Exogenous miRNA-146a Enhances the Therapeutic Efficacy of Human Mesenchymal Stem Cells by Increasing Vascular Endothelial Growth Factor Secretion in the Ischemia/Reperfusion-Injured Heart

Abstract

Adult stem cells have been studied as a promising therapeutic modality for the functional restoration of the damaged heart. In the present study, a strategy for enhancing the angiogenic efficacy of human mesenchymal stem cells (hMSCs) using micro-RNA was examined. We investigated whether micro-RNA-146a (miR-146a) influences the secretion of vascular endothelial growth factor (VEGF) and angiogenesis of MSCs. Our data indicated that miR-146a-transfected hMSCs (hMSC^miR-146a) decreased the expression of neurofibromin 2, an inhibitor of p21-activated kinase-1 (PAK1). miR-146a also increased the expression of Ras-related C3 botulinum toxin substrate 1 and PAK1, which are known to induce VEGF expression, and the formation of vascular branches was increased in hMSC^miR-146a compared to hMSCs treated with VEGF. VEGF and p-Akt were increased in hMSC^miR-146a. Furthermore, injection of hMSC^miR-146a after ischemia/reperfusion (I/R) injury led to a reduction of fibrosis area and increased VEGF expression, confirming the regenerative capacity such as reparative angiogenesis in the infarcted area. Cardiac functions in I/R injury were improved following injection of hMSC^miR-146a compared to the I/R group. Taken together, these data suggest that miR-146 is a novel microRNA that regulates VEGF expression, and its use may be an effective strategy for enhancing the therapeutic efficacy of hMSC transplantation into the I/R-injured heart.

Stem Cell Therapy in Heart Diseases – Cell Types, Mechanisms and Improvement Strategies

“…As already mentioned for DNA, the introduction of miRs was reported to modulate the paracrine activity of SCs. For instance, MSCs exhibited a 3-fold enhanced release of VEGF when transfected with miR-146, which in turn led to improved pro-angiogenic effects and cardiac performance after transplantation into rats [501]. A similar high level of VEGF expression was induced by application of miR-126 and miR-377 mimics [502][503][504].…”

MicroRNA as a Therapeutic Target in Cardiac Remodeling

“…Another research group also confirmed the antifibrotic effects of miR-29b in angiotensin II induced cardiac fibrosis model [64]. MiR-146a targets VEGF expression and suppresses VEGF dependent proliferation and expansion myofibroblasts [65]. The other miRNAs such as miR-142-3p and miR-433 target high mobility group box 1 (HMGB1), AZIN1, and JNK1, respectively, to ameliorate cardiac fibrosis [66, 67].…”

“…miR-126 also contributes to vascular angiogenesis through targeting Cysteine-rich 61 (CCN1) in PTEN/Akt pathway [157]. miR-146a promotes angiogenesis by increasing the expression of VEGF and reducing the fibrotic process at injury site [65]. …”

MicroRNA-155-5p suppresses cardiomyocytes apoptosis induced by hypoxia/reoxygenation via targeting fos-related antigen 2

“…Substantial studies have demonstrated that miRNAs play core roles in the regulation of a variety of cellular processes, including cells growth, cellular apoptosis and fibrosis [5][6][7]. Previously research has suggested miR-155 to be closely associated with cardiovascular heart diseases [8,9].…”