Inhibition of TGF-β Signaling Promotes Human Pancreatic β-Cell Replication

Diabetes. 2016 May;65(5):1208-18. doi: 10.2337/db15-1331. Epub 2016 Mar 2.

Abstract

Diabetes is associated with loss of functional pancreatic β-cells, and restoration of β-cells is a major goal for regenerative therapies. Endogenous regeneration of β-cells via β-cell replication has the potential to restore cellular mass; however, pharmacological agents that promote regeneration or expansion of endogenous β-cells have been elusive. The regenerative capacity of β-cells declines rapidly with age, due to accumulation of p16(INK4a), resulting in limited capacity for adult endocrine pancreas regeneration. Here, we show that transforming growth factor-β (TGF-β) signaling via Smad3 integrates with the trithorax complex to activate and maintain Ink4a expression to prevent β-cell replication. Importantly, inhibition of TGF-β signaling can result in repression of the Ink4a/Arf locus, resulting in increased β-cell replication in adult mice. Furthermore, small molecule inhibitors of the TGF-β pathway promote β-cell replication in human islets transplanted into NOD-scid IL-2Rg(null) mice. These data reveal a novel role for TGF-β signaling in the regulation of the Ink4a/Arf locus and highlight the potential of using small molecule inhibitors of TGF-β signaling to promote human β-cell replication.

MeSH terms

  • Animals
  • Benzamides / pharmacology
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p16 / agonists
  • Cyclin-Dependent Kinase Inhibitor p16 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Dioxoles / pharmacology
  • Female
  • Gene Expression Regulation / drug effects
  • Humans
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / physiology
  • Islets of Langerhans Transplantation / physiology
  • Male
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, SCID
  • Mice, Transgenic
  • Receptors, Transforming Growth Factor beta / agonists
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
  • Receptors, Transforming Growth Factor beta / metabolism
  • Regeneration / drug effects
  • Signal Transduction / drug effects*
  • Smad3 Protein / metabolism*
  • Tissue Banks
  • Transforming Growth Factor beta1 / antagonists & inhibitors*
  • Transforming Growth Factor beta1 / metabolism
  • Transplantation, Heterologous
  • Transplantation, Heterotopic

Substances

  • 4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide
  • Benzamides
  • Cyclin-Dependent Kinase Inhibitor p16
  • Dioxoles
  • Insulin
  • P16 protein, human
  • Receptors, Transforming Growth Factor beta
  • SMAD3 protein, human
  • Smad3 Protein
  • TGFB1 protein, human
  • Transforming Growth Factor beta1