Neonatal heart tissue-derived EVs alleviate adult ischemic cardiac injury via regulating the function of macrophages and cardiac regeneration in murine models.

Previous studies confirmed the regenerative capacity of the mammalian neonatal heart. We recently found that adult heart tissue-derived EVs can protect the heart from myocardial ischemia-reperfusion (I/R). However, the role of EVs from neonatal heart tissue in cardiac healing post-ischemia remains unclear. In the present study, we revealed that intramyocardial administration of neonatal cardiac tissue-derived EVs (ncEVs) alleviated cardiac inflammation, mitigated reperfusion injury, and improved cardiac function in murine I/R models. In vitro, ncEVs inhibited M1 polarization of macrophages induced by LPS while up-regulated their phagocytic function via the miR-133a-3p-Ash1l signaling pathway. Moreover, the administration of ncEVs contributed to cardiac angiogenesis and improved cardiac function in murine myocardial infarction models. Collectively, these results suggested that neonatal heart-derived EVs can regulate the function of macrophages and contribute to cardiac regeneration and function recovery in murine cardiac ischemic models. Therefore, the derivatives in neonatal heart tissue-derived EVs might serve as a potential therapeutic strategy in ischemic diseases.