Year: 2024
Type: article
Abstract: Fibrosis contributes to tissue repair, but excessive fibrosis disrupts organ function. Alagille syndrome (ALGS, caused by mutations in JAGGED1 ) results in liver disease and characteristic fibrosis. Here, we show that Jag1 Ndr/Ndr mice, a model for ALGS, recapitulate ALGS-like fibrosis. Single-cell RNA-seq and multi-color flow cytometry of the liver revealed immature hepatocytes and paradoxically low intrahepatic T cell infiltration despite cholestasis in Jag1 Ndr/Ndr mice. Thymic and splenic regulatory T cells (Tregs) were enriched and Jag1 Ndr/Ndr lymphocyte immune and fibrotic capacity was tested with adoptive transfer into Rag1 −/− mice, challenged with dextran sulfate sodium (DSS) or bile duct ligation (BDL). Transplanted Jag1 Ndr/Ndr lymphocytes were less inflammatory with fewer activated T cells than Jag1 +/+ lymphocytes in response to DSS. Cholestasis induced by BDL in Rag1 −/− mice with Jag1 Ndr/Ndr lymphocytes resulted in periportal Treg accumulation and three-fold less periportal fibrosis than in Rag1 −/− mice with Jag1 +/+ lymphocytes. Finally, the Jag1 Ndr/Ndr hepatocyte expression profile and Treg overrepresentation were corroborated in patients’ liver samples. Jag1-dependent hepatic and immune defects thus interact to determine the fibrotic process in ALGS.
Source: EMBO Molecular Medicine
Authors: Jan Mašek, Iva Filipovic, Noémi Van Hul, Lenka Belicová, Markéta Jiroušková, Daniel V Oliveira, Anna Maria Frontino, Simona Hankeova, Jingyan He, Fabio Turetti, Afshan Iqbal, Igor Červenka, Lenka Sarnová, Elisabeth Verboven, Tomáš Brabec, Niklas K Björkström, Martin Gregor, Jan Dobeš, Emma R Andersson
Language: English
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,890
Funders: Univerzita Karlova v Praze, Grantová Agentura, Univerzita Karlova, European Commission, Grantová Agentura České Republiky, Cancerfonden, Karolinska Institutet, Vetenskapsrådet, European Association for the Study of the Liver, HORIZON EUROPE Framework Programme, Uppsala Multidisciplinary Center for Advanced Computational Science, Center for Innovative Medicine, H2020 Marie Skłodowska-Curie Actions, HORIZON EUROPE Marie Sklodowska-Curie Actions, NextGenerationEU
Awards: G1005326806, G1140045064, G1241006667, G1273951262, G1513205627, G1661122724, G1671640789, G1892925485, Uncovering the Wnt Destruction complex effects on NOTCH receptor signaling in vertebrates, G2678520069, Mechanisms of cell plasticity in the liver, G3001329863, G3321450376, Unravelling the Notch code in hepatic portal vein mesenchyme: Master controller of portal triad development and architecture?, The role of Aire-expressing ILC3 like cells in the regulation of Th17 response, G5379855762, G5418730632, G6265702644, G6445529851, G712881263, Targeting mechanical properties and mechanotransduction in hepatocellular carcinoma, The function of NK and NKT cells in thymic negative selection, G796431723, G8309358643
OpenAlex ID: W4403067320