Role for beta1 integrin and its associated alpha3, alpha5, and alpha6 subunits in development of the human fetal pancreas.

The integrin receptors play a major role in tissue morphogenesis and homeostasis by regulating cell interactions with extracellular matrix proteins. We have examined the expression pattern of integrin subunits in the human fetal pancreas (8-20 weeks fetal age) and the relevance of beta1 integrin function for insulin gene expression and islet cell survival. Its subunits alpha3, alpha5, and alpha6 beta1 integrins are expressed in ductal cells at 8 weeks, before glucagon- and insulin-immunoreactive cells bud off; their levels gradually increase in both ductal cells and islet clusters up to 20 weeks. Colocalization of alpha3, alpha5 and alpha6 beta1 integrins with endocrine cell markers was frequently observed in 8- to 20-week fetal pancreatic cells. When the beta1 integrin receptor was functionally blocked in cultured islet-epithelial clusters with a beta1 immunoneutralizing antibody or following transient beta1 integrin small interfering RNA treatment, there was inhibition of cell adhesion to extracellular matrices, decreased expression of insulin, and increased cell apoptosis. These data offer evidence for dynamic and cell-specific changes in integrin expression during human pancreatic islet neogenesis. They also provide an initial insight into a molecular basis for cell-matrix interactions during islet development and suggest that beta1 integrin plays a vital role in regulating islet cell adhesion, gene expression, and survival.