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Small extracellular vesicles containing miR-486-5p promote angiogenesis after myocardial infarction in mice and nonhuman primates
- Source :
- Science translational medicine. 13(584)
- Publication Year :
- 2020
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 19466242
- Volume :
- 13
- Issue :
- 584
- Database :
- OpenAIRE
- Journal :
- Science translational medicine
- Accession number :
- edsair.doi.dedup.....f5f708644469dafd466834ad8e7b3241