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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Control of Pancreatic β Cell Regeneration by Glucose Metabolism
Shay Porat,Noa Weinberg-Corem,Sharona Tornovsky-Babaey,Rachel Schyr-Ben-Haroush,Ayat Hija,Miri Stolovich-Rain,Daniela Dadon,Zvi Granot,Vered Ben-Hur,Peter White,Christophe Girard,Rotem Karni,Klaus H. Kaestner,Frances M. Ashcroft,Mark A. Magnuson,Ann Saada,Joseph Grimsby,Benjamin Glaser,Yuval Dor +18 more
TL;DR: Intracellularly, genetic and pharmacologic manipulations reveal that glucose induces β cell replication via metabolism by glucokinase, the first step of glycolysis, followed by closure of K(ATP) channels and membrane depolarization, providing a molecular mechanism for homeostatic control of β cell mass by metabolic demand.
Journal ArticleDOI
Artemisinins Target GABAA Receptor Signaling and Impair α Cell Identity
Jin Li,Tamara Casteels,Thomas Frogne,Camilla Ingvorsen,Christian Honoré,Monica Courtney,Kilian Huber,Nicole Schmitner,Robin A. Kimmel,Roman A. Romanov,Roman A. Romanov,Caterina Sturtzel,Charles-Hugues Lardeau,Johanna Klughammer,Matthias Farlik,Sara Sdelci,Andhira Vieira,Fabio Avolio,François Briand,Igor Baburin,Peter Májek,Florian M. Pauler,Thomas Penz,Alexey Stukalov,Manuela Gridling,Katja Parapatics,Charlotte Barbieux,Ekaterine Berishvili,Ekaterine Berishvili,Andreas Spittler,Jacques Colinge,Keiryn L. Bennett,Steffen Hering,Thierry Sulpice,Christoph Bock,Christoph Bock,Christoph Bock,Martin Distel,Tibor Harkany,Tibor Harkany,Dirk Meyer,Giulio Superti-Furga,Giulio Superti-Furga,Patrick Collombat,Jacob Hecksher-Sørensen,Stefan Kubicek +45 more
TL;DR: It is shown that the protein gephyrin is the mammalian target of these antimalarial drugs and that the mechanism of action of these molecules depends on the enhancement of GABAA receptor signaling.
Journal ArticleDOI
Spatiotemporal patterns of multipotentiality in Ptf1a -expressing cells during pancreas organogenesis and injury-induced facultative restoration
Fong Cheng Pan,Eric D. Bankaitis,Daniel F. Boyer,Xiaobo Xu,Mark Van de Casteele,Mark A. Magnuson,Harry Heimberg,Christopher V.E. Wright +7 more
TL;DR: It is shown that acinar cells, without exogenously introduced factors, can regain aspects of embryonic multipotentiality under injury, and convert into mature β-cells.
Journal ArticleDOI
Direct Lineage Conversions: Unnatural but useful?
Thomas Vierbuchen,Marius Wernig +1 more
TL;DR: Direct lineage conversion could provide important new sources of human cells for modeling disease processes or for cellular-replacement therapies and develop methods for robustly and efficiently generating human cell types of interest.
Journal ArticleDOI
Gene expression profiles of Beta-cell enriched tissue obtained by laser capture microdissection from subjects with type 2 diabetes.
Lorella Marselli,Jeffrey Thorne,Sonika Dahiya,Dennis C. Sgroi,Arun Sharma,Susan Bonner-Weir,Piero Marchetti,Gordon C. Weir +7 more
TL;DR: This study made possible by LCM has identified many novel changes in gene expression that enhance understanding of the pathogenesis of T2D.
References
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Book
Manipulating the mouse embryo: A laboratory manual
TL;DR: Here are recorded the tech- niques for preparing, inserting and analysing DNA sequences, for retroviral infection of mice, for production and use of EC and EK cells as vehicles for engineered sequences and for nuclear transplantation - all against a background of the basic procedures required for pro- ducing and handling the em- bryos.
Journal ArticleDOI
Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus
Shankar Srinivas,Tomoko Watanabe,Chyuan-Sheng Lin,Chris M William,Yasuto Tanabe,Thomas M. Jessell,Frank Costantini +6 more
TL;DR: In contrast to existing lacZ reporter lines, where lacZ expression cannot easily be detected in living tissue, the EYFP and ECFP reporter strains are useful for monitoring the expression of Cre and tracing the lineage of these cells and their descendants in cultured embryos or organs.
Journal ArticleDOI
Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation.
TL;DR: This work introduces a method for genetic lineage tracing to determine the contribution of stem cells to a tissue of interest and suggests that terminally differentiated β-cells retain a significant proliferative capacity in vivo and casts doubt on the idea that adult stem cells have a significant role in β-cell replenishment.
Journal ArticleDOI
In vivo reprogramming of adult pancreatic exocrine cells to beta-cells.
TL;DR: This study identifies a specific combination of three transcription factors (Ngn3) Pdx1 and Mafa that reprograms differentiated pancreatic exocrine cells in adult mice into cells that closely resemble β-cells, and suggests a general paradigm for directing cell reprogramming without reversion to a pluripotent stem cell state.
Journal ArticleDOI
Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats.
TL;DR: It is reported that exendin-4, a long-acting GLP-I agonist, stimulates both the differentiation of beta-cells from ductal progenitor cells (neogenesis) and proliferation of Beta-cells when administered to rats and holds promise as a novel therapy to stimulate beta-cell growth and differentiation when administer to diabetic individuals with reduced beta- cell mass.
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