Small extracellular vesicles containing miR-486-5p promote angiogenesis after myocardial infarction in mice and nonhuman primates
| Autor: | Xinyang Hu, Shuhan Zhong, Wei Zhu, Dan Zhu, Rongrong Wu, Keyang Zhu, Jingyi Wang, Youqi Fan, Yingchao Wang, Reza Ardehali, Jing Zhao, Qingju Li, Yinchuan Xu, Cheng Ni, Jinyun Zhu, Yi Li, Yongjian Chen, Jian-an Wang, Jinghai Chen, Xuebiao Li, Changchen Xiao, Kaiqi Lv, Hong Yu, Zhiwei Zhong, Minjian Kong, Chengjia Liu, Qian Li, Fengjiang Zhang, Kan Wang, Jianyi Jay Zhang, Qi Chen |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cardiac function curve Primates Vascular Endothelial Growth Factor A Angiogenesis viruses Myocardial Infarction 030204 cardiovascular system & hematology Matrix metalloproteinase 03 medical and health sciences chemistry.chemical_compound Extracellular Vesicles Mice 0302 clinical medicine Extracellular Medicine Animals business.industry Mesenchymal stem cell virus diseases Endothelial Cells General Medicine respiratory system Vascular endothelial growth factor Vascular endothelial growth factor A MicroRNAs 030104 developmental biology chemistry Cancer research business MMP19 |
| Zdroj: | Science translational medicine. 13(584) |
| ISSN: | 1946-6242 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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