Modeling human pancreatic beta cell dedifferentiation
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 (...
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doaj-68b32ae0380845d7a7bc838551e3e8a72020-11-24T22:26:54ZengElsevierMolecular Metabolism2212-87782018-04-01107486Modeling human pancreatic beta cell dedifferentiationMarc Diedisheim0Masaya Oshima1Olivier Albagli2Charlotte Wennberg Huldt3Ingela Ahlstedt4Maryam Clausen5Suraj Menon6Alexander Aivazidis7Anne-Christine Andreasson8William G. Haynes9Piero Marchetti10Lorella Marselli11Mathieu Armanet12Fabrice Chimienti13Raphael Scharfmann14INSERM U1016, Institut Cochin, Université Paris Descartes, 123 Boulevard de Port-Royal, 75014 Paris, FranceINSERM U1016, Institut Cochin, Université Paris Descartes, 123 Boulevard de Port-Royal, 75014 Paris, FranceINSERM U1016, Institut Cochin, Université Paris Descartes, 123 Boulevard de Port-Royal, 75014 Paris, FranceCardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, SwedenCardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, SwedenDiscovery Sciences, Innovative Medicines and Early Development Biotech unit, AstraZeneca, Mölndal, SwedenRDI Operations, Granta Park, AstraZeneca, Cambridge, UKCardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, SwedenCardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, SwedenCardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, SwedenDepartment of Clinical and Experimental Medicine, University of Pisa, Pisa, ItalyDepartment of Clinical and Experimental Medicine, University of Pisa, Pisa, ItalyCell Therapy Unit, Hôpital Saint Louis, AP-HP, University Paris-Diderot, Paris, 75010, FranceCardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, SwedenINSERM U1016, Institut Cochin, Université Paris Descartes, 123 Boulevard de Port-Royal, 75014 Paris, France; Corresponding author. Institut Cochin, INSERM U1016, 123 bd du Port-Royal, 75014 Paris, France.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, Type 2 diabetes, Humanhttp://www.sciencedirect.com/science/article/pii/S2212877818300085 |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Marc Diedisheim Masaya Oshima Olivier Albagli Charlotte Wennberg Huldt Ingela Ahlstedt Maryam Clausen Suraj Menon Alexander Aivazidis Anne-Christine Andreasson William G. Haynes Piero Marchetti Lorella Marselli Mathieu Armanet Fabrice Chimienti Raphael Scharfmann |
spellingShingle |
Marc Diedisheim Masaya Oshima Olivier Albagli Charlotte Wennberg Huldt Ingela Ahlstedt Maryam Clausen Suraj Menon Alexander Aivazidis Anne-Christine Andreasson William G. Haynes Piero Marchetti Lorella Marselli Mathieu Armanet Fabrice Chimienti Raphael Scharfmann Modeling human pancreatic beta cell dedifferentiation Molecular Metabolism |
author_facet |
Marc Diedisheim Masaya Oshima Olivier Albagli Charlotte Wennberg Huldt Ingela Ahlstedt Maryam Clausen Suraj Menon Alexander Aivazidis Anne-Christine Andreasson William G. Haynes Piero Marchetti Lorella Marselli Mathieu Armanet Fabrice Chimienti Raphael Scharfmann |
author_sort |
Marc Diedisheim |
title |
Modeling human pancreatic beta cell dedifferentiation |
title_short |
Modeling human pancreatic beta cell dedifferentiation |
title_full |
Modeling human pancreatic beta cell dedifferentiation |
title_fullStr |
Modeling human pancreatic beta cell dedifferentiation |
title_full_unstemmed |
Modeling human pancreatic beta cell dedifferentiation |
title_sort |
modeling human pancreatic beta cell dedifferentiation |
publisher |
Elsevier |
series |
Molecular Metabolism |
issn |
2212-8778 |
publishDate |
2018-04-01 |
description |
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, Type 2 diabetes, Human |
url |
http://www.sciencedirect.com/science/article/pii/S2212877818300085 |
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