Delineating the Interference of Cellular Senescence in Experimental Normothermic Liver Perfusion

• Applicant: Dr. Pia-Franziska Koch
• Subject Area: General and Visceral Surgery ; Clinical Immunology and Allergology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 569138423

Liver transplantation is a critical procedure for patients with end-stage liver disease, acute liver failure, or specific liver cancers. Despite advances in transplantation, outcomes are affected by complications such as graft dysfunction, disease recurrence, and side effects from immunosuppressive therapy. A significant challenge in liver transplantation is the shortage of donor organs. Many patients wait for donor organs, but those from older donors have higher discard rates due to age-related functional decline and viability concerns. Data show that many of these organs remain unused, highlighting the need for improved organ utilization and quality. Cellular senescence, where cells stop dividing due to stress or injury, plays a major role in organ aging and dysfunction. Senescent cells contribute to inflammation, fibrosis, and tissue damage, especially in older donor organs. These cells secrete inflammatory factors that exacerbate organ damage and reduce the tissue repair capacity. In liver transplantation, senescence worsens graft dysfunction, particularly in older organs. Targeting senescent cells using senolytic agents like dasatinib and quercetin has shown promise in reducing inflammation and improving organ function. Studies suggest that senolytics can mitigate complications such as inflammation, fibrosis, and bile duct injury. Normothermic ex vivo liver perfusion (NMP) has shown particular promise in improving organ viability, assessing marginal donor organs, and extending preservation times. NMP allows for functional assessment of organs from extended donor criteria and it enables therapeutic interventions, such as toxin removal or the delivery of regenerative agents, to improve organ function prior to transplantation. MicroRNA (miRNA) are small non-coding RNA that regulate organ function, aging, and cellular senescence. In liver transplantation, miRNA play important roles in immune responses, graft function, and disease recurrence. Specific miRNA have been identified as biomarkers for organ damage, aging, and reconditioning during NMP. These miRNA could serve as reliable indicators of organ quality and the effects of senolytic treatments. Studies have shown that younger livers have more robust responses to oxidative stress during ex vivo perfusion than older livers, which may lack these adaptive miRNA responses. This makes older organs more susceptible to oxidative damage. Understanding these molecular mechanisms could improve strategies for organ preservation and rejuvenation. Combining senolytics, ex vivo perfusion, and miRNA-based biomarkers could enhance organ utilization, expand the donor pool, and improve long-term transplant outcomes.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Stefan Tullius, Ph.D.