novel technologies to increase the pool of donor organs at The University of Edinburgh

1st Supervisor: Prof Stuart Forbes 

About the Project

Liver transplantation is the only curative option for many patients with end-stage liver disease. Unfortunately, a fifth of donor livers cannot be used for transplantation due to pre-transplant physiological complications that result in tissue senescence and necrosis^1,2.

Normothermic machine perfusion is an organ preservation method based on delivery of oxygen and nutrition to the donor liver during pre-transplantation stages using a peristaltic pump². This novel technology allows maintenance of the organ in nearly physiological conditions, but is also an excellent platform to deliver therapeutic vectors while assessing the quality of the liver in real time.

To increase the number of livers fit for transplantation, we propose to use normothermic machine perfusion to rescue discarded human donor livers by combining:

• Perfusion with pro-regenerative macrophages to eliminate necrotic tissue, and
• Perfusion with senolytic reagents to eliminate senescent cells.

By doing so, we expect to uncover new therapeutic approaches to increase the pool of available donor livers.

This project builds on our previous work using macrophage cell therapy to resolve necrosis following liver injury³, our proof-of-concept senolytic perfusion of human livers, and our established collaborations with the Royal Infirmary of Edinburgh’s Liver Transplant Unit.

The student will test mouse models of liver disease and transplantation, rapidly progressing to human ex vivo perfusion, paving the way for clinical intervention with a transformative effect on treatment and outcomes for liver disease patients. The candidate will receive outstanding training, with direct input from an experienced team of interdisciplinary researchers and centres of excellence, namely:

• Animal models and human organs: Mouse models of acute liver damage and senescence and liver grafting; Human ex-vivo preparation and perfusion of human discarded livers.
• Molecular biology: Western blot; PCR; Flow cytometry; immunohistochemistry and microscopy (e.g., confocal and high-throughput microscopy).
• Tissue culture: Mouse and human macrophage culture; Organotypic cultures obtained from mouse and human livers.
• Interdisciplinary approach: Clinical translation of mice and human ex vivo perfusion to eventually deliver the first of its kind cell therapy (in collaboration with SNBTS and Cell and Gene Therapy Catapult).

References

1. Moroni et al. (2019) Nat Medicine 25:1560. DOI: 10.1038/s41591-019-0599-8
2. Ferreira-Gonzalez et al. (2022) Sci Transl Med 14(674). DOI: 10.1126/scitranslmed.abj4375
3. Starkey Lewis et al. J Hepatol (2020) 73:349. DOI: 10.1016/j.jhep.2020.02.031

Funding Notes

This opportunity is open to UK and international students and provides funding covering stipend and UK level tuition fees. The University of Edinburgh covers the difference between home and international fees meaning that the EASTBIO DTP offers fully-funded studentships to all appointees. Please see full advert description for further funding details.

Applications

Please review the full advert description here for details on the application process.