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David R. Hyde - One of the best experts on this subject based on the ideXlab platform.
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TNFα Induces Müller Glia to Transition From Non-proliferative Gliosis to a Regenerative Response in Mutant Zebrafish Presenting Chronic Photoreceptor Degeneration.
Frontiers in Cell and Developmental Biology, 2019Co-Authors: Maria Iribarne, David R. Hyde, Ichiro MasaiAbstract:Unlike mammals, zebrafish have the capacity to regenerate neurons in response to damage. Most zebrafish retinal injury models employ acute damage, which is unlike the chronic, gradual damage that occurs in human retinal diseases. Here, we studied the regenerative response in the zebrafish aipl1b mutant, gold rush (gosh). In gosh mutants, both cones and rods degenerate by 3 weeks post-fertilization (wpf). Muller glia do not exhibit a regenerative response by 3 wpf; however, they do present non-proliferative gliosis. Only at 5 wpf, is proliferation of Muller cells and rod precursor cells activated. Rods start to recover at 5 wpf and by 12 wpf they reach a level of recovery comparable to wild type, but cones remain absent in the adult stage. TNFα was detected in degenerating cones at 5-7 wpf and in Muller glia at 7 wpf in gosh mutants. At 5 wpf, proliferating Muller glia express Sox2, followed by Pax6 expression in neuronal progenitor cells (NPCs), confirming that the neuronal regeneration program is activated in gosh mutants after 5 wpf. Although acute light-induced damage did not activate proliferation of Muller glia, TNFα injection caused Muller glia to commence a proliferative response at 3 wpf in gosh mutants. These results suggest that Muller glia transition from non-proliferative gliosis to a regenerative state in gosh mutants, and that ectopic introduction of TNFα promotes this Muller cell transition even at 3 wpf. Thus, zebrafish gosh mutants provide a useful model to investigate mechanisms underlying retinal regeneration in a chronic photoreceptor degeneration model.
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sox2 regulates Muller glia reprogramming and proliferation in the regenerating zebrafish retina via lin28 and ascl1a
Experimental Eye Research, 2017Co-Authors: Ryne A. Gorsuch, Manuela Lahne, Clare Yarka, Michael Petravick, David R. HydeAbstract:Sox2 is a well-established neuronal stem cell-associated transcription factor that regulates neural development and adult neurogenesis in vertebrates, and is one of the critical genes used to reprogram differentiated cells into induced pluripotent stem cells. We examined if Sox2 was involved in the early reprogramming-like events that Muller glia undergo as they upregulate many pluripotency- and neural stem cell-associated genes required for proliferation in light-damaged adult zebrafish retinas. In the undamaged adult zebrafish retina, Sox2 is expressed in Muller glia and a subset of amacrine cells, similar to other vertebrates. Following 31 h of light damage, Sox2 expression significantly increased in proliferating Muller glia. Morpholino-mediated knockdown of Sox2 expression resulted in decreased numbers of proliferating Muller glia, while induced overexpression of Sox2 stimulated Muller glia proliferation in the absence of retinal damage. Thus, Sox2 is necessary and sufficient for Muller glia proliferation. We investigated the role of Wnt/β-catenin signaling, which is a known regulator of sox2 expression during vertebrate retinal development. While β-catenin 2, but not β-catenin 1, was necessary for Muller glia proliferation, neither β-catenin paralog was required for sox2 expression following retinal damage. Sox2 expression was also necessary for ascl1a (neurogenic) and lin28a (reprogramming) expression, but not stat3 expression following retinal damage. Furthermore, Sox2 was required for Muller glial-derived neuronal progenitor cell amplification and expression of the pro-neural marker Tg(atoh7:EGFP). Finally, loss of Sox2 expression prevented complete regeneration of cone photoreceptors. This study is the first to identify a functional role for Sox2 during Muller glial-based regeneration of the vertebrate retina.
