{Reference Type}: Journal Article
{Title}: Modeling bile duct ischemia and reoxygenation injury in human cholangiocyte organoids for screening of novel cholangio-protective agents.
{Author}: Shi S;Roest HP;van den Bosch TPP;Bijvelds MJC;Boehnert MU;de Jonge J;Dekker SO;de Vries AAF;de Jonge HR;Verstegen MMA;van der Laan LJW;
{Journal}: EBioMedicine
{Volume}: 88
{Issue}: 0
{Year}: Feb 2023
{Factor}: 11.205
{DOI}: 10.1016/j.ebiom.2022.104431
{Abstract}: <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.