Exploration Of Immune Remodeling In Mice Transplanted Liver

Background:In recent years,liver transplantation provides a cure for various end-stage liver diseases.After transplanted into the recipient,the liver graft becomes the recipient's new immune metabolic center and immediately undergoes immune remodeling by interacting with the recipient.Countless recipient-derived immune cells(RICs)were activated and recruited into the liver graft.The interaction between the RICs and donor-derived cells(e.g.donor-derived immune cells,DICs or hepatocytes)affects immunological function and metabolic homeostasis,which even promotes a variety of complications,including metabolic disorders and tumor recurrence.Therefore,the immune remodeling in the graft liver is deserved for further exploration to understand the pathogenesis of post-transplanted complications and develop treatment strategiesAims:To explore the immune remodeling in the liver graft following liver transplantation.Methods:We explore the immune remodeling in the liver graft during the perioperative period in a murine orthotopic liver transplantation model.Female mice liver expressing systemical eGFP were transplanted to wild type male recipients.Single cell RNA sequencing(scRNA-seq),mass spectrometry(CyTOF),immunohistochemistry and flow cytometer were used to monitor the immune remodeling in the liver graft.Results:During the first 12h,donor-derived cells in the liver graft sharply decreased to 34%,while the proportion of recipient-derived cells increased sharply from 0%to 66%.Recipient-derived cells became predominant in most of the cell subgroups,but others were still dominated by donor-derived cells,including hepatocytes,endothelial cells,and some natural killer cells(NK)and M2 macrophages.Two weeks later,we found that DICs only accounted for 5.6%in total immune cells,while 94.4%for RICs.Upon a closer evaluation of the subtypes of immune cells,some M2 macrophages and NK cell subsets still retain about half of DICs.Considering the important role of macrophages in liver homeostasis,we investigated the function of macrophages from donor and recipient.We found that pro-inflammatory M1 macrophages in charge of the recipient-derived macrophages(RMs),while both pro-inflammatory M1 and anti-inflammatory M2 macrophages contributed to the donor-derived macrophages(DMs).Conclusions:In conclusion,this study is the first to explore process of immune remodeling in the liver graft.It was striking that RICs took over the liver graft(>90%)so quickly,but RICs still played a role in M2 macrophages and NK cells.Because of the heterogeneity of macrophages and NK cells,differing genetics between donor and recipient may have a considerable impact on the function of macrophages and NK cells in response to specific environmental signals.Intensive research on macrophages and NK cells from donor or recipient may help to deepen the understanding of immune remodeling in liver graft and the pathogenesis of post-transplant complications.