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tumor necrosis factor alpha is produced by dying retinal neurons and is required for Muller glia proliferation during zebrafish retinal regeneration
The Journal of Neuroscience, 2013Co-Authors: Craig M. Nelson, Ryne A. Gorsuch, Travis J. Bailey, Kristin M. Ackerman, Patrick Ohayer, David R. HydeAbstract:Intense light exposure causes photoreceptor apoptosis in dark-adapted adult albino zebrafish (Danio rerio). Subsequently, Muller glia increase expression of the Achaete-scute complex-like 1a (Ascl1a) and Signal transducer and activator of transcription 3 (Stat3) transcription factors and re-enter the cell cycle to yield undifferentiated neuronal progenitors that continue to proliferate, migrate to the outer nuclear layer, and differentiate into photoreceptors. A proteomic analysis of light-damaged retinal homogenates, which induced Muller glia proliferation when injected into an undamaged eye, revealed increased expression of tumor necrosis factor α (TNFα) signaling proteins relative to undamaged retinal homogenates. TNFα expression initially increased in apoptotic photoreceptors and later in Muller glia. Morpholino-mediated knockdown of TNFα expression before light damage diminished the expression of both Ascl1a and Stat3 in Muller glia and significantly reduced the number of proliferating Muller glia without affecting photoreceptor cell death. Knockdown of TNFα expression in the Muller glia resulted in fewer proliferating Muller glia, suggesting that Muller glial-derived TNFα recruited additional Muller glia to re-enter the cell cycle. While TNFα is required for increased Ascl1a and Stat3 expression, Ascl1a and Stat3 are both necessary for TNFα expression in Muller glia. Apoptotic inner retinal neurons, resulting from intravitreal injection of ouabain, also exhibited increased TNFα expression that was required for Muller glia proliferation. Thus, TNFα is the first molecule identified that is produced by dying retinal neurons and is necessary to induce Muller glia to proliferate in the zebrafish retinal regeneration response.
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Stat3 defines three populations of Müller glia and is required for initiating maximal müller glia proliferation in the regenerating zebrafish retina.
The Journal of Comparative Neurology, 2012Co-Authors: Craig M. Nelson, Ryne A. Gorsuch, Travis J. Bailey, Kristin M. Ackerman, Sean C. Kassen, David R. HydeAbstract:We analyzed the role of Stat3, Ascl1a, and Lin28a in Muller glia reentry into the cell cycle following damage to the zebrafish retina. Immunohistochemical analysis was employed to determine the temporal and spatial expression of Stat3 and Ascl1a proteins following rod and cone photoreceptor cell apoptosis. Stat3 expression was observed in all Muller glia, whereas Ascl1a expression was restricted to only the mitotic Muller glia. Knockdown of Stat3 protein expression did not affect photoreceptor apoptosis, but significantly reduced, without abolishing, the number of proliferating Ascl1a-positive Muller glia. Knockdown of Ascl1a protein also did not change the extent of photoreceptor apoptosis, but did yield significantly fewer Muller glia that reentered the cell cycle relative to the stat3 morphant and significantly decreased the number and intensity of Stat3-expressing Muller glia. Finally, introduction of lin28a morpholinos resulted in decreased Muller glia expression of Stat3 and Ascl1a, significantly reducing the number of proliferating Muller glia. Thus, there are three populations of Muller glia in the light-damaged zebrafish retina: 1) Stat3-expressing Ascl1a-nonexpressing nonproliferating (quiescent) Muller glia; 2) Stat3-dependent Ascl1a-dependent proliferating Muller glia; and 3) Stat3-independent Ascl1a-dependent proliferating Muller glia. Whereas Ascl1a and Lin28a are required for Muller glia proliferation, Stat3 is necessary for the maximal number of Muller glia to proliferate during regeneration of the damaged zebrafish retina. J. Comp. Neurol. 520:4294–4311, 2012. © 2012 Wiley Periodicals, Inc.
