title: Mesenchymal stem cells improve mouse non-heart-beating liver graft survival by inhibiting Kupffer cell apoptosis via TLR4-ERK1/2-Fas/FasL-caspase3 pathway regulation.
abstract: 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. 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.
  
  
  
  In 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.
  
  
  
  MSCs 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.
  
  
  
  Our 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.
authors: Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China.
authors: Yang
authors: Y
authors: Tian
authors: Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China.
authors: Jingcheng
authors: J
authors: Wang
authors: Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China.
authors: Wei
authors: W
authors: Wang
authors: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors: Yuan
authors: Y
authors: Ding
authors: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors: Zhongquan
authors: Z
authors: Sun
authors: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors: Qiyi
authors: Q
authors: Zhang
authors: Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China.
authors: Yan
authors: Y
authors: Wang
authors: Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China.|Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, Zhejiang Province, China.
authors: Haiyang
authors: H
authors: Xie
authors: Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China. shengyan@zju.edu.cn.|Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. shengyan@zju.edu.cn.|Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, Zhejiang Province, China. shengyan@zju.edu.cn.
authors: Sheng
authors: S
authors: Yan
authors: Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China. shusenzheng@zju.edu.cn.|Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. shusenzheng@zju.edu.cn.|Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, Zhejiang Province, China. shusenzheng@zju.edu.cn.
authors: Shusen
authors: S
authors: Zheng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D018920:Coculture Techniques / Q000379:methods; D003643:Death; D053222:Fas Ligand Protein / Q000378:metabolism; D006085:Graft Survival / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D007728:Kupffer Cells / Q000166:cytology* / Q000378:metabolism; D008099:Liver / Q000166:cytology* / Q000378:metabolism; D016031:Liver Transplantation / Q000379:methods; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000502:physiology*; D014019:Tissue Donors; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: D053222:Fas Ligand Protein; C491899:Fas protein, mouse; C505658:Fasl protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D019014:fas Receptor; D053148:Caspase 3
keywords: Apoptosis; Donation after cardiac death; Graft survival; Kupffer cells; Mesenchymal stem cells