Modeling bile duct ischemia and reoxygenation injury in human cholangiocyte organoids for screening of novel cholangio-protective agents

作者：Shi, Shaojun; Roest, Henk P.; van den Bosch, Thierry P. P.; Bijvelds, Marcel J. C.; Boehnert, Markus U.; de Jonge, Jeroen; Dekker, Sven O.; de Vries, Antoine A. F.; de Jonge, Hugo R.; Verstegen, Monique M. A.; van der Laan, Luc J. W.^*

来源：EBioMedicine, 2023, 88: 104431.

DOI：10.1016/j.ebiom.2022.104431

• Ischemia-reperfusion injury
• Biliary injury
• Liver transplantation
• Organoid
• Drug screening

Background 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.Methods 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.Findings 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.Interpretation These findings demonstrate that ICOs recapitulate ischemic cholangiopathy in vitro and enable drug assessment studies for the discovery of new therapeutics for ischemic cholangiopathies.

• 单位
  广东省人民医院; 中国医科大学; 南方医科大学