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PDGF signalling controls age-dependent proliferation in pancreatic β-cells
Open accessAbstract
Determining the signalling pathways that direct tissue expansion is a principal goal of regenerative biology. Vigorous pancreatic β-cell replication in juvenile mice and humans declines with age, and elucidating the basis for this decay may reveal strategies for inducing β-cell expansion, a long-sought goal for diabetes therapy. Here we show that platelet-derived growth factor receptor (Pdgfr) signalling controls age-dependent β-cell proliferation in mouse and human pancreatic islets. With age, declining β-cell Pdgfr levels were accompanied by reductions in β-cell enhancer of zeste homologue 2 (Ezh2) levels and β-cell replication. Conditional inactivation of the Pdgfra gene in β-cells accelerated these changes, preventing mouse neonatal β-cell expansion and adult β-cell regeneration. Targeted human PDGFR-α activation in mouse β-cells stimulated Erk1/2 phosphorylation, leading to Ezh2-dependent expansion of adult β-cells. Adult human islets lack PDGF signalling competence, but exposure of juvenile human islets to PDGF-AA stimulated β-cell proliferation. The discovery of a conserved pathway controlling age-dependent β-cell proliferation indicates new strategies for β-cell expansion.
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“With age, declining β-cell Pdgfr levels were accompanied by reductions in β-cell enhancer of zeste homologue 2 (Ezh2) levels and β-cell replication.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Abstract
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“Adult human islets lack PDGF signalling competence, but exposure of juvenile human islets to PDGF-AA stimulated β-cell proliferation.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Abstract
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“Adult human islets lack PDGF signalling competence, but exposure of juvenile human islets to PDGF-AA stimulated β-cell proliferation.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Abstract
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“Conditional inactivation of the Pdgfra gene in β-cells accelerated these changes, preventing mouse neonatal β-cell expansion and adult β-cell regeneration.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Abstract
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“Conditional inactivation of the Pdgfra gene in β-cells accelerated these changes, preventing mouse neonatal β-cell expansion and adult β-cell regeneration.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Abstract
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“Conditional inactivation of the Pdgfra gene in β-cells accelerated these changes, preventing mouse neonatal β-cell expansion and adult β-cell regeneration.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Abstract
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“Targeted human PDGFR-α activation in mouse β-cells stimulated Erk1/2 phosphorylation, leading to Ezh2-dependent expansion of adult β-cells.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Abstract
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“βPdgfαKO mice at 3 weeks had mild hyperglycaemia during ad libitum feeding and impaired glucose tolerance in a glucose challenge test (Supplementary Fig. 3e, f).”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Age-dependent β-cell Pdgfr-α loss
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“By 3 months, β-cell Ezh2 expression had declined in control mice, but β-cell Ezh2 expression in βPDGFRαTg mice was maintained at elevated levels, a difference that persisted for 8–14 months (Fig. 3e, f).”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > PDGFR-α promotes functional β-cell expansion
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“In contrast, islet mRNAs encoding the insulin receptor, prolactin receptor, glucocorticoid receptor and intrinsic regulators of β-cell proliferation like Pdx1, Foxo1, Foxo3, Rb1 (hereafter referred to as Rb), p130 (also known as Rbl2) and E2f1, did not decline in mice with advancing age (Supplementary Fig. 2).”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Age-dependent β-cell Pdgfr-α loss
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“However, neither β-cell BrdU incorporation nor mass were increased in βEzh2KO-RαTg mice compared to controls (Fig. 4c, d and Supplementary Fig. 7).”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > PDGF-induced β-cell expansion requires Ezh2
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“Islet PDGFRAD842V mRNA levels in both βEzh2KO-RαTg and βEzh2HET-RαTg mice were elevated and indistinguishable (Fig. 4a).”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > PDGF-induced β-cell expansion requires Ezh2
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“In contrast, total pancreatic mass and islet architecture in βPDGFRαTg mice and controls were indistinguishable (Supplementary Figs 5c and 6b).”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > PDGFR-α promotes functional β-cell expansion
