人脐带间充质干细胞来源凋亡小体通过AMPK/TFEB自噬通路改善猪心肌梗死恢复

Abstract

Apoptotic bodies (ABs) are a type of extracellular vesicles (EVs) that could contribute to the paracrine effect of stem cells. However, their potential in treating cardiovascular diseases is largely unexplored. This study investigated the therapeutic effects of ABs derived from human umbilical cord mesenchymal stem cells (MSCs) on cardiac recovery in a porcine model of myocardial infarction (MI). In vitro, ABs reduced apoptosis and cytotoxicity in cardiomyocytes under oxygen and glucose deprivation (OGD) conditions and enhanced the capacity of migration and tube formation in endothelial cells. In vivo, akin to MSCs, administration of ABs improved contractile function, reduced infarct size, and mitigated adverse remodeling in pig hearts with MI, concomitantly with increased cardiomyocyte survival and angiogenesis. These cardioprotective effects were mediated through the regulation of autophagy by activating the adenosine monophosphate – activated protein kinase (AMPK) and transcription factor EB (TFEB) signaling pathways. microRNAs contained in ABs were sequenced, revealing that let-7f-5p was the most abundant. let-7f-5p promoted AMPK phosphorylation by targeting protein phosphatase 2 regulatory subunit B alpha (PPP2R2A) and decreased TFEB phosphorylation by targeting MAP4K3 to regulate autophagy, thereby contributing to the effects of ABs. Overall, these findings indicate that MSC-derived ABs have the potential to be a promising and effective acellular therapeutic option for treating MI.