Transforming growth factor beta is a critical regulator of adult human islet plasticity

摘要

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