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“PDGF/ERK signalling activates cell cycle regulators to stimulate proliferation24,25, and βPDGFRαTg islets had elevated levels of Ccnd1 mRNA encoding cyclin D1, and increased β-cells with nuclear cyclin D1 and phosphorylated Rb protein (Fig. 5c–e and Supplementary Fig. 9a).”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > β-cell PDGFR controls Ezh2 via Erk and Rb/E2f
What the sources say
- Not checked yetcites [24] Uhrbom, L., Nerio, E. & Holland, E. C. Dissecting tumor maintenance requirements using bioluminescence imaging of cell proliferation in a mouse glioma model. Nature Med. 10, 1257–1260 (2004) source
- Not checked yetcites [25] Furstoss, O., Manes, G. & Roche, S. Cyclin E and cyclin A are likely targets of Src for PDGF-induced DNA synthesis in fibroblasts. FEBS Lett. 526, 82–86 (2002) source
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“Islet ChIP studies revealed increased E2f1 association, and reduced E2f4 association with Ezh2 cis-regulatory elements (Supplementary Fig. 12d, e).”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > β-cell PDGFR controls Ezh2 via Erk and Rb/E2f
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“Ezh2 induction in juvenile wild-type islets exposed to PDGF-AA was blocked by U0126, which inhibits Erk1/2 activation23, but not by LY294002 or U-73122, inhibitors of PI3K or PLC-γ signalling (Supplementary Fig. 8a).”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > β-cell PDGFR controls Ezh2 via Erk and Rb/E2f
What the sources say
- Not checked yetcites [23] Duncia, J. V. et al. MEK inhibitors: the chemistry and biological activity of U0126, its analogs, and cyclization products. Bioorg. Med. Chem. Lett. 8, 2839–2844 (1998) source
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“To assess whether premature Pdgfr loss might compromise Ezh2-dependent neonatal β-cell proliferation, we generated RIP-Cre; Pdgfraf/f mice (abbreviated to βPdgfrαKO) that permit conditional Pdgfra inactivation in islet β-cells and loss of detectable Pdgfra mRNA and protein expression (Fig. 1d and Supplementary Fig. 3a).”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Age-dependent β-cell Pdgfr-α loss
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“As expected, β-cell BrdU incorporation and mass were increased in βEzh2HET-RαTg mice (Fig. 4c, d and Supplementary Fig. 7) compared to controls (either Ezh2f/f, R26-PDGFRαD842V or Ezh2f/+, R26-PDGFRαD842V genotype).”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > PDGF-induced β-cell expansion requires Ezh2
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“Consistent with this view, β-cell mass in control mice gradually recovered after STZ treatment, accompanied by increased β-cell Ezh2 expression and proliferation; in contrast, βPdgfαKO β-cells failed to increase Ezh2 or proliferation to restore β-cell mass (Fig. 2c–e).”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Pdgfr-α controls adult β-cell regeneration
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“We also detected increased phosphorylation of Erk1/2, but not phosphorylation of Akt or PLC-γ, in βPDGFRαTg islets compared to control islets (Fig. 5a, b).”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > β-cell PDGFR controls Ezh2 via Erk and Rb/E2f
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“In contrast to littermate controls, mice with the RIP-Cre; R26-PDGFRAD842V genotype (abbreviated to βPDGFRαTg) expressed human PDGFRA mRNA and PDGFR-a(D842V) protein in islet β-cells (Fig. 3a and Supplementary Fig. 5a).”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > PDGFR-α promotes functional β-cell expansion
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“ChIP studies also revealed that association of E2f1 with Ezh2 decreased, whereas association of E2f4 with Ezh2 elements increased in islets with age (Supplementary Fig. 11c, d).”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > β-cell PDGFR controls Ezh2 via Erk and Rb/E2f
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“By 3 months, β-cell Ezh2 expression had declined in control mice, but β-cell Ezh2 expression in βPDGFRαTg mice was maintained at elevated levels, a difference that persisted for 8–14 months (Fig. 3e, f).”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > PDGFR-α promotes functional β-cell expansion
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“Similarly, increased β-cell BrdU incorporation in islets exposed to PDGF-AA was blocked by U0126, but not by LY294002 (Supplementary Fig. 8b), indicating that Erk mediates β-cell Pdgf signalling responses.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > β-cell PDGFR controls Ezh2 via Erk and Rb/E2f
