Pancreatic epithelial plasticity mediated by acinar cell transdifferentiation and generation of nestin-positive intermediates

Anna L. Means, Ingrid M. Meszoely, Kazufumi Suzuki, Yoshiharu Miyamoto, Anil K. Rustgi, Robert J. Coffey, Christopher V.E. Wright, Doris A. Stoffers, Steven D. Leach

Research output: Contribution to journalArticlepeer-review

Abstract

Epithelial metaplasia occurs when one predominant cell type in a tissue is replaced by another, and is frequently associated with an increased risk of subsequent neoplasia. In both mouse and human pancreas, acinar-to-ductal metaplasia has been implicated in the generation of cancer precursors. We show that pancreatic epithelial explants undergo spontaneous acinar-to-ductal metaplasia in response to EGFR signaling, and that this change in epithelial character is associated with the appearance of nestin-positive transitional cells. Lineage tracing involving Cre/lox-mediated genetic cell labeling reveals that acinar-to-ductal metaplasia represents a true transdifferentiation event, mediated by initial dedifferentiation of mature exocrine cells to generate a population of nestin-positive precursors, similar to those observed during early pancreatic development. These results demonstrate that a latent precursor potential resides within mature exocrine cells, and that this potential is regulated by EGF receptor signaling. In addition, these observations provide a novel example of rigorously documented transdifferentiation within mature mammalian epithelium, and suggest that plasticity of mature cell types may play a role in the generation of neoplastic precursors.

Original languageEnglish (US)
Pages (from-to)3767-3776
Number of pages10
JournalDevelopment
Volume132
Issue number16
DOIs
StatePublished - Aug 2005

Keywords

  • Cancer
  • Differentiation
  • Metaplasia
  • Mouse
  • Pancreas
  • Stem cells
  • TGFα
  • Transdifferentiation

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

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