MiR218 Modulates Wnt Signaling in Mouse Cardiac Stem Cells by Promoting Proliferation and Inhibiting Differentiation through a Positive Feedback Loop.
MiR218 Modulates Wnt Signaling in Mouse Cardiac Stem Cells by Promoting Proliferation and Inhibiting Differentiation through a Positive Feedback Loop.
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MiR218 通过正反馈环促进增殖和抑制分化来调节小鼠心脏干细胞中的 Wnt 信号转导
DOI：
10.1038/srep20968
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发表时间：
2016-02-10
影响因子：
4.6
通讯作者：
Yu B
中科院分区：
文献类型：
--
作者：
Wang Y;Liu J;Cui J;Sun M;Du W;Chen T;Ming X;Zhang L;Tian J;Li J;Yin L;Liu F;Pu Z;Lv B;Hou J;Yu B
在增殖和分化的心肌细胞中， 干细胞（CSCs）通过全面的miRNA微阵列分析。我们选择 miR218用于功能性随访研究，以检查其在CSC中的意义。第一、 我们观察到，在分化过程中，miR 218在CSC中的表达发生了改变， 并转染miR 218模拟物或miR 218抑制剂， CSCs的心肌分化。此外，我们观察到， Wnt信号调节因子sFRP2是miR218的直接靶点， 在用合成的miR218转染的细胞中，sFRP2的水平增加 抑制剂.与此相反，用miR218模拟物转染降低了表达。 sFRP2和增强的Wnt信号传导。随后sFRP2的下调， shRNA增强Wnt信号传导，有助于基因表达程序， 对于CSC增殖和心脏分化重要。具体来说，canonical Wnt信号转导诱导miR218转录。因此，miR218和Wnt信号转导被抑制。 通过前馈正反馈回路耦合，形成生物 调节电路总之，这些结果提供了miR218 在CSC的增殖和分化中起重要作用， 经典Wnt信号通路。
MiRNA expression was determined in both proliferating and differentiated cardiac stem cells (CSCs) through a comprehensive miRNA microarray analysis. We selected miR218 for functional follow-up studies to examine its significance in CSCs. First, we observed that the expression of miR218 was altered in CSCs during differentiation into cardiomyocytes and transfection of an miR218 mimic or miR218 inhibitor affected the myocardial differentiation of CSCs. Furthermore, we observed that a negative regulator of Wnt signaling, sFRP2, was a direct target of miR218 and the protein levels of sFRP2 were increased in cells transfected with the synthetic miR218 inhibitor. In contrast, transfection with the miR218 mimic decreased the expression of sFRP2 and potentiated Wnt signaling. The subsequent down-regulation of sFRP2 by shRNA potentiated Wnt signaling, contributing to a gene expression program that is important for CSC proliferation and cardiac differentiation. Specifically, canonical Wnt signaling induced miR218 transcription. Thus, miR218 and Wnt signaling were coupled through a feed-forward positive feedback loop, forming a biological regulatory circuit. Together, these results provide the first evidence that miR218 plays an important role in CSC proliferation and differentiation through the canonical Wnt signaling pathway.