| Summary: | 碩士 === 中國醫藥大學 === 基礎醫學研究所碩士班 === 99 === Ischemic/reperfusion injury (I/R injury) is a major cause of death and disability worldwide. However, once cell damage from I/R injury is established, little can be done to restore pre-stroke conditions. Bone marrow mesenchymal stem cells (MSCs) are able to differentiate into cardiomyocytes and vascular endothelial cells. MSCs migration in the neo-angiogenic niches supporting revascularization of ischemic tissue is directly by chemokine, SDF-1, that activates its receptor CXCR4. Recently, a new SDF-1 receptor named CXCR7 has been discovered and enhanced expression of CXCR7 was observed in the neurons and blood vessels after cerebral ischemia in the rodent brain. Based on these rationales, CXCR7 may play a crucial role in ischemia-induced vasculogenesis. In this study, we investigated the role of CXCR7/SDF-1 in mediating angiogenesis in an animal model of limb ischemia. We used in vitro and in vivo molecular imaging approaches together with CXCR7 loss-of-function and CXCR7 gain-of-function techniques to examine the impact of CXCR7 in stem cell-mediated angiogenesis. The results derived from in vitro study demonstrate that up-regulation of CXCR7 in MSCs could increase cell survival and cell differentiation of MSCs into endothelium cell, and further promote angiogenesis. However, the chemotaxis assay showed that overexpression of CXCR7 or knockdown of CXCR7 in MSCs have no significant effect in chemotaxis to SDF-1. However, in vivo studies indicate that knockdown of CXCR7 in ischemic and surrounding tissues inhibited MSCs homing and tissue regeneration in ischemic tissues. Moreover, overexpression of CXCR7 in MSCs enhances the therapeutic efficiency of stem cell therapy, which improves neovascularization and blood flow recovery. We also found FOXC1, a transcription factor could bind to CXCR7 promoter region, and up-regulated under hypoxia. In summary, CXCR7 has multiple roles during ischemia-induced vasculogenesis. CXCR7 in stem cells regulates cell survival and differentiation, whereas CXCR7 in surrounding tissue mediates cell homing. Up-regulation of CXCR7 could enhance the therapeutic effects of MSCs therapy in limb ischemia.
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