title: Embryonic stem cells reduce liver fibrosis in CCl4-treated mice.
abstract: We transplanted undifferentiated embryonic stem (ES) cells into the spleens of carbon tetrachloride (CCl(4))-treated mice to determine their effects on liver fibrosis. Carbon tetrachloride at 0.5 ml/kg of body weight was injected intraperitoneally into C57BL/6 mice twice weekly for up to 20 weeks. Four weeks after the first injection, the mice were divided into two groups and those in group 1 received 1 x 10(5) ES cells genetically labelled with enhanced green fluorescent protein (GFP) in the spleens, while group 2 mice received 0.1 ml of phosphate-buffered saline. In group 1, GFP-immunopositive cells were retained and found in areas of fibrosis in the liver, and reduced liver fibrosis was observed as compared with group 2. Secondary transplantation of ES cells at 12 weeks after the initial transplantation enhanced the reduction in liver fibrosis. No teratoma formation or uncontrolled growth of ES cells in organs, including the liver and spleen, was observed in any of the mice. In the livers of group 1 mice, metalloproteinase 9-immunopositive cells derived from ES cells as well as those from the recipient were observed. These cells were also found to be immunopositive for the hepatoblast marker Delta-like (DlK-1), a member of the DlK-1 family of transmembrane proteins. These results suggest that ES-based cell therapy is potentially useful for liver fibrosis treatment and that reduction in CCl(4)-induced liver fibrosis by transplantation of ES cells may be related closely to the emergence of metalloproteinase-producing hepatoblast-like cells.
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Moriya
authors.forename: Masahide
authors.initials: M
authors.lastname: Yoshikawa
authors.forename: Yukiteru
authors.initials: Y
authors.lastname: Ouji
authors.forename: Ko
authors.initials: K
authors.lastname: Saito
authors.forename: Mariko
authors.initials: M
authors.lastname: Nishiofuku
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Matsuda
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Ishizaka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukui
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride; D002454:Cell Differentiation; D003094:Collagen / Q000032:analysis; D053595:Embryonic Stem Cells / Q000637:transplantation*; D005260:Female; D049452:Green Fluorescent Proteins / Q000008:administration & dosage / Q000032:analysis; D022781:Hepatocytes / Q000201:enzymology; D007150:Immunohistochemistry; D007267:Injections; D008099:Liver / Q000473:pathology*; D008103:Liver Cirrhosis / Q000473:pathology / Q000601:surgery*; D008106:Liver Cirrhosis, Experimental; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen
chemical_list: C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D003094:Collagen; D002251:Carbon Tetrachloride; D020780:Matrix Metalloproteinase 9