Clinical and Translational Research Center of Shanghai First Maternity & Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai, People's Republic of China.
Stem Cells. 2012 Aug;30(8):1645-54. doi: 10.1002/stem.1149.
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 3' 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.
诱导多能干细胞（iPS 细胞），特别是那些由患者体细胞重编程而来的细胞，在再生医学中有很大的应用潜力。p53 的表达已被证明是限制 iPS 细胞生成的关键障碍，但 p53 在细胞重编程过程中是如何被调控的仍不清楚。在这项研究中，我们发现 miR-138 的异位表达通过 Oct4、Sox2 和 Klf4（分别命名为 OSKM 或 OSK），在不牺牲生成的 iPS 细胞多能性特征的情况下，显著提高了 iPS 细胞生成的效率。机制探索表明，miR-138 直接靶向 p53 的 3'非翻译区（UTR），显著降低了 p53 及其下游基因的表达。此外，异位表达具有不能与 miR-138 结合的突变 3'-UTR 的 p53，严重损害了 miR-138 对 p53 信号和 OSKM 起始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，p53 信号通路的调控和 iPS 细胞的生成代表了 miR-138 一个未被揭示的重要功能。
