MiR-10a对人骨髓间充质干细胞衰老、凋亡、分化及治疗心梗的影响及意义

The age of the donor is a key factor related to the function of human mesenchymal stem cells (hMSCs) and the expression levels of microRNAs (miRNAs). However, data reported on aging-related changes in miRNAs in hMSC senescence, apoptosis,differentiation are limited. In our previous published paper, we have demonstrated that miR-10a is significant decreased in aged hMSCs compared with that of the young hMSCs. We found that correcting the levels of miR-10a can restore the differentiate ability of aged hMSCs. In addition, miR-10a can decrease cell senescence of aged hMSCs. In our recent preliminary study, we identified that miR-10a can decrease hypoxia-induced cell apoptosis; potentiate the differentiation ability of aged-hMSCs to cardiomyocyte. Furthermore, transplantation of miR-10a pre-treated aged-hMSCs improve the heart function after myocardial infarction. We postulate that miR-10a may facilitate all the beneficial effects through repressing the expression of KLF4 and the subsequent Bax/Bcl-2-caspase-3 pathway. The aim of the current proposal is to elucidate the molecular mechanisms of miR-10a responsible for promoting aged-hMSCs regeneration through the in vitro model of hypoxia-induced cell apoptosis and in vivo model of myocardial infarction in mice. This study can provide fundimental knowledge for stem cell therapy and miRNAs clinical application.

人骨髓间充质干细胞（human mesenchymal stem cells, hMSCs）的功能及microRNAs的表达受年龄因素的影响。而年龄因素引起表达发生改变的microRNAs对hMSCs衰老、凋亡、分化的调控机制仍不明确。前期我们已经发表文章报道：随供体年龄增加，hMSCs中miR-10a的表达下降最明显，并且可以促进hMSCs分化；减少hMSCs衰老。近期预实验我们发现：miR-10a可减少低氧刺激的hMSCs细胞凋亡；促进hMSCs向心肌细胞分化；促进hMSCs改善心梗后心脏功能。进一步研究发现，miR-10a可能通过抑制Kruppel样因子4(KLF4)及Bax/Bcl-2-caspase-3发挥调控作用。本项目将承前启后，通过细胞缺氧和小鼠心梗模型，证实miR-10a的调控作用；阐明其在心梗治疗中的意义，为microRNAs及hMSCs的临床运用提供新的理论依据。

年龄是影响人骨髓间充质干细胞（human mesenchymal stem cells, hMSCs）功能及其相关microRNA表达的关键因素之一。然而年龄相关microRNA对hMSCs功能调控作用的研究机制尚不明确。我们的前期研究发现，随供体年龄增加，hMSCs中miR-10a的表达明显下降；在hMSCs中过表达miR-10a，可通过抑制KLF4的表达，减少hMSCs衰老，促进hMSCs分化。本研究，体外实验我们发现miR-10a可通过KLF4-BAX/BCL2信号通路，减少年老hMSCs在缺氧条件下的细胞凋亡，促进细胞存活。体内研究证实，过表达10a可促进年老hMSCs在心梗后小鼠心脏的存活，并改善小鼠心脏功能。机制研究证实，过表达miR-10a可激活年老hMSCs的Akt信号通路,促进年老hMSCs在缺血小鼠心脏中分泌促血管生成因子。我们的研究证实，miR-10a可再生年老hMSCs功能，改善心梗后小鼠心脏功能。