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“We identified two conserved candidate E2f-binding elements near the Ezh2 promoter (Supplementary Fig. 10), and chromatin immunoprecipitation (ChIP) studies showed increased E2f1 association and reduced E2f4 association with these Ezh2 elements in βPDGFRαTg islets (Fig. 5f, g).”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > β-cell PDGFR controls Ezh2 via Erk and Rb/E2f
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“Exposure of 3-week-old islets to PDGF-AA increased phospho-Pdgfr-α levels and Ezh2 mRNA and protein levels, but not Ezh1 expression (Supplementary Fig. 4a–c).”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > PDGFR-α promotes functional β-cell expansion
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“By contrast, increased islet Ezh2 mRNA levels and β-cell Ezh2 protein were not observed in βEzh2KO-RαTg or βEzh2KO littermates (Fig. 4b and Supplementary Fig. 7), confirming Cre-mediated deletion of Ezh2 in these mice.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > PDGF-induced β-cell expansion requires Ezh2
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“Compared to controls, β-cell Ezh2 protein and islet Ezh2 mRNA levels were reduced whereas p16INK4a mRNA levels were increased in βPdgfrαKO islets (Fig. 1e and Supplementary Fig. 3a, b); in contrast, Pdgfrb and Ezh1 mRNA levels were unchanged in βPdgfrαKO islets (Supplementary Fig. 3c, d).”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Age-dependent β-cell Pdgfr-α loss
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“During re-feeding after overnight fast, βPDGFRαTg mice had a 25% reduction of blood glucose (Fig. 3g), associated with a modest elevation of plasma insulin levels (Supplementary Fig. 6i), and both changes were sustained for up to 14 months.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > PDGFR-α promotes functional β-cell expansion
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“Expression of R26-PDGFRαD842V did not affect endogenous islet Pdgfra mRNA levels (Fig. 3a) or β-cell expansion and glucose control in neonatal or juvenile βPDGFRαTg mice (Fig. 3b, c and Supplementary Figs 5b and 6a–d).”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > PDGFR-α promotes functional β-cell expansion
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“β-cell mass was increased in βPDGFRαTg mice at 3 months, and remained increased at 14 months compared to age-matched controls (Fig. 3b).”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > PDGFR-α promotes functional β-cell expansion
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“Consistent with these findings, we detected modest postprandial blood glucose reduction and increased blood insulin levels in βEzh2HET-RαTg mice, but not in βEzh2KO-RαTg mice (Fig. 4e, f).”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > PDGF-induced β-cell expansion requires Ezh2
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“In contrast, control mice became moderately diabetic immediately after STZ challenge, but achieved restored glucose control 3–4 weeks thereafter (Fig. 2f), coinciding with increases of β-cell mass (Fig. 2e).”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Pdgfr-α controls adult β-cell regeneration
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“In contrast, loss of β-cell Pdgf signalling in βPdgfαKO mice diminished islet levels of Ccnd1 mRNA, and reduced numbers of phospho-Erk1/2+ and phospho-Rb+ β-cells (Supplementary Fig. 9b, c).”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > β-cell PDGFR controls Ezh2 via Erk and Rb/E2f
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“Compared to controls, β-cell Ezh2 protein and islet Ezh2 mRNA levels were reduced whereas p16INK4a mRNA levels were increased in βPdgfrαKO islets (Fig. 1e and Supplementary Fig. 3a, b); in contrast, Pdgfrb and Ezh1 mRNA levels were unchanged in βPdgfrαKO islets (Supplementary Fig. 3c, d).”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Age-dependent β-cell Pdgfr-α loss
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“In contrast, basal EZH2 mRNA levels were lower in adult islets and not induced by PDGF-AA (Fig. 6c).”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > PDGF control of human β-cell proliferation
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“mRNA levels of EZH2, but not EZH1, were increased in juvenile human islets exposed to PDGF-AA, an effect blocked by Sunitinib or U0126 (Fig. 6c and Supplementary Fig. 13a).”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > PDGF control of human β-cell proliferation
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“In contrast, PDGFR-a was only detected in non-β-cells of islets from adult human donors, with little to no detectable phospho-ERK1/2, phospho-RB or EZH2 in β-cells (Fig. 6a, b), suggesting that PDGF signalling attenuation is a conserved feature of ageing islet β-cells.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > PDGF control of human β-cell proliferation
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“RbTriKO mice became hypoglycaemic and developed other islet and metabolic phenotypes reminiscent of insulinoma pathogenesis.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Discussion
