title: Spontaneous repopulation of β-catenin null livers with β-catenin-positive hepatocytes after chronic murine liver injury.
abstract: Prolonged exposure of mice to diet containing 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) results in hepatobiliary injury, atypical ductular proliferation, oval cell appearance, and limited fibrosis. Previously, we reported that short-term ingestion of DDC diet by hepatocyte-specific β-catenin conditional knockout (KO) mice led to fewer A6-positive oval cells than wildtype (WT) littermates. To examine the role of β-catenin in chronic hepatic injury and repair, we exposed WT and KO mice to DDC for 80 and 150 days. Paradoxically, long-term DDC exposure led to significantly more A6-positive cells, indicating greater atypical ductular proliferation in KO, which coincided with increased fibrosis and cholestasis. Surprisingly, at 80 and 150 days in KO we observed a significant amelioration of hepatocyte injury. This coincided with extensive repopulation of β-catenin null livers with β-catenin-positive hepatocytes at 150 days, which was preceded by appearance of β-catenin-positive hepatocyte clusters at 80 days and a few β-catenin-positive hepatocytes at earlier times. Intriguingly, occasional β-catenin-positive hepatocytes that were negative for progenitor markers were also observed at baseline in the KO livers, suggesting spontaneous escape from cre-mediated recombination. These cells with hepatocyte morphology expressed mature hepatocyte markers but lacked markers of hepatic progenitors. The gradual repopulation of KO livers with β-catenin-positive hepatocytes occurred only following DDC injury and coincided with a progressive loss of hepatic cre-recombinase expression. A few β-catenin-positive cholangiocytes were observed albeit only after long-term DDC exposure and trailed the appearance of β-catenin-positive hepatocytes.
  
  
  CONCLUSIONS
  In a chronic liver injury model, β-catenin-positive hepatocytes exhibit growth and survival advantages and repopulate KO livers, eventually limiting hepatic injury and dysfunction despite increased fibrosis and intrahepatic cholestasis.
authors: Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15261, USA.
authors: Michael D
authors: MD
authors: Thompson
authors: Emily D
authors: ED
authors: Wickline
authors: William B
authors: WB
authors: Bowen
authors: Amy
authors: A
authors: Lu
authors: Sucha
authors: S
authors: Singh
authors: Amalea
authors: A
authors: Misse
authors: Satdarshan P S
authors: SP
authors: Monga
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D056487:Chemical and Drug Induced Liver Injury, Chronic / Q000473:pathology*; D002908:Chronic Disease; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000187:drug effects* / Q000473:pathology; D007150:Immunohistochemistry; D008111:Liver Function Tests; D008115:Liver Regeneration / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D011725:Pyridines / Q000494:pharmacology*; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C530773:3,5-diethoxycarbonyl-1,4-dihydrocollidine; D011725:Pyridines; D051176:beta Catenin