1. Pleiotropic effects of extracellular vesicles from induced pluripotent stem cell-derived cardiomyocytes on ischemic cardiomyopathy: A preclinical study.
- Author
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Tominaga Y, Kawamura T, Ito E, Takeda M, Harada A, Torigata K, Sakaniwa R, Sawa Y, and Miyagawa S
- Subjects
- Rats, Animals, Myocytes, Cardiac, Endothelial Cells metabolism, Induced Pluripotent Stem Cells, Extracellular Vesicles metabolism, MicroRNAs genetics, Myocardial Infarction therapy, Cardiomyopathies
- Abstract
Background: Stem cell-secreted extracellular vesicles (EVs) play essential roles in intercellular communication and restore cardiac function in animal models of ischemic heart disease. However, few studies have used EVs derived from clinical-grade stem cells and their derivatives with stable quality. Moreover, there is little information on the mechanism and time course of the multifactorial effect of EV therapy from the acute to the chronic phase, the affected cells, and whether the effects are direct or indirect., Methods: Induced pluripotent stem cell-derived cardiomyocytes (iPSCM) were produced using a clinical-grade differentiation induction system. EVs were isolated from the conditioned medium by ultracentrifugation and characterized in silico, in vitro, and in vivo. A rat model of myocardial infarction was established by left anterior descending artery ligation and treated with iPSCM-derived EVs., Results: iPSCM-derived EVs contained microRNAs and proteins associated with angiogenesis, antifibrosis, promotion of M2 macrophage polarization, cell proliferation, and antiapoptosis. iPSCM-derived EV treatment improved left ventricular function and reduced mortality in the rat model by improving vascularization and suppressing fibrosis and chronic inflammation in the heart. EVs were uptaken by cardiomyocytes, endothelial cells, fibroblasts, and macrophages in the cardiac tissues. The pleiotropic effects occurred due to the direct effects of microRNAs and proteins encapsulated in EVs and indirect paracrine effects on M2 macrophages., Conclusions: Clinical-grade iPSCM-derived EVs improve cardiac function by regulating various genes and pathways in various cell types and may have clinical potential for treating ischemic heart disease., Competing Interests: Disclosure statement The authors declare no competing interests. This research was supported by the Japan Society for the Promotion of Science KAKENHI Grant (21K19528) and the Japan Agency for Medical Research and Development (AMED) Program Grant (JP22ym0126809)., (Copyright © 2023 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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