Ischemic Preconditioning Potentiates the Protective Effect of Stem Cells through Secretion of Exosomes by Targeting Mecp2 via miR-22

Mesenchymal stem cells (MSCs) have potential application for the treatment of ischemic heart diseases. Besides differentiation properties, MSCs protect ischemic cardiomyocytes by secretion of paracrine factors. In this study, we found exosomes enriched with miR-22 were secreted by MSCs following ischemic preconditioning (ExoIPC) and mobilized to cardiomyocytes where they reduced their apoptosis due to ischemia. Interestingly, by time-lapse imaging, we for the first time captured the dynamic shedding of miR-22 loaded exosomes from cytosol to extracellular space. Furthermore, the anti-apoptotic effect of miR-22 was mediated by direct targeting of methyl CpG binding protein 2 (Mecp2). In vivo data showed that delivery of ExoIPC significantly reduced cardiac fibrosis. Our data identified a significant benefit of ExoIPC for the treatment of cardiac diseases by targeting Mecp2 via miR-22.

间充质干细胞（Mesenchymal stem cells, MSCs）在缺血性心脏病的治疗中具备潜在应用价值。除分化特性外，MSCs还可通过分泌旁分泌因子对缺血心肌细胞发挥保护作用。本研究发现，经缺血预处理的MSCs会分泌富集miR-22的外泌体（exosomes，以下简称ExoIPC），并被转运至心肌细胞中，进而减轻缺血诱导的心肌细胞凋亡。值得关注的是，本研究通过延时成像首次捕捉到了负载miR-22的外泌体从胞质向细胞外间隙动态释放的过程。进一步研究表明，miR-22的抗凋亡作用是通过直接靶向甲基CpG结合蛋白2（methyl CpG binding protein 2, Mecp2）实现的。体内实验数据显示，递送ExoIPC可显著减轻心脏纤维化。综上，本研究证实ExoIPC可通过miR-22靶向Mecp2，为心脏疾病的治疗带来显著获益。