MiR-21-5p-enriched exosomes from hiPSC-derived cardiomyocytes exhibit superior cardiac repair efficacy compared to hiPSC-derived exosomes in a murine MI model

Heart disease remains a leading cause of mortality worldwide, with existing treatments often failing to effectively restore damaged myocardium. Human-induced pluripotent stem cells (hiPSCs) and their derivatives offer promising therapeutic options; however, challenges such as low retention, engraftment issues, and tumorigenic risks hinder their clinical utility. Recent focus has shifted to exosomes (exos) - nanoscale vesicles that facilitate intercellular communication - as a safer and more versatile alternative. Understanding the specific mechanisms and comparative efficacy of exos from hiPSCs vs hiPSC-derived cardiomyocytes (hiPSC-CMs) is crucial for advancing cardiac repair therapies. To evaluate and compare the therapeutic efficacy of exos secreted by hiPSCs and hiPSC-CMs in cardiac repair, and to elucidate the role of microRNA 21-5p (miR-21-5p) in the observed effects. We differentiated hiPSCs into CMs using small molecule methods and characterized the cells and their exos. Our findings indicate that hiPSC-CMs and their exos enhanced cardiac function, reduced infarct size, and decreased myocardial fibrosis in a murine myocardial infarction model. Notably, hiPSC-CM exos outperformed hiPSC-CM cell therapy, showing improved ejection fraction and reduced apoptosis. We identified miR-21-5p, a microRNA in hiPSC-CM exos, as crucial for CM survival. Exos with miR-21-5p were absorbed by AC16 cells, suggesting a mechanism for their cytoprotective effects. Overall, hiPSC-CM exos could serve as a potent therapeutic agent for myocardial repair, laying the groundwork for future research into exos as a treatment for ischemic heart disease.