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Diabetes recovery by age-dependent conversion of pancreatic δ-cells into insulin producers.

Chera S, Baronnier D, Ghila L, Cigliola V, Jensen JN, Gu G, Furuyama K, Thorel F, Gribble FM, Reimann F, Herrera PL - Nature (2014)

Bottom Line: We found that senescence does not alter α-cell plasticity: α-cells can reprogram to produce insulin from puberty through to adulthood, and also in aged individuals, even a long time after β-cell loss.This juvenile adaptability relies, at least in part, upon the combined action of FoxO1 and downstream effectors.A landscape with multiple intra-islet cell interconversion events is emerging, offering new perspectives for therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetic Medicine &Development, Faculty of Medicine, University of Geneva, 1 rue Michel-Servet, 1211 Geneva-4, Switzerland.

ABSTRACT
Total or near-total loss of insulin-producing β-cells occurs in type 1 diabetes. Restoration of insulin production in type 1 diabetes is thus a major medical challenge. We previously observed in mice in which β-cells are completely ablated that the pancreas reconstitutes new insulin-producing cells in the absence of autoimmunity. The process involves the contribution of islet non-β-cells; specifically, glucagon-producing α-cells begin producing insulin by a process of reprogramming (transdifferentiation) without proliferation. Here we show the influence of age on β-cell reconstitution from heterologous islet cells after near-total β-cell loss in mice. We found that senescence does not alter α-cell plasticity: α-cells can reprogram to produce insulin from puberty through to adulthood, and also in aged individuals, even a long time after β-cell loss. In contrast, before puberty there is no detectable α-cell conversion, although β-cell reconstitution after injury is more efficient, always leading to diabetes recovery. This process occurs through a newly discovered mechanism: the spontaneous en masse reprogramming of somatostatin-producing δ-cells. The juveniles display 'somatostatin-to-insulin' δ-cell conversion, involving dedifferentiation, proliferation and re-expression of islet developmental regulators. This juvenile adaptability relies, at least in part, upon the combined action of FoxO1 and downstream effectors. Restoration of insulin producing-cells from non-β-cell origins is thus enabled throughout life via δ- or α-cell spontaneous reprogramming. A landscape with multiple intra-islet cell interconversion events is emerging, offering new perspectives for therapy.

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Age-dependent effect of β-cell loss on δ-cellsa, b) Transcriptional variation of cell cycle regulators, PI3K/AKT/FoxO1network genes (a), and TGFβ and BMP components and effectors(b) in juvenile and adult δ cells 1 week after ablation, as comparedwith age-matched controls. c) β-cell loss before puberty triggersFoxO1 downregulation in δ-cells, while the opposite occurs in adults (see Extended Data Fig.9b). d)Experimental design to transiently inhibit FoxO1 in β-cell-ablated adult mice.e) Induction of δ-to-insulin cell conversion in diabetic adult mice.Scale bars: 20 μm. f,g) Insulin+ cells are 11-fold moreabundant in FoxO1 inhibitor-treated mice (treated: n=190 islets, 4 mice;untreated: n=95 islets, 3 mice (Welch’s test [inter-isletp<0.0001, inter-individual p=0.0065], Mann-Whitney [p<0.0001])(f), and they are YFP+ (93%) (treated: n=4, 894insulin+-cells scored; untreated: n=6, 370insulin+-cells scored, Welch’s test [p<0.0001], Mann-Whitney[p=0.0095]) (g). h) One fourth of δ-(YFP+)cells in adult β-cell-ablated FoxO1-inhibited mice dedifferentiate and becomeinsulin expressers (treated: n=4, 3,358 YFP+-cells scored;untreated: n=6, 2,559 YFP+-cells scored). Error bars:s.d.
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Figure 3: Age-dependent effect of β-cell loss on δ-cellsa, b) Transcriptional variation of cell cycle regulators, PI3K/AKT/FoxO1network genes (a), and TGFβ and BMP components and effectors(b) in juvenile and adult δ cells 1 week after ablation, as comparedwith age-matched controls. c) β-cell loss before puberty triggersFoxO1 downregulation in δ-cells, while the opposite occurs in adults (see Extended Data Fig.9b). d)Experimental design to transiently inhibit FoxO1 in β-cell-ablated adult mice.e) Induction of δ-to-insulin cell conversion in diabetic adult mice.Scale bars: 20 μm. f,g) Insulin+ cells are 11-fold moreabundant in FoxO1 inhibitor-treated mice (treated: n=190 islets, 4 mice;untreated: n=95 islets, 3 mice (Welch’s test [inter-isletp<0.0001, inter-individual p=0.0065], Mann-Whitney [p<0.0001])(f), and they are YFP+ (93%) (treated: n=4, 894insulin+-cells scored; untreated: n=6, 370insulin+-cells scored, Welch’s test [p<0.0001], Mann-Whitney[p=0.0095]) (g). h) One fourth of δ-(YFP+)cells in adult β-cell-ablated FoxO1-inhibited mice dedifferentiate and becomeinsulin expressers (treated: n=4, 3,358 YFP+-cells scored;untreated: n=6, 2,559 YFP+-cells scored). Error bars:s.d.

Mentions: δ-cells displayed a divergent regulation of FoxO1 in injuredjuvenile and adult mice. Consistent with FoxO1 downregulation in juvenileδ-cells, PDK1 and AKT levels were increased,cdkn1a/p21 and cdkn2b/p15Ink4b were downregulated, andCKS1b, CDK2 and SKP were upregulated(Fig. 3a), which is compatible with the proliferativecapacity of juvenile δ-cells after β-cell ablation. The opposite was found inδ-cells of ablated adults (Fig. 3a; Extended Data Fig.9b).


