缺氧预处理提高骨髓间充质干细胞心肌修复疗效：瘦素的作用及机制研究

Myocardial infarction is a major hazard disease to human health. Cell transplantation is one of the most promising treatment for myocardial tissue repair, and how to improve the repair efficacy is the key issue. Our preliminary study has confirmed that hypoxic preconditioning improved the therapeutic efficacy of bone marrow derived mesenchymal stem cells (MSC), which wasassociated with significantly upregulated expression of leptin; wild-type MSC had better enhanced myocardial repair capacity than leptin deficient MSC, suggesting that leptin plays an important role for hypoxic preconditioned MSC to promote cardiac repair. The proposed study will determine the signaling network of leptin in hypoxic preconditioned MSC, by comparing MSCs from wild type,leptin deficient，and leptin receptor deficient mice. We will define the role of leptin on MSC mobility，and on MSC preventing cardiomyocyte apoptosis,promoting the recruitingcardiac stem cells.By testing the "leptin-dependent" myocardial repair hypothesis in hypoxia preconditioned MSCs threpay,we will define the mechanism by which stem cells repair myocardial tissue. The results will enhance our understanding of stem cell biology, and will enable us to refine cell-based therapeutic strategies for the treatment of cardiovascular diseases.

心肌梗死是危害人类健康的重大疾病，细胞移植是心肌组织修复最有前景的治疗手段之一，如何提高其修复疗效是关键问题。本项目前期研究已证实缺氧预处理能提高骨髓间充质干细胞（MSC）疗效并伴有瘦素显著上调；野生型MSC较瘦素缺失MSC有更强的心肌修复能力，提示瘦素在缺氧预处理MSC促进心肌修复中起到重要作用。因此，本研究拟在前期工作基础上，深入探索以"瘦素在MSC缺氧预处理"为枢纽的信号网络调控，利用瘦素及其受体缺失小鼠研究瘦素在增强MSC体内入驻成活率，减少心肌细胞凋亡和改善干细胞募集等作用，论证缺氧预处理MSC"瘦素依赖性"心肌组织修复机制假说，从新的角度揭示干细胞修复心肌的机制及提高疗效的途径，更有可能为今后开发以瘦素关联分子为靶标的新型心肌修复治疗方法提供理论依据。

骨髓间充质干细胞（MSCs）治疗缺血性心肌病的疗效已在许多临床和基础研究中证实，是目前最有前景的治疗手段之一。我们的前期工作发现瘦素可能在缺氧预处理增强的MSCs对心脏的保护作用中起着关键作用。本研究拟在进一步明确瘦素是否能增强MSCs的抗凋亡能力，并探究其作用机制，从而为优化细胞治疗提供新的理论依据。