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“Similar to juvenile mouse islets with activated Pdgf signalling, ChIP studies demonstrated PDGF-AA-stimulated association of E2F1 with the human EZH2 locus, an effect blocked by Sunitinib (Fig. 6d).”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > PDGF control of human β-cell proliferation
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“Compared to vehicle-exposed controls, juvenile islets exposed to PDGF-AA had a sixfold increase of β-cell BrdU incorporation, an effect eliminated by simultaneous exposure to Sunitinib or U0126 (Fig. 6e, f).”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > PDGF control of human β-cell proliferation
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“Like in juvenile mice, PDGFR-α protein and phospho-ERK1/2 levels were readily detected in islets from young human donors (Fig. 6a, b).”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > PDGF control of human β-cell proliferation
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“Proliferating BrdU+ cells in juvenile islets stimulated by PDGF-AA were predominantly β-cells, verified by immuno-localization of BrdU+ nuclei within insulin+ cells and PDX1+ nuclei with confocal microscopy (Fig. 6f and Supplementary Fig. 13b, c).”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > PDGF control of human β-cell proliferation
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“However, pathological loss of all Rb family proteins in RbTriKO islets led to a fourfold increase in Ezh2 mRNA, and a 15-fold increase in β-cell proliferation.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Discussion
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“Ezh2 is a histone methyltransferase crucial for trimethylation of histone H3 on Lys 27 (H3K27me3), a modification mediating transcriptional repression14,15.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Abstract
What the sources say
- Not checked yetcites [14] Cao, R. et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298, 1039–1043 (2002) source
- Not checked yetcites [15] van der Vlag, J. & Otte, A. P. Transcriptional repression mediated by the human polycomb-group protein EED involves histone deacetylation. Nature Genet. 23, 474–478 (1999) source
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“Likewise, induction of human islet β-cell proliferation remains an unattained goal, with studies reporting inconsistent mitogenic responses5,6.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Abstract
What the sources say
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“We showed that the polycomb group protein Ezh2 represses Cdkn2a and promotes β-cell proliferation in juvenile mouse islets13.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Abstract
What the sources say
- Not checked yetcites [13] Chen, H. et al. Polycomb protein Ezh2 regulates pancreatic β-cell Ink4a/Arf expression and regeneration in diabetes mellitus. Genes Dev. 23, 975–985 (2009) source
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“In mice or other experimental animals, β-cell expansion from such efforts has been transient or limited, and often complicated by uncontrolled β-cell growth, loss of defining β-cell features and impaired metabolic control3,4.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Abstract
What the sources say
- Not checked yetcites [3] Vasavada, R. C. et al. Targeted expression of placental lactogen in the β-cells of transgenic mice results in β-cell proliferation, islet mass augmentation, and hypoglycemia. J. Biol. Chem. 275, 15399–15406 (2000) source
- Not checked yetcites [4] Garcia-Ocana, A. et al. Hepatocyte growth factor overexpression in the islet of transgenic mice increases β-cell proliferation, enhances islet mass, and induces mild hypoglycemia. J. Biol. Chem. 275, 1226–1232 (2000) source
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In the paper
“Pancreatic β-cell proliferation decreases rapidly in juvenile mice and humans, then declines more slowly in adults9,10.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Abstract
What the sources say
- Not checked yetcites [9] Teta, M. et al. Very slow turnover of β-cells in aged adult mice. Diabetes 54, 2557–2567 (2005) source
- Not checked yetcites [10] Meier, J. J. et al. β-Cell replication is the primary mechanism subserving the postnatal expansion of β-cell mass in humans. Diabetes 57, 1584–1594 (2008) source
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, premature loss of Pdgfra impairs β-cell proliferation and expansion and glucose control in young mice.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Age-dependent β-cell Pdgfr-α loss
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Modulation of β-cell Pdgf signalling attenuates age-dependent proliferative failure and Ezh2 loss, permitting in vivo expansion of β-cells with regulated function.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Abstract
