Abstract
BackgroundLiver transplantation is the optimal treatment option for end-stage liver disease, but organ shortages dramatically restrict its application. Donation after cardiac death (DCD) is an alternative approach that may expand the donor pool, but it faces challenges such as graft dysfunction, early graft loss, and cholangiopathy. Moreover, DCD liver grafts are no longer eligible for transplantation after their warm ischaemic time exceeds 30 min. Mesenchymal stem cells (MSCs) have been proposed as a promising therapy for treatment of certain liver diseases, but the role of MSCs in DCD liver graft function remains elusive.MethodsIn this study, we established an arterialized mouse non-heart-beating (NHB) liver transplantation model, and compared survival rates, cytokine and chemokine expression, histology, and the results of in vitro co-culture experiments in animals with or without MSC infusion.ResultsMSCs markedly ameliorated NHB liver graft injury and improved survival post-transplantation. Additionally, MSCs suppressed Kupffer cell apoptosis, Th1/Th17 immune responses, chemokine expression, and inflammatory cell infiltration. In vitro, PGE2 secreted by MSCs inhibited Kupffer cell apoptosis via TLR4-ERK1/2-caspase3 pathway regulation.ConclusionOur study uncovers a protective role for MSCs and elucidates the underlying immunomodulatory mechanism in an NHB liver transplantation model. Our results suggest that MSCs are uniquely positioned for use in future clinical studies owing to their ability to protect DCD liver grafts, particularly in patients for whom DCD organs are not an option according to current criteria.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0416-y) contains supplementary material, which is available to authorized users.
Highlights
Liver transplantation is the optimal treatment option for end-stage liver disease, but organ shortages dramatically restrict its application
We provide the first demonstration of the ability of Mesenchymal stem cell (MSC) to effectively ameliorate NHBinduced graft injury and significantly improve recipient survival by inhibiting Kupffer cell apoptosis
Our results indicated that Kupffer cell restoration, together with infused MSCs, suppresses chemokine expression and reduces neutrophil and T-cell infiltration into liver grafts post-transplantation
Summary
Liver transplantation is the optimal treatment option for end-stage liver disease, but organ shortages dramatically restrict its application. Donation after cardiac death (DCD) is an alternative approach that may expand the donor pool, but it faces challenges such as graft dysfunction, early graft loss, and cholangiopathy. DCD liver grafts are no longer eligible for transplantation after their warm ischaemic time exceeds 30 min. Mesenchymal stem cells (MSCs) have been proposed as a promising therapy for treatment of certain liver diseases, but the role of MSCs in DCD liver graft function remains elusive
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