Core Concepts
Jag1 mutation in a mouse model of Alagille syndrome leads to immature hepatocytes and altered T cell development, which interact to modulate the fibrotic response in the liver.
Abstract
The study investigates the mechanisms underlying liver fibrosis in a mouse model of Alagille syndrome (ALGS), a genetic disorder caused by mutations in the Notch ligand JAGGED1 (JAG1). Using a combination of single-cell RNA sequencing, flow cytometry, and adoptive immune cell transfer experiments, the authors demonstrate that Jag1 mutation in the ALGS mouse model (Jag1Ndr/Ndr) leads to:
Immature hepatocyte phenotype: Jag1Ndr/Ndr neonatal livers show an enrichment of proliferative hepatoblasts and depletion of mature hepatocytes, suggesting a hepatocyte differentiation/maturation defect. This immature hepatocyte phenotype is also observed in liver samples from ALGS patients.
Disrupted thymic development and T cell differentiation: Jag1Ndr/Ndr mice exhibit a smaller thymus, reduced double-positive thymocytes, and an increase in regulatory T cells (Tregs) in the thymus and spleen.
Attenuated T cell response to liver injury: Adoptive transfer of Jag1Ndr/Ndr lymphocytes into lymphodeficient mice results in less inflammation and fibrosis in response to dextran sodium sulfate (DSS)-induced colitis, compared to Jag1+/+ lymphocytes.
Reduced periportal fibrosis in cholestatic liver injury: Bile duct ligation (BDL) in lymphodeficient mice receiving Jag1Ndr/Ndr lymphocytes leads to a 3-fold reduction in periportal fibrosis compared to mice receiving Jag1+/+ lymphocytes, potentially due to the enrichment of Tregs in the Jag1Ndr/Ndr lymphocyte population.
These findings suggest that Jag1 mutation in ALGS impacts both hepatocyte maturation and immune system development, and the interaction between these two processes contributes to the atypical fibrotic response observed in ALGS.
Stats
Jag1Ndr/Ndr mice exhibit a 3-fold increase in proliferative hepatoblasts and a 1/3 reduction in mature hepatocytes compared to controls at postnatal day 3.
Jag1Ndr/Ndr livers show a 1.7-fold decrease in the mature hepatocyte marker CYP1A2 protein at postnatal day 10.
Jag1Ndr/Ndr mice have a 61% reduction in the frequency of CD4+ T cells in the liver compared to controls at postnatal day 3.
Bile duct ligation in lymphodeficient mice receiving Jag1Ndr/Ndr lymphocytes results in a 3-fold reduction in periportal fibrosis compared to mice receiving Jag1+/+ lymphocytes.
Quotes
"Jag1Ndr/Ndr hepatocytes exhibit an immature phenotype, with a limited capacity to transform into the activated pro-inflammatory state."
"The enrichment in Tregs in Jag1Ndr/Ndr mice is, however, in line with the reported Treg expansion upon Notch1 or RBPj inactivation."
"The fact that Jag1Ndr/Ndr lymphocytes limit periportal fibrosis after the BDL suggests that portal fibroblast-induced fibrosis may be limited by Jag1-deficient T cell populations."