Endogenous capability of the post-mitotic human heart holds great promise to restore the injured myocardium. Recent evidence indicates that the extracellular vesicles (EVs) regulate cardiac homeostasis and regeneration. Here, we investigated the molecular mechanism of EVs for self-repair. We isolated EVs from human iPSC-derived cardiomyocytes (iCMs), which were exposed to hypoxic (hEVs) and normoxic conditions (nEVs), and examined their roles in in vitro and in vivo models of cardiac injury. hEV treatment significantly improved the viability of hypoxic iCMs in vitro and cardiac function of severely injured murine myocardium in vivo. Microarray analysis of the EVs revealed significantly enriched expression of the miR-106a–363 cluster (miR cluster) in hEVs vs. nEVs. This miR cluster preserved survival and contractility of hypoxia-injured iCMs and maintained murine left-ventricular (LV) chamber size, improved LV ejection fraction, and reduced myocardial fibrosis of the injured myocardium. RNA-Seq analysis identified Jag1-Notch3-Hes1 as a target intracellular pathway of the miR cluster. Moreover, the study found that the cell cycle activator and cytokinesis genes were significantly up-regulated in the iCMs treated with miR cluster and Notch3 siRNA. Together, these results suggested that the miR cluster in the EVs stimulated cardiomyocyte cell cycle re-entry by repressing Notch3 to induce cell proliferation and augment myocardial self-repair. The miR cluster may represent an effective therapeutic approach for ischemic cardiomyopathy.

有丝分裂后的人类心脏的内源性能力有望恢复受损的心肌。最近的证据表明细胞外囊泡（EV）调节心脏稳态和再生。在这里，我们研究了电动汽车自我修复的分子机制。我们从暴露于缺氧（hEV）和常氧条件（nEV）的人 iPSC 衍生心肌细胞（iCM）中分离出 EV，并检查了它们在体外和体内心脏损伤模型中的作用。 hEV治疗显着改善了体外缺氧iCM的活力和体内严重损伤的小鼠心肌的心脏功能。 EV 的微阵列分析显示，与 nEV 相比，hEV 中 miR-106a-363​​ 簇（miR 簇）的表达显着富集。该 miR 簇保留了缺氧损伤的 iCM 的存活和收缩性，并维持了小鼠左心室 (LV) 室的大小，改善了 LV 射血分数，并减少了受损心肌的心肌纤维化。 RNA-Seq 分析确定Jag1-Notch3-Hes1是 miR 簇的靶细胞内通路。此外，研究发现，在用 miR 簇和 Notch3 siRNA 处理的 iCM 中，细胞周期激活剂和胞质分裂基因显着上调。总之，这些结果表明，EV 中的 miR 簇通过抑制 Notch3 刺激心肌细胞细胞周期重新进入，从而诱导细胞增殖并增强心肌自我修复。 miR簇可能代表了缺血性心肌病的有效治疗方法。