Hypoxia-challenged MSC-derived exosomes deliver miR-210 to attenuate post-infarction cardiac apoptosis
Hypoxia-challenged MSC-derived exosomes deliver miR-210 to attenuate post-infarction cardiac apoptosis
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DOI：
10.1186/s13287-020-01737-0
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发表时间：
2020-06-08
影响因子：
7.5
通讯作者：
Ma, Jianying
中科院分区：
文献类型：
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作者：
Cheng, Hao;Chang, Shufu;Ma, Jianying
背景心肌梗死(MI)是世界范围内的主要死亡原因。虽然经皮冠状动脉介入治疗和冠状动脉搭桥术可以延长生命，但心脏损伤仍然存在。特别是，心肌细胞没有再生能力。间充质干细胞(MSCs)是治疗心肌梗死的有吸引力的候选细胞。骨髓间充质干细胞对受损细胞发挥有益作用的方式是继续研究的来源。方法分离鉴定骨髓间充质干细胞外切体后，用基因芯片检测miR-210的表达。随后，通过获得和失去功能的方法来检测外体和外体-miR-210在心肌细胞增殖和凋亡中的作用以及体内MI。利用双荧光素酶报告基因系统对miR-210的目的基因进行鉴定。结果我们验证了MSC来源的外切体转导特定的miRNA以保护心肌细胞免于细胞凋亡的假设。有趣的是，在冠状动脉结扎后，直接心脏注射MSC外切体可以缩小梗塞范围并改善心功能。在体外，MSC外切体能增强心肌细胞对低氧的存活。证实了外切体在心肌细胞中摄取。双荧光素酶报告分析表明miR-210是治疗效果的介导物，AIFM3是下游靶点。高表达MSC外切体的miR-210治疗改善了对体外和体内应激的心肌细胞保护。此外，内源性和外源性miR-210具有相同的治疗效果。结论骨髓间充质干细胞外切体移植对心肌梗死后的保护作用至少部分来自于以miR-210为主的外切体的排泄。
Background Myocardial infarction (MI) is a major cause of death worldwide. Although percutaneous coronary intervention and coronary artery bypass grafting can prolong life, cardiac damage persists. In particular, cardiomyocytes have no regenerative capacity. Mesenchymal stem cells (MSCs) are attractive candidates for the treatment of MI. The manner by which MSCs exert a beneficial effect upon injured cells is a source of continued study. Methods After the isolation and identification of exosomes from MSCs, the expression of miR-210 was determined by microarray chip. Subsequently, gain- and loss-function approaches were conducted to detect the role of exosomes and exosomal-miR-210 in cell proliferation and apoptosis of cardiomyocytes, as well as the MI in vivo. Dual-Luciferase Report Gene System was used to demonstrate the target gene of miR-210. Results We tested the hypothesis that MSC-derived exosomes transfer specific miRNA to protect cardiomyocytes from apoptotic cell death. Interestingly, direct cardiac injection of MSC exosomes reduced infarct size and improved heart function after coronary ligation. In vitro, the MSC exosomes enhanced cardiomyocyte survival to hypoxia. Confirmation of exosome uptake in myocytes was confirmed. Dual-luciferase reporter assay implicated miR-210 as a mediator of the therapeutic effect and AIFM3 as a downstream target. Treatment with miR-210 overexpressing MSC exosomes improved myocyte protection to both in vitro and in vivo stress. Furthermore, the endogenous and exogenous miR-210 had the same therapeutic effects. Conclusion These results demonstrated that the beneficial effects offered by MSC-exosomes transplantation after MI are at least partially because of excreted exosome containing mainly miR-210.