1. A Mesenchymal-to-Epithelial Transition Initiates and Is Required for the Nuclear Reprogramming of Mouse Fibroblasts
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Duanqing Pei, Ting Zhou, Lingwen Zeng, Hong Song, Dajiang Qin, Ronghui Li, Huapeng Li, Feng Li, Miguel A. Esteban, Xiaobing Qing, Shipeng Feng, Biliang Zhang, Wen Li, Dongshan Yang, Liangxue Lai, Wenzhi He, Jiayin Yang, Yi Gan, Qiang Zhuang, Baoming Qin, Su Ni, Jianyong Xu, Jialiang Liang, and Jiekai Chen
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Chromatin Immunoprecipitation ,Induced Pluripotent Stem Cells ,Kruppel-Like Transcription Factors ,Enzyme-Linked Immunosorbent Assay ,Biology ,Cell fate determination ,Models, Biological ,Mesoderm ,Proto-Oncogene Proteins c-myc ,Kruppel-Like Factor 4 ,Mice ,SOX2 ,Genetics ,medicine ,Animals ,Induced pluripotent stem cell ,Fibroblast ,Transcription factor ,Cells, Cultured ,Reverse Transcriptase Polymerase Chain Reaction ,SOXB1 Transcription Factors ,Mesenchymal stem cell ,Epithelial Cells ,Cell Biology ,Fibroblasts ,Cadherins ,Cellular Reprogramming ,STEMCELL ,Cell biology ,medicine.anatomical_structure ,KLF4 ,Immunology ,embryonic structures ,Molecular Medicine ,Octamer Transcription Factor-3 ,Reprogramming - Abstract
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-beta1 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. PAPERCLIP
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