Apoptotic bodies derived from human umbilical cord mesenchymal stem cells improve recovery from myocardial infarction in swine

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.凋亡小体（Apoptotic bodies, ABs）是一类细胞外囊泡（extracellular vesicles, EVs），可介导干细胞的旁分泌效应。然而其在心血管疾病治疗中的潜力尚未得到充分探索。本研究探究了人脐带间充质干细胞（MSCs）来源的凋亡小体对心肌梗死（myocardial infarction, MI）猪模型心脏功能恢复的治疗作用。体外实验中，凋亡小体可减轻氧糖剥夺（OGD）环境下心肌细胞的凋亡与细胞毒性，并增强内皮细胞的迁移及管腔形成能力。体内实验中，与间充质干细胞类似，输注凋亡小体可改善心肌梗死模型猪的心脏收缩功能、缩小梗死面积并减轻不良心脏重构，同时可提高心肌细胞存活率与血管生成水平。上述心脏保护作用通过调控细胞自噬实现：其可激活腺苷酸活化蛋白激酶（AMPK）与转录因子EB（TFEB）信号通路。研究人员对凋亡小体所含的微小RNA（miRNAs）进行测序，发现let-7f-5p含量最为丰富。let-7f-5p可通过靶向蛋白磷酸酶2调节亚基Bα（PPP2R2A）促进AMPK磷酸化，并通过靶向MAP4K3降低TFEB磷酸化，从而调控细胞自噬，进而介导凋亡小体的上述治疗效应。综上，本研究结果表明，人脐带间充质干细胞来源的凋亡小体有望成为治疗心肌梗死的一种极具应用前景的有效无细胞治疗方案。