title: Hypoxia preconditioned bone marrow mesenchymal stem cells promote liver regeneration in a rat massive hepatectomy model.
abstract: BACKGROUND
  Bone marrow mesenchymal stem cells (BMMSCs) have been reported to facilitate liver regeneration after toxic injuries. However, the effect of BMMSCs on liver regeneration after massive hepatectomy is barely studied. Here we explored whether infusion of BMMSCs promotes liver regeneration in a rat massive hepatectomy model.
  
  
  METHODS
  Hypoxia preconditioning was achieved by culturing BMMSCs under a hypoxia environment. Then 85% hepatectomy was performed and hypoxia or normoxia preconditioned BMMSCs were infused into the portal vein. A group of rats received vascular endothelial growth factor (VEGF) neutralizing antibody perioperatively, and underwent 85% hepatectomy and a subsequent infusion of hypoxia preconditioned BMMSCs to verify the role of VEGF in the effects of BMMSCs on liver regeneration. Liver samples were collected and liver regeneration was evaluated postoperatively.
  
  
  RESULTS
  Hypoxia preconditioning enhanced the expression of VEGF in BMMSCs in vitro. Infusion of BMMSCs promoted proliferation of hepatocytes, reflected by elevated cyclin D1 expression and proliferating cell nuclear antigen-positive hepatocytes. However, BMMSC infusion did not improve the serum albumin level, liver weight/body weight ratio, and survival after operation. Infusion of hypoxia preconditioned BMMSCs significantly elevated cyclin D1, proliferating cell nuclear antigen-positive hepatocytes, liver weight/body weight ratio, and survival compared with normoxia preconditioned BMMSCs, accompanied by an increased serum albumin level. The level of VEGF in liver homogenate was much higher in hypoxia preconditioned BMMSC-treated animals than in other groups. In addition, the perioperative injection of VEGF neutralizing antibody significantly blocked the therapeutic effects of hypoxia preconditioned BMMSCs on liver injury and regeneration in this model.
  
  
  CONCLUSIONS
  Hypoxia preconditioned BMMSCs enhanced liver regeneration after massive hepatectomy in rats, possibly by upregulating the level of VEGF.
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.forename: Shengyong
authors.initials: S
authors.lastname: Yin
authors.forename: Wu
authors.initials: W
authors.lastname: Zhang
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.forename: Yuanxing
authors.initials: Y
authors.lastname: Liu
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Chen
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Jiangjuan
authors.initials: J
authors.lastname: He
authors.forename: Shusen
authors.initials: S
authors.lastname: Zheng
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism*; D015687:Cell Hypoxia; D049109:Cell Proliferation; D004195:Disease Models, Animal; D006498:Hepatectomy / Q000379:methods*; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley