<scp>IGFBP</scp>1 increases β‐cell regeneration by promoting α‐ to β‐cell transdifferentiation

Lü, Jing; Liu, Ka‐Cheuk; Schulz, Nadja; Karampelias, Christos; Charbord, Jérémie; Hilding, Agneta; Rautio, Linn; Bertolino, Philippe; Östenson, Claes‐Göran; Brismar, Kerstin; Andersson, Olov

doi:10.15252/embj.201592903

Cited by 74 publications

(73 citation statements)

References 62 publications

(95 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this regard, our previous unbiased screens have identified enhancers of β-cell regeneration through different mechanisms; e.g. adenosine signaling promotes β-cell regeneration via increasing β-cell proliferation [2], whereas IGFBP1 promotes β-cell regeneration via increasing α-to-β-cell transdifferentiation [29]. Together, this line of research highlights the importance of performing unbiased screens for identification of potent endogenous pathways and mechanisms that can increase the number of β-cells, as well as translating initial phenotypic findings in discovery models to functional outcomes in mice and ultimately humans.…”

Section: Discussionmentioning

confidence: 99%

“…The following previously published transgenic zebrafish lines were used: Tg(ins:Flag-NTR) s950 [2], Tg(sst2:NTR,cryaa:Cerulean) KI102 [29] and Tg(ins:Venus-zGeminin; cryaa:Venus) KI107 [29]. We ablated β- or δ-cells in Tg(ins:Flag-NTR) or Tg(sst:NTR) zebrafish larvae by incubating the larvae in E3 supplemented with 10 mM metronidazole (MTZ; Sigma–Aldrich), 1% DMSO (VWR), and 0.2 mM 1-phenyl-2-thiourea (PTU; Acros Organics) from 3 to 4 days post fertilization (dpf).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Critical role for adenosine receptor A2a in β-cell proliferation

Schulz

Liu

Charbord

et al. 2016

Molecular Metabolism

Self Cite

View full text Add to dashboard Cite

ObjectivePharmacological activation of adenosine signaling has been shown to increase β-cell proliferation and thereby β-cell regeneration in zebrafish and rodent models of diabetes. However, whether adenosine has an endogenous role in regulating β-cell proliferation is unknown. The objective of this study was to determine whether endogenous adenosine regulates β-cell proliferation—either in the basal state or states of increased demand for insulin—and to delineate the mechanisms involved.MethodsWe analyzed the effect of pharmacological adenosine agonists on β-cell proliferation in in vitro cultures of mouse islets and in zebrafish models with β- or δ-cell ablation. In addition, we performed physiological and histological characterization of wild-type mice and mutant mice with pancreas- or β-cell-specific deficiency in Adora2a (the gene encoding adenosine receptor A2a). The mutant mice were used for in vivo studies on the role of adenosine in the basal state and during pregnancy (a state of increased demand for insulin), as well as for in vitro studies of cultured islets.ResultsPharmacological adenosine signaling in zebrafish had a stronger effect on β-cell proliferation during β-cell regeneration than in the basal state, an effect that was independent of the apoptotic microenvironment of the regeneration model. In mice, deficiency in Adora2a impaired glucose control and diminished compensatory β-cell proliferation during pregnancy but did not have any overt phenotype in the basal state. Islets isolated from Adora2a-deficient mice had a reduced baseline level of β-cell proliferation in vitro, consistent with our finding that UK432097, an A2a-specific agonist, promotes the proliferation of mouse β-cells in vitro.ConclusionsThis is the first study linking endogenously produced adenosine to β-cell proliferation. Moreover, we show that adenosine signaling via the A2a receptor has an important role in compensatory β-cell proliferation, a feature that could be harnessed pharmacologically for β-cell expansion and future therapeutic development for diabetes.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Critical role for adenosine receptor A2a in β-cell proliferation

Schulz

Liu

Charbord

et al. 2016

Molecular Metabolism

Self Cite

View full text Add to dashboard Cite

show abstract

“…The overexpression models Tg(tp1:cdk5rap1;cmlc2:eGFP) KI108 and Tg(tp1:cdkal1;cmlc2:eGFP) KI109 were generated by the Tol2 transposon system similarly to our previous report (3), with the following modifications. The constructs were generated by MultiSite Gateway cloning (Invitrogen) with forward primers 59-GGGGACAAGTTTGTACAAAAAAGCAG-GCTCTgccaccATGAACAGAATTAGTACTTTCA-39 for cdk5rap1 and 59-GGGGACAAGTTTGTACAAAAAAGCAGGCTCTgccacc-ATGATGGCGTTGGTGTGTG-39 for cdkal1, together with reverse primers 59-GGGGACCACTTTGTACAAGAAAGCT-GGGTCTCAGGCTGTTTTTCTGTCAT-39 for cdk5rap1 and 59-GGGGACCACTTTGTACAAGAAAGCTGGGTCTCAGAGC-AGTTTCTCCATC-39 for cdkal1 in the PCR, resulting in an amplicon for the BP reaction.…”

