Transcriptomic signatures during normothermic liver machine perfusion correspond with graft quality and predict the early graft functionResearch in context
Theresa Hautz,
Hubert Hackl,
Hendrik Gottschling,
Raphael Gronauer,
Julia Hofmann,
Stefan Salcher,
Bettina Zelger,
Rupert Oberhuber,
Benno Cardini,
Annemarie Weissenbacher,
Thomas Resch,
Jakob Troppmair,
Stefan Schneeberger
Affiliations
Theresa Hautz
OrganLife Organ Regeneration Centre of Excellence and Daniel Swarovski Research Laboratory (DSL), Department of Visceral, Transplant and Thoracic Surgery, Centre of Operative Medicine, Medical University of Innsbruck, Anichstr. 35, A-6020, Innsbruck, Austria; Corresponding author.
Hubert Hackl
Institute of Bioinformatics, Biocentre, Medical University of Innsbruck, Innrain 80/82, A-6020, Innsbruck, Austria
Hendrik Gottschling
OrganLife Organ Regeneration Centre of Excellence and Daniel Swarovski Research Laboratory (DSL), Department of Visceral, Transplant and Thoracic Surgery, Centre of Operative Medicine, Medical University of Innsbruck, Anichstr. 35, A-6020, Innsbruck, Austria
Raphael Gronauer
Institute of Bioinformatics, Biocentre, Medical University of Innsbruck, Innrain 80/82, A-6020, Innsbruck, Austria
Julia Hofmann
OrganLife Organ Regeneration Centre of Excellence and Daniel Swarovski Research Laboratory (DSL), Department of Visceral, Transplant and Thoracic Surgery, Centre of Operative Medicine, Medical University of Innsbruck, Anichstr. 35, A-6020, Innsbruck, Austria
Stefan Salcher
Department of Internal Medicine V, Haematology and Oncology, Comprehensive Cancer Centre Innsbruck (CCCI), Medical University of Innsbruck, Anichstr. 35, A-6020, Innsbruck, Austria
Bettina Zelger
Institute of Pathology, Medical University of Innsbruck, Muellerstr. 44, A-6020, Innsbruck, Austria
Rupert Oberhuber
OrganLife Organ Regeneration Centre of Excellence and Daniel Swarovski Research Laboratory (DSL), Department of Visceral, Transplant and Thoracic Surgery, Centre of Operative Medicine, Medical University of Innsbruck, Anichstr. 35, A-6020, Innsbruck, Austria
Benno Cardini
OrganLife Organ Regeneration Centre of Excellence and Daniel Swarovski Research Laboratory (DSL), Department of Visceral, Transplant and Thoracic Surgery, Centre of Operative Medicine, Medical University of Innsbruck, Anichstr. 35, A-6020, Innsbruck, Austria
Annemarie Weissenbacher
OrganLife Organ Regeneration Centre of Excellence and Daniel Swarovski Research Laboratory (DSL), Department of Visceral, Transplant and Thoracic Surgery, Centre of Operative Medicine, Medical University of Innsbruck, Anichstr. 35, A-6020, Innsbruck, Austria
Thomas Resch
OrganLife Organ Regeneration Centre of Excellence and Daniel Swarovski Research Laboratory (DSL), Department of Visceral, Transplant and Thoracic Surgery, Centre of Operative Medicine, Medical University of Innsbruck, Anichstr. 35, A-6020, Innsbruck, Austria
Jakob Troppmair
OrganLife Organ Regeneration Centre of Excellence and Daniel Swarovski Research Laboratory (DSL), Department of Visceral, Transplant and Thoracic Surgery, Centre of Operative Medicine, Medical University of Innsbruck, Anichstr. 35, A-6020, Innsbruck, Austria
Stefan Schneeberger
OrganLife Organ Regeneration Centre of Excellence and Daniel Swarovski Research Laboratory (DSL), Department of Visceral, Transplant and Thoracic Surgery, Centre of Operative Medicine, Medical University of Innsbruck, Anichstr. 35, A-6020, Innsbruck, Austria
Summary: Background: A better understanding of the molecular events during liver normothermic machine perfusion (NMP) is warranted to develop a data-based approach for the identification of biomarkers representative of graft quality and posttransplant outcome. We analysed the dynamic transcriptional changes during NMP and linked them to clinical and biochemical parameters. Methods: 50 livers subjected to NMP for up to 24 h were enrolled. Bulk RNA sequencing was performed in serial biopsies collected pre and during NMP, and after reperfusion. Perfusate was sampled to monitor liver function. qPCR and immunohistochemistry were performed to validate findings. Molecular profiles were compared between transplanted and non-transplanted livers, and livers with and without early allograft dysfunction. Findings: Pathways related to immune and cell stress responses, cell trafficking and cell regulation were activated during NMP, while cellular metabolism was downregulated over time. Anti-inflammatory responses and genes involved in tissue remodelling were induced at later time-points, suggesting a counter-response to the immediate damage. NMP strongly induced a gene signature associated with ischemia-reperfusion injury. A 7-gene signature corresponds with the benchmarking criteria for transplantation or discard at 6 h NMP (area under curve 0.99). CD274 gene expression (encoding programmed cell-death ligand-1) showed the highest predictive value. LEAP2 gene expression at 6 h NMP correlated with impaired graft function. Interpretation: Assessment of gene expression markers could serve as a reliable tool to evaluate liver quality during NMP and predicts early graft function after transplantation. Funding: The research was supported by “In Memoriam Dr. Gabriel Salzner Stiftung”, Tiroler Wissenschaftsfond, Jubiläumsfonds-Österreichische Nationalbank and MUI Start grant.
