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Transforming Growth Factor ß Is a Critical Regulator of Adult Human Islet Plasticity

Department of Surgery, McGill University, and Centre for Pancreatic Diseases, McGill University Health Centre, Montreal, Quebec, Canada H3G 1A4

Address all correspondence and requests for reprints to: Dr. Lawrence Rosenberg, Montreal General Hospital C9-128, 1650 Cedar Avenue, Montreal, Quebec, Canada H3G 1A4. E-mail: lawrence.rosenberg{at}mcgill.ca.

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 TGFß 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 TGFß 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 TGFß caused a dose-dependent decrease in DLS formation. Although it was demonstrated that collagen-embedded islets secrete low levels of TGFß, antibody-mediated neutralization of this endogenously released TGFß improved DLS formation rates, suggesting local TGFß concentrations may in fact be higher. Time course studies indicated that TGFß 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 TGFß signaling molecules suggested that the action of TGFß is directly on the ß-cell to inhibit apoptosis and thus stabilize endocrine phenotype.