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Modeling ischemic cholangiopathy in human cholangiocyte organoid for screening of novel cholangio-protective agents

ABSTRACT: Ischemic cholangiopathy refers to biliary damage caused by disruption of blood supply in the peribiliary plexus. Detailed knowledge of ischemic cholangiopathy pathogenesis remains scarce due to the lack of appropriate in vitro models. We aimed to recapitulate ischemia-evoked biliary damage using human intrahepatic cholangiocyte organoids (ICOs) in vitro for the study of ischemic cholangiopathy and preclinical drug discovery. In our study, we found that ICOs can recapitulate ischemic cholangiopathy in vitro, featured by extensive apoptosis and reduced cell proliferation, which could be partially restored by reoxygenation. AAT is identified as a novel cholangiocellular protective agent by restoring proliferation and preventing apoptosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE198860 | GEO | 2022/11/01

REPOSITORIES: GEO

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Project description:Background and aims: Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies with features of biliary tract differentiation. Incidence is increasing worldwide and these cancers collectively represent the second most common primary liver tumour. CCAs are characterized by genetic and epigenetic alterations that determine their pathogenesis. Hypermethylation of the SOX17 promoter was recently reported in human CCA tumours. SOX17 seems to be a key transcription factor for biliary embryogenesis. Here, we evaluated the role of SOX17 in cholangiocyte differentiation and in cholangiocarcinogenesis. Methods: SOX17 expression and function was evaluated during the differentiation of human induced pluripotent stem cells (iPSC) into cholangiocytes, in the dedifferentiation of normal human cholangiocytes (NHC) and in cholangiocarcinogenesis. Lentiviruses overexpressing or knocking-down SOX17 (Lent-SOX17 and Lent-shRNA-SOX17, respectively) were used. Gene expression arrays were performed. Results: SOX17 expression is highly induced in the later stages of cholangiocyte differentiation from iPSC, and mediates the acquisition of the biliary markers cytokeratin (CK) 7 and 19, as well as fibronectin. In addition, SOX17 becomes progressively downregulated in NHC over serial cell passages in vitro and this event is associated with cellular senescence; however, experimental SOX17 knocking-down in differentiated NHC decreased the expression of both CK7 and 19 without affecting cellular senescence. SOX17 expression is reduced in CCA cells compared to NHC, as well as in human CCA tissue compared to human gallbladder tissue or NHC. In a murine xenograft model, overexpression of SOX17 in CCA cells decreased their tumorigenic capacity related to increased oxidative stress and apoptosis. Interestingly, overexpression of SOX17 in NHC did not affect their survival. Moreover, SOX17 overexpression inhibited the Wnt/β-catenin-dependent proliferation in CCA cells and was associated with upregulation of biliary epithelial markers and restoration of the primary cilium length. Both Wnt3a and TGFβ1 decreased SOX17 expression in NHC in a DNMT1-dependent manner. Inhibition of DNMT1 in CCA cells with siRNAs or pharmacological drugs upregulated SOX17 expression. Conclusion: SOX17 regulates the cholangiocyte phenotype and becomes epigenetically downregulated in CCA. SOX17 acts as a tumour suppressor in CCA, and restoration of its expression may have important therapeutic value.

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Modeling ischemic cholangiopathy in human cholangiocyte organoid for screening of novel cholangio-protective agents

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