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In the paper
“Pdgfr signalling promotes proliferation, survival and migration in diverse cell types16.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Abstract
What the sources say
- Not checked yetcites [16] Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 103, 211–225 (2000) source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Pdgf-induced actin polymerization in fibroblasts requires Ezh2 (ref. 19), suggesting that Pdgf signalling might regulate Ezh2 expression and age-dependent β-cell proliferation in islets.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Abstract
What the sources say
- Not checked yetcites [19] Su, I. et al. Polycomb group protein Ezh2 controls actin polymerization and cell signaling. Cell 121, 425–436 (2005) source
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, age-dependent attenuation of β-cell Pdgfr-α altered Erk and Rb/E2f signalling, resulting in reduced Ezh2 expression.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > β-cell PDGFR controls Ezh2 via Erk and Rb/E2f
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, PDGF-AA exposure was sufficient to stimulate β-cell replication in juvenile islets, but loss of competence for Pdgf prevented this response to PDGF-AA in adult islets.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > PDGFR-α promotes functional β-cell expansion
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, PDGFRaTg mice maintained normal glucose-regulated insulin release and glycaemic control, suggesting that β-cell function remained regulated in these mice.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > PDGFR-α promotes functional β-cell expansion
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Cardinal features of this pathway are conserved in human islets, permitting conditional induction of human β-cell replication.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Abstract
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In the paper
“However, the molecular basis for these observations and the roles of Pdgf signalling in islet β-cell growth and development were not established17,18,32.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Discussion
What the sources say
- Not checked yetcites [17] Swenne, I. et al. Effects of platelet-derived growth factor and somatomedin-C/insulin-like growth factor I on the deoxyribonucleic acid replication of fetal rat islets of Langerhans in tissue culture. Endocrinology 122, 214–218 (1988) source
- Not checked yetcites [18] Welsh, M. et al. Coexpression of the platelet-derived growth factor (PDGF) B chain and the PDGF beta receptor in isolated pancreatic islet cells stimulates DNA synthesis. Proc. Natl Acad. Sci. USA 87, 5807–5811 (1990) source
- Not checked yetcites [32] LeBras, S., Czernichow, P. & Scharfmann, R. A search for tyrosine kinase receptors expressed in the rat embryonic pancreas. Diabetologia 41, 1474–1481 (1998) source
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In the paper
“Proliferative responses to PDGF decline in some ageing cells30, and progenitor cell self-renewal is impaired by Pdgf signalling disruption31.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Discussion
What the sources say
- Not checked yetcites [30] Scherping, S. C., Jr et al. Effect of growth factors on the proliferation of ligament fibroblasts from skeletally mature rabbits. Connect. Tissue Res. 36, 1–8 (1997) source
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Institutional review board approval for research use of tissue was obtained from Stanford University School of Medicine.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > METHODS > Human pancreas and islet studies
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Our work also suggests that Mapk/Erk regulation links Pdgfr activation to Ezh2 induction and β-cell proliferation, consistent with studies demonstrating Erk regulation of Ezh2 in cancer cells33, and Erk activation that accompanies mouse β-cell expansion in pregnancy34.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Discussion
What the sources say
- Not checked yetcites [33] Fujii, S. et al. MEK–ERK pathway regulates EZH2 overexpression in association with aggressive breast cancer subtypes. Oncogene 10.1038/onc.2011.118 (18 April 2011) source
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“MIP-GFP+ β-cells with >95% purity were harvested and immediately lysed for RNA purification and real-time RT–PCR analysis.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > METHODS > β-cell purification by FACS
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found that β-cell Pdgfr signalling was required for Ezh2 induction, to sustain both physiological and regenerative β-cell proliferation.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, Rb proteins constrain Ezh2 expression and adult islet cell growth.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > β-cell PDGFR controls Ezh2 via Erk and Rb/E2f
