Conversion of adult pancreatic α-cells to β-cells after extreme β-cell loss
Fabrizio Thorel,Virginie Nepote,Isabelle Avril,Kenji Kohno,Renaud Desgraz,Simona Chera,Pedro Luis Herrera +6 more
TLDR
In this article, a transgenic model of diphtheria-toxin-induced acute selective near-total beta-cell ablation was used to investigate whether adult mammals can differentiate (regenerate) new beta-cells after extreme, total β-cell loss, as in diabetes.Abstract:
Pancreatic insulin-producing beta-cells have a long lifespan, such that in healthy conditions they replicate little during a lifetime. Nevertheless, they show increased self-duplication after increased metabolic demand or after injury (that is, beta-cell loss). It is not known whether adult mammals can differentiate (regenerate) new beta-cells after extreme, total beta-cell loss, as in diabetes. This would indicate differentiation from precursors or another heterologous (non-beta-cell) source. Here we show beta-cell regeneration in a transgenic model of diphtheria-toxin-induced acute selective near-total beta-cell ablation. If given insulin, the mice survived and showed beta-cell mass augmentation with time. Lineage-tracing to label the glucagon-producing alpha-cells before beta-cell ablation tracked large fractions of regenerated beta-cells as deriving from alpha-cells, revealing a previously disregarded degree of pancreatic cell plasticity. Such inter-endocrine spontaneous adult cell conversion could be harnessed towards methods of producing beta-cells for diabetes therapies, either in differentiation settings in vitro or in induced regeneration.read more
Citations
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Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice
Luc Baeyens,Marie Lemper,Gunter Leuckx,Sofie De Groef,Paola Bonfanti,Geert Stangé,Ruth Shemer,Christoffer Nord,David W. Scheel,Fong Cheng Pan,Ulf Ahlgren,Guoqiang Gu,Doris A. Stoffers,Yuval Dor,Jorge Ferrer,Gérard Gradwohl,Christopher V.E. Wright,Mark Van de Casteele,Michael S. German,Luc Bouwens,Harry Heimberg +20 more
TL;DR: It is shown that transient administration of epidermal growth factor and ciliary neurotrophic factor to adult mice with chronic hyperglycemia efficiently stimulates the conversion of terminally differentiated acinar cells to beta-like cells, which reinstate normal glycemic control for up to 248 d.
Journal ArticleDOI
The role of FOXO1 in β-cell failure and type 2 diabetes mellitus.
TL;DR: Advances in the understanding of the contribution of FOXO1 signalling to the development of β-cell failure in T2DM are discussed, suggesting a primary role for β- cell dysfunction in the pathogenesis of T2 DM.
Journal ArticleDOI
Liver-Specific Disruption of the Murine Glucagon Receptor Produces α-Cell Hyperplasia: Evidence for a Circulating α-Cell Growth Factor
Christine Longuet,Ana M. Robledo,E. Danielle Dean,Chunhua Dai,Safina Ali,Ian McGuinness,Vincent de Chavez,Patricia Vuguin,Maureen J. Charron,Alvin C. Powers,Daniel J. Drucker +10 more
TL;DR: Results suggest that a circulating factor generated after disruption of hepatic Gcgr signaling can increase α-cell proliferation independent of direct pancreatic input, which may facilitate the generation and expansion of α-cells for transdifferentiation into β-cells and the treatment of diabetes.
Journal ArticleDOI
Reduced Insulin Production Relieves Endoplasmic Reticulum Stress and Induces β Cell Proliferation
Marta Szabat,Melissa M. Page,Evgeniy Panzhinskiy,Søs Skovsø,Majid Mojibian,Juan Fernández-Tajes,Jennifer E. Bruin,Michael J. Bround,Jason T. C. Lee,Eric E. Xu,Farnaz Taghizadeh,Shannon O'Dwyer,Martijn van de Bunt,Kyung-Mee Moon,Sunita Sinha,Jun Han,Yong Fan,Francis C. Lynn,Massimo Trucco,Christoph H. Borchers,Leonard J. Foster,Corey Nislow,Timothy J. Kieffer,James D. Johnson +23 more
TL;DR: It is concluded that the normally high rate of insulin production suppresses β cell proliferation in a cell-autonomous manner after reduced insulin production independently of hyperglycemia.
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Virgin Beta Cells Persist throughout Life at a Neogenic Niche within Pancreatic Islets
Talitha van der Meulen,Alex M. Mawla,Michael R. DiGruccio,Michael W. Adams,Vera Nies,Sophie Dólleman,Siming Liu,Amanda M. Ackermann,Elena L. Caceres,Anna E. Hunter,Klaus H. Kaestner,Cynthia J. Donaldson,Mark O. Huising,Mark O. Huising +13 more
TL;DR: A population of immature beta cells that is present throughout life and forms from non-beta precursors at a specialized micro-environment or "neogenic niche" at the islet periphery is discovered.
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