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Exosomes are crucial in cardiovascular disease, yet their involvement in myocardial regeneration remains underexplored. To understand the role of cardiomyocyte\u2010derived exosomes (CM\u2010Exos) 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\u2009days after heart injury. The proliferation marker pH\u20093, Ki67, and Aurora B were detected 3\u2009days after surgery, which decreased in KO mice compared to WT mice. Intravenous injection of CM\u2010Exos increased cardiomyocyte proliferation and partially restored heart function in KO mice. Rab27a knockdown in\u00a0vitro reduced the expression of pH\u20093, Ki67, and Aurora B positive cardiomyocytes. However, the supplementation of CM\u2010Exos increased the proliferation of cardiomyocytes. Exosomal miRNA sequencing was subsequently applied, and miR\u201021\u20105p was a promising candidate that promoted cardiomyocyte proliferation through its target genes Spry\u20101 and PDCD4. Intravenous injection of miR\u201021\u20105p exhibited similar proliferative effects as CM\u2010Exos. Our results indicate that CM\u2010Exos promotes cardiomyocyte cycle reentry by delivering miR\u201021\u20105p, highlighting the endogenous factors of myocardial regeneration.<\/jats:p>","DOI":"10.1096\/fj.202400737rr","type":"journal-article","created":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T06:36:43Z","timestamp":1731998203000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Cardiomyocyte\u2010derived exosomes promote cardiomyocyte proliferation and neonatal heart regeneration"],"prefix":"10.1096","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2789-0034","authenticated-orcid":false,"given":"Jielei","family":"Gu","sequence":"first","affiliation":[{"name":"Guangdong Key Laboratory of Vascular Diseases, Guangzhou Institute of Cardiovascular Disease The Second Affiliated Hospital, Guangzhou Medical University  Guangzhou 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