Abstract
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.
Highlights
In vitro differentiation of human pluripotent stem cells into hepatocyte like cells (HLCs) or cholangiocyte like cells (CLCs) provide valuable tools for modelling hepatogenesis, studying liver-associated diseases, assessing toxicology and for drug screenings
The cells are of endodermal origin and have an epithelial morphology but are much larger than HLCs or cholangiocyte like cells (CLCs)
In order to characterize these endoderm derived epithelial cells (EDECs), we tried to produce a pure population by reducing cellular density during HLC differentiation
Summary
In vitro differentiation of human pluripotent stem cells (hPSCs) into hepatocyte like cells (HLCs) or cholangiocyte like cells (CLCs) provide valuable tools for modelling hepatogenesis, studying liver-associated diseases, assessing toxicology and for drug screenings. Cell density influences the fate of hepatoblasts differentiation towards the DE, HE and the beginning of the HLC/EDEC stage, medium was changed daily, but at later time points every other day.
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