Primary cilia as a targetable node between biliary injury, senescence and regeneration in liver transplantation

Background & Aims:Biliary complications are a major cause of morbidity and mortality in liver transplantation. Up to 25% ofpatients that develop biliary complications require additional surgical procedures, re-transplantation or die in the absence of asuitable regraft. Here, we investigate the role of the primary cilium, a highly specialised sensory organelle, in biliary injury leading topost-transplant biliary complications. Methods:Human biopsies were used to study the structure and function of primary cilia in liver transplant recipients that developbiliary complications (n = 7) in comparison with recipients without biliary complications (n = 12). To study the biological effects ofthe primary cilia during transplantation, we generated murine models that recapitulate liver procurement and cold storage, andassessed the elimination of the primary cilia in biliary epithelial cells in theK19CreERTKif3afl/flmouse model. To explore themolecular mechanisms responsible for the observed phenotypes we usedin vitromodels of ischemia, cellular senescence andprimary cilia ablation. Finally, we used pharmacological and genetic approaches to target cellular senescence and the primarycilia, both in mouse models and discarded human donor livers. Results:Prolonged ischemic periods before transplantation result in ciliary shortening and cellular senescence, an irreversible cellcycle arrest that blocks regeneration. Our results indicate that primary cilia damage results in biliary injury and a loss of regen-erative potential. Senescence negatively impacts primary cilia structure and triggers a negative feedback loop that further impairsregeneration. Finally, we explore how targeted interventions for cellular senescence and/or the stabilisation of the primary ciliaimprove biliary regeneration following ischemic injury. Conclusions:Primary cilia play an essential role in biliary regeneration and we demonstrate that senolytics and cilia-stabilisingtreatments provide a potential therapeutic opportunity to reduce the rate of biliary complications and improve clinical out-comes in liver transplantation. (c) 2024 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. This is an open access article underthe CC BY license (http://creativecommons.org/licenses/by/4.0/)