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.
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。