Rationale: Extracellular vesicles (EVs) are tiny membrane-enclosed droplets released by cells through membrane budding or exocytosis. The myocardial reparative abilities of EVs derived from induced pluripotent stem cells (iPSCs) have not been directly compared with the source iPSCs.

Objective: To examine whether iPSC-derived EVs can influence the biological functions of cardiac cells in vitro and to compare the safety and efficacy of iPSC-derived EVs (iPSC-EVs) and iPSCs for cardiac repair in vivo.

Methods and Results: Murine iPSCs were generated, and EVs isolated from culture supernatants by sequential centrifugation. Atomic force microscopy, high-resolution flow cytometry, real-time quantitative RT-PCR, and mass spectrometry were used to characterize EV morphology and contents. iPSC-EVs were enriched in miRNAs and proteins with proangiogenic and cytoprotective properties. iPSC-EVs enhanced angiogenic, migratory, and antiapoptotic properties of murine cardiac endothelial cells in vitro. To compare the cardiac reparative capacities in vivo, vehicle, iPSCs, and iPSC-EVs were injected intramyocardially at 48 hours after a reperfused myocardial infarction in mice. Compared with vehicle-injected mice, both iPSC- and iPSC-EV–treated mice exhibited improved left ventricular function at 35 d after myocardial infarction, albeit iPSC-EVs rendered greater improvement. iPSC-EV injection also resulted in reduction in left ventricular mass and superior perfusion in the infarct zone. Both iPSCs and iPSC-EVs preserved viable myocardium in the infarct zone, whereas reduction in apoptosis was significant with iPSC-EVs. iPSC injection resulted in teratoma formation, whereas iPSC-EV injection was safe.

Conclusions: iPSC-derived EVs impart cytoprotective properties to cardiac cells in vitro and induce superior cardiac repair in vivo with regard to left ventricular function, vascularization, and amelioration of apoptosis and hypertrophy. Because of their acellular nature, iPSC-EVs represent a safer alternative for potential therapeutic applications in patients with ischemic myocardial damage.

原理：细胞外囊泡（EVs）是细胞通过膜芽或胞吐作用释放的微小的膜包裹液滴。诱导多能干细胞（iPSC）衍生的EV的心肌修复能力尚未与来源iPSC进行直接比较。

目的：探讨源自iPSC的电动汽车是否能在体外影响心脏细胞的生物学功能，并比较源自iPSC的电动汽车（iPSC-EV）和iPSC在体内进行心脏修复的安全性和有效性。

方法和结果：产生小鼠iPSC，并通过连续离心从培养上清液中分离出EV。使用原子力显微镜，高分辨率流式细胞仪，实时定量RT-PCR和质谱法来表征EV的形态和含量。iPSC-EV富含具有促血管生成和细胞保护特性的miRNA和蛋白质。iPSC-EVs在体外增强了小鼠心脏内皮细胞的血管生成，迁移和抗凋亡特性。为了比较体内的心脏修复能力，在小鼠再灌注心肌梗死后48小时，在心肌内注射媒介物，iPSC和iPSC-EV。与注射媒介物的小鼠相比，iPSC和iPSC-EV治疗的小鼠在心肌梗死后35 d均表现出改善的左心室功能，尽管iPSC-EV表现出更大的改善。iPSC-EV注射还导致了左心室质量的减少和梗死区的良好灌注。iPSC和iPSC-EV均可在梗塞区中保存存活的心肌，而iPSC-EV则可显着降低细胞凋亡。iPSC注射导致畸胎瘤形成，而iPSC-EV注射是安全的。

结论：源自iPSC的EV在体外对心肌细胞具有细胞保护特性，并在体内在左心室功能，血管形成以及凋亡和肥大的改善方面诱导了出色的心脏修复。由于其无细胞特性，iPSC-EV代表了缺血性心肌损伤患者潜在治疗应用的更安全选择。