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 mice, a model for ALGS, recapitulate ALGS-like fibrosis. Single-cell RNA-seq a...
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Published in | EMBO molecular medicine |
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Main Authors | , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Germany
02.10.2024
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Subjects | |
Online Access | Get full text |
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Summary: | 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
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
mice. Thymic and splenic regulatory T cells (Tregs) were enriched and Jag1
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
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
lymphocytes resulted in periportal Treg accumulation and three-fold less periportal fibrosis than in Rag1
mice with Jag1
lymphocytes. Finally, the Jag1
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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1757-4684 1757-4684 |
DOI: | 10.1038/s44321-024-00145-8 |