Section: Zebrafishmentioning

confidence: 99%

“…Apart from proliferation (1,2) and transdifferentiation (3)(4)(5), neogenesis (differentiation of new b-cells from endocrine progenitors or stem cells) is one of the major mechanisms in b-cell regeneration (6)(7)(8)(9)(10). Recent studies in mice have shown that pancreatic ductal ligation (PDL) or overexpression of the transcription factor Pax4 in a-cells induces neogenesis of endocrine cells originating from the pancreatic duct (8)(9)(10).…”

mentioning

confidence: 99%

Inhibition of Cdk5 Promotes β-Cell Differentiation From Ductal Progenitors

et al. 2017

Self Cite

View full text Add to dashboard Cite

Inhibition of notch signaling is known to induce differentiation of endocrine cells in zebrafish and mouse. After performing an unbiased in vivo screen of ∼2,200 small molecules in zebrafish, we identified an inhibitor of Cdk5 (roscovitine), which potentiated the formation of β-cells along the intrapancreatic duct during concurrent inhibition of notch signaling. We confirmed and characterized the effect with a more selective Cdk5 inhibitor, (R)-DRF053, which specifically increased the number of duct-derived β-cells without affecting their proliferation. By duct-specific overexpression of the endogenous Cdk5 inhibitors Cdk5rap1 or Cdkal1 (which previously have been linked to diabetes in genome-wide association studies), as well as deleting , we validated the role of chemical Cdk5 inhibition in β-cell differentiation by genetic means. Moreover, the mutant zebrafish displayed an increased number of β-cells independently of inhibition of notch signaling, in both the basal state and during β-cell regeneration. Importantly, the effect of Cdk5 inhibition to promote β-cell formation was conserved in mouse embryonic pancreatic explants, adult mice with pancreatic ductal ligation injury, and human induced pluripotent stem (iPS) cells. Thus, we have revealed a previously unknown role of Cdk5 as an endogenous suppressor of β-cell differentiation and thereby further highlighted its importance in diabetes.

show abstract

“…b¡cell ablation or inhibition of insulin signaling alone induced a low level of islet cell transdifferentiation, 5,23,9,6 but this was enormously enhanced by PAR2 activation. 9 While we used a specific PAR2 agonist rather than relatively nonspecific proteases to activate PAR2, it should be noted that trypsin-like proteases are widely expressed, including in b¡cells.…”

Section: Discussionmentioning

confidence: 99%

Insulin acts as a repressive factor to inhibit the ability of PAR2 to induce islet cell transdifferentiation

Lee

Hao

Scharp

et al. 2018

Islets

View full text Add to dashboard Cite

Recently, we showed that pancreatitis in the context of profound β-cell deficiency was sufficient to induce islet cell transdifferentiation. In some circumstances, this effect was sufficient to result in recovery from severe diabetes. More recently, we showed that the molecular mechanism by which pancreatitis induced β-cell neogenesis by transdifferentiation was activation of an atypical GPCR called Protease-Activated Receptor 2 (PAR2). However, the ability of PAR2 to induce transdifferentiation occurred only in the setting of profound β-cell deficiency, implying the existence of a repressive factor from those cells. Here we show that the repressor from β-cells is insulin. Treatment of primary islets with a PAR2 agonist (2fLI) in combination with inhibitors of insulin secretion and signaling was sufficient to induce insulin and PAX4 gene expression. Moreover, in primary human islets, this treatment also led to the induction of bihormonal islet cells coexpressing glucagon and insulin, a hallmark of islet cell transdifferentiation. Mechanistically, insulin inhibited the positive effect of a PAR2 agonist on insulin gene expression and also led to an increase in PAX4, which plays an important role in islet cell transdifferentiation. The studies presented here demonstrate that insulin represses transdifferentiation of α- to β-cells induced by activation of PAR2. This provides a mechanistic explanation for the observation that α- to β-cell transdifferentiation occurs only in the setting of severe β-cell ablation. The mechanistic understanding of islet cell transdifferentiation and the ability to modulate that process using available pharmacological reagents represents an important step along the path towards harnessing this novel mechanism of β-cell neogenesis as a therapy for diabetes.

show abstract

IGFBP1 increases β‐cell regeneration by promoting α‐ to β‐cell transdifferentiation

Cited by 74 publications

References 62 publications

Critical role for adenosine receptor A2a in β-cell proliferation

Critical role for adenosine receptor A2a in β-cell proliferation

Inhibition of Cdk5 Promotes β-Cell Differentiation From Ductal Progenitors

Insulin acts as a repressive factor to inhibit the ability of PAR2 to induce islet cell transdifferentiation

Contact Info

Product

Resources

About