1, 78% and M2 + M3, 21% (p 14 years and gross cystic/necrotic features in the primary tumor. The size of the primary tumor, the degree of hydrocephalus at diagnosis, the presence of residual tumor in the post-operative CT/MRI, and the functional status of the patient prior to radiation treatment were not significant factors. Conclusions: Stage M0 + M1 was the most powerful favorable prognostic factor. In Saudi Arabia more patients present with advanced disseminated disease, 41% M2 + M3, than in the West, and this impacts adversely on overall survival. Total resection and standard radiation treatment were not sensitive prognostic factors in a treatment environment in which 78% of patients underwent at least 90% tumor resection and 60% received standard radiation treatment. In order to improve the proportion of patients able to complete radiation treatment, consideration should be given to limiting resection when the attainment of total resection is likely to be morbid, and to delaying rather than omitting radiation treatment in the patient severely compromised postoperatively

  3. Eukaryotic transcription factors

    DEFF Research Database (Denmark)

    Staby, Lasse; O'Shea, Charlotte; Willemoës, Martin

    2017-01-01

    Gene-specific transcription factors (TFs) are key regulatory components of signaling pathways, controlling, for example, cell growth, development, and stress responses. Their biological functions are determined by their molecular structures, as exemplified by their structured DNA-binding domains...... them to participate in large interactomes, how they use only a few hydrophobic residues, short sequence motifs, prestructured motifs, and coupled folding and binding for their interactions with co-activators, and how their accessibility to post-translational modification affects their interactions...

  4. Power Factor Controller

    Science.gov (United States)

    1997-01-01

    Frank Nola invented the Power Factor Controller (PFC) at Marshall Space Flight Center more than a decade ago. Nola came up with a way to curb power wastage in AC induction motors. The PFC matches voltage with the motor's actual need by continuously sensing shifts between voltage and current. When it senses a light load it cuts the voltage to the minimum needed. Potential energy savings range from 8 to 65 percent.

  5. Risk factors for cancer

    International Nuclear Information System (INIS)

    Lyman, G.H.

    1992-01-01

    It is no longer reasonable to divide cancers into those that are genetic in origin and those that are environmental in origin. With rare exception, carcinogenesis involves environmental factors that directly or indirectly exert a change in the cell's genome. Virtually all causes of cancer are multifactorial, sometimes involving an inherited predisposition to the carcinogenic effects of environmental factors, which include chemicals, ionizing radiation, and oncogenic virus. Carcinogenesis is a multistep process including induction, promotion, and progression. Initiation requires an irreversible change in the cellular genome, whereas promotion is commonly associated with prolonged and reversible exposure. Tumor progression results in genotypic and phenotypic changes associated with tumor growth, invasion, and metastasis. Most information on human cancer risk is based on epidemiologic studies involving both exposed and unexposed individuals. The quality of such studies depends on their ability to assess the strength of any association of exposure and disease and careful attention to any potential bias. Few cancers are inherited in a Mendelian fashion. Several preneoplastic conditions, however, are clearly inherited and several malignancies demonstrate weak familial patterns. Environmental factors may exert their effect on DNA in a random fashion, but certain consistent changes, including specific translocations of genetic information, are often found. Currently, there is great interest in the close proximity of certain oncogenes governing growth control to the consistent chromosomal changes observed. Such changes may represent a final common pathway of action for environmental carcinogens. Sufficient laboratory and epidemiologic evidence exists to establish a causal association of several chemical agents with cancer

  6. Human Factors Review Plan

    International Nuclear Information System (INIS)

    Paramore, B.; Peterson, L.R.

