Abstract
The development, homeostasis, and repair of intrahepatic and extrahepatic bile ducts are thought to involve distinct mechanisms including proliferation and maturation of cholangiocyte and progenitor cells. This study aimed to characterize human extrahepatic cholangiocyte organoids (ECO) using canonical Wnt-stimulated culture medium previously developed for intrahepatic cholangiocyte organoids (ICO). Paired ECO and ICO were derived from common bile duct and liver tissue, respectively. Characterization showed both organoid types were highly similar, though some differences in size and gene expression were observed. Both ECO and ICO have cholangiocyte fate differentiation capacity. However, unlike ICO, ECO lack the potential for differentiation towards a hepatocyte-like fate. Importantly, ECO derived from a cystic fibrosis patient showed no CFTR channel activity but normal chloride channel and MDR1 transporter activity. In conclusion, this study shows that ECO and ICO have distinct lineage fate and that ECO provide a competent model to study extrahepatic bile duct diseases like cystic fibrosis.
Highlights
The development, homeostasis, and repair of intrahepatic and extrahepatic bile ducts are thought to involve distinct mechanisms including proliferation and maturation of cholangiocyte and progenitor cells
epithelial cell adhesion molecule (EpCAM) and leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) frequencies were determined in the cells that were isolated from extrahepatic bile ducts (eBD) and liver biopsies
Cells isolated from intrahepatic cholangiocyte organoids (ICO) and extrahepatic cholangiocyte organoids (ECO) expressed ~ 100% EpCAM as shown before[14] (Supplementary Fig. S1)
Summary
The development, homeostasis, and repair of intrahepatic and extrahepatic bile ducts are thought to involve distinct mechanisms including proliferation and maturation of cholangiocyte and progenitor cells. Paired ECO and ICO were derived from common bile duct and liver tissue, respectively Characterization showed both organoid types were highly similar, though some differences in size and gene expression were observed. Both ECO and ICO have cholangiocyte fate differentiation capacity. Evidence suggests that these peribiliary glands provide a proliferative response upon damage of the bile duct providing new cholangiocytes to restore the biliary lining[5] These biliary progenitor cells have a different embryological origin than the bipotent progenitors found in the liver and share a common developmental origin with the pancreas and d uodenum[6,7]. These ICO organoids might not recapitulate unique features of eBD cells and might not be the favorable source to be used to model extrahepatic biliary diseases like cholangiocyte dysfunctions, biliary strictures and atresia
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