期刊
CELL STEM CELL
卷 7, 期 1, 页码 51-63出版社
CELL PRESS
DOI: 10.1016/j.stem.2010.04.014
关键词
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资金
- Chinese Academy of Sciences [KSCX2-YW-R-48, KSCX2-YW-R-221, KSCX2-YW-R-244]
- National Natural Science Foundation of China [30725012, 230725012, 90813033, 30630039]
- Ministry of Science and Technology [2006CB701504, 2006CB943600, 2007CB948002, 2007CB947804, 2007CB947900, 2009CB941102, 2009CB940902, 2010CB944800, 2010DFB30430]
- National High Technology Research and Development Program of China [2006AA02A103, 2007G-P034, 2007Z3-C7031]
- Bureau of Science and Technology of Guangzhou Municipality [2008A1-E4011]
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.
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