A proof-of-concept study in small and large animal models for coupling liver normothermic machine perfusion with mesenchymal stromal cell bioreactors

Umberto Cillo; Caterina Lonati; Alessandra Bertacco; Lucrezia Magnini; Michele Battistin; Liver NMP Consortium; Lara Borsetto; Francesco Dazzi; David Al-Adra; Enrico Gringeri; Maria Laura Bacci; Andrea Schlegel; Daniele Dondossola

doi:10.1038/s41467-024-55217-7

A proof-of-concept study in small and large animal models for coupling liver normothermic machine perfusion with mesenchymal stromal cell bioreactors

Nat Commun. 2025 Jan 2;16(1):283. doi: 10.1038/s41467-024-55217-7.

Authors

Collaborators

Liver NMP Consortium:
Domenico Ventrella, Camilla Aniballi, Margherita Carbonaro, Andrea Carlin, Alberto Elmi

Affiliations

¹ Hepato-Biliary-Pancreatic Surgery and Liver Transplant Unit, General Surgery 2, Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, Padua, Italy.
² Center for Preclinical Research, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Pace 9, 20100, Milan, Italy. [email protected].
³ Center for Preclinical Research, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Pace 9, 20100, Milan, Italy.
⁴ School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, London, UK.
⁵ Division of Transplantation, Department of Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA.
⁶ Department of Veterinary Medical Sciences, University of Bologna, Bologna, Italy.
⁷ Transplantation Center, Digestive Disease and Surgery Institute, Department of Immunity and Inflammation, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44106, USA.
⁸ General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20100, Milan, Italy.
⁹ Department of Pathophysiology and Transplantation, University of Milan, Via Francesco Sforza 35, 20100, Milan, Italy.

^# Contributed equally.

Abstract

To fully harness mesenchymal-stromal-cells (MSCs)' benefits during Normothermic Machine Perfusion (NMP), we developed an advanced NMP platform coupled with a MSC-bioreactor and investigated its bio-molecular effects and clinical feasibility using rat and porcine models. The study involved three work packages: 1) Development (n = 5): MSC-bioreactors were subjected to 4 h-liverless perfusion; 2) Rat model (n = 10): livers were perfused for 4 h on the MSC-bioreactor-circuit or with the standard platform; 3) Porcine model (n = 6): livers were perfused using a clinical device integrated with a MSC-bioreactor or in its standard setup. MSCs showed intact stem-core properties after liverless-NMP. Liver NMP induced specific, liver-tailored, changes in MSCs' secretome. Rat livers exposed to bioreactor-based perfusion produced more bile, released less damage and pro-inflammatory biomarkers, and showed improved mithocondrial function than those subjected to standard NMP. MSC-bioreactor integration into a clinical device resulted in no machine failure and perfusion-related injury. This proof-of-concept study presents a novel MSC-based liver NMP platform that could reduce the deleterious effects of ischemia/reperfusion before transplantation.

MeSH terms

Animals
Bioreactors*
Liver* / cytology
Liver* / metabolism
Male
Mesenchymal Stem Cell Transplantation / methods
Mesenchymal Stem Cells* / cytology
Mesenchymal Stem Cells* / metabolism
Models, Animal
Organ Preservation / instrumentation
Organ Preservation / methods
Perfusion* / instrumentation
Perfusion* / methods
Proof of Concept Study*
Rats
Swine