FAIM在改善老年骨髓间充质干细胞生存能力和功能优化中的作用及其机制研究

Transplantation of mesenchymal stem cells(MSCs) is a very promising therapy for myocardial infarction, which efficacy has been identified in quantity of clinical trials, but there are still some limitations in their clinical applications. Very low survival rate of the transplanted MSCs in the infarcted area and declined abilities of proliferation and differentiation in aged MSCs are the most important reasons that limit the curative effect of MSCs for ischemic heart disease. Besides, those who have ischemic heart disease are mostly from aged individuals. Therefore, how to improve the abilities of aged MSCs and enhance the survival rate after transplantation is the key scientific issue. It is reported that inhibition of exogenous Fas apoptosis signaling pathway can increase the therapeutic efficacy of MSCs. Our previous research found that the expression of Fas apoptosis inhibitory molecule (FAIM) in aged MSCs is decreased comparing with young MSCs. And the survival rate is significantly increased in FAIM overexpressed aged MSCs under stressed condition. Hence, our hypothesis is that FAIM is a potential target to improve the survival and abilities for aged MSCs. In this study, we will evaluate the effects of FAIM on survival and functional improvement of aged MSCs by using transgenic technology, MicroPET, protein identification via mass spectrometry in vitro and in vivo. We would like to explore a new method to improve the therapeutic efficacy of MSCs from aged population.

骨髓间充质干细胞(MSCs)作为一种具有良好应用前景的新疗法，已在大量临床试验中展现了确切疗效，但局限性也逐渐显露。其中限制其治疗缺血性心脏病疗效的重要原因：1）移植后的低生存率；2）老年来源的MSCs在增殖、分化等功能上显著下降。而患缺血性心脏病的大多是老年人，因此，如何优化老年MSCs功能并提高其移植后的生存率是关键科学问题。研究发现抑制外源性Fas凋亡通路可提高老年MSCs的疗效。我们前期研究发现，与年轻MSCs比较，老年MSCs的Fas凋亡抑制分子(FAIM)表达下降，FAIM基因高表达可改善其应激后的生存率，因此我们推测FAIM可能是改善老年MSCs生存和功能优化的潜在靶点。本研究拟通过转基因技术、MicroPET、蛋白质谱分析等手段，综合体内外实验对FAIM在改善老年MSCs生存和功能优化中的作用及其机制进行深入研究，进而为提高老年人MSCs自体移植治疗缺血性心脏病提供新思路。

骨髓间充质干细胞（MSCs）移植作为一种具有良好应用前景的新疗法，已在大量的临床试验中展现了确切的疗效，但其局限性也逐渐显露。其中限制其治疗缺血性心脏病疗效的重要原因是由于局部的恶劣微环境导致的移植后低生存率，如何优化MSCs功能并提高其移植后在缺血心肌微环境中的生存率是关键科学问题。研究发现抑制外源性Fas凋亡通路可以提高MSCs的疗效。我们在体外实验中利用缺氧缺血清模拟心肌梗死微环境诱导MSCs的凋亡，发现FAIM在缺氧环境中显著降低发现，而FAIM过表达可以增强MSCs的抗凋亡能力。在体实验中，过表达FAIM可以显著提高MSCs在小鼠心肌梗死微环境中的存活率，从而改善心功能，促进心梗周边区的血管新生，减少心脏纤维化。机制研究中，我们发现FAIM主要通过外源性凋亡通路调节MSCs的凋亡，同时发现FAIM过表达后，c-FLIP这一外源性凋亡的抑制分子的蛋白水平显著升高。我们揭示了FAIM通过影响JNK的磷酸化激活调节c-FLIP的泛素化，减少其降解，从而提高了细胞抵御凋亡的能力。因此我们得出结论，FAIM可以通过JNK通路调节c-FLIP泛素化改善MSCs的抗凋亡能力，从而提高MSCs移植疗效。这一发现将为提高MSCs移植治疗缺血性心脏病提供新思路。