{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T17:43:11Z","timestamp":1768671791243,"version":"3.49.0"},"reference-count":21,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2023,4,26]],"date-time":"2023-04-26T00:00:00Z","timestamp":1682467200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003134","name":"Fonds pour la Formation \u00e0 la Recherche dans l\u2019Industrie et dans l\u2019Agriculture","doi-asserted-by":"publisher","award":["FC29559"],"award-info":[{"award-number":["FC29559"]}],"id":[{"id":"10.13039\/501100003134","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Introduction<\/jats:title>\n<jats:p>Alagille syndrome (ALGS) is an autosomal dominant disease characterized by a multisystem involvement including bile duct paucity and cholestasis, caused by <jats:italic>JAG1<\/jats:italic> or <jats:italic>NOTCH2<\/jats:italic> mutations in most of the cases. Jagged1-Notch2 interactions are known to be crucial for intrahepatic biliary tract development, but the Notch signaling pathway is also involved in the juxtacrine transmission of senescence and in the induction and modulation of the senescence-associated secretory phenotype (SASP).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Aim<\/jats:title>\n<jats:p>Our aim was to investigate premature senescence and SASP in ALGS livers.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Liver tissue from ALGS patients was prospectively obtained at the time of liver transplantation (n = 5) and compared to control livers (n = 5).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Results<\/jats:title>\n<jats:p>We evidenced advanced premature senescence in the livers of five <jats:italic>JAG1<\/jats:italic> mutated ALGS pediatric patients through increased senescence-associated beta-galactosidase activity (p&lt;0.05), increased p16 and p21 gene expression (p&lt;0.01), and increased p16 and \u03b3H2AX protein expression (p&lt;0.01). Senescence was located in hepatocytes of the whole liver parenchyma as well as in remaining bile ducts. The classical SASP markers TGF-\u03b21, IL-6, and IL-8 were not overexpressed in the livers of our patients.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec005\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>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.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0285019","type":"journal-article","created":{"date-parts":[[2023,4,26]],"date-time":"2023-04-26T17:35:25Z","timestamp":1682530525000},"page":"e0285019","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Premature senescence of the liver in Alagille 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Magn\u00e9e","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberto","family":"Tambucci","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Evraerts","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joachim","family":"Ravau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7329-9635","authenticated-orcid":true,"given":"Mustapha","family":"Najimi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Etienne Marc","family":"Sokal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,4,26]]},"reference":[{"issue":"11","key":"pone.0285019.ref001","article-title":"Alagille Syndrome: Diagnostic Challenges and Advances in Management","volume":"10","author":"MD Ayoub","year":"2020","journal-title":"Diagnostics (Basel)"},{"issue":"3","key":"pone.0285019.ref002","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1002\/hep4.1468","article-title":"Outcomes of Childhood Cholestasis in Alagille Syndrome: Results of a Multicenter Observational Study","volume":"4","author":"BM Kamath","year":"2020","journal-title":"Hepatol Commun"},{"issue":"12","key":"pone.0285019.ref003","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1002\/humu.23879","article-title":"Alagille syndrome mutation update: Comprehensive overview of JAG1 and NOTCH2 mutation frequencies and insight into missense variant classification","volume":"40","author":"MA Gilbert","year":"2019","journal-title":"Hum Mutat"},{"key":"pone.0285019.ref004","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1146\/annurev-pathmechdis-012418-013013","article-title":"Development of the Intrahepatic and 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