ABSTRACT
Fibrosis is a physiological tissue repair mechanism, but excessive fibrosis can disrupt organ function. Alagille syndrome (ALGS), which is caused by mutations in the Notch ligand JAGGED1, results in bile duct paucity, neonatal cholestasis, and a characteristic fibrotic response. Here, we show that Jag1Ndr/Ndr mice, a model for ALGS, recapitulates ALGS-like pericellular fibrosis. Single-cell RNA-seq and multi-color flow cytometry characterization of the liver and spleen revealed immature hepatocytes and paradoxically low intrahepatic T cell infiltration in cholestatic Jag1Ndr/Ndr mice, despite an enrichment in extrahepatic (thymic and splenic) regulatory T cells (Tregs). Jag1Ndr/Ndr lymphocyte immune and fibrotic capacity was tested with adoptive immune cell transplantation 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, we show that the Jag1Ndr/Ndr hepatocyte expression profile and Treg overrepresentation are corroborated by transcriptomic data from children with ALGS. In sum, these data lead to a model in which Jag1-driven developmental hepatic and immune defects interact to determine the fibrotic process in ALGS.
Competing Interest Statement
The authors declare no conflict of interest. ERA has formerly collaborated with Travere, and Moderna, with no per-sonal remuneration and no conflict of interest.
Footnotes
The authors declare no conflict of interest. ERA has formerly collaborated with Travere, and Moderna, with no personal remuneration and no conflict of interest.
How each author was involved with the manuscript (e.g., 1study concept and design; 2acquisition of data; 3 analysis and interpretation of data; 4drafting of the manuscript; 5critical revision of the manuscript for important intellectual content; 6statistical analysis; 7obtained funding; 8technical, or material support; 9study supervision) 123456789JM12345679, IF12356, NVH2358, LB3456, MJ2356, DVO236, AMF236, SH2358, JH2356, FT236, AI236, IČ36, LS28, EV28, TB8, NB13789, MG13789, JD13579, ERA12345679
Fixed an issue with Figure Legend numbering.