title: Mesenchymal stem cells promote liver regeneration and prolong survival in small-for-size liver grafts: involvement of C-Jun N-terminal kinase, cyclin D1, and NF-κB.
abstract: BACKGROUND
  The therapeutic potential of mesenchymal stem cells (MSCs) has been highlighted recently for treatment of acute or chronic liver injury, by possibly differentiating into hepatocyte-like cells, reducing inflammation, and enhancing tissue repair. Despite recent progress, exact mechanisms of action are not clearly elucidated. In this study, we attempted to explore whether and how MSCs protected hepatocytes and stimulated allograft regeneration in small-for-size liver transplantation (SFSLT).
  
  
  METHODS
  SFSLT model was established with a 30% partial liver transplantation (30PLT) in rats. The differentiation potential and characteristics of bone marrow derived MSCs were explored in vitro. MSCs were infused transvenously immediately after graft implantation in therapy group. Expressions of apoptosis-, inflammatory-, anti-inflammatory-, and growth factor-related genes were measured by RT-PCR, activities of transcription factors AP-1 and NF-κB were analyzed by EMSA, and proliferative responses of the hepatic graft were evaluated by immunohistochemistry and western blot.
  
  
  RESULTS
  MSCs were successfully induced into hepatocyte-like cells, osteoblasts and adipocytes in vitro. MSCs therapy could not only alleviate ischemia reperfusion injury and acute inflammation to promote liver regeneration, but also profoundly improve one week survival rate. It markedly up-regulated the mRNA expressions of HGF, Bcl-2, Bcl-XL, IL-6, IL-10, IP-10, and CXCR2, however, down-regulated TNF-α. Increased activities of AP-1 and NF-κB, as well as elevated expressions of p-c-Jun, cyclin D1, and proliferating cell nuclear antigen (PCNA), were also found in MSCs therapy group.
  
  
  CONCLUSIONS
  These data suggest that MSCs therapy promotes hepatocyte proliferation and prolongs survival in SFSLT by reducing ischemia reperfusion injury and acute inflammation, and sustaining early increased expressions of c-Jun N-terminal Kinase, Cyclin D1, and NF-κB.
authors.affiliation: Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Department of Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou University School of Medicine, Zhengzhou, Henan Province, China.
authors.forename: Weijie
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Hepatobiliary Surgery, Central Hospital of Wuhan, Wuhan, Hubei Province, China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Du
authors.affiliation: Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Jiqi
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Di
authors.initials: D
authors.lastname: Ma
authors.affiliation: Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Minmin
authors.initials: M
authors.lastname: Shi
authors.affiliation: Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Mingjun
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Chenghong
authors.initials: C
authors.lastname: Peng
authors.affiliation: Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D064987:Cell- and Tissue-Based Therapy; D019938:Cyclin D1 / Q000096:biosynthesis* / Q000235:genetics; D022781:Hepatocytes / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D008115:Liver Regeneration / Q000235:genetics*; D016031:Liver Transplantation; D059630:Mesenchymal Stem Cells; D016328:NF-kappa B / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D015427:Reperfusion Injury / Q000235:genetics / Q000628:therapy
chemical_list: C530106:Ccnd1 protein, rat; D016328:NF-kappa B; D019938:Cyclin D1; D048031:JNK Mitogen-Activated Protein Kinases