骨髓间充质干细胞源外泌体在调节机体胰岛素敏感性中的作用机制研究

The key pathogenesis of Type 2 Diabetes Mellitus (T2DM) is insulin resistance. In the preliminary study, we found the insulin sensitivity of mice is decreased when treated with exosome derived from BMSCs of high-fat diet（HFD) fed mice, and we screened out the key factor miR-29b-3p in the exosome. Based on these findings, we propose a hypothesis that the miR-29b-3p in BMSCs is transmitted to peripheral metabolic organ via secreting of exosome, thus participating in the regulation of insulin sensitivity. To prove this hypothesis, we will construct BMSCs specific miR-29b-1 knockout mice, to explore 1) the effects of exosome derived from BMSCs of HFD-fed miR-29b-1 knockout mice on insulin sensitivity; 2) the roles and underlying mechanisms of BMSCs derived exosome in regulating insulin sensitivity of peripheral metabolic organ; and 3) the effects of inhibition of miR-29b-3p levels in BMSCs derived exosome on insulin sensitivity to HFD fed mice. Together, this study will reveal novel insights to the pathogenesis and treatment of T2DM.

机体胰岛素抵抗是2型糖尿病的核心病理特征。我们前期研究发现，高脂喂养小鼠骨髓间充质干细胞（BMSCs）分泌的外泌体会降低机体胰岛素敏感性，并筛选到外泌体中关键信号因子：miR-29b-3p。因此，我们提出“BMSCs通过分泌外泌体将miR-29b-3p传递到外周代谢性器官进行信号应答，从而参与机体胰岛素敏感性调控”这一假说。为验证此假说，本项目将构建BMSCs特异性miR-29b-1基因敲除小鼠，观察高脂喂养的miR-29b-1基因敲除小鼠BMSCs分泌的外泌体对机体胰岛素敏感性的影响；查明BMSCs分泌的外泌体对外周代谢性器官胰岛素敏感性的影响及机制；并探究降低高脂喂养小鼠BMSCs分泌的外泌体中 miR-29b-3p水平是否可以缓解机体胰岛素抵抗。本项目将为探索2型糖尿病的发病机理与防治策略提供新思路和新的潜在药物靶点。

胰岛素抵抗是2型糖尿病的的主要病理特征，老年人经常会胰岛素抵抗。然而与衰老相关的胰岛素抵抗仍不清楚。在这里，我们展示了骨髓间充质细胞释放的外泌体可被脂肪细胞、肌细胞和肝细胞，产生胰岛素体内和体外抗药性。使用microRNA（miRNA）芯片分析，我们发现miR-29b-3p的量在老年小鼠BMSCs外泌体中是增加的。在机制上，SIRT1（sirtuin 1）被鉴定为作为外泌体miR-29b-3p的下游靶点调节胰岛素抵抗。值得注意的是，利用适配体介导的纳米复合物递送系统降低BMSCs外泌体中miR-29b-3p的水平显著改善了老年小鼠的胰岛素抵抗。同时，骨髓间充质干细胞特异性miR-29b-3p的过表达诱导了年轻小鼠的胰岛素抵抗。综合起来，这些发现表明骨髓间充质干细胞衍生的外泌体miR-29b-3p可以调节衰老相关的胰岛素抵抗，其可作为衰老相关胰岛素抵抗的潜在治疗靶点.