Transforming growth factor beta is a critical regulator of adult human islet plasticity.
Tissue plasticity is well documented in the context of pancreatic regeneration and carcinogenesis, with recent reports implicating dedifferentiated islet cells both as endocrine progenitors and as the cell(s) of origin in pancreatic adenocarcinoma. Accordingly, it is noteworthy that accumulating evidence suggests that TGFbeta signaling is essential to pancreatic endocrine development and maintenance, whereas its loss is associated with the progression to pancreatic adenocarcinoma. The aim of this study was to examine the role of TGFbeta in an in vitro model of islet morphogenetic plasticity. Human islets were embedded in a collagen gel and cultured under conditions that induced transformation into duct-like epithelial structures (DLS). Addition of TGFbeta caused a dose-dependent decrease in DLS formation. Although it was demonstrated that collagen-embedded islets secrete low levels of TGFbeta, antibody-mediated neutralization of this endogenously released TGFbeta improved DLS formation rates, suggesting local TGFbeta concentrations may in fact be higher. Time course studies indicated that TGFbeta signaling was associated with an increase in ERK and p38 MAPK phosphorylation, although inhibitor-based studies were consistent with an islet endocrine-stabilizing effect mediated by p38 alone. Localization of TGFbeta signaling molecules suggested that the action of TGFbeta is directly on the beta-cell to inhibit apoptosis and thus stabilize endocrine phenotype.
Hanley
Stephen
S
Department of Surgery, McGill University, and Centre for Pancreatic Diseases, McGill University Health Centre, Montreal, Quebec, Canada H3G 1A4.
Rosenberg
Lawrence
L
D000328:Adult; D002454:Cell Differentiation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007515:Islets of Langerhans / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D010183:Pancreatic Ducts / Q000166:cytology / Q000254:growth & development; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000494:pharmacology / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4