Senolytic therapies have a place in pediatric biliary cirrhosis
(2022) 2nd International Congress on Biliary Atresia and Related Diseases (BARD) — Location: Bruges, Belgique (17.June.2022)
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- Authors
Sokal, Etienne 
- Abstract
- Aim of the study: Premature senescence has been extensively characterized in adult chronic hepatobiliary diseases and can worsen liver function and fibrosis evolution. Since new therapeutic options are needed in pediatric biliary cirrhosis to delay liver transplantation, our aim was to investigate the presence of premature senescence in biliary atresia (BA) and to test the senolytic properties of Medicinal Signaling Cells in a preclinical model of biliary cirrhosis. Method: Senescence was investigated through senescence-associated β-galactosidase activity assay (SA-β-gal) as well as p16 and p21 gene/protein expression in BA livers at the time of hepatoportoenterostomy (n=5) or liver transplantation (n=30) as compared to control livers (n=10). Co-localized expression of senescence (γH2AX or p21) with CK19, HNF4α, αSMA and Ki67 was also assessed. Bile duct ligation (BDL) was performed on 2-months old rats and senescence was characterized in the model through above-mentioned techniques. Human allogeneic liver-derived progenitor cells (HALPC) were injected in BDL rats 48 hours after the surgery at high (12.5 x 106 cells/kg, n=6) versus low dose (1.25 x 106 cells/kg, n=6) and compared to the vehicle (n=6). Results: Senescence was similarly increased in both BA stages as compared to control livers (SA-β-gal: 5.9±1.4 and 5.4±1 vs 0.6±0.1 %stained area/total, p<0.01) and was also confirmed in BDL livers one and two weeks after the surgery (SA-β-gal: 1.6±0.6 and 6.6±2.4 vs 0.2±0.1 %stained area/total, p<0.05). The pattern of senescence in BA and BDL was similar as senescence first appeared in cholangiocytes of the ductular reaction and subsequently developed in hepatocytes. HALPC transplantation at both doses decreased senescence in BDL rats (p21 gene expression: 0.4±0.04 fold change and 0.5±0.1 vs 1±0.2; p<0.05). Conclusion: Premature senescence occurs in BA livers and HALPC display senolytic properties in a preclinical model of biliary cirrhosis
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Citations
Jannone, G., Bonaccorsi Riani, E., De Magnée, C., Tambucci, R., Evraerts, J., Ravau, J., Najimi, M., & Sokal, E. (2022). Senolytic therapies have a place in pediatric biliary cirrhosis. 2nd International Congress on Biliary Atresia and Related Diseases (BARD), Bruges, Belgique. https://hdl.handle.net/2078.5/103354