The mesenchymal transcription factor SNAI-1 instructs human liver specification

Stem Cell Res. 2016 Jul;17(1):62-8. doi: 10.1016/j.scr.2016.05.007. Epub 2016 May 21.


Epithelial-mesenchymal transition (EMT) and the mesenchymal-epithelial transition (MET) are processes required for embryo organogenesis. Liver develops from the epithelial foregut endoderm from which the liver progenitors, hepatoblasts, are specified. The migrating hepatoblasts acquire a mesenchymal phenotype to form the liver bud. In mid-gestation, hepatoblasts mature into epithelial structures: the hepatocyte cords and biliary ducts. While EMT has been associated with liver bud formation, nothing is known about its contribution to hepatic specification. We previously established an efficient protocol from human embryonic stem cells (hESC) to generate hepatic cells (Hep cells) resembling the hepatoblasts expressing alpha-fetoprotein (AFP) and albumin (ALB). Here we show that Hep cells express both epithelial (EpCAM and E-cadherin) and mesenchymal (vimentin and SNAI-1) markers. Similar epithelial and mesenchymal hepatoblasts were identified in human and mouse fetal livers, suggesting a conserved interspecies phenotype. Knock-down experiments demonstrated the importance of SNAI-1 in Hep cell hepatic specification. Moreover, ChIP assays revealed direct binding of SNAI-1 in the promoters of AFP and ALB genes consistent with its transcriptional activator function in hepatic specification. Altogether, our hESC-derived Hep cell cultures reveal the dual mesenchymal and epithelial phenotype of hepatoblast-like cells and support the unexpected transcriptional activator role of SNAI-1 in hepatic specification.

Keywords: Hepatic differentiation; Human embryonic stem cell; Liver development; Liver specification; SNAI-1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cadherins / genetics
  • Cadherins / metabolism
  • Cell Differentiation
  • Chromatin Immunoprecipitation
  • Epithelial Cell Adhesion Molecule / genetics
  • Epithelial Cell Adhesion Molecule / metabolism
  • Fetus / cytology
  • Hepatocytes / cytology
  • Hepatocytes / metabolism*
  • Humans
  • Liver / cytology
  • Liver / metabolism
  • Mice
  • Microscopy, Fluorescence
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Real-Time Polymerase Chain Reaction
  • Snail Family Transcription Factors / antagonists & inhibitors
  • Snail Family Transcription Factors / genetics
  • Snail Family Transcription Factors / metabolism*
  • Vimentin / genetics
  • Vimentin / metabolism


  • Cadherins
  • Epithelial Cell Adhesion Molecule
  • RNA, Small Interfering
  • SNAI1 protein, human
  • Snail Family Transcription Factors
  • Vimentin