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

Author:

Hayes Heather L.12,Zhang Lu12,Becker Thomas C.13,Haldeman Jonathan M.12,Stephens Samuel B.12,Arlotto Michelle12,Moss Larry G.13,Newgard Christopher B.123,Hohmeier Hans E.13

Affiliation:

1. Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, USA

2. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA

3. Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA

Abstract

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.

Funder

HHS | National Institutes of Health

American Diabetes Association

JDRF

Janssen Research and Development

Publisher

American Society for Microbiology

Subject

Cell Biology,Molecular Biology

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