肝臓移植の成功率を高める可能性のある薬剤の発見(Drug discovery may boost liver transplant success)

既存の薬剤が、移植の過程でドナーの肝臓を損傷から守り、移植後に起こる合併症を軽減する可能性があることが示唆された。 An existing drug could protect donor livers from damage during the transplantation process and reduce complications that occur afterwards, a study suggests.

2022-12-21 エディンバラ大学

<関連情報>

• https://www.ed.ac.uk/news/2022/drug-discovery-may-boost-liver-transplant-success
• https://www.science.org/doi/10.1126/scitranslmed.abj4375

低温保存中に細胞の老化により失われた胆道再生能力を、セノリティック処理により保存することができる Senolytic treatment preserves biliary regenerative capacity lost through cellular senescence during cold storage

Sofia Ferreira-Gonzalez,Tak Yung Man,Hannah Esser,Rhona Aird,Alastair M. Kilpatrick,Daniel Rodrigo-Torres,Nicholas Younger,Lara Campana,Victoria L. Gadd,Benjamin Dwyer,Niya Aleksieva ,Luke Boulter,Mark T. Macmillan ,Yinmiao Wang,Katie J. Mylonas,David A. Ferenbach ,Timothy J. Kendall,Wei-Yu Lu,Juan Carlos Acosta,Dominic Kurian,Stephen O’Neill,Gabriel C. Oniscu ,Jesus M. Banales,Paul J. Krimpenfort,Stuart J. Forbes
Science Translational Medicine  Published:7 Dec 2022
DOI: 10.1126/scitranslmed.abj4375

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.

Preserving pretransplantation livers

Cold storage of human livers prior to transplantation can impede organ function and subsequent graft survival. Ferreira-Gonzalez et al. now suggest an approach to prevent pre-transplant ex vivo liver degradation. They found that cellular senescence helps drive biliary injury during cold storage, with differential responses among cholangiocytes and hepatocytes. Administration of a senolytic to mouse and human donor livers before cold storage resulted in improved tissue architecture. It remains to be seen if senolytic treatment improves liver engraftment and function.—CAC