衰老对内皮祖细胞CXCR4表达及其促血管新生能力的影响

Vascular occlusion resulting in ischemia is a major cause of heart attack, stroke and peripheral arterial disease. Stem cell based therapy is considered as a new effective treatment for cardiovascular diseases. However, in the aged patients who could most benefit, the supply of progenitor cells is depleted and the cells' angiogenic capacity is blunted, which result in the poorer efficacy of cell therapy in the old population. We have discovered that SDF-1 is inefficient to promote angiogenesis in aged mice. CXCR4 surface expression on bone marrow derived cells (BMC) from old mice is significantly lower than that of young mice, and cannot be augmented when exposed to stimulators. The association of impaired CXCR4 surface expression with the poorer pro-angiogenesis activity of progenitor cells has yet been solved. The goal of this project is to determine specific changes responsible for the impaired revascularization ability of aged BMCs, especially in the subpopulation of endothelial progenitor cells (EPC). We hypothesize that EPC from aged mice are defective in both CXCR4 surface expression and SDF-1/CXCR4 signaling, which diminishes their mobility in responding to SDF-1 to promote angiogenesis. We will determine the effect of aging on CXCR4 expression of EPC and define the dysfunction of SDF-1/CXCR4 interaction and signaling in EPC from old mice. By determining the role of CXCR4 expression on EPC in angiogenesis, the mechanism by which EPC promote angiogenesis will be illustrated. These fundamental mechanistic studies will define the impact of aging on endothelial progenitor cells, and identify the functional deficiency in aged progenitor cells. The results will enhance our understanding of stem cell biology, and will enable us to refine cell-based therapeutic strategies for ischemic diseases.

细胞治疗动脉阻塞引发的缺血性疾病已成为研究的热点。但最有可能从中获益的老年患者却因自身祖细胞数量的减少和细胞活性及功能的衰退使之在该人群中疗效不佳。申请人已发现老年小鼠骨髓细胞表面CXCR4表达较年轻细胞显著减少，但这种缺陷与干细胞促血管生成能力的下降是否相关尚待明确。我们假设：衰老造成内皮祖细胞CXCR4膜表面表达下降，由此降低了内皮祖细胞对细胞趋化因子SDF-1的响应，损害了其促进血管新生能力；提高CXCR4表达可以增强内皮祖细胞迁移和抗凋亡能力，由此提高其血管修复能力。本项目将采用骨髓置换及联体模型等手段，探讨衰老对内皮祖细胞参与血管生成的影响，明确其中CXCR4的重要性。通过阐明衰老对骨髓源内皮祖细胞CXCR4表达的影响及其相关分子机制，明确老年对内皮祖细胞CXCR4/SDF-1信号通路的损害机理，和内皮祖细胞参与血管生成的相关机制，为提高临床细胞治疗疗效提供理论依据。

血管堵塞引起的心血管疾病已成为威胁我国人民健康的重大疾病。目前，这些疾病的传统治疗手段不但花费昂贵而且疗效有限，极需寻求新的治疗方法。干细胞移植疗法为这些疾病的治疗提供了新的方法和手段。然而，最有可能从中获益的老年患者却因自身祖细胞数量的减少和细胞功能的衰退使细胞治疗在该人群中不能达到理想疗效。我们的研究结果表明衰老致使干细胞活性降低。探讨衰老对干细胞活性及其参与血管生成过程的具体影响，明确其中调控的分子机制，对突破目前临床上细胞治疗疗效不佳的瓶颈问题十分必要。本课题主要围绕衰老造成祖细胞活性下降，促血管新生能力受损等问题，研究如何增强祖细胞迁移和抗凋亡能力，由此提高其血管修复能力。.本项目通过分析衰老对干细胞特殊基因表达的影响，探讨通过预处理提高干细胞活性，以增强其治疗缺血性疾病的效果。我们发现通过Statin药物处理，或缺氧或激动剂预处理干细胞，可以提高干细胞CXCR4表达，增强干细胞迁移能力和存活率，从而达到提高干细胞治疗效果。这对突破目前临床上细胞治疗疗效不佳的瓶颈问题有重要的意义。缺氧预处理的研究结果可以直接应用于临床上细胞治疗心血管疾病，提高老年人群中细胞治疗疗效。在此基金资助期间，有27篇论文发表，其中有6篇直接受本基金资助，另外还有 3篇在投稿或准备中。并获得了国家基金面上项目和国际合作项目，及科技部973项目。培养了3名博士生，3名硕士生。