Total or near-total loss of insulin-producing β-cells occurs in type 1 diabetes1,2. 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 autoimmunity3. 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 proliferation3. 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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Chromatin accessibility differences between alpha, beta, and delta cells identifies common and cell type-specific enhancers
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We are grateful to D. Belin, P. Vassalli, R. Stein, A. Cookson, A. Ruiz i Altaba, M. González Gaitán, B. Galliot and I. Rodríguez for comments, support and discussions, and to G. Gallardo, O. Fazio, K. Hammad and B. Polat for technical help. We thank G. Gradwohl for the Ngn3-YFP mice. F.M.G. and F.R. were funded by Wellcome Trust grants WT088357/Z/09/Z and WT084210/Z/07/Z, respectively. This work was funded with grants from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (Beta Cell Biology Consortium), the Juvenile Diabetes Research Foundation and the Swiss National Science Foundation (NRP63) to P.L.H.
The authors declare no competing financial interests.
Extended data figures and tables
a, Evolution of glycaemia in β-cell-ablated adults (middle-aged) and aged mice. The area under the curve (AuC) in middle-aged (2-month-old, n = 4) and aged (1- and 1.5-year-old, n = 5 and n = 3) mice before and after stopping insulin administration revealed no statistical difference between groups (Welch’s test, P0–4.5 mpa = 0.1029, 0.3321; P4.5–7 mpa = 0.1748, 0.5007; one-way analysis of variance (ANOVA), P = 0.1161, P = 0.2681; and Mann–Whitney, P = 0.1640, 0.4519). b, Evolution of glycaemia in 14 aged mice over a period of 14 months post-ablation (mpa). Mice were treated with insulin for 4.5 months; most of them (5/7 in each group) subsequently recovered from diabetes. c–e, Pancreatic islets before (c) and after (d, e) β-cell ablation in 1.5-year-old mice; β-cell mass increases 3.5-fold between 0.5 and 1 mpa, 12-fold at 7 mpa and 32-fold at 14 mpa, in all age groups. Percentages (0.3% and 4.4%) indicate β-cell mass relative to unablated controls (Supplementary Table 1). Two-month-old: n0.5 mpa = 4; n1 mpa = 4; n7 mpa = 4; 1-year-old: n0.5 mpa = 5, n1 mpa = 5, n7 mpa = 5, n14 mpa = 8; 1.5-year-old: n0.5 mpa = 3; n1 mpa = 3; n7 mpa = 3, n14 mpa = 8. f, β-Cell proliferation is very low in aged mice, whether control (1.5%; n = 8; 39,790 insulin+-cells scored) or ablated (0.2%; n = 6; 938 insulin+-cells scored) (Supplementary Table 2). g, Proportion of insulin+ cells also containing glucagon after DT is not different between groups (Supplementary Table 3). Control: n2-month-old = 3; n1-year-old = 3; n1.5-year-old = 3; 0.5 mpa: n2-month-old = 5; n1-year-old = 5; n1.5-year-old = 6; 1 mpa: n2-month-old = 4; n1-year-old = 6; n1.5-year-old = 4; 7 mpa: n2-month-old = 5; n1-year-old = 5; n1.5-year-old = 6. One-way ANOVA (P = 0.6796, 0.4297, 0.9266, 0.2411); note that 40% of the cells containing insulin at 1 mpa also contained glucagon. The proportion of glucagon+/insulin+ cells remains constant between 0.5 and 7 mpa, while the number of insulin+ cells increases with time (e; Supplementary Table 1), suggesting that there is a cumulative recruitment of α-cells into insulin production. h, Islet with YFP+/glucagon+/insulin+ cells in 1-year-old glucagon-rtTA; TetO-Cre; R26-YFP; RIP-DTR mice, 7 mpa; rtTA expression allows the selective irreversible YFP labelling of adult α-cells upon administration of doxycycline (DOX) before β-cell ablation. i, Proportion of YFP-labelled insulin-expressing cells in DOX-treated mice. Eighty per cent of insulin+ cells are YFP+ after 7 mpa, in all age groups (Supplementary Table 4). Control: n2-month-old = 3; n1-year-old = 3; n1.5-year-old = 