    1985-12-01

    ''Human Factors'' is concerned with the incorporation of human user considerations into a system in order to maximize human reliability and reduce errors. This Review Plan is intended to assist in the assessment of human factors conditions in existing DOE facilities. In addition to specifying assessment methodologies, the plan describes techniques for improving conditions which are found to not adequately support reliable human performance. The following topics are addressed: (1) selection of areas for review describes techniques for needs assessment to assist in selecting and prioritizing areas for review; (2) human factors engineering review is concerned with optimizing the interfaces between people and equipment and people and their work environment; (3) procedures review evaluates completeness and accuracy of procedures, as well as their usability and management; (4) organizational interface review is concerned with communication and coordination between all levels of an organization; and (5) training review evaluates training program criteria such as those involving: trainee selection, qualification of training staff, content and conduct of training, requalification training, and program management

  7. Human Factors Review Plan

    Energy Technology Data Exchange (ETDEWEB)

    Paramore, B.; Peterson, L.R. (eds.)

    1985-12-01

    ''Human Factors'' is concerned with the incorporation of human user considerations into a system in order to maximize human reliability and reduce errors. This Review Plan is intended to assist in the assessment of human factors conditions in existing DOE facilities. In addition to specifying assessment methodologies, the plan describes techniques for improving conditions which are found to not adequately support reliable human performance. The following topics are addressed: (1) selection of areas for review describes techniques for needs assessment to assist in selecting and prioritizing areas for review; (2) human factors engineering review is concerned with optimizing the interfaces between people and equipment and people and their work environment; (3) procedures review evaluates completeness and accuracy of procedures, as well as their usability and management; (4) organizational interface review is concerned with communication and coordination between all levels of an organization; and (5) training review evaluates training program criteria such as those involving: trainee selection, qualification of training staff, content and conduct of training, requalification training, and program management.

  8. Molecular factors in migraine

    Science.gov (United States)

    Kowalska, Marta; Prendecki, Michał; Kozubski, Wojciech; Lianeri, Margarita; Dorszewska, Jolanta

    2016-01-01

    Migraine is a common neurological disorder that affects 11% of adults worldwide. This disease most likely has a neurovascular origin. Migraine with aura (MA) and more common form - migraine without aura (MO) – are the two main clinical subtypes of disease. The exact pathomechanism of migraine is still unknown, but it is thought that both genetic and environmental factors are involved in this pathological process. The first genetic studies of migraine were focused on the rare subtype of MA: familial hemiplegic migraine (FHM). The genes analysed in familial and sporadic migraine are: MTHFR, KCNK18, HCRTR1, SLC6A4, STX1A, GRIA1 and GRIA3. It is possible that migraine is a multifactorial disease with polygenic influence. Recent studies have shown that the pathomechanisms of migraine involves both factors responsible for immune response and oxidative stress such as: cytokines, tyrosine metabolism, homocysteine; and factors associated with pain transmission and emotions e.g.: serotonin, hypocretin-1, calcitonin gene-related peptide, glutamate. The correlations between genetic variants of the HCRTR1 gene, the polymorphism 5-HTTLPR and hypocretin-1, and serotonin were observed. It is known that serotonin inhibits the activity of hypocretin neurons and may affect the appearance of the aura during migraine attack. The understanding of the molecular mechanisms of migraine, including genotype-phenotype correlations, may contribute to finding markers important for the diagnosis and treatment of this disease. PMID:27191890

  9. Human and Organizational Factors

    International Nuclear Information System (INIS)

    Eshiett, P.B.S.

    2016-01-01

    The Human and Organizational Factors Approach to Industrial Safety (HOFS) consists of identifying and putting in place conditions which encourage a positive contribution from operators (individually and in a team) with regards to industrial safety. The knowledge offered by the HOFS approach makes it possible better to understand what conditions human activity and to act on the design of occupational situations and the organization, in the aim of creating the conditions for safe work. Efforts made in this area can also lead to an improvement in results in terms of the quality of production or occupational safety (incidence and seriousness rates) (Daniellou, F., et al., 2011). Research on industrial accidents shows that they rarely happen as a result of a single event, but rather emerge from the accumulation of several, often seemingly trivial, malfunctions, misunderstandings, incorrect assumptions and other issues. The nuclear community has established rigorous international safety standards and concepts to ensure the protection of people and the environment from harmful effects of ionizing radiation (IAEA, 2014). A review of major human induced disasters in a number of countries and in different industries yields insights into several of the human and organizational factors involved in their occurrence. Some of these factors relate to failures in: • Design or technology; • Training; • Decision making; • Communication; • Preparation for the unexpected; • Understanding of organizational interdependencies

  10. Human factoring administrative procedures

    International Nuclear Information System (INIS)

    Grider, D.A.; Sturdivant, M.H.

