Bone marrow mesenchymal stem cells modified with heme oxygenase-1 alleviate rejection of donation after circulatory death liver transplantation by inhibiting dendritic cell maturation in rats

Abstract

Immature dendritic cells induce immune tolerance and mature dendritic cells induce acute rejection. We infused bone marrow mesenchymal stem cells (BMMSCs) expressing heme oxygenase 1 (HO-1) (HO-1/BMMSCs) into donation after circulatory death (DCD) livers using normothermic machine perfusion (NMP), and then performed transplantation, with the aim of determining the effects of HO 1/BMMSCs on liver DC maturation and graft rejection. A rat model of acute liver transplantation rejection was established from Lewis to BN rats, in which six experimental groups were set up: Sham operation, static cold storage, NMP, BMMSCs + NMP, HO-1/BMMSCs + NMP (HBP), and NMP + FK506 gavage. Flow cytometry was performed to detect the maturation of DCs and the activation of CD4+ T cells in the liver. In vitro, HO-1/BMMSCs were cocultured with liver DCs, and then the phenotype and ability to stimulate lymphocyte proliferation of DCs were measured. MAPK inhibitors were added to observe the effect of MAPK signaling on DC maturation. The resultsindicatedthatHO-1/BMMSCs could stably colonize the transplanted liver. In the HBP group, rejection was reduced, the maturation of DCs was inhibited, and the infiltration and activation of CD4+ T cells were reduced. In vitro, DCs cocultured with HO-1/BMMSCs showed an immature phenotype and inhibited T cell proliferation. HO-1/BMMSCs inhibited the maturation of DCs by blocking the phosphorylation of p38 and ERK1/2. This study suggested that infusion of HO-1/BMMSCs into DCD livers could reduce acute rejection significantly by inhibiting DC maturation. DC maturation regulation by HO-1/BMMSCs involves ERK1/2/MAPK and p38/MAPK signaling.