Modeling ischemic cholangiopathy in human cholangiocyte organoid for screening of novel cholangio-protective agents

Ischemic cholangiopathy refers to biliary damage caused by disruption of blood supply in the peribiliary plexus. Detailed knowledge of ischemic cholangiopathy pathogenesis remains scarce due to the lack of appropriate in vitro models. We aimed to recapitulate ischemia-evoked biliary damage using human intrahepatic cholangiocyte organoids (ICOs) in vitro for the study of ischemic cholangiopathy and preclinical drug discovery. In our study, we found that ICOs can recapitulate ischemic cholangiopathy in vitro, featured by extensive apoptosis and reduced cell proliferation, which could be partially restored by reoxygenation. AAT is identified as a novel cholangiocellular protective agent by restoring proliferation and preventing apoptosis. Examine the transcriptional profiles of human cholangiocyte organoids cultured under different oxygen concentrations, including normoxia (21%), hypoxia (1%) and hypoxia followed by reoxygenation (1% to 21%).