Jag1 insufficiency alters liver fibrosis via T cell and hepatocyte differentiation defects
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<sup>Ndr/Ndr</sup> 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<sup>Ndr/Ndr</sup> mice. Thymic and splenic regulatory T cells (Tregs) were enriched and Jag1<sup>Ndr/Ndr</sup> lymphocyte immune and fibrotic capacity was tested with adoptive transfer into Rag1<sup>-/-</sup> mice, challenged with dextran sulfate sodium (DSS) or bile duct ligation (BDL). Transplanted Jag1<sup>Ndr/Ndr</sup> lymphocytes were less inflammatory with fewer activated T cells than Jag1<sup>+/+</sup> lymphocytes in response to DSS. Cholestasis induced by BDL in Rag1<sup>-/-</sup> mice with Jag1<sup>Ndr/Ndr</sup> lymphocytes resulted in periportal Treg accumulation and three-fold less periportal fibrosis than in Rag1<sup>-/-</sup> mice with Jag1<sup>+/+</sup> lymphocytes. Finally, the Jag1<sup>Ndr/Ndr</sup> 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.
Authors
- Lenka Sarnová
- Martin Gregor (ORCID: https://orcid.org/0000-0001-6841-9527)
- Iva Filipovic (ORCID: https://orcid.org/0000-0002-8166-5500)
- Markéta Jiroušková (ORCID: https://orcid.org/0009-0004-7173-2177)
- Niklas K. Björkström (ORCID: https://orcid.org/0000-0002-0967-076X)
- Lenka Belicová (ORCID: https://orcid.org/0000-0002-6687-630X)
- Anna Maria Frontino (ORCID: https://orcid.org/0000-0001-7154-9103)
- Igor Červenka (ORCID: https://orcid.org/0000-0002-9438-5161)
- Simona Hankeová (ORCID: https://orcid.org/0000-0002-7797-3818)
- Emma Andersson (ORCID: https://orcid.org/0000-0002-8608-625X)
- Tomáš Brabec (ORCID: https://orcid.org/0000-0002-2498-1128)
- Afshan Iqbal (ORCID: https://orcid.org/0009-0006-4246-9925)
- Jingyan He (ORCID: https://orcid.org/0000-0002-7405-5800)
- Fabio Turetti (ORCID: https://orcid.org/0000-0003-0440-5489)
- J. Mašek (ORCID: https://orcid.org/0000-0003-2904-3808)
- Noémi Van Hul (ORCID: https://orcid.org/0000-0003-1410-8808)
- Daniel V. Oliveira (ORCID: https://orcid.org/0000-0003-0622-2934)
- Elisabeth Verboven (ORCID: https://orcid.org/0000-0003-1432-2791)
- Jan Dobeš (ORCID: https://orcid.org/0000-0003-1853-1603)
Institutions
- Karolinska University Hospital (SE)
- Czech Academy of Sciences (CZ)
- Charles University (CZ)
- Karolinska Institutet (SE)
- Institute of Molecular Genetics (RU)
- Czech Academy of Sciences, Institute of Molecular Genetics (CZ)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2024-10-02
- DOI
- https://doi.org/10.1038/s44321-024-00145-8
- Citations
- 3
- Primary Topic
- Pediatric Hepatobiliary Diseases and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 1.72
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