    1991-01-01

    In nonnuclear business, administrative procedures bring to mind such mundane topics as filing correspondence and scheduling vacation time. In the nuclear industry, on the other hand, administrative procedures play a vital role in assuring the safe operation of a facility. For some time now, industry focus has been on improving technical procedures. Significant efforts are under way to produce technical procedure requires that a validated technical, regulatory, and administrative basis be developed and that the technical process be established for each procedure. Producing usable technical procedures requires that procedure presentation be engineered to the same human factors principles used in control room design. The vital safety role of administrative procedures requires that they be just as sound, just a rigorously formulated, and documented as technical procedures. Procedure programs at the Tennessee Valley Authority and at Boston Edison's Pilgrim Station demonstrate that human factors engineering techniques can be applied effectively to technical procedures. With a few modifications, those same techniques can be used to produce more effective administrative procedures. Efforts are under way at the US Department of Energy Nuclear Weapons Complex and at some utilities (Boston Edison, for instance) to apply human factors engineering to administrative procedures: The techniques being adapted include the following

  11. The focus factor

    DEFF Research Database (Denmark)

    Nicolaisen, Jeppe; Frandsen, Tove Faber

    2015-01-01

    Introduction. We present a new bibliometric indicator to measure journal specialisation over time, named the focus factor. This new indicator is based on bibliographic coupling and counts the percentage of re-citations given in subsequent years. Method. The applicability of the new indicator is d...... on either simple citation analysis or bibliographic coupling are found to be close relatives. Measures based on journal self-citation are found to be only weakly correlated with the focus factor. Measures based on co-citation analysis remain to be studied and compared.......Introduction. We present a new bibliometric indicator to measure journal specialisation over time, named the focus factor. This new indicator is based on bibliographic coupling and counts the percentage of re-citations given in subsequent years. Method. The applicability of the new indicator...... is demonstrated on a selection of general science journals and on a selection of medical journals. The reference lists of each journal are compared year by year, and the percentage of re-citations is calculated by dividing the number of re-citations with the total number of citations each year. Analysis...

  12. -Bioactive factors in milk-.

    Science.gov (United States)

    Buts, J P

    1998-03-01

    Human milk as well as the milk of several mammalian species contains, beside major nutrients and anti-infectious and immunocompetent substances, a group of biologically active substances called "milk-borne trophic factors" or "growth modulators". Milk-borne trophic can be classified into three groups: hormones and trophic peptides; nucleotides, nucleosides and derived substances; and polyamines, especially spermine and spermidine. Certain hormones and peptides such as growth hormone, insulin, insulin like-growth factor I (IGF-I), epidermal growth factor (EGF), prolactin and growth hormone releasing factor (GHRF) can influence directly newborn's metabolism after intestinal absorption and promote growth and differentiation of several organs and target tissues. They could exert a cytoprotective effect against toxins and toxic substances and reduce the potential risk of necrotizing enterocolitis. Nucleotides are present in human milk at high levels, and are precursors of nucleic acids, which implies that they can enhance growth and differentiation of several organs and tissues, especially the liver. Nucleotides from milk enhance lipid metabolism, lipoprotein synthesis and liver cell function and regeneration. In addition, they have a determinant action on the development of the gut associated lymphoid tissue (GALT). Lastly, polyamines, mainly spermine and spermidine, are polycationic substances virtually present in all cells, whose concentration in human milk is about ten times higher than in infant formulae. In addition, spermine and spermidine levels increase markedly during the first 3 days of lactation reaching, after 1 week, plateau levels which are respectively 12 and eight times higher than the levels measured at day 0. Although several experimental studies have shown that polyamines from the milk of lactating mammals determine important mitogenic, metabolic and immunological effects promoting growth and differentiation of the immature gastrointestinal tract of

