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Bone Marrow Endothelial Progenitor Cell Transplantation After Ischemic Stroke: An Investigation Into Its Possible Mechanism.

ABSTRACT: AIMS:We tested the hypothesis that endothelial progenitor cell (EPC)-mediated functional recovery after stroke may be associated with the endothelial nitric oxide synthase (eNOS)/brain-derived neurotrophic factor (BDNF) signaling pathway. METHODS:Mice were infused with either EPCs or saline after being subjected to middle cerebral artery occlusion. The EPC-treated mice also received intravenous injections of either N?-nitro-l-arginine methyl ester (L-NAME, the NOS inhibitor) or saline. RESULTS:The activation of eNOS and the expression of BDNF were significantly increased in ischemic brain of the EPC-treated mice, along with increased angiogenesis and neurogenesis. On diffusion tensor imaging (DTI), significant increases in fractional anisotropy and fiber count were observed in white matter, indicating axonal growth stimulated by EPCs. However, the EPC-treated mice that were received an L-NAME injection failed to exhibit the observed increases in angiogenesis, neurogenesis, and axonal growth. In addition, the neurons cocultured with EPCs in vitro exhibited the increased expression of BDNF and decreased apoptosis after oxygen-glucose deprivation compared with the control group. This EPC-induced protective effect was virtually absent in the L-NAME treatment group. CONCLUSION:The eNOS/BDNF pathway may be involved in the EPC-mediated functional recovery of stroke mice. DTI is feasible for dynamically tracking the orientation of axonal projections after EPC treatment.

SUBMITTER: Bai YY

PROVIDER: S-EPMC6493116 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Bone Marrow Endothelial Progenitor Cell Transplantation After Ischemic Stroke: An Investigation Into Its Possible Mechanism.

Bai Ying-Ying YY Peng Xin-Gui XG Wang Li-Shan LS Li Zi-Hui ZH Wang Yuan-Cheng YC Lu Chun-Qiang CQ Ding Jie J Li Pei-Cheng PC Zhao Zhen Z Ju Sheng-Hong SH

CNS neuroscience & therapeutics 20150919 11

<h4>Aims</h4>We tested the hypothesis that endothelial progenitor cell (EPC)-mediated functional recovery after stroke may be associated with the endothelial nitric oxide synthase (eNOS)/brain-derived neurotrophic factor (BDNF) signaling pathway.<h4>Methods</h4>Mice were infused with either EPCs or saline after being subjected to middle cerebral artery occlusion. The EPC-treated mice also received intravenous injections of either Nω-nitro-l-arginine methyl ester (L-NAME, the NOS inhibitor) or sa ...[more]

PMID: 26384586

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Project description:RATIONALE:Endothelial progenitor cell (EPC) survival and function in the injured myocardium is adversely influenced by hostile microenvironment such as ischemia, hypoxia, and inflammatory response, thereby compromising full benefits of EPC-mediated myocardial repair. OBJECTIVE:We hypothesized that interleukin-10 (IL-10) modulates EPC biology leading to enhanced survival and function after transplantation in the ischemic myocardium. METHODS AND RESULTS:Myocardial infarction (MI)-induced mobilization of bone marrow EPC (Sca-1+Flk1+cells) into the circulation was significantly impaired in IL-10 knockout (KO) mice. Bone marrow transplantation to replace IL-10 KO marrow with wild-type (WT) marrow attenuated these effects. Impaired mobilization was associated with lower stromal cell-derived factor (SDF)-1 expression levels in the myocardium of KO mice. Interestingly, SDF-1 administration reversed mobilization defect in KO mice. In vitro, hypoxia-mediated increases in CXCR4 expression and cell survival were lower in IL-10-deficient EPCs. Furthermore, SDF-1-induced migration of WT EPCs was inhibited by AMD3100, an inhibitor of CXCR4. To further study the effect of IL-10 on in vivo EPC survival and engraftment into vascular structures, GFP-labeled EPC were injected intramyocardially after induction of MI, and the mice were treated with either saline or recombinant IL-10. The IL-10-treated group showed increased retention of transplanted EPCs in the myocardium and was associated with significantly reduced EPC apoptosis after MI. Interestingly, increased EPC retention and their association with the vascular structures was observed in IL-10-treated mice. Increased EPC survival and angiogenesis in the myocardium of IL-10-treated mice corroborated with improved left ventricular function, reduced infarct size, and fibrosis in the myocardium. In vitro, IL-10-induced increase in VEGF expression in WT EPC was abrogated by STAT3 inhibitor, suggesting IL-10 signals through STAT3 activation. CONCLUSIONS:Taken together, our studies demonstrate that MI-induced EPC mobilization was impaired in IL-10 KO mice and that IL-10 increases EPC survival and function possibly through activation of STAT3/VEGF signaling cascades, leading to attenuation of MI-induced left ventricular dysfunction and remodeling.

Dataset Information

Bone Marrow Endothelial Progenitor Cell Transplantation After Ischemic Stroke: An Investigation Into Its Possible Mechanism.

Publications

Bone Marrow Endothelial Progenitor Cell Transplantation After Ischemic Stroke: An Investigation Into Its Possible Mechanism.

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