Disrupted Hepatocyte Maturation and Immune Cell Development Contribute to Altered Fibrosis in a Mouse Model of Alagille Syndrome

Belangrijkste concepten

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.

Samenvatting

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.

Statistieken

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.

Citaten

"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."

Belangrijkste Inzichten Gedestilleerd Uit

Jag1 Insufficiency Disrupts Neonatal T Cell Differentiation and Impairs Hepatocyte Maturation, Leading to Altered Liver Fibrosis

by Masek,J., Fi... om www.biorxiv.org 10-25-2022

https://www.biorxiv.org/content/10.1101/2022.10.24.513578v3

Diepere vragen

How do the developmental defects in hepatocytes and T cells interact to determine the specific fibrotic patterns observed in Alagille syndrome, such as the predominance of pericellular fibrosis over bridging fibrosis?

In Alagille syndrome (ALGS), the developmental defects in hepatocytes and T cells interact to influence the fibrotic patterns observed in the liver. The hepatocyte immaturity observed in ALGS, characterized by an immature hepatocyte phenotype and a limited capacity to transform into an activated pro-inflammatory state, can impact the fibrotic response. Immature hepatocytes may fail to attract T cells to the liver due to their low inflammatory signature, leading to a reduced inflammatory response in the liver. This reduced inflammatory response may contribute to the specific fibrotic patterns observed in ALGS, such as the predominance of pericellular fibrosis over bridging fibrosis. Pericellular fibrosis, characterized by fibrotic changes around individual hepatocytes, may be more prominent in ALGS due to the altered interaction between immature hepatocytes and T cells, leading to a localized fibrotic response in the liver.

What are the potential therapeutic implications of modulating Notch signaling to target both the hepatocyte and immune system abnormalities in Alagille syndrome?

Modulating Notch signaling presents potential therapeutic implications for targeting both the hepatocyte and immune system abnormalities in Alagille syndrome. By targeting Notch signaling pathways that regulate hepatocyte maturation and injury response, it may be possible to promote the differentiation of immature hepatocytes into mature, functional hepatocytes. This could help improve liver function and reduce the progression of fibrosis in ALGS. Additionally, modulating Notch signaling in the immune system, particularly in T cell development and function, could help restore immune balance and reduce inflammation in the liver. Targeting Notch signaling pathways in both hepatocytes and immune cells may offer a comprehensive approach to addressing the underlying abnormalities in ALGS and potentially mitigating liver fibrosis progression.

Given the role of Notch signaling in regulating stem/progenitor cell function, could the altered Notch signaling in Alagille syndrome also impact liver regenerative capacity and susceptibility to liver cancer?

The altered Notch signaling in Alagille syndrome could indeed impact liver regenerative capacity and susceptibility to liver cancer. Notch signaling plays a crucial role in regulating stem/progenitor cell function in the liver, influencing processes such as cell differentiation, proliferation, and regeneration. In ALGS, where Notch signaling is disrupted due to mutations in JAGGED1, the liver's regenerative capacity may be compromised. This could lead to impaired regeneration of damaged liver tissue and contribute to the progression of fibrosis and liver dysfunction in ALGS.
Furthermore, dysregulated Notch signaling in ALGS may also affect the balance between cell proliferation and differentiation in the liver, potentially increasing the risk of liver cancer development. Notch signaling pathways are known to be involved in both promoting and suppressing tumor growth, depending on the context and cellular environment. Therefore, the altered Notch signaling in ALGS could influence the liver's susceptibility to developing cancerous lesions. Monitoring and potentially modulating Notch signaling pathways in the context of ALGS may be important for managing liver regenerative capacity and reducing the risk of liver cancer in affected individuals.