3; 1 mpa: n2-month-old = 5; n1-year-old = 3; n1.5-year-old = 3; 7 mpa: n2-month-old = 5; n1-year-old = 5; n1.5-year-old = 5. One-way ANOVA (P = 0.9417, 0.8910, 0.9641). j, k, YFP+/glucagon+/insulin+ cells at 7 mpa, following DOX pulse-labelling at 5.5 months after β-cell loss (Supplementary Table 5). Control: n1-year-old = 5; n1.5-year-old = 5; 7 mpa: n1-year-old = 5; n1.5-year-old = 5; Welch’s correction (P = 0.8272, 0.8926), Mann–Whitney (P = 0.9444). On average, 15% of the insulin+ cells found were YFP labelled, some of which no longer contained glucagon as in j, bottom row. Note the decreased proportion of YFP-labelled insulin+ cells when α-cells are tagged late after ablation (from 80% to 15%; compare i and k), and the presence of YFP-labelled insulin+/glucagon-negative cells in the latter situation (j), suggesting that bihormonal α-cells slowly but gradually lose glucagon gene activity. Scale bars, 20 µm. Error bars show s.d.
a, Evolution of glycemia (AuC) between 2.5 and 4 mpa, in pups and adults (see Fig. 1b) (Welch’s test, P = 0.0188). b, qPCR of insulin 2 messenger RNA after β-cell ablation; insulin 2 transcripts are 25-fold more abundant in pups than in adults at 2 mpa (n = 3 mice per group, each individual sample was run in triplicate in each reaction for a total of three independent reactions). Built-in Welch’s test (P = 0.0134, 0.0049). Error bars show s.d. c, Glucose tolerance tests (IPGTT) for DT-treated (4.5 mpa, n = 4) and age-matched controls (n = 4); note the fold increase between glucose injection and the glycaemic peak during IPGTT for each animal, and fold decrease between glycaemic peak and T120 (two-tailed unpaired t-test, PI = 0.5836, PII = 0.4937). d, Plasma insulin at time point (in min) T0, T15 and T30 during the IPGTT. Control: n = 4; DT: n = 4; two-tailed paired t-test (P = 0.0008). e, Insulin tolerance tests (ITT) performed 1.5 years after β-cell ablation at 2 weeks of age. Controls: n = 7; DT: n = 10. f, 4.5 months after β-cell ablation (at 2 weeks), three mice became normoglycaemic and received a second treatment with DT. Ablation of regenerated insulin+ cells in recovered mice leads to the appearance of glucagon+/insulin+ cells, corresponding to the type of ‘α-cell-dependent’ regeneration observed in adults (31% of insulin+ cells also contained glucagon; Supplementary Table 8). Arrow indicates glucagon+/insulin+ bihormonal cell. Error bars show standard error of the mean (s.e.m.). g, β-cell proliferation is very low in regenerating pups (Supplementary Table 9). Control: n1-month-old = 3, 6,006 insulin+-cells scored; n2-month-old = 3, 6,358 insulin+-cells scored; DT: n0.5 mpa = 5, 412 insulin+-cells scored; n1.5 mpa = 3, 675 insulin+-cells scored; Welch’s test (P = 0.1197, P = 0.0688). Error bars show s.e.m. h, Islet cell proliferation is increased (3.5-fold; Ki67+ cells) in islets of DT-treated pups at 0.5 mpa. Control: n1-month-old = 3, 95 islets scored; n1.5-month-old = 3, 94 islets scored; n2-month-old = 3, 90 islets scored; n2.5-month-old = 3, 89 islets scored; n3-month-old ctrl = 3, 91 islets scored; n3.5-month-old = 3, 93 islets scored; n18.5-month-old = 3, 83 islets scored; n19-month-old ctrl = 3, 83 islets scored; n19.5-month-old = 3, 88 islets scored; DT (2-week-old): n0.5 mpa = 6, 333 islets scored; n1 mpa = 3, 91 islets scored; n1.5 mpa = 3, 90 islets scored; DT (2-month-old): n0.5 mpa = 3, 76 islets scored; n1 mpa = 3, 77 islets scored; n1.5 mpa = 3, 81 islets scored; DT (1.5-year-old): n0.5 mpa = 3, 74 islets scored; n1 mpa = 3, 81 islets scored; n1.5 mpa = 3, 77 islets scored. Error bars show s.d. Welch’s test, one-way ANOVA (P < 0.001), Mann–Whitney (P = 0.0238). i, Ki67+ cells are hormone, chromogranin-A-negative; lineage-traced α- and DT-spared β-cells are Ki67-negative. Scale bars, 20 µm.
