title: Extensive conversion of hepatic biliary epithelial cells to hepatocytes after near total loss of hepatocytes in zebrafish.
abstract: OBJECTIVE
  Biliary epithelial cells (BECs) are considered to be a source of regenerating hepatocytes when hepatocyte proliferation is compromised. However, there is still controversy about the extent to which BECs can contribute to the regenerating hepatocyte population, and thereby to liver recovery. To investigate this issue, we established a zebrafish model of liver regeneration in which the extent of hepatocyte ablation can be controlled.
  
  
  METHODS
  Hepatocytes were depleted by administration of metronidazole to Tg(fabp10a:CFP-NTR) animals. We traced the origin of regenerating hepatocytes using short-term lineage-tracing experiments, as well as the inducible Cre/loxP system; specifically, we utilized both a BEC tracer line Tg(Tp1:CreER(T2)) and a hepatocyte tracer line Tg(fabp10a:CreER(T2)). We also examined BEC and hepatocyte proliferation and liver marker gene expression during liver regeneration.
  
  
  RESULTS
  BECs gave rise to most of the regenerating hepatocytes in larval and adult zebrafish after severe hepatocyte depletion. After hepatocyte loss, BECs proliferated as they dedifferentiated into hepatoblast-like cells; they subsequently differentiated into highly proliferative hepatocytes that restored the liver mass. This process was impaired in zebrafish wnt2bb mutants; in these animals, hepatocytes regenerated but their proliferation was greatly reduced.
  
  
  CONCLUSIONS
  BECs contribute to regenerating hepatocytes after substantial hepatocyte depletion in zebrafish, thereby leading to recovery from severe liver damage.
authors.affiliation: Department of Developmental Biology, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Tae-Young
authors.initials: TY
authors.lastname: Choi
authors.affiliation: Department of Biochemistry and Biophysics, Programs in Developmental and Stem Cell Biology, Genetics and Human Genetics, Diabetes Center, and Liver Center, University of California, San Francisco, San Francisco, California.
authors.forename: Nikolay
authors.initials: N
authors.lastname: Ninov
authors.affiliation: Department of Biochemistry and Biophysics, Programs in Developmental and Stem Cell Biology, Genetics and Human Genetics, Diabetes Center, and Liver Center, University of California, San Francisco, San Francisco, California.
authors.forename: Didier Y R
authors.initials: DY
authors.lastname: Stainier
authors.affiliation: Department of Developmental Biology, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address: donghuns@pitt.edu.
authors.forename: Donghun
authors.initials: D
authors.lastname: Shin
mesh_terms: D055011:Ablation Techniques; D000818:Animals; D001659:Biliary Tract / Q000166:cytology*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000166:cytology*; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects; D008099:Liver / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D008115:Liver Regeneration / Q000502:physiology*; D008795:Metronidazole / Q000494:pharmacology; D023421:Models, Animal; D009154:Mutation / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics; D015027:Zebrafish / Q000502:physiology*
chemical_list: D051153:Wnt Proteins; C492031:Wnt2b protein, mouse; D008795:Metronidazole
keywords: Dedifferentiation; Liver Regeneration; Oval Cells; Stem Cells