  13. Cross-culturally recurrent personality factors : Analyses of three factors

    NARCIS (Netherlands)

    De Raad, B.; Peabody, D

    This study proceeds from an earlier one that examined the 'Big Five' factors (Peabody & De Raad, 2002). That study considered the substantive nature of five factors from six European psycholexical studies. The results supported Big Five Factor III (Conscientiousness), but Factors I (Extraversion)

  14. Milestones and Impact Factors

    Directory of Open Access Journals (Sweden)

    Grandjean Philippe

    2010-07-01

    Full Text Available Abstract Environmental Health has just received its first Impact Factor by Thomson ISI. At a level of 2.48, this achievement is quite satisfactory and places Environmental Health in the top 25% of environmental science journals. When the journal was launched in 2002, it was still unclear whether the Open Access publishing model could be made into a viable commercial enterprise within the biomedical field. During the past eight years, Open Access journals have become widely available, although still covering only about 15% of journal titles. Major funding agencies and institutions, including prominent US universities, now require that researchers publish in Open Access journals. Because of the profound role of scientific journals for the sharing of results and communication between researchers, the advent of Open Access may be of as much significance as the transition from handwriting to printing via moveable type. As Environmental Health is an electronic Open Access journal, the numbers of downloads at the journal website can be retrieved. The top-20 list of articles most frequently accessed shows that all of them have been downloaded over 10,000 times. Back in 2002, the first article published was accessed only 49 times during the following month. A year later, the server had over 1,000 downloads per month, and now the total number of monthly downloads approaches 50,000. These statistics complement the Impact Factor and confirm the viability of Open Access in our field of research. The advent of digital media and its decentralized mode of distribution - the internet - have dramatically changed the control and financing of scientific information dissemination, while facilitating peer review, accelerating editorial handling, and supporting much needed transparency. Both the meaning and means of "having an impact" are therefore changing, as will the degree and way in which scientific journals remain "factors" in that impact.

  15. Factor 4 planning

    International Nuclear Information System (INIS)

    Bariol-Mathais, Brigitte; Lavoillotte, Philippine; Gall-Sorrentino, Florence; Malez, Marianne; Sanna, Daniela; Marsauche, Maud; Marquet, Sarah; Debergue, Sophie; Aminu, Olufunmi; Bernard, Helene; Marchand, Jean-Michel; Blin, Frederic; Grange, Jerome; Caillierez, Sophie; Muller, Dania; Clement, Bob; Desire, Jean-Charles; Metais, Benedicte; Lannuzel, Philippe; Pezet-Kuhn, Murielle; Pons, Anne; Rivoire-Meley, Benedicte; Tissot, Heloise

    2015-07-01

    Factor 4 is the goal of cutting our greenhouse gas emissions by 75% by 2050. Achieving this objective will necessitate radical changes in our practices, in particular concerning transport and housing; the measures currently implemented, such as positive-energy buildings, low-impact mobility and eco-neighbourhoods, will not be enough to meet this goal. These measures must be conceived in the framework of broad territorial planning that integrates environmental and energy objectives far upstream. To this end, the French Environment and Energy Management Agency (ADEME) and the French network of Urban Planning Agencies (FNAU), pursuing their missions in their respective areas of competence, have joined forces to make infrastructure and land use planning an integral part of the environmental and energy transition process. In 2013, the two organisations signed a partnership agreement and compiled an inventory of practices that are relevant to Factor 4 planning. This work was led by Epures, Saint-etienne urban planning agency, along with FNAU, drawing upon the expertise of a dozen urban planning agencies in precursor territories. This inventory describes the stakes, resources and strengths for each territory, which have led to cross-sectoral territorial planning exercises with ambitious environmental and energy objectives; the importance of evaluation in attaining these goals is emphasised. Current experience, questions and available methodological tools are summarised in this document, to encourage territories and help them design their planning policies along a trajectory to achieve Factor 4 goals. The compilation also aims to be a contribution to the COP21 climate conference

