Modeling human pancreatic beta cell dedifferentiation

Molecular Metabolism
Marc DiedisheimRaphaël Scharfmann

Abstract

Dedifferentiation could explain reduced functional pancreatic β-cell mass in type 2 diabetes (T2D). Here we model human β-cell dedifferentiation using growth factor stimulation in the human β-cell line, EndoC-βH1, and human pancreatic islets. 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. 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.

Citations

Dec 7, 2018·Nature Reviews. Endocrinology·Mostafa BakhtiHeiko Lickert
Sep 4, 2019·The Journal of Clinical Investigation·Raphael ScharfmannOlivier Albagli
Nov 2, 2019·International Journal of Molecular Sciences·Ciro SalinnoMostafa Bakhti
Dec 19, 2019·Diabetes/metabolism Research and Reviews·Laura NigiGuido Sebastiani
Aug 20, 2019·The Journal of Clinical Investigation·Laura I HudishLori Sussel
Dec 20, 2019·Clinical Medicine Insights. Endocrinology and Diabetes·Jens F Rehfeld
Apr 3, 2020·International Journal of Molecular Sciences·Gitika ThakurGyu-Jin Rho
Mar 18, 2020·The Journal of Clinical Investigation·Neha ShresthaLing Qi
Jun 20, 2019·Nature Communications·Chiara MontemurroSlavica Tudzarova
Mar 14, 2020·Current Diabetes Reports·Liliana Muñoz-HernándezCarlos Alberto Aguilar-Salinas
Oct 29, 2020·Physiological Reports·Mario A MirandaHeather A Lawson
Dec 24, 2019·Cell Metabolism·Ahmad Al-MrabehRoy Taylor
Feb 9, 2021·JCI Insight·Mridusmita SaikiaBethany P Cummings
Feb 16, 2021·American Journal of Physiology. Endocrinology and Metabolism·Mario A MirandaHeather A Lawson
May 18, 2020·Seminars in Cell & Developmental Biology·Piero MarchettiLorella Marselli
Nov 23, 2021·Frontiers in Immunology·Floris LeendersFrançoise Carlotti

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Datasets Mentioned

BETA
GSE103383
GSE25724

Methods Mentioned

BETA
electron microscopy
PCR
RNA-Seq
transfection
ELISA
confocal microscopy

Software Mentioned

featureCounts
ImageQuant
Primer
- BLAST
Hisat2 aligner
package
limma
DESeq2
Colombus
R

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