Differentiation of pancreatic acinar cells to hepatocytes requires an intermediate cell type

S Y Wu, C C Hsieh, R R Wu, J Susanto, T T Liu, C R Shen, Y Chen, C C Su, F P Chang, H M Chang, David Tosh, C N Shen

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background and aims: 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.

Original languageEnglish
Pages (from-to)2519-2530
Number of pages12
JournalGastroenterology
Volume138
Issue number7
Early online date22 Feb 2010
DOIs
Publication statusPublished - Jun 2010

Keywords

  • pancreas
  • transdifferentiation
  • metaplasia
  • plasticity

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