  16. Improved Balanced Incomplete Factorization

    Czech Academy of Sciences Publication Activity Database

    Bru, R.; Marín, J.; Mas, J.; Tůma, Miroslav

    2010-01-01

    Roč. 31, č. 5 (2010), s. 2431-2452 ISSN 0895-4798 R&D Projects: GA AV ČR IAA100300802 Grant - others:GA AV ČR(CZ) M100300902 Institutional research plan: CEZ:AV0Z10300504 Source of funding: I - inštitucionálna podpora na rozvoj VO Keywords : preconditioned iterative methods * sparse matrices * incomplete decompositions * approximate inverses * Sherman-Morrison formula * nonsymmetric matrices Subject RIV: BA - General Mathematics Impact factor: 1.725, year: 2010

  17. Accidents and human factors

    International Nuclear Information System (INIS)

    Nishiwaki, Y.; Kawai, H.; Morishima, H.; Terano, T.; Sugeno, M.

    1984-01-01

    When the TMI accident occurred it was 4 a.m., an hour when the error potential of the operators would have been very high. The frequency of car and train accidents in Japan is also highest between 4 a.m. and 6 a.m. The error potential may be classified into five phases corresponding to the electroencephalogramic pattern (EEG). At phase 0, when the delta wave appears, a person is unconscious and in deep sleep; at phase I, when the theta wave appears, he is very tired, sleepy and subnormal; at phase II, when the alpha wave appears, he is normal, relaxed and passive; at phase III, when the beta wave appears, he is normal, clear-minded and active; at phase IV, when the strong beta or epileptic wave appears, he is hypernormal, excited and incapable of normal judgement. Should an accident occur at phase II, the brain condition may jump to phase IV. At this phase the error or accident potential is maximum. The response of the human brain to different types of noises and signals may vary somewhat for different individuals and for different groups of people. Therefore, the possibility that such differences in brain functions may influence the mental structure would be worthy of consideration in human factors and in the design of man-machine systems. Human reliability and performance would be affected by many factors: medical, physiological and psychological, etc. The uncertainty involved in human factors may not necessarily be probabilistic, but fuzzy. Therefore, it would be important to develop a theory by which both non-probabilistic uncertainties, or fuzziness, of human factors and the probabilistic properties of machines can be treated consistently. From the mathematical point of view, probabilistic measure is considered a special case of fuzzy measure. Therefore, fuzzy set theory seems to be an effective tool for analysing man-machine systems. To minimize human error and the possibility of accidents, new safety systems should not only back up man and make up for his

  18. Perinatal risk factors for strabismus

    DEFF Research Database (Denmark)

    Torp-Pedersen, Tobias; Boyd, Heather A; Poulsen, Gry

    2010-01-01

    Little is known about the aetiological factors underlying strabismus. We undertook a large cohort study to investigate perinatal risk factors for strabismus, overall and by subtype.......Little is known about the aetiological factors underlying strabismus. We undertook a large cohort study to investigate perinatal risk factors for strabismus, overall and by subtype....

  19. Risk Factors for Eating Disorders

    Science.gov (United States)

    Striegel-Moore, Ruth H.; Bulik, Cynthia M.

    2007-01-01

    The authors review research on risk factors for eating disorders, restricting their focus to studies in which clear precedence of the hypothesized risk factor over onset of the disorder is established. They illustrate how studies of sociocultural risk factors and biological factors have progressed on parallel tracks and propose that major advances…

  20. Activation of human factor V by factor Xa and thrombin

    International Nuclear Information System (INIS)

    Monkovic, D.D.; Tracy, P.B.

