title: Human urokinase-type plasminogen activator gene-modified bone marrow-derived mesenchymal stem cells attenuate liver fibrosis in rats by down-regulating the Wnt signaling pathway.
abstract: OBJECTIVE
  To evaluate the therapeutic effects of bone marrow-derived mesenchymal stem cells (BMSCs) with human urokinase-type plasminogen activator (uPA) on liver fibrosis, and to investigate the mechanism of gene therapy.
  
  
  METHODS
  BMSCs transfected with adenovirus-mediated human urokinase plasminogen activator (Ad-uPA) were transplanted into rats with CCl4-induced liver fibrosis. All rats were sacrificed after 8 wk, and their serum and liver tissue were collected for biochemical, histopathologic, and molecular analyzes. The degree of liver fibrosis was assessed by hematoxylin and eosin or Masson's staining. Western blot and quantitative reverse transcription-polymerase chain reaction were used to determine protein and mRNA expression levels.
  
  
  RESULTS
  Serum levels of alanine aminotransferase, aminotransferase, total bilirubin, hyaluronic acid, laminin, and procollagen type III were markedly decreased, whereas the levels of serum albumin were increased by uPA gene modified BMSCs treatment. Histopathology revealed that chronic CCl4-treatment resulted in significant fibrosis while uPA gene modified BMSCs treatment significantly reversed fibrosis. By quantitatively analysing the fibrosis area of liver tissue using Masson staining in different groups of animals, we found that model animals with CCl4-induced liver fibrosis had the largest fibrotic area (16.69% ± 1.30%), while fibrotic area was significantly decreased by BMSCs treatment (12.38% ± 2.27%) and was further reduced by uPA-BMSCs treatment (8.31% ± 1.21%). Both protein and mRNA expression of β-catenin, Wnt4 and Wnt5a was down-regulated in liver tissues following uPA gene modified BMSCs treatment when compared with the model animals.
  
  
  CONCLUSIONS
  Transplantation of uPA gene modified BMSCs suppressed liver fibrosis and ameliorated liver function and may be a new approach to treating liver fibrosis. Furthermore, treatment with uPA gene modified BMSCs also resulted in a decrease in expression of molecules of the Wnt signaling pathway.
authors.affiliation: Zhi-Gang Ma, Lan Chen, Qi-Yuan Zou, Ji-Qiao Xiang, Jiao-Li Qin, Wei-Wei Zhang, Zhao-Jing Zeng, Hui Jin, Hai-Xing Jiang, Xiao-Ping Lv, Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China.
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Ma
authors.affiliation: Zhi-Gang Ma, Lan Chen, Qi-Yuan Zou, Ji-Qiao Xiang, Jiao-Li Qin, Wei-Wei Zhang, Zhao-Jing Zeng, Hui Jin, Hai-Xing Jiang, Xiao-Ping Lv, Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China.
authors.forename: Xiao-Dan
authors.initials: XD
authors.lastname: Lv
authors.affiliation: Zhi-Gang Ma, Lan Chen, Qi-Yuan Zou, Ji-Qiao Xiang, Jiao-Li Qin, Wei-Wei Zhang, Zhao-Jing Zeng, Hui Jin, Hai-Xing Jiang, Xiao-Ping Lv, Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China.
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Zhan
authors.affiliation: Zhi-Gang Ma, Lan Chen, Qi-Yuan Zou, Ji-Qiao Xiang, Jiao-Li Qin, Wei-Wei Zhang, Zhao-Jing Zeng, Hui Jin, Hai-Xing Jiang, Xiao-Ping Lv, Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Chen
authors.affiliation: Zhi-Gang Ma, Lan Chen, Qi-Yuan Zou, Ji-Qiao Xiang, Jiao-Li Qin, Wei-Wei Zhang, Zhao-Jing Zeng, Hui Jin, Hai-Xing Jiang, Xiao-Ping Lv, Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China.
authors.forename: Qi-Yuan
authors.initials: QY
authors.lastname: Zou
authors.affiliation: Zhi-Gang Ma, Lan Chen, Qi-Yuan Zou, Ji-Qiao Xiang, Jiao-Li Qin, Wei-Wei Zhang, Zhao-Jing Zeng, Hui Jin, Hai-Xing Jiang, Xiao-Ping Lv, Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China.
authors.forename: Ji-Qiao
authors.initials: JQ
authors.lastname: Xiang
authors.affiliation: Zhi-Gang Ma, Lan Chen, Qi-Yuan Zou, Ji-Qiao Xiang, Jiao-Li Qin, Wei-Wei Zhang, Zhao-Jing Zeng, Hui Jin, Hai-Xing Jiang, Xiao-Ping Lv, Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China.
authors.forename: Jiao-Li
authors.initials: JL
authors.lastname: Qin
authors.affiliation: Zhi-Gang Ma, Lan Chen, Qi-Yuan Zou, Ji-Qiao Xiang, Jiao-Li Qin, Wei-Wei Zhang, Zhao-Jing Zeng, Hui Jin, Hai-Xing Jiang, Xiao-Ping Lv, Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China.
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Zhang
authors.affiliation: Zhi-Gang Ma, Lan Chen, Qi-Yuan Zou, Ji-Qiao Xiang, Jiao-Li Qin, Wei-Wei Zhang, Zhao-Jing Zeng, Hui Jin, Hai-Xing Jiang, Xiao-Ping Lv, Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China.
authors.forename: Zhao-Jing
authors.initials: ZJ
authors.lastname: Zeng
authors.affiliation: Zhi-Gang Ma, Lan Chen, Qi-Yuan Zou, Ji-Qiao Xiang, Jiao-Li Qin, Wei-Wei Zhang, Zhao-Jing Zeng, Hui Jin, Hai-Xing Jiang, Xiao-Ping Lv, Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Jin
authors.affiliation: Zhi-Gang Ma, Lan Chen, Qi-Yuan Zou, Ji-Qiao Xiang, Jiao-Li Qin, Wei-Wei Zhang, Zhao-Jing Zeng, Hui Jin, Hai-Xing Jiang, Xiao-Ping Lv, Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China.
authors.forename: Hai-Xing
authors.initials: HX
authors.lastname: Jiang
authors.affiliation: Zhi-Gang Ma, Lan Chen, Qi-Yuan Zou, Ji-Qiao Xiang, Jiao-Li Qin, Wei-Wei Zhang, Zhao-Jing Zeng, Hui Jin, Hai-Xing Jiang, Xiao-Ping Lv, Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China.
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Lv
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002251:Carbon Tetrachloride; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000601:surgery*; D004790:Enzyme Induction; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000601:surgery*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000201:enzymology*; D017207:Rats, Sprague-Dawley; D014162:Transfection; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis* / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics; D000071818:Wnt-5a Protein / Q000235:genetics / Q000378:metabolism; D060528:Wnt4 Protein / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C495268:Ctnnb1 protein, rat; D000071818:Wnt-5a Protein; D060528:Wnt4 Protein; C555583:Wnt4 protein, rat; C491837:Wnt5a protein, rat; D051176:beta Catenin; D002251:Carbon Tetrachloride; D014568:Urokinase-Type Plasminogen Activator
keywords: Bone marrow-derived mesenchymal stem cells; Liver fibrosis; Urokinase plasminogen activator; Wnt signaling pathway