a, The number of Sst+ cells transiently decreases by 80% during the second week after ablation. ncontrol = 255 islets, 7 mice; n3 dpa = 240 islets, 5 mice; n5 dpa = 228 islets, 5 mice; n7 dpa = 251 islets, 5 mice; n0.5 mpa = 267 islets, 6 mice; n1 mpa = 266 islets, 5 mice; n1.5 mpa = 206 islets, 5 mice. Error bars show s.d. Welch’s test (P = 0.0008, 0.0229, 0.006, 0.035), one-way ANOVA (P < 0.0001), Mann–Whitney (P = 0.0043). b, Relative Sst gene expression sharply decreases 2 weeks after β-cell ablation in 2-week-old mice (n = 3 mice per group, each individual sample of each experimental group was run in triplicate, in three independent reactions). Built-in Welch’s test (P = 0.0002). Error bars show s.d. c, Sst-Cre; R26-YFP mice. Cre activity efficiently and specifically occurs in δ-cells (box: enlarged cell). Scale bar, 20 µm. d, Quantitative values of reporter gene expression in islet cells (n = 4; 1,263 YFP+-cells scored).
Extended Data Figure 4 δ-cells dedifferentiate, proliferate and reprogram into insulin production after extreme β-cell loss in juvenile mice.
Observed and expected numbers of Sst+ and insulin+ cells per islet section, before and after β-cell ablation. Cells scored after 6 weeks (Extended Data Fig. 3a) correspond (χ2 test) with estimates made assuming that dedifferentiated proliferating δ-cells yield two types of progeny (as deduced from Fig. 2c, e). Dashed arrows indicate phenotypic stability; plain arrows indicate dynamic behaviour (dedifferentiation and replication).
a, Immunofluorescence showing YFP-labelled insulin+ cells at 1.5 month following streptozotocin (STZ)-induced ablation of β-cells in 2-week-old mice. Arrows indicate YFP+/insulin+ cells; arrowhead indicates YFP+/Sst+ cell; asterisks indicate escaping β-cells. b, Number of remaining β-cells per islet section at 2 weeks after streptozotocin or DT treatment in pups, reflecting difference in ablation efficiency of the two methods (Supplementary Table 18). nSTZ = 87 islets, 3 mice; nDT = 361 islets, 4 mice. Welch’s test (inter-islet P < 0.0001; inter-individual P = 0.0109), Mann–Whitney (P < 0.001). c, The number of YFP+/insulin+ cells per islet section at 1.5 mpa is not significantly different between the two β-cell ablation methods (Supplementary Table 19). nSTZ = 88 islets, 3 mice; nDT = 193 islets, 7 mice. Welch’s test (P = 0.4786). d, δ-cell numbers per islet section in controls (n = 3, 174 islets scored), 0.5 mpa (n = 4, 140 islets scored) and 1 mpa (n = 3, 86 islets scored). Unpaired t-test, two-tailed (P = 0.6386; P = 0.5406). e, Immunofluorescence for YFP and Ki67 2 weeks (0.5 mpa) after DT, in Sst-Cre; R26-YFP; RIP-DTR mice. f, Experimental design for δ-cell tracing in β-cell-ablated Sst-Cre; R26-YFP; RIP-DTR mice at 2 months of age, and immunofluorescence for Sst, YFP and insulin at 1.5 mpa. Arrow indicates YFP+/insulin+/Sst− cell. g, At 1.5 mpa, 17% of insulin+ cells co-express YFP versus almost 100% in ablated prepubescent mice. Control: n = 4; DT: n = 8; unpaired t-test, two-tailed (P = 0.0462). h, At 1.5 mpa, 98% of the YFP+ cells are Sst+, and 1% are insulin+ cells (versus 44% in mice ablated before puberty; n = 8, unpaired t-test, two-tailed). Scale bars, 20 µm. Error bars show s.d.