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the inhibitor of phagocytosis o phospho l serine suppresses Muller glia proliferation and cone cell regeneration in the light damaged zebrafish retina
Experimental Eye Research, 2010Co-Authors: Travis J. Bailey, Jacob E Montgomery, Sara L Fossum, Shane M Fimbel, David R. HydeAbstract:Abstract The damaged zebrafish retina replaces lost neurons through a regenerative response that initiates with the asymmetric cell division of Muller glia to produce neuronal progenitor cells that proliferate and migrate to the damaged retinal layer, where they differentiate into the lost neuronal cell types. Because Muller glia are known to phagocytose apoptotic retinal cells during development, we tested if Muller glia engulfed apoptotic rod cell bodies in light-damaged retinas. After 24 h of constant intense light, damaged retinas revealed both a strong nuclear TUNEL signal in photoreceptors and a weak cytoplasmic TUNEL signal in Muller glia, although Muller glial apoptosis is not observed in the light-damaged retina. Light damage of a rod-specific transgenic reporter line, Tg(XlRho:EGFP) fl1 , resulted in some Muller glia containing both TUNEL signal and EGFP, which indicated that this subset of Muller glia engulfed apoptotic photoreceptor cell bodies. To determine if phagocytosis induced the Muller glial proliferative response in the light-damaged retina, we utilized O-phospho- l -serine (L-SOP), a molecule that mimics the phosphatidylserine head group and partially blocks microglial phagocytosis of apoptotic cells. Intravitreal injection of L-SOP immediately prior to beginning constant intense light treatment: i) did not significantly reduce light-induced photoreceptor cell death, ii) significantly reduced the number of PCNA-positive Muller glia, and iii) significantly reduced the number of cone photoreceptors in the regenerated retina relative to control retinas. Because L-SOP is also a specific group III metabotropic glutamate receptor (mGluR) agonist, we also tested if the more potent specific group III agonist, l -2-amino-4-phosphonobutyrate (L-AP4), the specific group III antagonist ( RS )-α-Methylserine- O -phosphate (MSOP) or the specific group I antagonist, l -2-amino-3-phophonopropanoic acid (L-AP3) affected Muller glial proliferation. We found no changes with any of these factors compared to control retinas, revealing that metabotropic glutamate receptors were not necessary in the Muller glia proliferative response. Furthermore, ascl1a and stat3 expression were unaffected in either the L-SOP or MSOP-injected retinas relative to controls, suggesting L-SOP disrupts Muller glia proliferation subsequent to or in parallel with ascl1a and stat3 activation. This implies that at least one signaling mechanism, in addition to the process disrupted by L-SOP, is required to activate Muller glia proliferation in the light-damaged retina.
Giovanni Passalacqua - One of the best experts on this subject based on the ideXlab platform.
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Vespa crabro immunotherapy versus Vespula-venom immunotherapy in Vespa crabro allergy: a comparison study in field re-stings
World Allergy Organization Journal, 2018Co-Authors: Donatella Macchia, Gabriele Cortellini, Marina Mauro, Elisa Meucci, Oliviero Quercia, Mariangela Manfredi, Alessandro Massolo, Maurizio Valentini, Maurizio Severino, Giovanni PassalacquaAbstract:Background In ascertained allergic sensitization to Vespa crabro (VC) venom, the European guidelines still consider venom immunotherapy (VIT) with Vespula (VE) venom sufficient to achieve an adequate protection against VC. However, antigen 5 immunoblotting studies showed that a genuine sensitization to VC venom may exist. In such cases, a specific VC venom would be preferable for VIT treatment. Since in the last few years, VC venom extracts became available for diagnosis and desensitization, we assessed the efficacy and safety of VIT with a VC-VIT, compared to VE extract. Methods Patients stung by VC, and carefully diagnosed for specific sensitization and indication to VIT underwent a 5-year course of immunotherapy with either VE or VC extracts . The severity of reactions at the first sting (pre-VIT) and after field re-stings (during VIT) were compared. Results Eighty-three patients, treated with VE extract and 130 patients treated with VC extract completed the 5-year course of VIT. Only a fraction of those patients (43,8%) were field-re-stung by VC: 64 patients on VC VIT and 69 on VE VIT. In the VC VIT group, reactions at re-sting were: 50 negative, 12 large local reactions, 4 systemic reactions (Muller grade I). In this group the VC VIT efficacy was 93,8%. In the VE VIT treated group the reactions at VC re-sting were: 51 negative, 10 large local reactions and 9 systemic reactions (5 Muller I, 3 Mueller III, 1 Muller IV). In this group the overall efficacy of VIT was 87,0%. The difference in efficacy between the two groups was not statistically significant, as previously reported in literature. Nonetheless, field sting systemic reactions Muller III and IV were recorded only in those patients receiving VE VIT. Conclusion This observation suggests that in patients with ascertained VC-induced allergic reactions a specific VC VIT, where available, would be more adequate, at least concerning the safety profile.
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Vespa crabro immunotherapy versus Vespula-venom immunotherapy in Vespa crabro allergy: a comparison study in field re-stings.
