MiR-138 Promotes Induced Pluripotent Stem Cell Generation Through the Regulation of the P53 Signaling
MiR-138 Promotes Induced Pluripotent Stem Cell Generation Through the Regulation of the P53 Signaling
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MiR-138 通过调节 P53 信号传导促进诱导多能干细胞生成
DOI：
10.1002/stem.1149
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发表时间：
2012-08-01
期刊：
影响因子：
5.2
通讯作者：
Kang, Jiuhong
中科院分区：
文献类型：
--
作者：
Ye, Dan;Wang, Guiying;Kang, Jiuhong
诱导性多能干细胞（iPS），特别是从患者体细胞重编程而来的iPS细胞，在再生医学中具有巨大的应用潜力。p53的表达已被证明是限制iPS细胞生成的关键屏障，但p53在细胞重编程期间如何调节仍不清楚。在这项研究中，我们发现miR-138的异位表达显著提高了iPS细胞生成的效率，通过Oct 4，Sox 2和Klf 4，有或没有c-Myc（分别命名为OSKM或OSK），而不会牺牲所产生的iPS细胞的多能性特征。其作用机制的探讨表明，miR-138直接靶向p53的30个非翻译区（UTR），显著降低了p53及其下游基因的表达。此外，具有不能被miR-138结合的突变体3 '-UTR的p53的异位表达严重损害了miR-138对p53信号传导和OSKM启动的体细胞重编程的作用。结合miR-138在成纤维细胞、iPS细胞和胚胎干细胞中内源性表达的事实，我们的研究表明，调节p53信号通路和促进iPS细胞生成代表了miR-138未揭示的重要功能。干细胞2012; 30：1645-1654
Induced pluripotent stem (iPS) cells, especially those reprogrammed from patient somatic cells, have a great potential usage in regenerative medicine. The expression of p53 has been proven as a key barrier limiting iPS cell generation, but how p53 is regulated during cell reprogramming remains unclear. In this study, we found that the ectopic expression of miR-138 significantly improved the efficiency of iPS cell generation via Oct4, Sox2, and Klf4, with or without c-Myc (named as OSKM or OSK, respectively), without sacrificing the pluripotent characteristics of the generated iPS cells. Exploration of the mechanism showed that miR-138 directly targeted the 30 untranslated region (UTR) of p53, significantly decreasing the expression of p53 and its downstream genes. Furthermore, the ectopic expression of p53 having a mutant 3'-UTR, which cannot be bound by miR-138, seriously impaired the effect of miR-138 on p53 signaling and OSKM-initiated somatic cell reprogramming. Combined with the fact that miR-138 is endogenously expressed in fibroblasts, iPS cells, and embryonic stem cells, our study demonstrated that regulation of the p53 signaling pathway and promotion of iPS cell generation represent an unrevealed important function of miR-138. STEM CELLS 2012; 30:1645-1654