Extended Data Figure 6 δ-to-β-cell conversion after β-cell ablation is maintained in young islets ablated underneath the kidney capsule of adult hosts.
a, Islet transplantation design: 400–600 islets isolated from 2-week-old Sst-Cre; R26-YFP; RIP-DTR transgenics were transferred under the kidney capsule of 2-month-old immunodeficient (SCID) mice (n = 3). b, Experimental design: after 1 week of engraftment, adult host mice were DT-treated and left to regenerate for 6 weeks. c, δ-to-β conversion was observed in β-cell-ablated engrafted islets, like in the pancreas of juvenile mice. Scale bars, 20 µm.
a, Once differentiated from δ-cells (YFP+), the newly formed β-cells re-enter the cell cycle (Ki67+ cells). Two waves of massive replication occur, at 3 and 4 months after injury, respectively (Supplementary Table 23). b, qPCR for β-cell-specific genes using RNA extracted from islets isolated from control and DT-treated mice, either 2 weeks or 4 months after DT administration (0.5 mpa and 4 mpa). Note that after an initial extreme downregulation of all the β-cell-specific markers explored, their levels significantly recover after 4 months, which correlates with the observed robust regeneration and diabetes recovery. Values represent the ratio between each regeneration time-point and its age-matched control. c, Experimental design. d, qPCR comparison between regenerated mCherry+/insulin+ cells isolated from mice 4 months after β-cell ablation, and mCherry+ β-cells obtained from age-matched controls (4.5-month-old). All markers tested are expressed at identical levels in both groups; non-β-cell markers are expressed at extremely reduced levels (threshold cycle (CT) ranging from 28 to 31), showing the same degree of purity in both types of cell preparations. e, f, Interestingly, in contrast to bona fide β-cells isolated from 4.5-month-old controls, regenerated insulin+ cells have lower levels of cyclin-dependent kinase inhibitors, FoxO1 and Smad3. This correlates with their increased proliferative capacity at this specific time-point. Scale bars, 20 µm. qPCRs: n = 3 mice per group; each individual sample of each experimental group was run in triplicate, in three independent reactions; built-in Welch’s test. Error bars show s.d.
Extended Data Figure 8 Ngn3 activation is required for insulin expression in dedifferentiated δ-cells.
