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Nat Cell Biol. 2018 Nov;20(11):1267-1277. doi: 10.1038/s41556-018-0216-y. Epub 2018 Oct 22.

Pancreatic islet-autonomous insulin and smoothened-mediated signalling modulate identity changes of glucagon+ α-cells.

Author information

1
Department of Genetic Medicine and Development, iGE3 and Centre facultaire du diabète, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
2
Department of Cell Biology, Duke University Medical Center, Durham, NC, USA.
3
Department of Clinical Science and KG Jebsen Center for Diabetes Research, University of Bergen, Bergen, Norway.
4
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, USA.
5
Department of Metabolism and Endocrinology, Graduate School of Medicine , Juntendo University , Tokyo, Japan.
6
Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan.
7
Departments of Molecular Physiology and Biophysics, Center for Stem Cell Biology, Vanderbilt University, Nashville, TN, USA.
8
Department of Pediatrics and Cellular and Molecular Medicine, University of California, San Diego, CA, USA.
9
Department of Cell and Developmental Biology, Program in Developmental Biology and Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
10
Department of Genetic Medicine and Development, iGE3 and Centre facultaire du diabète, Faculty of Medicine, University of Geneva, Geneva, Switzerland. pedro.herrera@unige.ch.

Abstract

The mechanisms that restrict regeneration and maintain cell identity following injury are poorly characterized in higher vertebrates. Following β-cell loss, 1-2% of the glucagon-producing α-cells spontaneously engage in insulin production in mice. Here we explore the mechanisms inhibiting α-cell plasticity. We show that adaptive α-cell identity changes are constrained by intra-islet insulin- and Smoothened-mediated signalling, among others. The combination of β-cell loss or insulin-signalling inhibition, with Smoothened inactivation in α- or δ-cells, stimulates insulin production in more α-cells. These findings suggest that the removal of constitutive 'brake signals' is crucial to neutralize the refractoriness to adaptive cell-fate changes. It appears that the maintenance of cell identity is an active process mediated by repressive signals, which are released by neighbouring cells and curb an intrinsic trend of differentiated cells to change.

PMID:
30361701
PMCID:
PMC6215453
[Available on 2019-04-22]
DOI:
10.1038/s41556-018-0216-y

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