Modeling human pancreatic beta cell dedifferentiation

Mol Metab. 2018 Apr;10:74-86. doi: 10.1016/j.molmet.2018.02.002. Epub 2018 Feb 8.

Abstract

Objective: Dedifferentiation could explain reduced functional pancreatic β-cell mass in type 2 diabetes (T2D).

Methods: Here we model human β-cell dedifferentiation using growth factor stimulation in the human β-cell line, EndoC-βH1, and human pancreatic islets.

Results: Fibroblast growth factor 2 (FGF2) treatment reduced expression of β-cell markers, (INS, MAFB, SLC2A2, SLC30A8, and GCK) and activated ectopic expression of MYC, HES1, SOX9, and NEUROG3. FGF2-induced dedifferentiation was time- and dose-dependent and reversible upon wash-out. Furthermore, FGF2 treatment induced expression of TNFRSF11B, a decoy receptor for RANKL and protected β-cells against RANKL signaling. Finally, analyses of transcriptomic data revealed increased FGF2 expression in ductal, endothelial, and stellate cells in pancreas from T2D patients, whereas FGFR1, SOX,9 and HES1 expression increased in islets from T2D patients.

Conclusions: We thus developed an FGF2-induced model of human β-cell dedifferentiation, identified new markers of dedifferentiation, and found evidence for increased pancreatic FGF2, FGFR1, and β-cell dedifferentiation in T2D.

Keywords: Beta-cell; Dedifferentiation; Human; Type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Dedifferentiation*
  • Cells, Cultured
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diabetes Mellitus, Type 2 / pathology
  • Fibroblast Growth Factor 2 / pharmacology
  • Humans
  • Insulin-Secreting Cells / cytology*
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Osteoprotegerin / genetics
  • Osteoprotegerin / metabolism
  • RANK Ligand / metabolism
  • Receptor, Fibroblast Growth Factor, Type 1 / genetics
  • Receptor, Fibroblast Growth Factor, Type 1 / metabolism
  • SOX9 Transcription Factor / genetics
  • SOX9 Transcription Factor / metabolism
  • Transcription Factor HES-1 / genetics
  • Transcription Factor HES-1 / metabolism

Substances

  • Osteoprotegerin
  • RANK Ligand
  • SOX9 Transcription Factor
  • SOX9 protein, human
  • TNFRSF11B protein, human
  • Transcription Factor HES-1
  • Fibroblast Growth Factor 2
  • HES1 protein, human
  • FGFR1 protein, human
  • Receptor, Fibroblast Growth Factor, Type 1