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Repurposing cAMP-modulating medications to promote ?-cell replication.

ABSTRACT: Loss of ?-cell mass is a cardinal feature of diabetes. Consequently, developing medications to promote ?-cell regeneration is a priority. cAMP is an intracellular second messenger that modulates ?-cell replication. We investigated whether medications that increase cAMP stability or synthesis selectively stimulate ?-cell growth. To identify cAMP-stabilizing medications that promote ?-cell replication, we performed high-content screening of a phosphodiesterase (PDE) inhibitor library. PDE3, -4, and -10 inhibitors, including dipyridamole, were found to promote ?-cell replication in an adenosine receptor-dependent manner. Dipyridamole's action is specific for ?-cells and not ?-cells. Next we demonstrated that norepinephrine (NE), a physiologic suppressor of cAMP synthesis in ?-cells, impairs ?-cell replication via activation of ?(2)-adrenergic receptors. Accordingly, mirtazapine, an ?(2)-adrenergic receptor antagonist and antidepressant, prevents NE-dependent suppression of ?-cell replication. Interestingly, NE's growth-suppressive effect is modulated by endogenously expressed catecholamine-inactivating enzymes (catechol-O-methyltransferase and l-monoamine oxidase) and is dominant over the growth-promoting effects of PDE inhibitors. Treatment with dipyridamole and/or mirtazapine promote ?-cell replication in mice, and treatment with dipyridamole is associated with reduced glucose levels in humans. This work provides new mechanistic insights into cAMP-dependent growth regulation of ?-cells and highlights the potential of commonly prescribed medications to influence ?-cell growth.

SUBMITTER: Zhao Z

PROVIDER: S-EPMC4179632 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Repurposing cAMP-modulating medications to promote β-cell replication.

Zhao Zhenshan Z Low Yen S YS Armstrong Neali A NA Ryu Jennifer Hyoje JH Sun Sara A SA Arvanites Anthony C AC Hollister-Lock Jennifer J Shah Nigam H NH Weir Gordon C GC Annes Justin P JP

Molecular endocrinology (Baltimore, Md.) 20140801 10

Loss of β-cell mass is a cardinal feature of diabetes. Consequently, developing medications to promote β-cell regeneration is a priority. cAMP is an intracellular second messenger that modulates β-cell replication. We investigated whether medications that increase cAMP stability or synthesis selectively stimulate β-cell growth. To identify cAMP-stabilizing medications that promote β-cell replication, we performed high-content screening of a phosphodiesterase (PDE) inhibitor library. PDE3, -4, an ...[more]

PMID: 25083741

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Project description:UnlabelledRetinal pigment epithelium (RPE) cell integrity is critical to the maintenance of retinal function. Many retinopathies such as age-related macular degeneration (AMD) are caused by the degeneration or malfunction of the RPE cell layer. Replacement of diseased RPE with healthy, stem cell-derived RPE is a potential therapeutic strategy for treating AMD. Human embryonic stem cells (hESCs) differentiated into RPE progeny have the potential to provide an unlimited supply of cells for transplantation, but challenges around scalability and efficiency of the differentiation process still remain. Using hESC-derived RPE as a cellular model, we sought to understand mechanisms that could be modulated to increase RPE yield after differentiation. We show that RPE epithelialization is a density-dependent process, and cells seeded at low density fail to epithelialize. We demonstrate that activation of the cAMP pathway increases proliferation of dissociated RPE in culture, in part through inhibition of transforming growth factor-β (TGF-β) signaling. This results in enhanced uptake of epithelial identity, even in cultures seeded at low density. In line with these findings, targeted manipulation of the TGF-β pathway with small molecules produces an increase in efficiency of RPE re-epithelialization. Taken together, these data highlight mechanisms that promote epithelial fate acquisition in stem cell-derived RPE. Modulation of these pathways has the potential to favorably impact scalability and clinical translation of hESC-derived RPE as a cell therapy.SignificanceStem cell-derived retinal pigment epithelium (RPE) is currently being evaluated as a cell-replacement therapy for macular degeneration. This work shows that the process of generating RPE in vitro is regulated by the cAMP and transforming growth factor-β signaling pathway. Modulation of these pathways by small molecules, as identified by phenotypic screening, leads to an increased efficiency of generating RPE cells with a higher yield. This can have a potential impact on manufacturing transplantation-ready cells at large scale and is advantageous for clinical studies using this approach in the future.

Project description:Type I interferons (IFNs) are key mediators of the innate immune response. Although members of this family of cytokines signal through a single shared receptor, biochemical and functional variation exists in response to different IFN subtypes. While previous work has demonstrated that type I IFNs are essential to control infection by chikungunya virus (CHIKV), a globally emerging alphavirus, the contributions of individual IFN subtypes remain undefined. To address this question, we evaluated CHIKV pathogenesis in mice lacking IFN-? (IFN-? knockout [IFN-?-KO] mice or mice treated with an IFN-?-blocking antibody) or IFN-? (IFN regulatory factor 7 knockout [IRF7-KO] mice or mice treated with a pan-IFN-?-blocking antibody). Mice lacking either IFN-? or IFN-? developed severe clinical disease following infection with CHIKV, with a marked increase in foot swelling compared to wild-type mice. Virological analysis revealed that mice lacking IFN-? sustained elevated infection in the infected ankle and in distant tissues. In contrast, IFN-?-KO mice displayed minimal differences in viral burdens within the ankle or at distal sites and instead had an altered cellular immune response. Mice lacking IFN-? had increased neutrophil infiltration into musculoskeletal tissues, and depletion of neutrophils in IFN-?-KO but not IRF7-KO mice mitigated musculoskeletal disease caused by CHIKV. Our findings suggest disparate roles for the IFN subtypes during CHIKV infection, with IFN-? limiting early viral replication and dissemination and IFN-? modulating neutrophil-mediated inflammation.IMPORTANCE Type I interferons (IFNs) possess a range of biological activity and protect against a number of viruses, including alphaviruses. Despite signaling through a shared receptor, there are established biochemical and functional differences among the IFN subtypes. The significance of our research is in demonstrating that IFN-? and IFN-? both have protective roles during acute chikungunya virus (CHIKV) infection but do so by distinct mechanisms. IFN-? limits CHIKV replication and dissemination, whereas IFN-? protects from CHIKV pathogenesis by limiting inflammation mediated by neutrophils. Our findings support the premise that the IFN subtypes have distinct biological activities in the antiviral response.

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Repurposing cAMP-modulating medications to promote ?-cell replication.

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Repurposing cAMP-modulating medications to promote β-cell replication.

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