a, qPCR for Ngn3 mRNA after β-cell ablation reveals a transitory fivefold upregulation of Ngn3 transcripts 6 weeks after β-cell ablation when β-cell ablation is performed before puberty, but not in adult mice. Controls: n1-month-old = 3; n1.5-month-old = 3; n2-month-old = 6; n2.5-month-old = 3; n2.5-month-old = 3; n3-month-old = 3; n3.5-month-old = 3; n4-month-old = 3; DT (2-week-old): n0.5 mpa = 3; n1 mpa = 3; n1.5 mpa = 6; n2 mpa = 3; DT (2-month-old): n0.5 mpa = 3; n1 mpa = 3; n1.5 mpa = 3; n2 mpa = 3. Each individual sample (mouse) was run in triplicate, in each of three independent reactions. Built-in Welch’s test (P = 0.0112, 0.0178). b, Ngn3 transcriptional activity can be monitored in Ngn3-YFP knock-add-on mice because Ngn3 promoter activity results in YFP expression. In non-ablated age-matched control pups, or in ablated adults, no islet YFP+ cells were found (data not shown), yet when β-cells are ablated at 2 weeks of age, 86% of insulin+ cells also express YFP+ at 1.5 mpa. Control: n = 3, 6,358 insulin+-cells scored; DT: n = 3, 675 insulin+-cells scored; Welch’s test (P = 0.0010). c, At 1.5 mpa, 81% of YFP+ cells co-express insulin, but no glucagon, Sst or PP (data not shown). Two weeks later, YFP+ cells are almost absent, reflecting the downregulation of Ngn3 expression reported in a, and suggesting that insulin+ cells originate from cells transiently activating Ngn3 expression after ablation. Control: n1-month-old = 3; n1.5-month-old = 3; n2-month-old = 3; n2.5-month-old = 3; absent YFP+ cells in all control conditions; DT: n0.5 mpa = 3, 31 YFP+ cells; n1 mpa = 3, 123 YFP+ cells; n1.5 mpa = 3, 729 YFP+ cells; n2 mpa = 3; 47 YFP+ cells. Welch’s test and ANOVA (P < 0.0001). d, Irreversible lineage tracing of Ngn3-expressing cells at 1 and 1.5 mpa upon tamoxifen (TAM) administration in Ngn3-CreERT; R26-YFP; RIP-DTR mice; immunofluorescence analyses reveal that in the absence of β-cell ablation, there is no YFP induction (controls). In ablated mice, nearly all insulin+ cells are YFP+ with time (arrows). At early time-points (1 mpa), YFP+/hormone-negative cells are found: these are probably differentiating cells before insulin expression. e, f, In β-cell-ablated Ngn3-CreERT; R26-YFP; RIP-DTR pups, 91% of insulin+ cells co-express YFP+ (control: n = 3, 3,472 insulin+-cells scored, DT: n = 3, 489 insulin+-cells scored) (e) and inversely, 93% of the YFP+ cells are insulin+ (f) (control: n = 3; absent YFP+-cells in all control conditions; DT: n = 3, 478 YFP+-cells scored). g, Experimental design to block Ngn3 upregulation in β-cell-ablated prepubescent mice by administrating DOX to mice bearing five mutant alleles: Ngn3-tTA+/+; TRE-Ngn3+/+; RIP-DTR. In these mice the Ngn3 coding region is replaced by a DOX-sensitive transactivator gene (tTA); the endocrine pancreas develops normally because Ngn3 expression is allowed in the absence of DOX by the binding of tTA to the promoter of the TRE-Ngn3 transgene. Pups were given DT at 2 weeks of age and then DOX 2 weeks later, to block Ngn3 upregulation. They were euthanized when Ngn3 peaks after ablation (2-month-old). h, Islets from non-ablated (no DT) and ablated (DT) mice, exposed (Ngn3 inhibition) or not (normal Ngn3 expression) to DOX treatment from 4 weeks of age. β-Cell regeneration is efficient in absence of DOX (as previously shown), but decreases after Ngn3 blockade, resulting in the appearance of glucagon/insulin bihormonal cells. i, Sharply decreased regeneration by blocking Ngn3 expression in DOX-treated mice reveals the requirement of Ngn3 for efficient β-cell regeneration in pups. DT: n = 266 islets scored, 3 mice; DT+DOX: n = 167, 4 mice. Welch’s test (inter-islet P < 0.0001; inter-animal P = 0.0352), Mann–Whitney (P < 0.0001). j, Glucagon+/insulin+ bihormonal cells appear in DOX-treated β-cell-ablated pups (Ngn3 inhibition), suggesting a switch to an ‘adult-like’, less efficient, mechanism of regeneration. Control+DOX: n = 3, 9,233 insulin+-cells scored; DT: n = 3, 1,385 insulin+-cells scored; DT+DOX: n = 4, 141 insulin+-cells scored. Welch’s test (P = 0.0081), ANOVA (P < 0.0001). k, Combined double lineage tracing of δ-cells (Tomato+) and Ngn3-expressing cells (YFP+) shows by immunofluorescence that nearly all insulin+ cells express both reporters, but no Sst (arrows). Sst+ cells (arrowheads) are YFP- and insulin-negative. Scale bars, 20 µm. Error bars show s.d.
