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A Mesenchymal-to-Epithelial Transition Initiates and Is Required for the Nuclear Reprogramming of Mouse Fibroblasts
- Source :
- Cell Stem Cell. (1):51-63
- Publisher :
- Elsevier Inc.
-
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
- Subjects :
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 19345909
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Cell Stem Cell
- Accession number :
- edsair.doi.dedup.....eaf195149bd07f28709122da6c70517f
- Full Text :
- https://doi.org/10.1016/j.stem.2010.04.014