The World Allergy Organization journal, 2018Co-Authors: Donatella Macchia, Gabriele Cortellini, Marina Mauro, Elisa Meucci, Oliviero Quercia, Mariangela Manfredi, Alessandro Massolo, Maurizio Valentini, Maurizio Severino, Giovanni PassalacquaAbstract:In ascertained allergic sensitization to Vespa crabro (VC) venom, the European guidelines still consider venom immunotherapy (VIT) with Vespula (VE) venom sufficient to achieve an adequate protection against VC. However, antigen 5 immunoblotting studies showed that a genuine sensitization to VC venom may exist. In such cases, a specific VC venom would be preferable for VIT treatment. Since in the last few years, VC venom extracts became available for diagnosis and desensitization, we assessed the efficacy and safety of VIT with a VC-VIT, compared to VE extract. Patients stung by VC, and carefully diagnosed for specific sensitization and indication to VIT underwent a 5-year course of immunotherapy with either VE or VC extracts. The severity of reactions at the first sting (pre-VIT) and after field re-stings (during VIT) were compared. Eighty-three patients, treated with VE extract and 130 patients treated with VC extract completed the 5-year course of VIT. Only a fraction of those patients (43,8%) were field-re-stung by VC: 64 patients on VC VIT and 69 on VE VIT. In the VC VIT group, reactions at re-sting were: 50 negative, 12 large local reactions, 4 systemic reactions (Muller grade I). In this group the VC VIT efficacy was 93,8%. In the VE VIT treated group the reactions at VC re-sting were: 51 negative, 10 large local reactions and 9 systemic reactions (5 Muller I, 3 Mueller III, 1 Muller IV). In this group the overall efficacy of VIT was 87,0%. The difference in efficacy between the two groups was not statistically significant, as previously reported in literature. Nonetheless, field sting systemic reactions Muller III and IV were recorded only in those patients receiving VE VIT. This observation suggests that in patients with ascertained VC-induced allergic reactions a specific VC VIT, where available, would be more adequate, at least concerning the safety profile.
Andreas Reichenbach - One of the best experts on this subject based on the ideXlab platform.
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new functions of Muller cells
Glia, 2013Co-Authors: Andreas Reichenbach, Andreas BringmannAbstract:Muller cells, the major type of glial cells in the retina, are responsible for the homeostatic and metabolic support of retinal neurons. By mediating transcellular ion, water, and bicarbonate transport, Muller cells control the composition of the extracellular space fluid. Muller cells provide trophic and anti-oxidative support of photoreceptors and neurons and regulate the tightness of the blood-retinal barrier. By the uptake of glutamate, Muller cells are more directly involved in the regulation of the synaptic activity in the inner retina. This review gives a survey of recently discoved new functions of Muller cells. Muller cells are living optical fibers that guide light through the inner retinal tissue. Thereby they enhance the signal/noise ratio by minimizing intraretinal light scattering and conserve the spatial distribution of light patterns in the propagating image. Muller cells act as soft, compliant embedding for neurons, protecting them in case of mechanical trauma, and also as soft substrate required for neurite growth and neuronal plasticity. Muller cells release neuroactive signaling molecules which modulate neuronal activity, are implicated in the mediation of neurovascular coupling, and mediate the homeostasis of the extracellular space volume under hypoosmotic conditions which are a characteristic of intense neuronal activity. Under pathological conditions, a subset of Muller cells may differentiate to neural progenitor/stem cells which regenerate lost photoreceptors and neurons. Increasing knowledge of Muller cell function and responses in the normal and diseased retina will have great impact for the development of new therapeutic approaches for retinal diseases.
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effects of ischemia reperfusion on physiological properties of Muller glial cells in the porcine retina
Investigative Ophthalmology & Visual Science, 2011Co-Authors: Antje Wurm, Andreas Bringmann, Ianors Iandiev, Peter Wiedemann, Andreas Reichenbach, Susann Uhlmann, Thomas PannickeAbstract:Purpose Transient retinal ischemia-reperfusion is associated with neuronal degeneration and activation of Muller glial cells. Reactive gliosis may impede the homeostatic functions of Muller cells. A viable animal model for human ischemic events should display similarities in eye size and retinal blood supply. Therefore, pigs were used in this investigation of physiological alterations in Muller cells after ischemia-reperfusion. Methods Transient retinal ischemia was induced in young adult pigs by high intraocular pressure in one eye for 1 hour. After 3 days of reperfusion, the retinal tissue and isolated Muller cells were used for osmotic swelling recordings, whole-cell patch-clamp experiments, Ca(2+) microfluorimetry, and immunohistochemistry. Results Muller cells in retinal slices from postischemic eyes but not control cells displayed a significant swelling of the somata when osmotic stress was applied by hypotonic extracellular solution. The amplitude of K(+) inward currents was significantly reduced (∼60% of the control value). This decrease was accompanied by a depolarization of the cell membrane. The number of Muller cell end feet displaying a Ca(2+) increase after application of adenosine 5'-triphosphate was increased in the ischemic retina. Moreover, reactive Muller cell gliosis was characterized by an (increased) expression of vimentin, glial fibrillary acidic protein, the phosphorylated mitogen-activated protein kinases extracellular signal-related kinase (ERK) 1 and 2, and the transcription factor c-fos. Conclusions The alterations of reactive Muller cells after transient ischemia of the pig eye were similar to those found in rat and rabbit models, demonstrating that the porcine retina is a suitable model for the investigation of ischemic injury.
