Exosomes secreted by hiPSC-derived cardiac cells improve recovery from myocardial infarction in swine.

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.