Modeling Ischemic-Type Biliary Lesions in Human Cholangiocyte Organoids

Ischemic-type biliary lesions (ITBL) is a significant and challenging biliary complication following liver transplantation, characterized by nonanastomotic strictures on cholangiogram and usually leading to graft failure or mortality. While risk factors such as ischemia-, bile salt toxicity- and immune response-induced injury have been identified, the precise cellular and molecular mechanisms underlying bile duct injury in ITBL remains unexplored. This knowledge gap stems from the lack of relevant primary models that recapitulate in vivo conditions. Using human liver or bile biopsies-derived cholangiocyte organoids (intrahepatic cholangiocyte organoids, IHCO or bile cholangiocyte organoids, BCO) as a model, we demonstrated both cholangiocyte organoids derived from healthy donor closely resemble primary cholangiocytes in terms of key biliary marker expression, tubular morphogenesis and functional properties. In contrast, organoids emerged from ITBL livers or bile develop only cystic spheres, failing to generate branching duct network resembling in vivo architecture. Cells in ITBL-organoids exhibited aberrant apical-basal polarity, reduced expression of cholangiocyte transporters and enzymes, and diminished responsiveness to hormone stimulation. Our findings provide cellular and functional insights into the extensive biliary injury observed in ITBL patients. Further studies will be focused on how bile duct epithelial damage in donor livers leads to post-transplant cholangiopathies

Publication History

Article published online:
20 January 2025