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Objectives: Premature senescence has been extensively characterized in adult chronic hepatobiliary diseases and worsens liver function and fibrosis evolution, generating a need for senolytic therapies that can be translated to clinical applications. Mesenchymal stem cells (MSCs), also referred as medicinal signaling cells, repeatedly demonstrated to improve liver function and histology in chronic liver disease and even reduced cardiac and skin senescence in aging rats. However, the effect of MSCs on liver senescence has never been investigated. Our aim was to study the effect of human adult liver-derived progenitor cells (HALPC), a suspension of liver-derived signaling cells obtained from healthy adult human liver, on liver senescence in a preclinical model of juvenile biliary cirrhosis. Methods: Bile duct ligation (BDL) was performed on 2-months old male Wistar rats and controls underwent sham procedure. Liver senescence was extensively characterized in the BDL model through senescence-associated beta-galactosidase (SA-β-gal) activity, p21 and p16 protein/gene expression, multiple immunofluorescence staining (p21, CK19, HNF4α) and gene expression of senescence-associated secretory phenotype (SASP) markers. HALPC were then transplanted through the penile vein of BDL rats 48 hours after the surgery at two doses (12.5 x 106 cells/kg versus 1.25 x 106 cells/kg, n=6 for each group) and compared to the vehicle (n=6). All animals were sacrificed 72 hours after the injection. Results: Our results show the progressive development of senescence in BDL livers, the earliest marker of senescence being p21, already detectable 48 hours after the surgery (p<0.05). Senescence first developed in cholangiocytes and subsequently extended to hepatocytes in the parenchyma. Gene expression of SASP markers IL6, IL1β and TGFβ1 increased in diseased livers (p<0.05). The progression of senescence strongly correlated with fibrosis and ductular reaction (DR) development in our model of biliary cirrhosis (r=0.96 and 0.97 respectively; p<0.0001). HALPC injections (high and low doses) decreased senescence in BDL rats (p21 gene expression) (p<0.05). The high dose injection also improved biliary injury (serum γGT) and DR (Sox9 gene expression) as compared to low dose and vehicle subgroups (p<0.05). Conclusions: Our data position BDL as a robust model of senescence and provide evidence that HALPC can decrease liver senescence and modulate DR in biliary cirrhosis. Those results place liver-derived signaling cells as a potential senolytic tool to develop in chronic hepatobiliary diseases in order to limit the worsening of the disease related to senescence progression.
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Jannone, G., Bonaccorsi Riani, E., De Magnée, C., Tambucci, R., Evraerts, J., Ravau, J., Najimi, M., & Sokal, E. (2022). Liver-derived signaling cells improve senescence and modulate ductular reaction in biliary cirrhosis. Bioregate Forum, Louvain-la-Neuve. https://hdl.handle.net/2078.5/101442