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

Abstract

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.

Human Induced Pluripotent Stem Cell-Derived Exosomes as a New Therapeutic Strategy for Various Diseases

“…These cardioprotective effects were demonstrated to be associated with the delivery of protective miRNA such as Nanog-regulated miR-21 and hypoxia-inducible factor (HIF)-1α-regulated miR-210 to H9C2 cardiomyocytes in vitro. Gao et al [32] demonstrated that exosomes from human induced pluripotent stem cell-derived cardiomyocytes (iCM) also have cardioprotective effects in a swine MI model by the measurement of left ventricular ejection fraction, wall stress, myocardial bioenergetics and cardiac hypertrophy. These exosomes exhibited anti-apoptotic and angiogenic functions.…”

Engineering Human Cardiac Muscle Patch Constructs for Prevention of Post-infarction LV Remodeling

“…These data collectively suggest an alternative mechanism of action, based on paracrine signaling, where cell secreted signals, including extracellular vesicles, mediate cardiac repair via increasing CM survival and neovascularization and decreasing apoptosis and inflammation (206). Paracrine signaling was further evidenced by a study where exosomes secreted from combination of iPSC-derived CMs, ECs, and SMCs yielded cardioprotective effects similar to that obtained from direct cells injection in a porcine model of MI (195). Further, acellular hCMPs composed of non-viable/irradiated cells (39) or decellularized porcine myocardial tissues (139) have shown therapeutic benefits after transplantation, through the proposed mechanism of mechanical stabilization.…”

Stem Cells in Cardiovascular Diseases: 30,000-Foot View

“…Long-term imaging of the patch was not reported. Pre-clinical research from Menasche's lab suggests that many if not all the benefits of this approach might be due to paracrine effects [156].…”

“…Advances are being made in adequate cell isolation; expansion and growth of patches large enough for large animal testing and eventual human use; and adequate maturation of cardiomyocytes into structures that mirror those in native myocardium both structurally and functionally, including excitability and contractility, action potential conduction, calcium handling, and proper cardiomyocyte size and function [154,[157][158][159]. As with many of the findings in the field of cell therapy, much of the improvement observed in several of these studies is felt to be due to cell secretomes, and not a direct action of the cells themselves [156]. An interesting approach to a cell-free patch approach has recently been reported, suggesting that even cellular bioengineering approaches may find clinical application through a cell-free route [160].…”