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First published online 14 July 2005
doi: 10.1242/dev.01925
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1 Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN
37232, USA
2 Department of Medicine, Vanderbilt University School of Medicine, Nashville,
TN 37232, USA
3 Department of Surgery, Johns Hopkins University School of Medicine, Baltimore,
MD 21287, USA
4 Division of Gastroenterology, Department of Genetics and Abramson Cancer
Center University of Pennsylvania School of Medicine, Philadelphia, PA 19104,
USA
5 Department of Cell and Developmental Biology, Vanderbilt University School of
Medicine, Nashville, TN 37232, USA
6 Division of Endocrinology, Diabetes and Metabolism, University of Pennsylvania
School of Medicine, Philadelphia, PA 19104, USA
7 Department of Oncology, Johns Hopkins University School of Medicine,
Baltimore, MD 21287, USA
8 Department of Cell Biology, Johns Hopkins University School of Medicine,
Baltimore, MD 21287, USA
* Author for correspondence (e-mail: stleach{at}jhmi.edu)
Accepted 1 June 2005
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.
Key words: Pancreas, Metaplasia, Differentiation, Transdifferentiation, Stem cells, TGF
, Cancer, Mouse
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