TY - JOUR
T1 - Modeling bile duct ischemia and reoxygenation injury in human cholangiocyte organoids for screening of novel cholangio-protective agents
AU - Shi, Shaojun
AU - Roest, Henk P.
AU - van den Bosch, Thierry P.P.
AU - Bijvelds, Marcel J.C.
AU - Boehnert, Markus U.
AU - de Jonge, Jeroen
AU - Dekker, Sven O.
AU - de Vries, Antoine A.F.
AU - de Jonge, Hugo R.
AU - Verstegen, Monique M.A.
AU - van der Laan, Luc J.W.
N1 - 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)
PY - 2023/1/1
Y1 - 2023/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85145858436&partnerID=8YFLogxK
U2 - 10.1016/j.ebiom.2022.104431
DO - 10.1016/j.ebiom.2022.104431
M3 - Article
C2 - 36608526
AN - SCOPUS:85145858436
VL - 88
JO - EBioMedicine
JF - EBioMedicine
SN - 2352-3964
M1 - 104431
ER -