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“β-cell mass and proliferation were morphometrically quantified13 by independent researchers blinded to sample identity.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > METHODS SUMMARY > Histology, immunohistochemistry and molecular studies
What the sources say
- Not checked yetcites [13] Chen, H. et al. Polycomb protein Ezh2 regulates pancreatic β-cell Ink4a/Arf expression and regeneration in diabetes mellitus. Genes Dev. 23, 975–985 (2009) source
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“PDGF ligands are measurable in serum, and regulation of such circulating signalling agonists may provide an additional level of growth control in competent islet β-cells.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Discussion
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Human pancreases or islets from organ donors were procured by arrangement with the National Disease Resource Interchange and the University of Alabama, Birmingham with appropriate consent.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > METHODS > Human pancreas and islet studies
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In the paper
“Although the mechanisms underlying pancreatic β-cell expansion in physiological settings may differ between species36,37, age-dependent restriction of β-cell proliferation is a conserved feature in mice and humans9,10.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Discussion
What the sources say
- Not checked yetcites [36] Butler, A. E. et al. Adaptive changes in pancreatic β-cell fractional area and β-cell turnover in human pregnancy. Diabetologia 53, 2167–2176 (2010) source
- Not checked yetcites [37] Rieck, S. & Kaestner, K. H. Expansion of β-cell mass in response to pregnancy. Trends Endocrinol. Metab. 21, 151–158 (2010) source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Our work also suggests that Mapk/Erk regulation links Pdgfr activation to Ezh2 induction and β-cell proliferation, consistent with studies demonstrating Erk regulation of Ezh2 in cancer cells33, and Erk activation that accompanies mouse β-cell expansion in pregnancy34.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Discussion
What the sources say
- Not checked yetcites [34] Gupta, R. K. et al. Expansion of adult β-cell mass in response to increased metabolic demand is dependent on HNF-4α. Genes Dev. 21, 756–769 (2007) source
Strength:boosted· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Prior studies correlated increased PDGFR and EZH2 expression in human endocrine neoplasias38, and disrupted PDGF signalling in β-cells of humans with type 2 diabetes39.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Discussion
What the sources say
- Not checked yetcites [38] Ebert, M. et al. Induction of platelet-derived growth factor A and B chains and over-expression of their receptors in human pancreatic cancer. Int. J. Cancer 62, 529–535 (1995) source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“All animal experiments and methods were approved by the Institutional Animal Care and Use Committee of Stanford University.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > METHODS > Animals
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Experiments were repeated onmultiple pancreas sections for every donor pancreas and similar results were obtained.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > METHODS > Human pancreas and islet studies
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Proliferative responses to PDGF decline in some ageing cells30, and progenitor cell self-renewal is impaired by Pdgf signalling disruption31.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Discussion
What the sources say
- Not checked yetcites [31] Pallante, B. A. et al. Bone marrow Oct3/4+ cells differentiate into cardiac myocytes via age-dependent paracrine mechanisms. Circ. Res. 100, e1–e11 (2007) source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Mice used in this study were age- and gender-matched littermates including both sexes.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > METHODS > Animals
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, our demonstration that PDGF signalling regulates EZH2,CDKN2A and β-cell proliferation in human islets combines several observations into a new molecular model for physiological and pathological β-cell growth.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Discussion
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In the paper
“Images were analysed with an ImagePro program by observers blinded to genotype, and pancreatic β-cell mass and percentage of BrdU+ β-cells were calculated as described previously13.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > METHODS > Histology, immunofluorescence and immunohistochemistry
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In vivo activation of β-cell PDGFR-α signalling increased Ezh2 expression and mitigated age-dependent decline of β-cell proliferation.”
