Abstract
Livers from donors after circulatory death (DCD) are inevitably exposed to a longer warm ischemic period, which might increase the incidence of postoperative bile duct complications. Bone marrow mesenchymal stem cells (BMMSCs) have tissue repair properties. The present study was aimed at exploring the repair effect of heme oxygenase-1- (HO-1-) modified BMMSCs (HO-1/BMMSCs) combined with normothermic machine perfusion (NMP) on bile duct injury after DCD liver transplantation and at revealing the underlying mechanisms. Rat livers were exposed to in situ warm ischemia for 30 min; then, NMP was performed through the portal vein for 4 h with BMMSCs, HO-1/BMMSCs, or neither before implantation. Obvious bile duct histological damage and liver functional damage were observed postoperatively. In the group treated with HO-1/BMMSCs combined with NMP (HBP group), liver functions and bile duct histology were improved; meanwhile, cell apoptosis was reduced and cell proliferation was active. A large number of regenerative cells appeared at the injured site, and the defective bile duct epithelium was restored. Dilatation of peribiliary glands (PBGs), proliferation of PBG cells, high expression of vascular endothelial growth factor (VEGF), and increased proportion of bile duct progenitor cells with stem/progenitor cells biomarkers were observed. Blocking Wnt signaling significantly inhibited the repair effect of HO-1/BMMSCs on bile duct injury. In conclusion, HO-1/BMMSCs combined with NMP were relevant to the activation of biliary progenitor cells in PBGs which repaired bile duct injury in DCD liver transplantation via the Wnt signaling pathway. Proliferation and differentiation of PBG cells were involved in the renewal of the injured biliary epithelium.
Highlights
Liver transplantation is a life-saving therapy for patients with end-stage liver disease; organ shortage is currently the biggest obstacle to successful treatment, which directly leads to the death of thousands of patients on waiting lists each year [1]
We aimed to evaluate the repair effect of heme oxygenase-1 (HO-1)/Bone marrow mesenchymal stem cells (BMMSCs) combined with normothermic machine perfusion (NMP) on bile duct International reperfusion injury (IRI) in donors after circulatory death (DCD) liver transplantation, to observe changes in peribiliary glands (PBGs) cells, and to further investigate the underlying mechanisms
Levels of serum ALT, AST, gamma-glutamyl transpeptidase (GGT), and total bilirubin (TBil) in the HBP group were significantly lower than those in the other groups (Figure 3(c)), indicating that HO-1/BMMSCs combined with NMP could effectively improve liver function after liver transplantation
Summary
Liver transplantation is a life-saving therapy for patients with end-stage liver disease; organ shortage is currently the biggest obstacle to successful treatment, which directly leads to the death of thousands of patients on waiting lists each year [1]. Many liver transplantation centers currently accept grafts from extended criterion donors (ECD), a large proportion of which are donors after circulatory death (DCD). Biliary complications are important factors affecting the survival rate and longterm outcome of liver transplantation. The incidence of biliary complications after DCD liver transplantation is between 25 and 60%, while that of DBD liver transplantation is 10 to 30% [3]. Traditional static cold storage can reduce cell metabolism and has a decent preservation effect on grafts from standard criterion donors (SCD); it does not work satisfactorily in the preservation of ECD organs, including DCD livers [4]. It is important to explore new strategies to improve the quality of DCD livers, reduce postoperative biliary complications, and prolong survival time
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