miR-4732-3p in Extracellular Vesicles From Mesenchymal Stromal Cells Is Cardioprotective During Myocardial Ischemia

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.

Mining the Mesenchymal Stromal Cell Secretome in Patients with Chronic Left Ventricular Dysfunction

“…In the setting of cardiac infarct, microRNA-containing EXO-MSCs regulate immune cell activation and inflammation [22] while also mitigating the effects of hypoxia-induced apoptosis [23]. Specifically, miR-4732-3p, which was upregulated among the improver cohort in this study, exerts protection through its effects on various cardiac cell types, limiting fibrosis, enhancing angiogenesis, and insulating cardiomyocytes against reactive oxygen species and cell death [24].…”

Space flight associated changes in astronauts’ plasma‐derived small extracellular vesicle microRNA: Biomarker identification

“…Further, miR-4732-3p is upregulated in mesenchymal stro-mal cell-derived sEVs following oxygen-glucose deprivation and contributes to cardioprotection via reduction of apoptosis and levels of reactive oxygen species. 10 Further longitudinal studies using samples from a larger astronaut cohort with paired clinical data are warranted to validate the utility of miR-4732-3p as a potential biomarker for monitoring astronauts' health.…”

From cerebral ischemia towards myocardial, renal, and hepatic ischemia: Exosomal miRNAs as a general concept of intercellular communication in ischemia-reperfusion injury

“… 106 , 107 Exosomes, in the meantime, could be taken up by neighboring or distant myocardial cells, given their various targets, which they modulate by posttranscriptional regulation of gene expression; miRNAs loaded into exosomes are potent repair factors. 108 There is increasing evidence that miRNAs are selectively enriched in exosomes, exerting biological functions via modulating specific aspects of myocardial ischemia and, as such, participating in cardiomyocyte survival, cardiac functional recovery, inflammatory responses, and angiogenesis, 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 as indicated in Table 2 and Figure 4 and further discussed in the following sections.…”

“…As such, a series of miRNAs were shuttled via exosomes, including miR-21, miR-98-5p, miR-25, miR-30e, miR-125b, miR-126, miR-4732-3p, miR-146a, miR-185, miR-150-5p, miR-210, miR-212-5p, miR-31, miR-486-5p, miR-338, and miR-671, which, collected from MSCs, cardiac progenitor cells, endothelial cells, endothelial progenitor cells, or patient serum, promoted cardiomyocyte survival by downregulating miRNA targets including PDCD4, FASL, TLR4, PTEN, LOX1, p53, BAK, or SOCS2. 112 , 114 , 117 , 118 , 120 , 123 , 124 , 127 , 129 , 130 , 131 , 132 , 133 , 137 , 138 , 140 , 141 , 142 In addition to the effect on cardiomyocyte survival, several miRNAs, namely miR-24, miR-98-5p, miR-125b, miR-126, miR-133a-3p, miR-150-5p, miR-338, miR-4732-3p, miR-31, miR-210, and miR-486-5p, loading into exosomes from cardiomyocytes, MSCs, or endothelial cells were identified to promote cardiac function recovery by promoting cardiomyocyte survival, anti-inflammation, angiogenesis, or anti-fibrosis. 114 , 117 , 118 , 120 , 124 , 127 , 131 , 138 , 141 , 142 Suggestively, exosomal miRNAs play momentous roles in coordinating responses to cardioprotective effects, i.e., by promoting cardiomyocyte survival and cardiac functional recovery.…”

“… 112 , 114 , 117 , 118 , 120 , 123 , 124 , 127 , 129 , 130 , 131 , 132 , 133 , 137 , 138 , 140 , 141 , 142 In addition to the effect on cardiomyocyte survival, several miRNAs, namely miR-24, miR-98-5p, miR-125b, miR-126, miR-133a-3p, miR-150-5p, miR-338, miR-4732-3p, miR-31, miR-210, and miR-486-5p, loading into exosomes from cardiomyocytes, MSCs, or endothelial cells were identified to promote cardiac function recovery by promoting cardiomyocyte survival, anti-inflammation, angiogenesis, or anti-fibrosis. 114 , 117 , 118 , 120 , 124 , 127 , 131 , 138 , 141 , 142 Suggestively, exosomal miRNAs play momentous roles in coordinating responses to cardioprotective effects, i.e., by promoting cardiomyocyte survival and cardiac functional recovery. Notably, not all miRNAs encapsulated in exosome samples have a cardioprotective effect.…”