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

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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

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.

Original languageEnglish
Article number104431
JournalEBioMedicine
Volume88
Early online date1 Jan 2023
DOIs
Publication statusE-pub ahead of print - 1 Jan 2023

Bibliographical note

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.

Publisher Copyright:
© 2022 The Author(s)

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