Cardiomyocyte‐derived exosomes promote cardiomyocyte proliferation and neonatal heart regeneration

Abstract Heart regeneration was mainly achieved by intrinsic capacity. Exosomes are crucial in cardiovascular disease, yet their involvement in myocardial regeneration remains underexplored. To understand the role of cardiomyocyte‐derived exosomes (CM‐Exos) in heart regeneration. We established mouse models of myocardial infarction and apical resection in neonates to investigate the potential benefits of exosomes in response to injury. Rab27a knockout (KO) mice were constructed as an exosome decrease model. Distinct fibrosis appears in the infarcted and resection area in the KO mice 21 days after heart injury. The proliferation marker pH 3, Ki67, and Aurora B were detected 3 days after surgery, which decreased in KO mice compared to WT mice. Intravenous injection of CM‐Exos increased cardiomyocyte proliferation and partially restored heart function in KO mice. Rab27a knockdown in vitro reduced the expression of pH 3, Ki67, and Aurora B positive cardiomyocytes. However, the supplementation of CM‐Exos increased the proliferation of cardiomyocytes. Exosomal miRNA sequencing was subsequently applied, and miR‐21‐5p was a promising candidate that promoted cardiomyocyte proliferation through its target genes Spry‐1 and PDCD4. Intravenous injection of miR‐21‐5p exhibited similar proliferative effects as CM‐Exos. Our results indicate that CM‐Exos promotes cardiomyocyte cycle reentry by delivering miR‐21‐5p, highlighting the endogenous factors of myocardial regeneration.