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Jag1 insufficiency alters liver fibrosis via T cell and hepatocyte differentiation defects

J. Mašek, I. Filipovic, N. Van Hul, L. Belicová, M. Jiroušková, DV. Oliveira, AM. Frontino, S. Hankeova, J. He, F. Turetti, A. Iqbal, I. Červenka, L. Sarnová, E. Verboven, T. Brabec, NK. Björkström, M. Gregor, J. Dobeš, ER. Andersson

. 2024 ; 16 (11) : 2946-2975. [pub] 20241002

Jazyk angličtina Země Německo

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc25003619

Grantová podpora
24-10622S Czech Science Foundation
21-21736S Czech Science Foundation
21-22435M Czech Science Foundation
22-30879S Czech Science Foundation
LX22NPO5102 Next Generation EU
Post Doc Fellowship Cancerfonden (Swedish Cancer Society)
CZ.02.01.01/00/22_008/0004597 One Health framework
Primus/21/MED/003 Charles University
PRIMUS/21/SCI/006 Charles University
Junior Fund Charles University
LL2315 Ministry of Education, Youth and Sports Grant ERC CZ
2-560/2015-280 Karolinska Institutet (KI)
2-2110/2019-7 Karolinska Institutet (KI)
2-195/2021 Karolinska Institutet (KI)
CIMED; 2-538/2014-29 Karolinska Institutet (KI)
2018-05973 Vetenskapsrådet (VR)
CZ.02.01.01/00/22_010/0002902 MSCA Fellowships CZ
Daniel Alagille Award 2017 European Association for the Study of the Liver (EASL)
Sheila Sherlock Post Doc fellowship European Association for the Study of the Liver (EASL)
101057846 EC | Horizon Europe | Excellent Science | HORIZON EUROPE Marie Sklodowska-Curie Actions (MSCA)
2019-01350 the Swedish Research Council / Vetenskapsrådet

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 Jag1Ndr/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 Jag1Ndr/Ndr mice. Thymic and splenic regulatory T cells (Tregs) were enriched and Jag1Ndr/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 Jag1Ndr/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 Jag1Ndr/Ndr lymphocytes resulted in periportal Treg accumulation and three-fold less periportal fibrosis than in Rag1-/- mice with Jag1+/+ lymphocytes. Finally, the Jag1Ndr/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.

Citace poskytuje Crossref.org

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