Modeling bile duct ischemia and reoxygenation injury in human cholangiocyte organoids for screening of novel cholangio-protective agentsResearch in context
Shaojun Shi,
Henk P. Roest,
Thierry P.P. van den Bosch,
Marcel J.C. Bijvelds,
Markus U. Boehnert,
Jeroen de Jonge,
Sven O. Dekker,
Antoine A.F. de Vries,
Hugo R. de Jonge,
Monique M.A. Verstegen,
Luc J.W. van der Laan
Affiliations
Shaojun Shi
Department of Surgery, Erasmus MC Transplant Institute, University Medical Center, Rotterdam 3015CE, the Netherlands; Department of Organ Transplantation, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
Henk P. Roest
Department of Surgery, Erasmus MC Transplant Institute, University Medical Center, Rotterdam 3015CE, the Netherlands
Thierry P.P. van den Bosch
Department of Pathology, Erasmus MC-University Medical Center, Rotterdam 3015CE, the Netherlands
Marcel J.C. Bijvelds
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam 3015CE, the Netherlands
Markus U. Boehnert
Department of Surgery, Erasmus MC Transplant Institute, University Medical Center, Rotterdam 3015CE, the Netherlands
Jeroen de Jonge
Department of Surgery, Erasmus MC Transplant Institute, University Medical Center, Rotterdam 3015CE, the Netherlands
Sven O. Dekker
Department of Cardiology, Leiden University Medical Center, Leiden 2300 RA, the Netherlands
Antoine A.F. de Vries
Department of Cardiology, Leiden University Medical Center, Leiden 2300 RA, the Netherlands
Hugo R. de Jonge
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam 3015CE, the Netherlands
Monique M.A. Verstegen
Department of Surgery, Erasmus MC Transplant Institute, University Medical Center, Rotterdam 3015CE, the Netherlands
Luc J.W. van der Laan
Department of Surgery, Erasmus MC Transplant Institute, University Medical Center, Rotterdam 3015CE, the Netherlands; Corresponding author. ‘s-Gravendijkwal 230, Room Na-1008, Rotterdam 3015CE, the Netherlands.
Summary: 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. Funding: Dutch Digestive Foundation MLDS 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.
