%0 Journal Article
%T Modeling bile duct ischemia and reoxygenation injury in human cholangiocyte organoids for screening of novel cholangio-protective agents.
%A Shi S
%A Roest HP
%A van den Bosch TPP
%A Bijvelds MJC
%A Boehnert MU
%A de Jonge J
%A Dekker SO
%A de Vries AAF
%A de Jonge HR
%A Verstegen MMA
%A van der Laan LJW
%J EBioMedicine
%V 88
%N 0
%D Feb 2023
%M 36608526
%F 11.205
%R 10.1016/j.ebiom.2022.104431
%X <B>BACKGROUND: </B>Ischemia of the bile duct is a common feature in liver disease and transplantation, which represents a major cause of morbidity and mortality, especially after liver transplantation. Detailed knowledge of its pathogenesis remains incomplete due to the lack of appropriate in vitro models.<BR><B>METHODS: </B>To recapitulate biliary damage induced by ischemia and reperfusion in vitro, human intrahepatic cholangiocyte organoids (ICOs) were grown at low oxygen levels of 1% up to 72 h, followed by re-oxygenation at normal levels.<BR><B>RESULTS: </B>ICOs stressed by ischemia and subsequent re-oxygenation represented the dynamic change in biliary cell proliferation, upregulation of epithelial-mesenchymal transition (EMT)-associated markers, and the evocation of phase-dependent cell death programs similar to what is described in patients. Clinical-grade alpha-1 antitrypsin was identified as a potent inhibitor of both ischemia-induced apoptosis and necroptosis.<BR><B>CONCLUSIONS: </B>These findings demonstrate that ICOs recapitulate ischemic cholangiopathy in vitro and enable drug assessment studies for the discovery of new therapeutics for ischemic cholangiopathies.<BR><B>BACKGROUND: </B>Dutch Digestive FoundationMLDS D16-26; TKI-LSH (Topconsortium Kennis en Innovatie-Life Sciences & Health) grant RELOAD, EMC-LSH19002; Medical Delta program "Regenerative Medicine 4D"; China Scholarship Council No. 201706230252.