microRNA-124 Regulates Cardiomyocyte Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells Via Targeting STAT3 Signaling
microRNA-124 Regulates Cardiomyocyte Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells Via Targeting STAT3 Signaling
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microRNA-124 通过靶向 STAT3 信号传导调节骨髓间充质干细胞的心肌细胞分化
DOI：
10.1002/stem.1154
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发表时间：
2012-08-01
期刊：
影响因子：
5.2
通讯作者：
Lu, Yanjie
中科院分区：
文献类型：
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作者：
Cai, Benzhi;Li, Jianping;Lu, Yanjie
越来越多的证据表明，骨髓间充质干细胞(BMSCs)可以转分化为心肌细胞，替代凋亡的心肌，从而改善受损心脏的功能。然而，关于骨髓间充质干细胞成肌转化的分子机制知之甚少。MicroRNAs作为内源性非编码小分子，通过与靶mRNAs的互补序列结合，在转录后抑制蛋白质翻译。在此，我们报道了在与心肌细胞共培养诱导BMSCs向心肌细胞分化的过程中，miR-124表达显著下调。在共培养的BMSCs中，miR-124的强制表达导致心脏特异性标志物-ANP、TnT和α-MHC蛋白的显著下调，以及心肌钾通道电流的减少。相反，内源性miR-124及其反义寡核苷酸AMO-124可明显逆转ANP、TnT和α-MHC蛋白的变化，增加心肌钾通道电流。进一步的研究表明，miR-124靶向STAT3基因的3‘非编码区，从而抑制STAT3蛋白的表达，但不影响其mRNA水平。STAT3抑制剂AG490、WP1066和S3I-201可抑制AMO-124共培养的骨髓间充质干细胞ANP、TNT、α-MHC、GATA-4蛋白和mRNAs的表达增强。此外，GATA-4 siRNA降低了共培养的BMSCs ANP、TNT、α-MHC和GATA-4蛋白的表达，但不影响STAT3蛋白的表达，表明GATA-4是STAT3的效应器。综上所述，我们发现miR-124通过靶向STAT3mRNA调控BMSCs的成肌分化，这为研究BMSCs心肌发生的分子机制提供了新的思路。干细胞2012；30：1746-1755
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 alpha-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 alpha-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, alpha-MHC, GATA-4 proteins, and mRNAs in cocultured BMSCs with AMO-124 transfection. Moreover, GATA-4 siRNA reduced the expression of ANP, TNT, alpha-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. STEM CELLS 2012;30:1746-1755