Abstract
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.
Highlights
Coronary artery disease remains the primary cause of death in emerging and developed countries
We analyzed the Extracellular vesicles (EVs) cargo by RNA-seq analysis and we examined for miRNAs that were regulated by hypoxia in parental mesenchymal stromal cells (MSCs)-T
Analysis of absolute copy number of miR-4732-3p per 0.5 × 106 seeded cells was 73.46 ± 119.49 copies in Neonatal rat cardiomyocytes (NRCM) 434.45 ± 134.51 in human umbilical vein endothelial cells (EC) and 595.02 ± 159.38 in rat cardiac fibroblasts. When these cultures were independently subjected to oxygen/glucose deprivation (OGD), the levels of intracellular miR-4732-3p were measured by qPCR and normalized to miRNA levels in cells cultured in standard conditions
Summary
Coronary artery disease remains the primary cause of death in emerging and developed countries. Acute myocardial infarction (AMI), is characterized by the occlusion of a coronary artery, which interrupts blood supply and oxygen and can lead to sudden death (Shao et al, 2020). Cell therapy is gaining traction as a promising alternative to conventional therapies for many diseases, including cardiac tissue repair. In this setting, mesenchymal stromal cells (MSCs) miR-4732 in EVs Mediates Cardioprotection have been investigated in-depth, and are believed to act largely in a paracrine manner (Gnecchi et al, 2005; Armiñán et al, 2010). A particular strength of this approach is that EV-based therapies have fewer safety issues than cell-based therapies, and handling of these biological products is less complex (Zhang et al, 2021)
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