title: Mouse model of carbon tetrachloride induced liver fibrosis: Histopathological changes and expression of CD133 and epidermal growth factor.
abstract: BACKGROUND
  In the setting of chronic liver injury in humans, epidermal growth factor (EGF) and EGF receptor (EGFR) are up-regulated and have been proposed to have vital roles in both liver regeneration and development of hepatocellular carcinoma (HCC). Chronic liver injury also leads to hepatic stellate cell (HSC) differentiation and a novel subpopulation of HSCs which express CD133 and exhibit properties of progenitor cells has been described in rats. The carbon tetrachloride (CCl4)-induced mouse model has been historically relied upon to study liver injury and regeneration. We exposed mice to CCl4 to assess whether EGF and CD133+ HSCs are up-regulated in chronically injured liver.
  
  
  METHODS
  CCl4 in olive oil was administered to strain A/J mice three times per week by oral gavage.
  
  
  RESULTS
  Multiple well-differentiated HCCs were found in all livers after 15 weeks of CCl4 treatment. Notably, HCCs developed within the setting of fibrosis and not cirrhosis. CD133 was dramatically up-regulated after CCl4 treatment, and increased expression of desmin and glial fibrillary acidic protein, representative markers of HSCs, was also observed. EGF expression significantly decreased, contrary to observations in humans, whereas the expression of amphiregulin, another EGFR ligand, was significantly increased.
  
  
  CONCLUSIONS
  Species-specific differences exist with respect to the histopathological and molecular pathogenesis of chronic liver disease. CCl4-induced chronic liver injury in A/J mice has important differences compared to human cirrhosis leading to HCC.
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Fujii
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Fuchs
authors.forename: Suguru
authors.initials: S
authors.lastname: Yamada
authors.forename: Gregory Y
authors.initials: GY
authors.lastname: Lauwers
authors.forename: Yakup
authors.initials: Y
authors.lastname: Kulu
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Goodwin
authors.forename: Michael
authors.initials: M
authors.lastname: Lanuti
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Tanabe
mesh_terms: D000071916:AC133 Antigen; D066258:Amphiregulin; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D002251:Carbon Tetrachloride / Q000009:adverse effects*; D002454:Cell Differentiation; D003893:Desmin / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism*; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010455:Peptides / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000071916:AC133 Antigen; C587848:AREG protein, human; D066258:Amphiregulin; D015703:Antigens, CD; C587849:Areg protein, mouse; C587850:Areg protein, rat; D003893:Desmin; D066255:EGF Family of Proteins; D005904:Glial Fibrillary Acidic Protein; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; C000606025:Prom1 protein, rat; D004815:Epidermal Growth Factor; D002251:Carbon Tetrachloride; D066246:ErbB Receptors