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

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.

Pancreas organogenesis: From bud to plexus to gland

“…For example, diverting just a few percent away for conversion to b-cells might not compromise overall organ function. Several in vitro acinar cell culture studies demonstrated a potential acinar to endocrine/duct conversion when treated with EGF, nicotinamide, or TGF-a (for example, Means et al, 2005;Minami et al, 2005). Upon caerulein treatment in vivo, acinar cells transiently dedifferentiate to a progenitor-like state, based on the observation of Pdx1, Foxa2, Sox9, and Hes1 positivity (Jensen et al, 2005).…”

Reprogrammation des cellules pancréatiques en cellules β

“…La partie exocrine du pancréas, composée principalement des cellules acinaires, est très majoritaire et pourrait ainsi représenter une source attractive de précurseurs que l'on pourrait « convertir » en cellules endocrines. De récentes études ont en effet démontré la plasticité de ces cellules in vitro et in vivo, et leur capacité de transdifférenciation vers un destin endocrine [16][17][18]. Ainsi, les travaux de Zhou et al [19] suggèrent la possibilité d'une reprogrammation des cellules acinaires différenciées.…”

Murine Embryonic Stem Cell–Derived Pancreatic Acinar Cells Recapitulate Features of Early Pancreatic Differentiation

“…Upon stress, acinar cells readily undergo a phenotypic switch resulting in loss of differentiation and acquisition of duct-like features both in vivo and in vitro (2)(3)(4)(5)(6). Together with their minimal proliferative potential, these effects hamper the study of acinar differentiation.…”