Research ArticleMyocardial Infarction

Small extracellular vesicles containing miR-486-5p promote angiogenesis after myocardial infarction in mice and nonhuman primates

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Science Translational Medicine  10 Mar 2021:
Vol. 13, Issue 584, eabb0202
DOI: 10.1126/scitranslmed.abb0202

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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.

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