A Pdx-1-Regulated Soluble Factor Activates Rat and Human Islet Cell Proliferation

Abstract

The homeodomain transcription factor Pdx-1 has important roles in pancreas and islet development as well as in β-cell function and survival. We previously reported that Pdx-1 overexpression stimulates islet cell proliferation, but the mechanism remains unclear. Here, we demonstrate that overexpression of Pdx-1 triggers proliferation largely by a non-cell-autonomous mechanism mediated by soluble factors. Consistent with this idea, overexpression of Pdx-1 under the control of a β-cell-specific promoter (rat insulin promoter [RIP]) stimulates proliferation of both α and β cells, and overexpression of Pdx-1 in islets separated by a Transwell membrane from islets lacking Pdx-1 overexpression activates proliferation in the untreated islets. Microarray and gene ontology (GO) analysis identified inhibin beta-B (Inhbb), an activin subunit and member of the transforming growth factor β (TGF-β) superfamily, as a Pdx-1-responsive gene. Overexpression of Inhbb or addition of activin B stimulates rat islet cell and β-cell proliferation, and the activin receptors RIIA and RIIB are required for the full proliferative effects of Pdx-1 in rat islets. In human islets, Inhbb overexpression stimulates total islet cell proliferation and potentiates Pdx-1-stimulated proliferation of total islet cells and β cells. In sum, this study identifies a mechanism by which Pdx-1 induces a soluble factor that is sufficient to stimulate both rat and human islet cell proliferation.

ACKNOWLEDGMENTS

This work was supported by a grant from the National Institutes of Health β-Cell Biology Consortium (BCBC) (U01 DK-089538) to C.B.N., grants from the Juvenile Diabetes Research Foundation (JDRF) to C.B.N. (17-2011-15) and H.E.H. (17-2011-614), postdoctoral fellowships from the American Diabetes Association to L.Z. (1-16-PDF-136) and the JDRF to H.L.H. (3-2009-561) and a sponsored research agreement from Janssen (to H.E.H.).

We thank Danhong Lu, Helena Winfield, Lisa Poppe, Taylor Rosa, and Paul Anderson for expert technical assistance. We are also very grateful to Robert Mercer and family for generous support over many years for our diabetes and islet research.