Senescence and senotherapies in biliary atresia and biliary cirrhosis.

Autor:	Jannone G; Pediatric Hepatology and Cell Therapy Unit, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium., Bonaccorsi Riani E; Abdominal Transplantation Unit, Department of Surgery, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium., de Magnée C; Pediatric Surgery and Transplantation Unit, Department of Surgery, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium., Tambucci R; Pediatric Surgery and Transplantation Unit, Department of Surgery, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium., Evraerts J; Pediatric Hepatology and Cell Therapy Unit, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium., Ravau J; Pediatric Hepatology and Cell Therapy Unit, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium., Baldin P; Department of Anatomopathology, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium., Bouzin C; IREC Imaging Platform (2IP), Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium., Loriot A; Computational Biology and Bioinformatics Unit, de Duve Institute, UCLouvain, Brussels, Belgium., Gatto L; Computational Biology and Bioinformatics Unit, de Duve Institute, UCLouvain, Brussels, Belgium., Decottignies A; Genetic and Epigenetic Alterations of Genomes Group, de Duve Institute, UCLouvain, Brussels, Belgium., Najimi M; Pediatric Hepatology and Cell Therapy Unit, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium., Sokal EM; Pediatric Hepatology and Cell Therapy Unit, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium.
Jazyk:	angličtina
Zdroj:	Aging [Aging (Albany NY)] 2023 May 18; Vol. 15 (11), pp. 4576-4599. Date of Electronic Publication: 2023 May 18.
DOI:	10.18632/aging.204700
Abstrakt:	Background: Premature senescence occurs in adult hepatobiliary diseases and worsens the prognosis through deleterious liver remodeling and hepatic dysfunction. Senescence might also arises in biliary atresia (BA), the first cause of pediatric liver transplantation. Since alternatives to transplantation are needed, our aim was to investigate premature senescence in BA and to assess senotherapies in a preclinical model of biliary cirrhosis. Methods: BA liver tissues were prospectively obtained at hepatoportoenterostomy (n=5) and liver transplantation (n=30) and compared to controls (n=10). Senescence was investigated through spatial whole transcriptome analysis, SA-β-gal activity, p16 and p21 expression, γ-H2AX and senescence-associated secretory phenotype (SASP). Human allogenic liver-derived progenitor cells (HALPC) or dasatinib and quercetin (D+Q) were administrated to two-month-old Wistar rats after bile duct ligation (BDL). Results: Advanced premature senescence was evidenced in BA livers from early stage and continued to progress until liver transplantation. Senescence and SASP were predominant in cholangiocytes, but also present in surrounding hepatocytes. HALPC but not D+Q reduced the early marker of senescence p21 in BDL rats and improved biliary injury (serum γGT and Sox9 expression) and hepatocytes mass loss ( Hnf4a ). Conclusions: BA livers displayed advanced cellular senescence at diagnosis that continued to progress until liver transplantation. HALPC reduced early senescence and improved liver disease in a preclinical model of BA, providing encouraging preliminary results regarding the use of senotherapies in pediatric biliary cirrhosis.
Databáze:	MEDLINE
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