a, Cartoon depicting the FoxO1 network involved in the regulation of cell cycle progression and cellular senescence: FoxO1 arrests the cell cycle by repressing activators (cyclin D1, cyclin D2) and inducing inhibitors (Cdkn1a, Cdkn1b, Cdkn2b, Cdkn1c) (PMID: 10102273; PMID: 17873901). Cdkn1a and Cdkn2b activation, a sign of cellular senescence (PMID: 17667954), is regulated by FoxO1 through direct interaction with Skp2 protein. In turn, Skp2 blocks FoxO1 and, together with CKS1b, CDK1 and CDK2, triggers the direct degradation of Cdkn1a and Cdkn1b, thus promoting proliferation (PMID: 15668399). FoxO proteins are inhibited mainly through PI3K/AKT-mediated phosphorylation (PMID: 10102273; PMID: 12621150; PMID: 21708191; PMID: 10217147; PMID: 17604717]: PDK1, the master kinase of the pathway, stimulates cell proliferation and survival by directly activating AKT, which phosphorylates (inhibits) the FoxOs (PMID: 10698680; PMID: 19635472). The PI3K/AKT/FoxO1 circuit requires active TGF-β/SMAD signalling (PMID: 24238962; PMID: 15084259) in order to co-regulate Cdkn1a-dependent cell senescence. Active TGF-β signalling downregulates the BMP pathway downstream effectors ID1 and ID2, known to promote dedifferentiation and proliferation during embryogenesis and cancer progression, probably through Cdkn2b regulation (PMID: 11840321; PMID: 16034366). b, β-cell ablation in adults triggers FoxO1 upregulation and the subsequent cell cycle arrest in δ-cells.
a–d, The 1 week FoxO1 inhibition with the compound AS1842856 in control unablated adult mice (a) results in dedifferentiation of one-fourth of the δ-cell population (b; Supplementary Table 30) (treated: n = 3, 1,347 YFP+-cells scored; untreated: n = 4, 1,224 YFP+-cells scored; error bars show s.d.), without leading to insulin (c; Supplementary Table 31) (treated: n = 3, 3,249 insulin+-cells scored; untreated: n = 4, 9,562 insulin+-cells scored; error bars show s.d.; Welch’s test (P = 0.1590)) or glucagon (d; Supplementary Table 32) (treated: n = 2, 728 YFP+-cells scored; error bar show s.e.m.) expression. e, One month following FoxO1 transient inhibition in β-cell-ablated adults, dedifferentiated δ-cells do not express glucagon (Supplementary Table 36) (treated: n = 2, 986 YFP+-cells scored; error bars show s.e.m.). f, Transient FoxO1 inhibition a long time (1 month) after β-cell ablation also leads to the appearance of lineage-traced dedifferentiated δ-cells that express insulin (Supplementary Tables 37–39) (treated: n = 3, 71 islets scored; 300 insulin+-cells scored; 1,216 YFP+-cells scored; error bars show s.d.). Scale bars, 20 µm.
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Chera, S., Baronnier, D., Ghila, L. et al. Diabetes recovery by age-dependent conversion of pancreatic δ-cells into insulin producers. Nature 514, 503–507 (2014). https://doi.org/10.1038/nature13633
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