A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts.
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:
Li
Ronghui
R
Stem Cell and Cancer Biology Group, Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
Liang
Jialiang
J
Ni
Su
S
Zhou
Ting
T
Qing
Xiaobing
X
Li
Huapeng
H
He
Wenzhi
W
Chen
Jiekai
J
Li
Feng
F
Zhuang
Qiang
Q
Qin
Baoming
B
Xu
Jianyong
J
Li
Wen
W
Yang
Jiayin
J
Gan
Yi
Y
Qin
Dajiang
D
Feng
Shipeng
S
Song
Hong
H
Yang
Dongshan
D
Zhang
Biliang
B
Zeng
Lingwen
L
Lai
Liangxue
L
Esteban
Miguel Angel
MA
Pei
Duanqing
D
D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000235:genetics / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D005347:Fibroblasts / Q000166:cytology; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008954:Models, Biological; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism
D015820:Cadherins; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C489428:Myc protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse