Cell therapy treatment of myocardial infarction (MI) is mediated, in part, by exosomes secreted from transplanted cells. Thus, we compared the efficacy of treatment with a mixture of cardiomyocytes (CMs; 10 million), endothelial cells (ECs; 5 million), and smooth muscle cells (SMCs; 5 million) derived from human induced pluripotent stem cells (hiPSCs), or with exosomes extracted from the three cell types, in pigs after MI. Female pigs received sham surgery; infarction without treatment (MI group); or infarction and treatment with hiPSC-CMs, hiPSC-ECs, and hiPSC-SMCs (MI + Cell group); with homogenized fragments from the same dose of cells administered to the MI + Cell group (MI + Fra group); or with exosomes (7.5 mg) extracted from a 2:1:1 mixture of hiPSC-CMs:hiPSC-ECs:hiPSC-SMCs (MI + Exo group). Cells and exosomes were injected into the injured myocardium. In vitro, exosomes promoted EC tube formation and microvessel sprouting from mouse aortic rings and protected hiPSC-CMs by reducing apoptosis, maintaining intracellular calcium homeostasis, and increasing adenosine 5′-triphosphate. In vivo, measurements of left ventricular ejection fraction, wall stress, myocardial bioenergetics, cardiac hypertrophy, scar size, cell apoptosis, and angiogenesis in the infarcted region were better in the MI + Cell, MI + Fra, and MI + Exo groups than in the MI group 4 weeks after infarction. The frequencies of arrhythmic events in animals from the MI, MI + Cell, and MI + Exo groups were similar. Thus, exosomes secreted by hiPSC-derived cardiac cells improved myocardial recovery without increasing the frequency of arrhythmogenic complications and may provide an acellular therapeutic option for myocardial injury.

心肌梗塞 (MI) 的细胞疗法治疗部分是由移植细胞分泌的外泌体介导的。因此，我们比较了源自人类诱导多能干细胞 (hiPSC) 的心肌细胞 (CM；1000 万)、内皮细胞 (EC；500 万) 和平滑肌细胞 (SMC；500 万) 的混合物的治疗效果，或从三种细胞类型中提取的外泌体，在 MI 后的猪中进行。母猪接受假手术；未经治疗的梗死（心肌梗死组）；或梗塞和用 hiPSC-CM、hiPSC-EC 和 hiPSC-SMC（MI + 细胞组）治疗；将来自相同剂量细胞的均质碎片施用于 MI + 细胞组（MI + Fra 组）；或从 hiPSC-CMs:hiPSC-ECs:hiPSC-SMCs（MI + Exo 组）的 2:1:1 混合物中提取的外泌体（7.5 mg）。将细胞和外泌体注射到受伤的心肌中。在体外，外泌体通过减少细胞凋亡、维持细胞内钙稳态和增加腺苷 5'-三磷酸促进 EC 管形成和从小鼠主动脉环发芽并保护 hiPSC-CM。在体内，MI + Cell、MI + Fra 和 MI + Exo 组的左心室射血分数、壁应力、心肌生物能量学、心脏肥大、瘢痕大小、细胞凋亡和血管生成的测量结果优于 MI + Cell、MI + Fra 和 MI + Exo 组MI组在梗死后4周。MI、MI + Cell 和 MI + Exo 组动物心律失常事件的频率相似。因此，