Livers of patients with ALGS display significant premature senescence despite Jagged1 mutation
The livers of pediatric patients with Alagille syndrome (ALGS) display significant premature senescence despite Jagged1 mutation, underscoring the complexity of senescence and SASP development pathways, according to a new study.
The findings highlight the need for further research into the role of Jagged1 and Notch2 signaling in the development of senescence and senescence-associated secretory phenotype (SASP) in the liver, with the ultimate aim of developing targeted therapies for patients with ALGS.
The researchers prospectively obtained liver tissue from patients with ALGS at the time of liver transplantation (n = 5) and compared it to control livers (n = 5). They found evidence of advanced premature senescence in the livers of all five JAG1 mutated ALGS pediatric patients, as indicated by increased senescence-associated beta-galactosidase activity (P < 0.05), increased p16 and p21 gene expression (P < 0.01), and increased p16 and γH2AX protein expression (P < 0.01).
The researchers observed senescence in hepatocytes of the entire liver parenchyma as well as in the remaining bile ducts. However, the classical SASP markers TGF-β1, IL-6, and IL-8 were not overexpressed in the livers of the patients studied.
Jannone G, de Magnée C, Tambucci R, et al. Premature senescence of the liver in Alagille patients. PLoS One. 2023;18(4):e0285019. doi: 10.1371/journal.pone.0285019. PMID: 37099537; PMCID: PMC10132695.