Senolytic treatment preserves biliary regenerative capacity lost through cellular senescence during cold storage

Abstract

Liver transplantation is the only curative option for patients with end-stage liver disease. Despite improvements in surgical techniques, nonanastomotic strictures (characterized by the progressive loss of biliary tract architecture) continue to occur after liver transplantation, negatively affecting liver function and frequently leading to graft loss and retransplantation. To study the biological effects of organ preservation before liver transplantation, we generated murine models that recapitulate liver procurement and static cold storage. In these models, we explored the response of cholangiocytes and hepatocytes to cold storage, focusing on responses that affect liver regeneration, including DNA damage, apoptosis, and cellular senescence. We show that biliary senescence was induced during organ retrieval and exacerbated during static cold storage, resulting in impaired biliary regeneration. We identified decoy receptor 2 (DCR2)–dependent responses in cholangiocytes and hepatocytes, which differentially affected the outcome of those populations during cold storage. Moreover, CRISPR-mediated DCR2 knockdown in vitro increased cholangiocyte proliferation and decreased cellular senescence but had the opposite effect in hepatocytes. Using the p21 KO model to inhibit senescence onset, we showed that biliary tract architecture was better preserved during cold storage. Similar results were achieved by administering senolytic ABT737 to mice before procurement. Last, we perfused senolytics into discarded human donor livers and showed that biliary architecture and regenerative capacities were better preserved. Our results indicate that cholangiocytes are susceptible to senescence and identify the use of senolytics and the combination of senotherapies and machine-perfusion preservation to prevent this phenotype and reduce the incidence of biliary injury after transplantation.

An Analysis of 10,000 Cases of Living Donor Liver Transplantation in Japan

“…To treat aged liver specimens, approaches, such as the use of senolytics with or without machine perfusion to restore old or damaged liver tissue, have been reported. 33 Several agents, such as quercetin, can reportedly eliminate senile cells that exert a detrimental effect on the liver. 34 Other reports have demonstrated the utility of stem cell therapy to strengthen and recondition aged liver tissue before implantation or even before donor surgery in countries where deceased donors are scarce.…”

“…To treat aged liver specimens, approaches, such as the use of senolytics with or without machine perfusion to restore old or damaged liver tissue, have been reported 33 . Several agents, such as quercetin, can reportedly eliminate senile cells that exert a detrimental effect on the liver 34 .…”

Emerging Therapeutic Approaches to Target the Dark Side of Senescent Cells: New Hopes to Treat Aging as a Disease and to Delay Age-Related Pathologies

“…PTEN deficiency causes PICS without initiating DDR via the PI3K/AKt/mTOR-p53-p21 signaling pathway. Mammalian rapamycin target complexes 1 and 2 (mTORC1 and mTORC2) interact with the mouse double minute 2 (MDM2) homolog to control p53 by direct phosphorylation and, subsequently, accumulation of p21 induces senescence [ 70 ]. PICS is convenient for pro-senescent cancer therapy, as it is not followed by typical hyperproliferation or DDR.…”

Targeting Cellular Senescence in Organ Transplantation

“…7 The work by Stuart J. Forbes and coworkers in Science Translational Medicine contributes to another milestone in the "senescence story" demonstrating that the depletion of senescent cells preserved biliary architecture and regenerative capacities in cold storage preserved livers. 8 The authors observed that hepatocytes and cholangiocytes (epithelial cells representing the inner lining of bile ducts) behaved differently in response to cold storage. Although prolonged cold storage did not alter the gross anatomy of the liver, detachment of cholangiocytes into the lumen was observed.…”