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

Mol Cell Biol. 2016 Nov 14;36(23):2918-2930. doi: 10.1128/MCB.00103-16. Print 2016 Dec 1.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Proliferation
  • Cells, Cultured
  • Gene Expression Profiling
  • Glucagon-Secreting Cells / cytology
  • Glucagon-Secreting Cells / metabolism
  • Homeodomain Proteins / metabolism*
  • Humans
  • Inhibin-beta Subunits / genetics*
  • Insulin / genetics*
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / metabolism
  • Islets of Langerhans / cytology*
  • Islets of Langerhans / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Promoter Regions, Genetic
  • Rats
  • Trans-Activators / metabolism*


  • Homeodomain Proteins
  • INHBB protein, human
  • Inhbb protein, rat
  • Insulin
  • Trans-Activators
  • pancreatic and duodenal homeobox 1 protein
  • Inhibin-beta Subunits