间充质干细胞来源的miR-106b-25基因簇调控FoxO3a信号通路减轻移植肝缺血再灌注损伤的作用及机制研究

肝缺血再灌注损伤（HIRI）是移植肝功能障碍的重要原因，干细胞治疗展现良好前景，明确主要机制并行干预可望显著提高干细胞的治疗效果。我们已证实核转录因子FoxO3a通过调控凋亡及DNA修复而减轻器官损伤（前国自项目）；采用基因芯片发现源于间充质干细胞（MSCs）的miR-106b-25基因簇在移植肝保护中可能发挥重要作用；生物信息学结合预实验结果显示该基因簇可以通过缝隙连接或外泌体传递到肝细胞，通过调节PI3K/Akt和HIC1/Sirt1信号通路而影响FoxO3a的活性。因此推测源于MSCs的miR-106b-25基因簇通过调控FoxO3a对移植肝产生保护作用。本项目拟在前期工作基础上，通过体内外实验探讨miR-106b-25基因簇从MSCs传递至肝细胞的途径、对FoxO3a活性的调控以及在移植肝保护中的作用等，以期发现MSCs减轻移植肝HIRI的新机制，为其临床转化应用提供新的理论依据。

Hepatic ischemia-reperfusion injury (HIRI) is an important cause of liver graft dysfunction. Stem cell therapy shows good prospects. Thus, we believe that it is helpful to significantly improve the therapeutic effect of stem cells through exploring the underlying mechanism of liver graft injury and taking appropriate intervention measures. We have confirmed that the nuclear transcription factor FoxO3a affected liver transplantation-induced organ damage through regulating apoptosis and DNA repair (National Natural Science Foundation of China, No.81571926). We analyzed the results of the gene chip and found that the miR-106b-25 gene cluster derived from mesenchymal stem cells (MSCs) might play an important role in the protection of liver graft. Bioinformatics combined with pretest results showed that miR-106b-25 gene clusters could be transferred to hepatocytes through gap junction or exosomes, and affect the activity of FoxO3a through regulating PI3K/Akt and HIC1/Sirt1 signaling pathways. Therefore, we speculate that the miR-106b-25 gene cluster derived from MSCs can protect the liver graft through regulating FoxO3a. This project is based on our previous studies, which explores the way of miR-106b-25 gene cluster transferring to hepatocytes from MSCs, the mechanism of miR-106b-25 regulating the activity of FoxO3a, and the role of miR-106b-25 in the protection of liver graft, so as to find out a new mechanism of MSCs protecting against HIRI of liver graft, providing new theoretical basis for its clinical transformation and application.