Telomere dysfunction promotes cholangiocyte senescence and biliary fibrosis in Primary Sclerosing Cholangitis.

Abstract

Cellular senescence and biliary fibrosis are prototypical features of obliterative cholangiopathies, such as Primary Sclerosing Cholangitis (PSC). Telomere dysfunction can lead to senescence either through telomere erosion or damaged telomeres. Our goal was to investigate a mechanistic relationship between telomere damage and biliary fibrosis in PSC. Telomere attrition was observed in the bile ducts of PSC patients along with a reduction in telomerase reverse transcriptase (TERT) expression compared to normal livers. Similarly, liver tissue from mice models of biliary fibrosis showed telomere attrition with increased damage at telomeres measured as telomere-associated foci (TAF). Cellular models of senescence induction increased the TAFs in cholangiocytes. This coincided with decreased TERT expression and increased senescence, which was rescued by modulating TERT levels. Epigenetic analysis revealed increased acquisition of repressive histone methylation at the TERT promoter which correlated with decreased TERT transcription. Cholangiocyte-selective deletion of TERT in mice exacerbated fibrosis whereas androgen therapy towards telomerase rescued liver fibrosis and liver function in genetic mouse model of PSC. Our results demonstrate a mechanistic role for telomere dysfunction in cellular senescence and fibrosis that characterize PSC. This suggests that PSC may be, in part, a telomere biology disorder, and identifies TERT as a potential therapeutic target.