Aging (senescent) bile duct cells , i.e., cholangiocytes, demonstrate an arrest of the cell cycle, hypersecretion of inflammatory molecules and resistance to cell death. O’Hara et al., previously reported that aging of cholangiocytes is a feature in PSC patients, and that this event is regulated by a central molecular pathway (Ras signaling) as well as the transcription factor, ETS1. In a recently published manuscript, his team further explored the molecular mechanisms regulating senescent cholangiocyte resistance to cell death. Using PSC patients derived tissues and an inducible cell culture model of cholangiocyte senescence, O’Hara et al., reported that the transcription factor, ETS1, interacts with a chromatin modifying enzyme, called p300, to induce the expression of a pro-survival protein, BCL-xL, which in turn promotes senescent cholangiocyte resistance to cell death. These new exciting data suggest that ETS1 is a central regulator of the senescent cholangiocyte phenotype. This novel knowledge provides the basis for exploring new targets for the therapeutic removal of aging cholangiocyte as an approach to treat PSC.
Read the full abstract from the PSC team.