A Mesenchymal-to-Epithelial Transition Initiates and Is Required for the Nuclear Reprogramming of Mouse Fibroblasts
A Mesenchymal-to-Epithelial Transition Initiates and Is Required for the Nuclear Reprogramming of Mouse Fibroblasts
复制标题
间充质到上皮的转变启动并且是小鼠成纤维细胞核重编程所必需的
DOI：
10.1016/j.stem.2010.04.014
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发表时间：
2010-07-02
期刊：
影响因子：
23.9
通讯作者：
Pei, Duanqing
中科院分区：
文献类型：
--
作者：
Li, Ronghui;Liang, Jialiang;Pei, Duanqing
上皮细胞向间质细胞转化（EMT）是决定细胞命运的重要发育过程。成纤维细胞是EMT的产物，可以通过外源性转录因子重置为诱导多能干细胞（iPSC），但其潜在机制尚不清楚。在这里，我们表明，从小鼠成纤维细胞产生iPSC需要通过抑制培养基中的pro-EMT信号和激活细胞内的上皮程序来协调间充质到上皮的转变（MET）。在转录水平，Sox 2/Oct 4抑制EMT介导因子Snail，c-Myc下调TGF-β 1和TGF-β受体2，Klf 4诱导上皮基因，包括E-钙粘蛋白。阻断MET会损害成纤维细胞的重编程，而在用血清培养的上皮细胞中阻止EMT可以产生不含Klf 4和c-Myc的iPSC。我们的工作不仅确立了MET作为诱导多能性的关键细胞机制，而且还证明了iPSC的产生是定义的因子和细胞外环境之间的合作过程。
Epithelial-to-mesenchymal transition (EMT) is a developmental process important for cell fate determination. Fibroblasts, a product of EMT, can be reset into induced pluripotent stem cells (iPSCs) via exogenous transcription factors but the underlying mechanism is unclear. Here we show that the generation of iPSCs from mouse fibroblasts requires a mesenchymal-to-epithelial transition (MET) orchestrated by suppressing pro-EMT signals from the culture medium and activating an epithelial program inside the cells. At the transcriptional level, Sox2/Oct4 suppress the EMT mediator Snail, c-Myc downregulates TGF-beta 1 and TGF-beta receptor 2, and Klf4 induces epithelial genes including E-cadherin. Blocking MET impairs the reprogramming of fibroblasts whereas preventing EMT in epithelial cells cultured with serum can produce iPSCs without Klf4 and c-Myc. Our work not only establishes MET as a key cellular mechanism toward induced pluripotency, but also demonstrates iPSC generation as a cooperative process between the defined factors and the extracellular milieu.