Cell fate decisions of human iPSC-derived bipotential hepatoblasts depend on cell density

PLoS One. 2018 Jul 10;13(7):e0200416. doi: 10.1371/journal.pone.0200416. eCollection 2018.


During embryonic development bipotential hepatoblasts differentiate into hepatocytes and cholangiocytes- the two main cell types within the liver. Cell fate decision depends on elaborate interactions between distinct signalling pathways, namely Notch, WNT, TGFβ, and Hedgehog. Several in vitro protocols have been established to differentiate human pluripotent stem cells into either hepatocyte or cholangiocyte like cells (HLC/CLC) to enable disease modelling or drug screening. During HLC differentiation we observed the occurrence of epithelial cells with a phenotype divergent from the typical hepatic polygonal shape- we refer to these as endoderm derived epithelial cells (EDECs). These cells do not express the mature hepatocyte marker ALB or the progenitor marker AFP. However they express the cholangiocyte markers SOX9, OPN, CFTR as well as HNF4α, CK18 and CK19. Interestingly, they express both E Cadherin and Vimentin, two markers that are mutually exclusive, except for cancer cells. EDECs grow spontaneously under low density cell culture conditions and their occurrence was unaffected by interfering with the above mentioned signalling pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cadherins / metabolism
  • Cell Count
  • Cell Culture Techniques*
  • Cell Differentiation / physiology*
  • Cell Line
  • Epithelial Cells / cytology
  • Epithelial Cells / physiology
  • Hepatocytes / cytology
  • Hepatocytes / physiology*
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / physiology*
  • Transcriptome
  • Vimentin / metabolism


  • Cadherins
  • Vimentin

Grant support

N.G. acknowledges support from the Research commission of the Medical faculty of Heinrich Heine University Düsseldorf (www.medizin.hhu.de/dekanat/gremien-und-kommissionen/kommissionen/forschungskommission.html). J.A. acknowledges support from the Medical faculty of Heinrich Heine University Düsseldorf. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript