Cellular senescence exacerbates injury and impairs regeneration in biliary disease

Abstract

Senescence is a highly efficient mechanism that provides an irreversible barrier to cell cycle progression to prevent undesired proliferation. However, under pathological circumstances, senescence can adversely affect organ function, viability and regeneration. In the context of biliary disease, we hypothesize that senescence is initiated in the bile ducts and spreads to the liver parenchyma, impairing the liver’s regenerative capacity and aggravating the condition.

We have developed a mouse model of biliary senescence, based on the conditional deletion of Mdm2 in bile ducts, that mimics clinical features of biliary disease. Using this model, we studied the underlying mechanisms that characterize biliary disease, and established an essential role of TGFβ in paracrine senescence-associated regeneration.

Lastly, we disrupted TGFβ signalling to therapeutically rescue this phenotype in our model of biliary senescence.

These results reveal the detrimental role of senescence in biliary disease, and a TGFβ- dependent mechanism for dissemination of senescence from the biliary epithelium to the parenchyma, impairing liver function. Finally, we have identified TGFβ signalling disruption as a potential therapeutic target to limit senescence-dependent aggravation in human cholangiopathies.