In patients with Alagille syndrome (ALGS), JAG1-mutated livers display advanced premature senescence beginning early in life, according to findings from a prospective study published in PLoS One.
In individuals with ALGS, multisystem involvement typically includes the development of cholestasis and bile duct paucity. When ALGS-related initial cholestasis is reported, more than 75% of patients require a liver transplant prior to the age of 18 years. In fact, in more than 90% of reported cases of ALGS, a mutation in JAG1, which encodes the protein Jagged1, is linked to the senescence-associated secretory phenotype (SASP). In the absence of JAG1 anomalies, mutations in NOTCH1 are observed in up to 4% of patients with ALGS.
Although Jagged1-Notch 2 interactions are critical for development of the intrahepatic biliary tract, the Notch signaling pathway plays a role in the juxtacrine transmission of senescence, as well as in modulation and induction of the SASP. The researchers sought to explore premature senescence and SASP in the livers of patients with ALGS.
Five individuals with genetically confirmed ALGS who received a liver transplant were recruited prospectively from the pediatric gastroenterology and hepatology unit of Cliniques Universitaires Saint-Luc, in Brussels, Belgium, from 2018 through 2022. A fragment of the explanted liver was obtained from all patients with ALGS at the time of transplantation and was compared with tissue obtained from 5 control livers. Biochemical data were obtained from all patients on the day prior to transplantation but were not available for the controls.
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Overall, 1 control hepatic fragment was obtained from an explanted liver during transplant for the metabolic defect hyperoxaluria type 1, whereas 4 additional hepatic fragments were collected from diseased donors when their livers were not approved for transplantation or when a portion of their liver was not transplanted because of surgical issues.
The 5 individuals with ALGS underwent liver transplantation at a pediatric age (1-11 years). Of the 5 patients with ALGS, 3 were female and 2 were male. Of the 5 controls, 2 were adults and 3 were children.
In all patients with ALGS, a heterozygous mutation of JAG1 was substantiated. Of the 5 individuals who underwent liver transplantation, 2 received transplants because of end-stage liver disease with cirrhosis and portal hypertension, whereas 3 received transplants because of inferior quality of life associated with jaundice and pruritus.
Advanced premature senescence was observed in the livers of the 5 pediatric patients with JAG1-mutated ALGS via the following statistically significant findings:
- Increased senescence-linked beta-galactosidase activity (P <.05)
- Increased p16 and p21 gene expression (P <.01)
- Increased p16 and γH2AX protein expression (P <.01)
Results of the study demonstrated that senescence was located in the hepatocytes of the whole liver parenchyma, along with the remaining bile ducts. The livers of the 5 transplanted patients with ALGS did not overexpress the classic SASP markers—that is, transforming growth factor-beta 1, interleukin (IL)-6, and IL-8.
The researchers concluded, “We demonstrate for the first time that ALGS livers display important premature senescence despite Jagged1 mutation, underlying the complexity of senescence and SASP development pathways.”
Jannone G, de Magnée C, Tambucci R, et al. Premature senescence of the liver in Alagille patients. PLoS One. Published online April 26, 2023. doi:10.1371/journal.pone.0285019