Diabetes recovery by age-dependent conversion of pancreatic δ-cells into insulin producers.

Chera S, Baronnier D, Ghila L, Cigliola V, Jensen JN, Gu G, Furuyama K, Thorel F, Gribble FM, Reimann F, Herrera PL - Nature (2014)

Age-dependent effect of β-cell loss on δ-cellsa, b) Transcriptional variation of cell cycle regulators, PI3K/AKT/FoxO1network genes (a), and TGFβ and BMP components and effectors(b) in juvenile and adult δ cells 1 week after ablation, as comparedwith age-matched controls. c) β-cell loss before puberty triggersFoxO1 downregulation in δ-cells, while the opposite occurs in adults (see Extended Data Fig.9b). d)Experimental design to transiently inhibit FoxO1 in β-cell-ablated adult mice.e) Induction of δ-to-insulin cell conversion in diabetic adult mice.Scale bars: 20 μm. f,g) Insulin+ cells are 11-fold moreabundant in FoxO1 inhibitor-treated mice (treated: n=190 islets, 4 mice;untreated: n=95 islets, 3 mice (Welch’s test [inter-isletp<0.0001, inter-individual p=0.0065], Mann-Whitney [p<0.0001])(f), and they are YFP+ (93%) (treated: n=4, 894insulin+-cells scored; untreated: n=6, 370insulin+-cells scored, Welch’s test [p<0.0001], Mann-Whitney[p=0.0095]) (g). h) One fourth of δ-(YFP+)cells in adult β-cell-ablated FoxO1-inhibited mice dedifferentiate and becomeinsulin expressers (treated: n=4, 3,358 YFP+-cells scored;untreated: n=6, 2,559 YFP+-cells scored). Error bars:s.d.
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Related In: Results  -  Collection

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Figure 3: Age-dependent effect of β-cell loss on δ-cellsa, b) Transcriptional variation of cell cycle regulators, PI3K/AKT/FoxO1network genes (a), and TGFβ and BMP components and effectors(b) in juvenile and adult δ cells 1 week after ablation, as comparedwith age-matched controls. c) β-cell loss before puberty triggersFoxO1 downregulation in δ-cells, while the opposite occurs in adults (see Extended Data Fig.9b). d)Experimental design to transiently inhibit FoxO1 in β-cell-ablated adult mice.e) Induction of δ-to-insulin cell conversion in diabetic adult mice.Scale bars: 20 μm. f,g) Insulin+ cells are 11-fold moreabundant in FoxO1 inhibitor-treated mice (treated: n=190 islets, 4 mice;untreated: n=95 islets, 3 mice (Welch’s test [inter-isletp<0.0001, inter-individual p=0.0065], Mann-Whitney [p<0.0001])(f), and they are YFP+ (93%) (treated: n=4, 894insulin+-cells scored; untreated: n=6, 370insulin+-cells scored, Welch’s test [p<0.0001], Mann-Whitney[p=0.0095]) (g). h) One fourth of δ-(YFP+)cells in adult β-cell-ablated FoxO1-inhibited mice dedifferentiate and becomeinsulin expressers (treated: n=4, 3,358 YFP+-cells scored;untreated: n=6, 2,559 YFP+-cells scored). Error bars:s.d.
Mentions: δ-cells displayed a divergent regulation of FoxO1 in injuredjuvenile and adult mice. Consistent with FoxO1 downregulation in juvenileδ-cells, PDK1 and AKT levels were increased,cdkn1a/p21 and cdkn2b/p15Ink4b were downregulated, andCKS1b, CDK2 and SKP were upregulated(Fig. 3a), which is compatible with the proliferativecapacity of juvenile δ-cells after β-cell ablation. The opposite was found inδ-cells of ablated adults (Fig. 3a; Extended Data Fig.9b).

Bottom Line: We found that senescence does not alter α-cell plasticity: α-cells can reprogram to produce insulin from puberty through to adulthood, and also in aged individuals, even a long time after β-cell loss.This juvenile adaptability relies, at least in part, upon the combined action of FoxO1 and downstream effectors.A landscape with multiple intra-islet cell interconversion events is emerging, offering new perspectives for therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetic Medicine &Development, Faculty of Medicine, University of Geneva, 1 rue Michel-Servet, 1211 Geneva-4, Switzerland.

ABSTRACT
Total or near-total loss of insulin-producing β-cells occurs in type 1 diabetes. Restoration of insulin production in type 1 diabetes is thus a major medical challenge. We previously observed in mice in which β-cells are completely ablated that the pancreas reconstitutes new insulin-producing cells in the absence of autoimmunity. The process involves the contribution of islet non-β-cells; specifically, glucagon-producing α-cells begin producing insulin by a process of reprogramming (transdifferentiation) without proliferation. Here we show the influence of age on β-cell reconstitution from heterologous islet cells after near-total β-cell loss in mice. We found that senescence does not alter α-cell plasticity: α-cells can reprogram to produce insulin from puberty through to adulthood, and also in aged individuals, even a long time after β-cell loss. In contrast, before puberty there is no detectable α-cell conversion, although β-cell reconstitution after injury is more efficient, always leading to diabetes recovery. This process occurs through a newly discovered mechanism: the spontaneous en masse reprogramming of somatostatin-producing δ-cells. The juveniles display 'somatostatin-to-insulin' δ-cell conversion, involving dedifferentiation, proliferation and re-expression of islet developmental regulators. This juvenile adaptability relies, at least in part, upon the combined action of FoxO1 and downstream effectors. Restoration of insulin producing-cells from non-β-cell origins is thus enabled throughout life via δ- or α-cell spontaneous reprogramming. A landscape with multiple intra-islet cell interconversion events is emerging, offering new perspectives for therapy.

Show MeSH
Related in: MedlinePlus