Small extracellular vesicles containing miR-486-5p promote angiogenesis after myocardial infarction in mice and nonhuman primates
Small extracellular vesicles containing miR-486-5p promote angiogenesis after myocardial infarction in mice and nonhuman primates
复制标题
含有 miR-486-5p 的小细胞外囊泡促进小鼠和非人灵长类动物心肌梗死后的血管生成
DOI：
10.1126/scitranslmed.abb0202
复制
发表时间：
2021-03-10
影响因子：
17.1
通讯作者：
Hu, Xinyang
中科院分区：
文献类型：
--
作者：
Li, Qingju;Xu, Yinchuan;Hu, Xinyang
含有miR-486- 5 p的细胞外囊泡通过靶向成纤维细胞Mmp 19增强小鼠和非人灵长类动物MI后的血管生成。通过增强血管生成克服梗死促进心肌梗死后血管生长是保护存活心肌组织和改善心脏功能的一种策略。在这里，Li等人研究了在常氧或缺氧条件下预处理的间充质干细胞（MSC）产生的细胞外囊泡（EV）中含有的microRNA。他们专注于miR-486- 5 p，其在来自缺氧预处理的MSC的EV中上调，并且下调成纤维细胞中的基质金属蛋白酶19，减少细胞外血管内皮生长因子的切割，并促进血管生成。用含miR-486- 5 p的EV治疗的啮齿动物和非人灵长类动物MI模型显示出较小的梗死和改善的心脏功能，而不增加心律失常。结果突出了这种miRNA在MI后增强血管生成中的作用。干细胞衍生的小细胞外囊泡（sEV）促进心肌梗死（MI）后的血管生成。然而，导致这些效应的sEV组分以及工程sEV治疗MI的安全性和有效性仍未得到解决。在这里，我们观察到用来自低氧预处理（HP）间充质干细胞（MSC）的sEV（HP-sEV）处理的小鼠的心脏功能改善，血管密度增加，并且比用常氧预处理（N）MSC（N-sEV）处理的小鼠的梗死面积更小。microRNA分析显示，HP-sEV中miR-486- 5 p的丰度高于N-sEV，miR-486- 5 p失活消除了HP-sEV治疗的益处，而miR-486- 5 p上调增强了N-sEV治疗的益处。HP-sEV处理的小鼠心脏中基质金属蛋白酶19（MMP 19）丰度低于N-sEV处理的小鼠心脏，但在心脏成纤维细胞（CF）中富集，并且Mmp 19被鉴定为miR-486- 5 p的靶基因之一。来自过表达miR-486- 5 p或沉默MMP 19的CF的条件培养基增加了内皮细胞的血管生成活性;然而，来自同时过表达Mmp 19和miR-486- 5 p的CF的培养基消除了这种作用。CF中Mmp 19沉默减少了细胞外血管内皮生长因子（VEGF）的切割。此外，在非人灵长类动物（NHP）MI模型中，miR-486- 5 p过表达的N-sEV治疗促进了血管生成和心脏恢复，而不增加心律失常并发症。总的来说，这项研究强调了sEV miR-486- 5 p通过成纤维细胞MMP 19-VEGFA切割信号在促进心脏血管生成中的关键作用。在NHP MI模型中，递送miR-486- 5 p工程改造的sEV安全地增强了血管生成和心脏功能，并可能促进心脏修复。
Extracellular vesicles containing miR-486-5p augment angiogenesis after MI in mice and nonhuman primates by targeting fibroblastic Mmp19. Overcoming infarction by augmenting angiogenesis Promoting blood vessel growth after myocardial infarction is one strategy to preserve viable myocardial tissue and improve heart function. Here, Li et al. studied the microRNAs contained in extracellular vesicles (EVs) produced from mesenchymal stem cells (MSCs) preconditioned under normoxia or hypoxia. They focused on miR-486-5p, which was up-regulated in EVs from hypoxia-preconditioned MSCs and which down-regulated matrix metalloproteinase 19 in fibroblasts, reduced cleavage of extracellular vascular endothelial growth factor, and promoted angiogenesis. Rodent and nonhuman primate models of MI treated with miR-486-5p–containing EVs showed smaller infarcts and improved cardiac function without increased arrhythmia. Results highlight the role of this miRNA in augmenting angiogenesis after MI. Stem cell–derived small extracellular vesicles (sEVs) promote angiogenesis after myocardial infarction (MI). However, the components of sEVs that contribute to these effects and the safety and efficiency of engineered sEV treatment for MI remain unresolved. Here, we observed improved cardiac function, enhanced vascular density, and smaller infarct size in mice treated with the sEVs from hypoxia-preconditioned (HP) mesenchymal stem cells (MSCs) (HP-sEVs) than in mice treated with normoxia-preconditioned (N) MSCs (N-sEVs). MicroRNA profiling revealed a higher abundance of miR-486-5p in HP-sEVs than in N-sEVs, and miR-486-5p inactivation abolished the benefit of HP-sEV treatment, whereas miR-486-5p up-regulation enhanced the benefit of N-sEV treatment. Matrix metalloproteinase 19 (MMP19) abundance was lower in HP-sEV–treated than N-sEV–treated mouse hearts but was enriched in cardiac fibroblasts (CFs), and Mmp19 was identified as one of the target genes of miR-486-5p. Conditioned medium from CFs that overexpressed miR-486-5p or silenced MMP19 increased the angiogenic activity of endothelial cells; however, medium from CFs that simultaneously overexpressed Mmp19 and miR-486-5p abolished this effect. Mmp19 silencing in CFs reduced the cleavage of extracellular vascular endothelial growth factor (VEGF). Furthermore, miR-486-5p–overexpressing N-sEV treatment promoted angiogenesis and cardiac recovery without increasing arrhythmia complications in a nonhuman primate (NHP) MI model. Collectively, this study highlights the key role of sEV miR-486-5p in promoting cardiac angiogenesis via fibroblastic MMP19-VEGFA cleavage signaling. Delivery of miR-486-5p–engineered sEVs safely enhanced angiogenesis and cardiac function in an NHP MI model and may promote cardiac repair.