A sequential EMT-MET mechanism drives the differentiation of human embryonic stem cells towards hepatocytes

Nat Commun. 2017 May 3;8:15166. doi: 10.1038/ncomms15166.


Reprogramming has been shown to involve EMT-MET; however, its role in cell differentiation is unclear. We report here that in vitro differentiation of hESCs to hepatic lineage undergoes a sequential EMT-MET with an obligatory intermediate mesenchymal phase. Gene expression analysis reveals that Activin A-induced formation of definitive endoderm (DE) accompanies a synchronous EMT mediated by autocrine TGFβ signalling followed by a MET process. Pharmacological inhibition of TGFβ signalling blocks the EMT as well as DE formation. We then identify SNAI1 as the key EMT transcriptional factor required for the specification of DE. Genetic ablation of SNAI1 in hESCs does not affect the maintenance of pluripotency or neural differentiation, but completely disrupts the formation of DE. These results reveal a critical mesenchymal phase during the acquisition of DE, highlighting a role for sequential EMT-METs in both differentiation and reprogramming.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activins / metabolism
  • Cell Differentiation / physiology
  • Cell Line
  • Cell Movement
  • Cellular Reprogramming Techniques / methods*
  • Endoderm / cytology*
  • Epithelial-Mesenchymal Transition / physiology*
  • GATA6 Transcription Factor / biosynthesis
  • Hepatocytes / cytology*
  • Human Embryonic Stem Cells / cytology*
  • Human Embryonic Stem Cells / physiology
  • Humans
  • Nanog Homeobox Protein / biosynthesis
  • Octamer Transcription Factor-3 / biosynthesis
  • Pluripotent Stem Cells / physiology*
  • SOXF Transcription Factors / biosynthesis
  • Snail Family Transcription Factors / genetics*
  • Transforming Growth Factor beta1 / metabolism


  • GATA6 Transcription Factor
  • GATA6 protein, human
  • NANOG protein, human
  • Nanog Homeobox Protein
  • Octamer Transcription Factor-3
  • POU5F1 protein, human
  • SNAI1 protein, human
  • SOX17 protein, human
  • SOXF Transcription Factors
  • Snail Family Transcription Factors
  • TGFB1 protein, human
  • Transforming Growth Factor beta1
  • activin A
  • Activins