Wallace H. Coulter Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology, Atlanta, GA 30322, USA.
Department of Molecular Science and Technology, Ajou University, Suwon 16499, South Korea.
Sci Adv. 2023 Mar 3;9(9):eabo4616. doi: 10.1126/sciadv.abo4616.
Small extracellular vesicles (sEVs) play a critical role in cardiac cell therapy by delivering molecular cargo and mediating cellular signaling. Among sEV cargo molecule types, microRNA (miRNA) is particularly potent and highly heterogeneous. However, not all miRNAs in sEV are beneficial. Two previous studies using computational modeling identified miR-192-5p and miR-432-5p as potentially deleterious in cardiac function and repair. Here, we show that knocking down miR-192-5p and miR-432-5p in cardiac c-kit cell (CPC)-derived sEVs enhances the therapeutic capabilities of sEVs in vitro and in a rat in vivo model of cardiac ischemia reperfusion. miR-192-5p- and miR-432-5p-depleted CPC-sEVs enhance cardiac function by reducing fibrosis and necrotic inflammatory responses. miR-192-5p-depleted CPC-sEVs also enhance mesenchymal stromal cell-like cell mobilization. Knocking down deleterious miRNAs from sEV could be a promising therapeutic strategy for treatment of chronic myocardial infarction.
细胞外小泡 (sEVs) 通过传递分子货物和介导细胞信号在心脏细胞治疗中发挥关键作用。在 sEV 货物分子类型中，微小 RNA (miRNA) 特别有效且高度异质。然而，并非所有 sEV 中的 miRNA 都是有益的。之前的两项使用计算模型的研究表明，miR-192-5p 和 miR-432-5p 在心脏功能和修复方面可能具有潜在的危害性。在这里，我们表明，敲低心脏 c-kit 细胞 (CPC) 衍生的 sEV 中的 miR-192-5p 和 miR-432-5p 可增强 sEV 在体外和大鼠心肌缺血再灌注体内模型中的治疗能力。miR-192-5p 和 miR-432-5p 耗尽的 CPC-sEV 通过减少纤维化和坏死性炎症反应来增强心脏功能。miR-192-5p 耗尽的 CPC-sEV 还增强间充质基质细胞样细胞的动员。从 sEV 中敲除有害 miRNA 可能是治疗慢性心肌梗死的一种有前途的治疗策略。
