title: Cross-species immunohistochemical investigation of the activation of the liver progenitor cell niche in different types of liver disease.
abstract: BACKGROUND
  When hepatocyte replication during liver disease is insufficient for regeneration, liver progenitor cells (LPCs) are activated. The cells and stroma in the immediate environment of LPCs, together termed the LPC niche, are thought to play an important role in this activation. Among these cells are the hepatic stellate cells (HSCs)/myofibroblasts (MFs).
  
  
  OBJECTIVE
  We assessed the activation of HSC/MFs and LPCs in relation to the histological location and extent of liver disease in immunohistochemically (double) stained serial sections. Markers of HSC/MFs [alpha-smooth muscle actin, glial fibrillary acidic protein (GFAP), neurotrophin 3 and neural-cell adhesion molecule], markers of LPCs (keratin 7 and keratin 19) and a proliferation marker (Ki67) were used. A very relevant spontaneous model to evaluate LPC niche activation in a translational approach seems to be the dog. Therefore, both human and canine liver diseases with different degree of fibrosis and disease activity were included.
  
  
  RESULTS
  In human and canine liver disease, type and extent of LPC niche activation depended on type and severity of disease (P<0.05) and corresponded to the main location of disease. Activated HSCs surrounded the activated LPCs. In chronic hepatitis and non-alcoholic steatohepatitis lobular-type HSCs were activated, while during biliary disease portal/septal MFs were mainly activated. In canine liver, GFAP further presented as an early marker of HSC activation. Activation of the LPCs correlated with disease location and severity (P<0.01), and was inversely related to hepatocyte proliferation, as was previously shown in man.
  
  
  CONCLUSIONS
  A shared involvement of HSC/MFs, LPCs and disease severity during hepatic disease processes is shown, which is highly similar in man and dog.
authors.affiliation: Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands. b.a.schotanus@uu.nl
authors.forename: Baukje A
authors.initials: BA
authors.lastname: Schotanus
authors.forename: Ted S G A M
authors.initials: TS
authors.lastname: van den Ingh
authors.forename: Louis C
authors.initials: LC
authors.lastname: Penning
authors.forename: Jan
authors.initials: J
authors.lastname: Rothuizen
authors.forename: Tania A
authors.initials: TA
authors.lastname: Roskams
authors.forename: Bart
authors.initials: B
authors.lastname: Spee
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004285:Dogs; D019084:Fluorescent Antibody Technique, Indirect / Q000379:methods*; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques / Q000379:methods*; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008107:Liver Diseases / Q000473:pathology / Q000662:veterinary*; D013045:Species Specificity
chemical_list: D015415:Biomarkers