    1990-01-01

    The activation of human factor V by factor Xa and thrombin was studied by functional assessment of cofactor activity and sodium dodecyl sulfate-polycarylamide gel electrophoresis followed by either autoradiography of 125 I-labeled factor V activation products or Western blot analyses of unlabeled factor V activation products. Cofactor activity was measured by the ability of the factor V/Va peptides to support the activation of prothrombin. The factor Xa catalyzed cleavage of factor V was observed to be time, phospholipid, and calcium ion dependent, yielding a cofactor with activity equal to that of thrombin-activated factor V (factor Va). The cleavage pattern differed markedly from the one observed in the bovine system. The factor Xa activated factor V subunits expressing cofactor activity were isolated and found to consist of peptides of M r 220,000 and 105,000. Although thrombin cleaved the M r 220,000 peptide to yield peptides previously shown to be products of thrombin activation, cofactor activity did not increase. N-Terminal sequence analysis confirmed that both factor Xa and thrombin cleave factor V at the same bond to generate the M r 220,000 peptide. The factor Xa dependent functional assessment of 125 I-labeled factor V coupled with densitometric analyses of the cleavage products indicated that the cofactor activity of factor Xa activated factor V closely paralleled the appearance of the M r 220,000 peptide. The data indicate that factor Xa is as efficient an enzyme toward factor V as thrombin

  1. Organizational factors in Korean NPPs

    International Nuclear Information System (INIS)

    Jang, D. J.; Kim, Y. I.; Jeong, C. H.; Kim, J. W.

    2003-01-01

    Organizational factors are referred to as the factors that influence the achievement of a goal of an organization. Latent problems of an organization could contribute to causing human errors in such stages as design, operation and maintenance, and furthermore, leading to an severe accident. In order to evaluate an organization from the safety viewpoint, it is necessary to identify the organizational factors in a systematic fashion. In this paper, some efforts to identify the organizational factors in Korean NPPs are presented. The study was performed in the following steps: 1) Reviewing the definitions and range of the organizational factors used by the previous 13 researches, 2) Structuring the organizational factors by screening and collating factors, 3) Analysing the organizational factors that is considered to have contributed to the trip events based on the trip report of Korean NPPs, 4) Suggesting a more reliable taxonomy of organizational factors for event analysis by applying the Onion Structure Model to the selected factors

  2. Risk Factors in Pemphigus

    Directory of Open Access Journals (Sweden)

    Gülşen Tükenmez Demirc

    2011-09-01

    Full Text Available Background and Design: There have been reports suggesting the involvement of environmental factors in the disease process of pemphigus. In this study, we aimed to find out the risk factors which could play role in the etiopathogenesis in our pemphigus patients.Material and method: A total of 42 patients (15 male and 27 female who were diagnosed as pemphigus with histopathological and direct immunoflurosence examinations in our clinic between the years 1998-2004, were interviewed for assessment of regarding with the subjects of the demographic properties, occupational groups, educational level, the number of pregnancies, stressfull life events, diet habits, smoking and alcohol consumption before the onset of the disease and the results were compared to 42 age and gender-matched controls with similar socioeconomic circumstances. Results: Working in agriculture and livestock, multi-parity, absence of smoking and stressfull life events were found to be statistically significant in pemphigus patients than in controls. Conclusion: Working in agriculture and livestock, multi-parity, absence of smoking and stressfull life events were assumed to play role in the etiopathogenesis and course of pemphigus.

  3. Eclipse telescope design factors

    Science.gov (United States)

    Hull, Tony; Trauger, John T.; Macenka, Steven A.; Moody, Dwight; Olarte, Guillermo; Sepulveda, Cesar; Tsuha, Walter; Cohen, David

    2003-02-01

    Very high contrast imagery, required for exoplanet image acquisition, imposes significantly different criteria upon telescope architecture than do the requirements imposed upon most spaceborne telescopes. For the Eclipse Mission, the fundamental figure-of-merit is a stellar contrast, or brightness reduction ratio, reaching a factor</