A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts.

By Ronghui Li, Jialiang Liang, Su Ni, Ting Zhou, Xiaobing Qing, Huapeng Li, Wenzhi He, Jiekai Chen, Feng Li, Zhuang Qiang and 14 more. Cell Stem Cell, 2010

1,163 citations recorded by the source corpus.

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:

Subfields: Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/21d043f39d87f86ec74f49f1406b52dacf170c28

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Citations in the corpus

Signaling mechanisms of the epithelial-mesenchymal transition (2014, background): “In the embryo, multiple rounds of EMT and MET are necessary to complete gastrulation and primitive streak formation, highlighting the reversibility of this process (16).”
Epithelial Plasticity: A Common Theme in Embryonic and Cancer Cells (2013, background): “In fact, the Yamanaka factors (Sox2, Klf4, Oct4, and Myc) act together with BMP7 to repress TGFb signaling and EMT-TFs to revert fibroblasts to the epithelial phenotype (64).”
Single-cell expression analyses during cellular reprogramming reveal an early stochastic and a late hierarchic phase. (2012, background): “To gain insight into the early markers and MET at the singlecell level, we quantified transcripts of (1) Snail, E-cadherin, and Esrrb; (2) Snail, E-cadherin, and Utf1; and (3) Snail, E-cadherin, and Sall4 in single NGFP2 MEFs on dox for 6 and 12 days.”
Induced pluripotency: history, mechanisms, and applications. (2010, background): “…signal inhibition might be partly explained by facilitating the activation of the Nanog locus (Ichida et al. 2009), another interpretation is that blocking TGFb signaling might be critical to initiate a MET that occurs early during reprogramming (Li et al. 2010; Samavarchi-Tehrani et al. 2010).”
Facilitators and Impediments of the Pluripotency Reprogramming Factors’ Initial Engagement with the Genome (2012, positive): “Klf4 targets CDH1 at multiple sites at 48 hr (Figures 2B and S3C), which is in concordance with ectopic Klf4, but not OSM, potently inducing CDH1 (Li et al., 2010).”
Senescence impairs successful reprogramming to pluripotent stem cells. (2009, background): “inducing Nanog in mouse cells, it may also promote the mesenchymal-to-epithelial transition, which is required in the early stages of reprogramming of mouse and human fibroblasts to iPS cells (Li et al., 2010; Samavarchi-Tehrani et al., 2010).”
Implications of the Hybrid Epithelial/Mesenchymal Phenotype in Metastasis (2015, background): “Importantly, EMT and MET, whether in physiological or pathological contexts, are not binary processes (5, 6).”
Multiple targets of miR-302 and miR-372 promote reprogramming of human fibroblasts to induced pluripotent stem cells (2011, background): “Recent work has shown that mouse fibroblasts undergo a mesenchymal-epithelial transition (MET) early in the process of reprogrammin”