Journal
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
Volume 9, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fcell.2021.734143
Keywords
extracellular vesicles; mesenchymal stromal (stem) cell (MSC); miR-4732-3p; angiogenesis; myocardial infarction; fibrosis; cardiac function analysis
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Funding
- Instituto de Salud Carlos III [PI19/0245, RD16/0011/0004]
- FEDER Una manera de hacer Europa
- Conselleria de Sanitat Universal i Salut Publica [ACIF/2017/318, ACIF/2018/254, ACIF2019/257, ACIF2019/250]
- European Union through the Operational Programme European Regional Development Fund (FEDER) of the Valencian Community 2014-2020.
- Agencia Valenciana de la Innovacion [INNCON-2020-6-CARVEMO]
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Extracellular vesicles derived from mesenchymal stromal cells (MSCs) and containing miR-4732-3p microRNA show potential for cardioprotection, with miR-4732-3p being regulated by hypoxia and exerting protective actions against ischemic insult.
Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) are an emerging alternative to cell-based therapies to treat many diseases. However, the complexity of producing homogeneous populations of EVs in sufficient amount hampers their clinical use. To address these limitations, we immortalized dental pulp-derived MSC using a human telomerase lentiviral vector and investigated the cardioprotective potential of a hypoxia-regulated EV-derived cargo microRNA, miR-4732-3p. We tested the compared the capacity of a synthetic miR-4732-3p mimic with EVs to confer protection to cardiomyocytes, fibroblasts and endothelial cells against oxygen-glucose deprivation (OGD). Results showed that OGD-induced cardiomyocytes treated with either EVs or miR-4732-3p showed prolonged spontaneous beating, lowered ROS levels, and less apoptosis. Transfection of the miR-4732-3p mimic was more effective than EVs in stimulating angiogenesis in vitro and in vivo and in reducing fibroblast differentiation upon transforming growth factor beta treatment. Finally, the miR-4732-3p mimic reduced scar tissue and preserved cardiac function when transplanted intramyocardially in infarcted nude rats. Overall, these results indicate that miR-4732-3p is regulated by hypoxia and exerts cardioprotective actions against ischemic insult, with potential application in cell-free-based therapeutic strategies.
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