Pancreatic epithelial plasticity mediated by acinar cell transdifferentiation and generation of nestin-positive intermediates.
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.
Means
Anna L
AL
Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Meszoely
Ingrid M
IM
Suzuki
Kazufumi
K
Miyamoto
Yoshiharu
Y
Rustgi
Anil K
AK
Coffey
Robert J
RJ
Wright
Christopher V E
CV
Stoffers
Doris A
DA
Leach
Steven D
SD
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage; D004848:Epithelium / Q000033:anatomy & histology / Q000473:pathology* / Q000502:physiology*; D066246:ErbB Receptors / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism*; D008679:Metaplasia; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D064231:Nestin; D010179:Pancreas / Q000033:anatomy & histology*; D015398:Signal Transduction / Q000502:physiology; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D019076:Transgenes
D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D016211:Transforming Growth Factor alpha; D066246:ErbB Receptors