Exosomal miR-21a-5p mediates cardioprotection by mesenchymal stem cells
Exosomal miR-21a-5p mediates cardioprotection by mesenchymal stem cells
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DOI：
10.1016/j.yjmcc.2018.04.012
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发表时间：
2018-06-01
影响因子：
5
通讯作者：
Jones, W. Keith
中科院分区：
文献类型：
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作者：
Luther, Kristin M.;Haar, Lauren;Jones, W. Keith
虽然是实验性的，但干细胞移植有可能改善心肌梗死后的心脏状况。它通过减少梗死面积和诱导心肌及其血液供应的修复来实现。间充质干细胞（MSC）在临床前动物模型和临床试验中已被发现是有效的，但它们诱导心脏保护和修复的机制仍不完全清楚。被称为外泌体的小细胞外囊泡现在被认为是有益MSC旁分泌效应的关键介质，并且它们转移miRNA以改变受体细胞中的基因表达的概念是当前的治疗兴趣。我们对MSC外泌体货物进行了完整的深度miRNA测序，发现在几种心脏保护性miRNA中，miR-21 a-5 p是最丰富的。由于miR-21 a-5 p是一种众所周知的心脏保护性miRNA，我们研究了MSC外泌体可以通过增加受体心脏细胞中miR-21 a-5 p的水平来保护心脏的假设，从而下调心肌中促凋亡基因产物PDCD 4、PTEN、Peli 1和FasL的表达。我们证实了外泌体miR-21 a-5 p被转移到心肌中，并且是由MSC产生的主要的心脏保护性旁分泌因子，其通过在多个途径上的协同活性起作用。数据支持残余的心脏保护作用可能是由于其他ncRNA或蛋白质货物。计算机模拟分析支持MSC外泌体也可能有助于血管生成、细胞增殖和心脏修复的其他方面。
Though experimental, stem cell transplantation has the potential to improve the condition of the heart after myocardial infarction. It does so by reducing infarct size and inducing repair of heart muscle and its blood supply. Mesenchymal stem cells (MSC) have been found to be effective in pre-clinical animal models and clinical trials, but the mechanisms by which they induce cardioprotection and repair are still not fully understood Small extracellular vesicles known as exosomes are now recognized to be key mediators of beneficial MSC paracrine effects, and the concept that they transfer miRNA to change gene expression in recipient cells is of current therapeutic interest. We present complete deep miRNA sequencing of MSC exosome cargo, and found that of several cardioprotective miRNAs, miR-21a-5p was the most abundant. Because miR-21a-5p is a well-known cardioprotective miRNA, we investigated the hypothesis that MSC exosomes can cardioprotect the heart by increasing the level of miR-21a-5p in recipient cardiac cells, thereby downregulating expression of the proapoptotic gene products PDCD4, PTEN, Peli1 and FasL in the myocardium Using miR-21 mimic transfection and treatment with wild type and miR-21a knockout MSC exosomes, we confirmed that exosomal miR-21a-5p is transferred into myocardium and is a major cardioprotective paracrine factor produced by MSCs acting via synergistic activity on multiple pathways. The data supports that residual cardioprotective effect may be due to other ncRNA or protein cargo. In silico analyses support that MSC exosomes may also contribute to angiogenesis, cell proliferation and other aspects of cardiac repair.