§ PDGF signalling controls age-dependent proliferation in pancreatic β-cells > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Such a mechanism has been shown recently to operate in the pancreas, where PDGF regulates the levels of Ink4a in pancreatic  cells.42”
From Fibroblast growth factor-7 partially reverses murine thymocyte progenitor aging by repression of Ink4a (2012) · cites this paper as [42]
In the citing paper
“A key tenet of the model shown in Figure 6 is that exogenous factors in the microenvironment can affect the senescent state of target cells by regulating gene expression in them.”
From Fibroblast growth factor-7 partially reverses murine thymocyte progenitor aging by repression of Ink4a (2012) · cites this paper as [42]
Citations
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DNA methylation-based biomarkers and the epigenetic clock theory of ageing
Horvath, S., & Raj, K. (2018) · Nature Reviews Genetics · doi:10.1038/s41576-018-0004-3 · Cited by 3,095
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Senescence in Health and Disease
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Self-citation
Metadata
- Authors
- Chen, H., Gu, X., Liu, Y., Wang, J., Wirt, S. E., Bottino, R., Schorle, H., Sage, J., & Kim, S. K.
- Affiliations
- Stanford Medicine (US)
- University of Pittsburgh (US)
- University of Bonn (DE)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Kim, Seung K.
- ORCID
- Venue
- Nature
- Published
- 2011-10
- Volume
- 478
- Issue
- 7369
- Pages
- 349-355
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3503246
- OpenAlex
- W2061620419
- Cited by
- 278
- References
- 44
- Citations by year
- 2026: 5 · 2025: 17 · 2024: 11 · 2023: 17 · 2022: 12 · 2021: 13 · 2020: 17 · 2019: 18 · 2018: 17 · 2017: 24 · 2016: 23 · 2015: 23 · 2014: 22 · 2013: 37 · 2012: 22
- FWCI
- 26.54
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Foundation for the National Institutes of Health
- Howard Hughes Medical Institute
- Stem Cell Network
- Deutsche Krebshilfe
- National Cancer Institute (R01CA114102, T32CA009302)
- National Institute of Diabetes and Digestive and Kidney Diseases (U01DK089532, U01DK089572, U01 DK89572, R01DK056709, R01DK075919, U01 DK89532, R01DK072184)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- PDGF signaling, platelet-derived growth factor receptor, pancreatic beta cells, beta-cell proliferation, aging, EZH2, beta-cell expansion, islets, diabetes treatment, ERK1/2 phosphorylation, conditional gene inactivation, human islets
- MeSH terms
- Enhancer of Zeste Homolog 2 Protein, Age Factors, Animals, Cells, Cultured, Diabetes Mellitus, Experimental, Female, Humans, Male, Mice, Inbred C57BL, Histone-Lysine N-Methyltransferase, Signal Transduction, Gene Expression Regulation, Enzymologic, Retinoblastoma Protein, Receptors, Platelet-Derived Growth Factor, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Cell Proliferation, Insulin-Secreting Cells, E2F Transcription Factors, Mice, Gene Knockout Techniques, Polycomb Repressive Complex 2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-06, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-06 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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