microRNA‐124 Regulates Cardiomyocyte Differentiation of Bone Marrow‐Derived Mesenchymal Stem Cells Via Targeting STAT3 Signaling

Abstract

Accumulating evidence demonstrated that bone marrow-derived mesenchymal stem cells (BMSCs) may transdifferentiate into cardiomyocytes and replace apoptotic myocardium so as to improve functions of damaged hearts. However, little information is known about molecular mechanisms underlying myogenic conversion of BMSCs. microRNAs as endogenous noncoding small molecules function to inhibit protein translation post-transcriptionally by binding to complementary sequences of targeted mRNAs. Here, we reported that miR-124 was remarkably downregulated during cardiomyocyte differentiation of BMSCs induced by coculture with cardiomyocytes. Forced expression of miR-124 led to a significant downregulation of cardiac-specific markers-ANP, TNT, and α-MHC proteins as well as reduction of cardiac potassium channel currents in cocultured BMSCs. On the contrary, the inhibition of endogenous miR-124 with its antisense oligonucleotide AMO-124 obviously reversed the changes of ANP, TNT, and α-MHC proteins and increased cardiac potassium channel currents. Further study revealed that miR-124 targeted the 3'UTR of STAT3 gene so as to suppress the expression of STAT3 protein but did not affect its mRNA level. STAT3 inhibitors AG490, WP1066, and S3I-201 were shown to attenuate the augmented expression of ANP, TNT, α-MHC, GATA-4 proteins, and mRNAs in cocultured BMSCs with AMO-124 transfection. Moreover, GATA-4 siRNA reduced the expression of ANP, TNT, α-MHC, and GATA-4 proteins but did not impact STAT3 protein in cocultured BMSCs, indicating GATA-4 serves as an effector of STAT3. In summary, we found that miR-124 regulated myogenic differentiation of BMSCs via targeting STAT3 mRNA, which provides new insights into molecular mechanisms of cardiomyogenesis of BMSCs.

MicroRNA-124–Mediated Regulation of Inhibitory Member of Apoptosis-Stimulating Protein of p53 Family in Experimental Stroke

“…Recent studies confirmed that miR-124 can inhibit cell proliferation and promote cell differentiation. 19,33,34 Downregulation of iASPP expression inhibits cell proliferation and induces apoptosis, and iASPP overexpression antagonizes apoptosis in cancer cells. [35][36][37][38][39] Our study indicates that miR-124 may contribute to cell apoptosis by targeting iASPP in early stage of cerebral ischemia.…”

MicroRNAs as novel regulators of stem cell fate

“…In addition to ESCs, cardiac stem cells, and cardiomyocyte progenitor cells, a recent study showed that the overexpression of miR-499 in rat MSCs induced cardiac differentiation through the Wnt/β-catenin signaling pathway [90] . Additionally, miR-204 is required for human cardiomyocyte progenitor cell differentiation, which occurs through targeting ATF-2 [91] , whereas miR-124 inhibits the cardiomyocyte differentiation of MSCs by targeting STAT3 [92] . Finally, the deletion of the miR-17-92 cluster led to very specific defects in the development of the heart [93] ; however, the function of the miR-17-92 cluster in cardiac differentiation and development remains unclear.…”

MicroRNAs in pathophysiology of acute myocardial infarction and cardiogenic shock

“…The values were not different after 24 hours from the development of cardiogenic shock, even in the follow-up after 6 months. MiRNA-124a is able to regulate the differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) into cardiomyocytes (13,43). Bone marrow-derived mesenchymal stem cells (BMSCs) may trans-differentiate into cardiomyocytes, replace apoptotic myocardium and improve myocardial functions after the damage.…”

“…On the other hand, miRNA-124a has been related to apoptosis, cell proliferation and infl ammation with targets genes affecting cell chemotaxis and infi ltration (11,11). Furthermore, the studies suggest a potential role of miRNA-124a in remodeling the cardiac tissue following a myocardial ischemic insult (12,13). The remodeling of the tissue is connected to the imbalance in synthesis and degradation of extracellular matrix (ECM), which could be induced by many pathways, leading to altered activation of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) (14,15).…”