title: Intraportal mesenchymal stem cell transplantation prevents acute liver failure through promoting cell proliferation and inhibiting apoptosis.
abstract: BACKGROUND
  Transplantation of mesenchymal stem cells (MSCs) has been regarded as a potential treatment for acute liver failure (ALF), but the optimal route was unknown. The present study aimed to explore the most effective MSCs transplantation route in a swine ALF model.
  
  
  METHODS
  The swine ALF model induced by intravenous injection of D-Gal was treated by the transplantation of swine MSCs through four routes including intraportal injection (InP group), hepatic intra-arterial injection (AH group), peripheral intravenous injection (PV group) and intrahepatic injection (IH group). The living conditions and survival time were recorded. Blood samples before and after MSCs transplantation were collected for the analysis of hepatic function. The histology of liver injury was interpreted and scored in terminal samples. Hepatic apoptosis was detected by TUNEL assay. Apoptosis and proliferation related protein expressions including cleaved caspase-3, survivin, AKT, phospho-AKT (Ser473), ERK and phospho-ERK (Tyr204) were analyzed by Western blotting.
  
  
  RESULTS
  The average survival time of each group was 10.7+/-1.6 days (InP), 6.0+/-0.9 days (AH), 4.7+/-1.4 days (PV), 4.3+/-0.8 days (IH), respectively, when compared with the average survival time of 3.8+/-0.8 days in the D-Gal group. The survival rates between the InP group and D-Gal group revealed a statistically significant difference (P<0.01). Pathological and biochemical analysis showed that liver damage was the worst in the D-Gal group, while less injury in the InP group. Histopathological scores revealed a significant decrease in the InP group (3.17+/-1.04, P<0.01) and AH group (8.17+/-0.76, P<0.05) as compared with that in the D-Gal group (11.50+/-1.32). The apoptosis rate in the InP group (25.0%+/-3.4%, P<0.01) and AH group (40.5%+/-1.0%, P<0.05) was lower than that in the D-Gal group (70.6%+/-8.5%). The expression of active caspase-3 was inhibited, while the expression of survivin, AKT, phospho-AKT (Ser473), ERK and phospho-ERK (Tyr204) was elevated in the InP group.
  
  
  CONCLUSIONS
  Intraportal injection was superior to other pathways for MSC transplantation. Intraportal MSC transplantation could improve liver function, inhibit apoptosis and prolong the survival time of swine with ALF. The transplanted MSCs may participate in liver regeneration via promoting cell proliferation and suppressing apoptosis during the initial stage of ALF.
authors.affiliation: Department of General Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China. yitaoding@hotmail.com.
authors.forename: Jian-Feng
authors.initials: JF
authors.lastname: Sang
authors.forename: Xiao-Lei
authors.initials: XL
authors.lastname: Shi
authors.forename: Bin
authors.initials: B
authors.lastname: Han
authors.forename: Tao
authors.initials: T
authors.lastname: Huang
authors.forename: Xu
authors.initials: X
authors.lastname: Huang
authors.forename: Hao-Zhen
authors.initials: HZ
authors.lastname: Ren
authors.forename: Yi-Tao
authors.initials: YT
authors.lastname: Ding
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005688:Galactosamine; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008111:Liver Function Tests; D008115:Liver Regeneration; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D010641:Phenotype; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013552:Swine; D013556:Swine, Miniature; D013997:Time Factors
chemical_list: D051017:Apoptosis Regulatory Proteins; D005688:Galactosamine; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases