近日,，干細(xì)胞研究領(lǐng)域國際著名刊物《Stem Cells》在線發(fā)表了同濟(jì)大學(xué)生命科學(xué)與技術(shù)學(xué)院康九紅教授研究組關(guān)于miRNA調(diào)節(jié)p53從而調(diào)節(jié)誘導(dǎo)多能干細(xì)胞（iPS細(xì)胞）誘導(dǎo)的研究成果,。
通過過表達(dá)四因子Oct4,、Sox2、Klf4和c-Myc重編程體細(xì)胞可獲得iPS細(xì)胞,。iPS在細(xì)胞倍增能力,、分化能力等方面都與胚胎干細(xì)胞相似,。這一技術(shù)給基于干細(xì)胞的再生醫(yī)學(xué)和個性化治療帶來了光明的前景。目前干細(xì)胞研究人員正在致力于iPS細(xì)胞形成的分子調(diào)控機制的研究,。
之前有研究顯示抑制p53可以顯著提高iPS細(xì)胞誘導(dǎo)效率,，同時p53在體細(xì)胞重編程中還具有保證獲得的iPS細(xì)胞基因組完整性的作用。那么,，在iPS細(xì)胞形成過程中,，細(xì)胞內(nèi)精細(xì)調(diào)控p53，以維持其在重編程效率和細(xì)胞基因組穩(wěn)定性維持二方面的功能平衡的機制是什么呢,？康九紅教授組的研究成果首次發(fā)現(xiàn),小鼠胚胎成纖維細(xì)胞內(nèi)源性的一個小非編碼RNA,，miR-138能夠在誘導(dǎo)過程中特異性地作用于p53，在一定程度上降低P53的表達(dá),，從而提高誘導(dǎo)效率,。多能性分析檢測表明利用miR-138和四因子誘導(dǎo)得到的iPS具有與胚胎干細(xì)胞類似的多能性，并且具有激活的Dlk1-Dio3區(qū)域,。這顯示miR-138是體細(xì)胞重編程過程中p53的內(nèi)源調(diào)節(jié)者,，既可以顯著提高iPS誘導(dǎo)效率，也沒有犧牲iPS細(xì)胞的質(zhì)量,。該研究成果增加了我們對iPS形成機制的了解，對重編程過程中如何保證獲得的iPS細(xì)胞基因組穩(wěn)定性等品質(zhì)也具有一定的指導(dǎo)意義,。
該研究主要由課題組研究生葉丹同學(xué)完成,。本研究工作得到科技部973項目、科技部國際合作項目,、自然科學(xué)基金委,、教育部創(chuàng)新團(tuán)隊以及上海市科委項目的支持。在10月生物谷主辦的“2012LSAC生命科技論壇：干細(xì)胞技術(shù)與應(yīng)用”上,，康九紅教授將以“組蛋白修飾在誘導(dǎo)多能干細(xì)胞形成中的作用與機制”為題發(fā)表精彩演講,。(生物谷 Bioon.com)
doi:10.1002/stem.1149
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MiR-138 Promotes Induced Pluripotent Stem Cell Generation Through the Regulation of the p53 Signaling
Dan Ye, Guiying Wang, Yang Liu, Wenfei Huang, Minjuan Wu, Songcheng Zhu, Wenwen Jia, An-Mei Deng, Houqi Liu, Jiuhong Kang,
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. STEM Cells2012;30:1645–1654
