title: Differentiation of pancreatic acinar cells to hepatocytes requires an intermediate cell type.
abstract: OBJECTIVE
  The appearance of hepatic foci in pancreas has been well-documented in animal experiments and in patients with pancreatic cancer. We previously demonstrated that transdifferentiation of pancreatic exocrine cells to hepatocytes required members of the CCAAT enhancer binding protein family. Although the molecular basis of hepatic transdifferentiation is understood, the early cellular events remain to be defined.
  
  
  METHODS
  Dexamethasone and oncostatin M were used to induce transdifferentiation of primary cultures of mouse acinar cells and exocrine cell lines into hepatocytes. Fluorescent-activated cell sorting was used to identify intermediate cell types and side-population characteristics. Cre-loxP-based lineage tracing was used to investigate whether acinar cells contribute directly to hepatocytes via intermediates that express adenosine triphosphate-binding cassette subfamily G member 2 (ABCG2).
  
  
  RESULTS
  Lineage tracing studies showed that hepatocytes were derived directly from pancreatic cells via ABCG2-expressing intermediates. Exposure of cells to insulin increased Akt phosphorylation, ABCG2 expression, and hepatic transdifferentiation. Inhibition of the phosphoinositide 3-kinase pathway, through addition of LY294002 or overexpression of a dominant-negative form of Akt, was sufficient to prevent transdifferentiation. When ABCG2-expressing cells were incubated with glucagon-like-peptide 1 or epidermal growth factor, the intermediate cells could differentiate into insulin-producing beta-like cells.
  
  
  CONCLUSIONS
  The phosphoinositide 3-kinase pathway is important in the transdifferentiation of acinar cells to hepatocytes and those hepatocytes arise from acinar cells via ABCG2-expressing intermediates. Furthermore, ABCG2-expressing cells are multipotent and able to differentiate into hepatocytes and insulin-producing beta cells.
authors.affiliation: Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Sung-Yu
authors.initials: SY
authors.lastname: Wu
authors.forename: Chi-Che
authors.initials: CC
authors.lastname: Hsieh
authors.forename: Ruei-Ren
authors.initials: RR
authors.lastname: Wu
authors.forename: Jimmy
authors.initials: J
authors.lastname: Susanto
authors.forename: Tsung-Ta
authors.initials: TT
authors.lastname: Liu
authors.forename: Chia-Rui
authors.initials: CR
authors.lastname: Shen
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Chien-Chang
authors.initials: CC
authors.lastname: Su
authors.forename: Fang-Pei
authors.initials: FP
authors.lastname: Chang
authors.forename: Hsiao-Min
authors.initials: HM
authors.lastname: Chang
authors.forename: David
authors.initials: D
authors.lastname: Tosh
authors.forename: Chia-Ning
authors.initials: CN
authors.lastname: Shen
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000502:physiology; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology*; D007328:Insulin / Q000494:pharmacology; D051379:Mice; D046790:Pancreas, Exocrine / Q000166:cytology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D051381:Rats; D015398:Signal Transduction
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D022782:CCAAT-Enhancer-Binding Protein-beta; D007328:Insulin; D004815:Epidermal Growth Factor; D003907:Dexamethasone; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt