The Delivery of Multipotent Adult Progenitor Cells to Extended Criteria Human Donor Livers Using Normothermic Machine Perfusion

Frontiers in Immunology

Anthony E. Ting¹  Samantha Stubblefield¹  Ricky H. Bhogal²  Darius F. Mirza²  Hynek Mergental²  Andrea Schlegel²  Richard W. Laing²  Philip N. Newsome²  Simon C. Afford²  Yuri L. Boteon²  Gary M. Reynolds³  Lorraine Wallace³  Valerie D. Roobrouck⁴ 

[1] Athersys Inc., Cleveland, OH, United States;Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom;NIHR Liver Biomedical Research Unit, Centre for Liver Research, College of Medical and Dental Sciences, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom;ReGenesys BVBA, Leuven, Belgium;

关键词: liver transplantation;    organ preservation;    organ donation;    mesenchymal progenitor cells;    machine perfusion;    stem cell therapy;   

DOI  :  10.3389/fimmu.2020.01226

来源: DOAJ

【 摘 要 】

Background: Pre-clinical research with multi-potent adult progenitor cells (MAPC® cells, Multistem, Athersys Inc., Cleveland, Ohio) suggests their potential as an anti-inflammatory and immunomodulatory therapy in organ transplantation. Normothermic machine perfusion of the liver (NMP-L) has been proposed as a way of introducing therapeutic agents into the donor organ. Delivery of cellular therapy to human donor livers using this technique has not yet been described in the literature. The primary objectives of this study were to develop a technique for delivering cellular therapy to human donor livers using NMP-L and demonstrate engraftment.Methods: Six discarded human livers were perfused for 6 h at 37°C using the Liver Assist (Organ Assist, Groningen). 50 × 106 CMPTX-labeled MAPC cells were infused directly into the right lobe via the hepatic artery (HA, n = 3) or portal vein (PV, n = 3) over 20 min at different time points during the perfusion. Perfusion parameters were recorded and central and peripheral biopsies were taken at multiple time-points from both lobes and subjected to standard histological stains and confocal microscopy. Perfusate was analyzed using a 35-plex multiplex assay and proteomic analysis.Results: There was no detrimental effect on perfusion flow parameters on infusion of MAPC cells by either route. Three out of six livers met established criteria for organ viability. Confocal microscopy demonstrated engraftment of MAPC cells across vascular endothelium when perfused via the artery. 35-plex multiplex analysis of perfusate yielded 13 positive targets, 9 of which appeared to be related to the infusion of MAPC cells (including Interleukin's 1b, 4, 5, 6, 8, 10, MCP-1, GM-CSF, SDF-1a). Proteomic analysis revealed 295 unique proteins in the perfusate from time-points following the infusion of cellular therapy, many of which have strong links to MAPC cells and mesenchymal stem cells in the literature. Functional enrichment analysis demonstrated their immunomodulatory potential.Conclusion: We have demonstrated that cells can be delivered directly to the target organ, prior to host immune cell population exposure and without compromising the perfusion. Transendothelial migration occurs following arterial infusion. MAPC cells appear to secrete a host of soluble factors that would have anti-inflammatory and immunomodulatory benefits in a human model of liver transplantation.

【 授权许可】

Unknown