A novel model to study mechanisms of cholestasis in human cholangiocytes reveals a role for the SIPR2 pathway

作者：Diana Islam, Izza Israr, Mohamed A. B. Taleb, A. Nagaraja Rao, Robel Yosief, Rukhsar Sultana, Fotios Sampaziotis, Olivia Tysoe, Michael Trauner, Saul J. Karpen, Anand Ghanekar, Binita M. Kamath · 发表于：Hepatology Communications · 年份：2024 · DOI：10.1097/hc9.0000000000000389 · 被引用次数：8 · 研究领域：Liver physiology and pathology、Drug Transport and Resistance Mechanisms、Liver Diseases and Immunity

BACKGROUND: Ductular reactivity is central to the pathophysiology of cholangiopathies. Mechanisms underlying the reactive phenotype activation by exogenous inflammatory mediators and bile acids are poorly understood. METHODS: Using human extrahepatic cholangiocyte organoids (ECOs) we developed an injury model emulating the cholestatic microenvironment with exposure to inflammatory mediators and various pathogenic bile acids. Moreover, we explored roles for the bile acid activated Sphingosine-1-phosphate receptor 2 (S1PR2) and potential beneficial effects of therapeutic bile acids UDCA and norUDCA. RESULTS: Synergistic exposure to bile acids (taurocholic acid, glycocholic acid, glycochenodeoxycholic acid) and TNF-α for 24 hours induced a reactive state as measured by ECO diameter, proliferation, lactate dehydrogenase activity and reactive phenotype markers. While NorUDCA and UDCA treatments given 8 hours after injury induction both suppressed reactive phenotype activation and most injury parameters, proliferation was improved by NorUDCA only. Extrahepatic cholangiocyte organoid stimulation with S1PR2 agonist sphingosine-1-phosphate reproduced the cholangiocyte reactive state and upregulated S1PR2 downstream mediators; these effects were suppressed by S1PR2 antagonist JET-013 (JET), downstream mediator extracellular signal-regulated kinase 1/2 inhibitor, and by norUDCA or UDCA treatments. JET also partially suppressed reactive phenotype after bile acid injury. CONCLUSIONS: We d...