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.
RESULTS: 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.
CONCLUSIONS: These findings demonstrate that ICOs recapitulate ischemic cholangiopathy in vitro and enable drug assessment studies for the discovery of new therapeutics for ischemic cholangiopathies.
BACKGROUND: 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.
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.
RESULTS: 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.
CONCLUSIONS: These findings demonstrate that ICOs recapitulate ischemic cholangiopathy in vitro and enable drug assessment studies for the discovery of new therapeutics for ischemic cholangiopathies.
BACKGROUND: 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.
摘要：
背景：胆管缺血是肝脏疾病和移植的共同特征，这是发病率和死亡率的主要原因，尤其是肝移植后。由于缺乏适当的体外模型，对其发病机理的详细了解仍然不完整。
方法：对体外缺血再灌注引起的胆道损伤进行综述,人肝内胆管细胞类器官（ICOs）在1％的低氧水平下生长直至72小时，然后是正常水平的再氧合。
结果：由缺血和随后的再氧合引起的ICOs代表了胆道细胞增殖的动态变化，上皮间质转化（EMT）相关标志物的上调，和类似于患者描述的相位依赖性细胞死亡程序的诱发。临床级α-1抗胰蛋白酶被确定为局部缺血诱导的细胞凋亡和坏死的有效抑制剂。
结论：这些发现表明，ICOs在体外概括了缺血性胆管病，并使药物评估研究能够发现缺血性胆管病的新疗法。
背景：荷兰消化基金会MLDSD16-26；TKI-LSH（TopsortiumKennisenInnovatie-LifeSciences&Health）授予RELOAD，EMC-LSH19002；医疗三角洲计划“再生医学4D”；中国国家留学基金委编号：201706230252。
方法：对体外缺血再灌注引起的胆道损伤进行综述,人肝内胆管细胞类器官（ICOs）在1％的低氧水平下生长直至72小时，然后是正常水平的再氧合。
结果：由缺血和随后的再氧合引起的ICOs代表了胆道细胞增殖的动态变化，上皮间质转化（EMT）相关标志物的上调，和类似于患者描述的相位依赖性细胞死亡程序的诱发。临床级α-1抗胰蛋白酶被确定为局部缺血诱导的细胞凋亡和坏死的有效抑制剂。
结论：这些发现表明，ICOs在体外概括了缺血性胆管病，并使药物评估研究能够发现缺血性胆管病的新疗法。
背景：荷兰消化基金会MLDSD16-26；TKI-LSH（TopsortiumKennisenInnovatie-LifeSciences&Health）授予RELOAD，EMC-LSH19002；医疗三角洲计划“再生医学4D”；中国国家留学基金委编号：201706230252。