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Muller cells in the healthy and diseased retina
2010Co-Authors: Andreas Bringmann, Thomas Pannicke, Peter Wiedemann, Neville N. Osborne, Jens Grosche, Mike Francke, Serguei N Skatchkov, Andreas ReichenbachAbstract:Muller glial cells span the entire thickness of the tissue, and ensheath all retinal neurons, in vertebrate retinae of all species. This morphological relationship is reflected by a multitude of functional interactions between neurons and Muller cells, including a 'metabolic symbiosis' and the processing of visual information. Muller cells are also responsible for the maintenance of the homeostasis of the retinal extracellular milieu (ions, water, neurotransmitter molecules, and pH). In vascularized retinae, Muller cells may also be involved in the control of angiogenesis, and the regulation of retinal blood flow. Virtually every disease of the retina is associated with a reactive Muller cell gliosis which, on the one hand, supports the survival of retinal neurons but, on the other hand, may accelerate the progress of neuronal degeneration: Muller cells protect neurons via a release of neurotrophic factors, the uptake and degradation of the excitotoxin, glutamate, and the secretion of the antioxidant, glutathione. However, gliotic Muller cells display a dysregulation of various neuron- supportive functions. This contributes to a disturbance of retinal glutamate metabolism and ion homeostasis, and causes the development of retinal edema and neuronal cell death. Moreover, there are diseases evoking a primary Muller cell insufficiency, such as hepatic retinopathy and certain forms of glaucoma. Any impairment of supportive functions of Muller cells, primary or secondary, must cause and/or aggravate a dysfunction and loss of neurons, by increasing the susceptibility of neurons to stressful stimuli in the diseased retina. On the contrary, Muller cells may be used in the future for novel therapeutic strategies to protect neurons against apoptosis (somatic gene therapy), or to differentiate retinal neurons from Muller/stem cells. Meanwhile, a proper understanding of the gliotic responses of Muller cells in the diseased retina, and of their protective vs. detrimental effects, is essential for the development of efficient therapeutic strategies that use and stimulate the neuron-supportive/protective—and prevent the destructive—mechanisms of gliosis.
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Cellular signaling and factors involved in Müller cell gliosis: neuroprotective and detrimental effects.
Progress in Retinal and Eye Research, 2009Co-Authors: Andreas Bringmann, Ianors Iandiev, Thomas Pannicke, Antje Wurm, Margrit Hollborn, Peter Wiedemann, Neville N. Osborne, Andreas ReichenbachAbstract:Muller cells are active players in normal retinal function and in virtually all forms of retinal injury and disease. Reactive Muller cells protect the tissue from further damage and preserve tissue function by the release of antioxidants and neurotrophic factors, and may contribute to retinal regeneration by the generation of neural progenitor/stem cells. However, Muller cell gliosis can also contribute to neurodegeneration and impedes regenerative processes in the retinal tissue by the formation of glial scars. This article provides an overview of the neuroprotective and detrimental effects of Muller cell gliosis, with accounts on the cellular signal transduction mechanisms and factors which are implicated in Muller cell-mediated neuroprotection, immunomodulation, regulation of Muller cell proliferation, upregulation of intermediate filaments, glial scar formation, and the generation of neural progenitor/stem cells. A proper understanding of the signaling mechanisms implicated in gliotic alterations of Muller cells is essential for the development of efficient therapeutic strategies that increase the supportive/protective and decrease the destructive roles of gliosis.
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Muller cells as players in retinal degeneration and edema
Graefes Archive for Clinical and Experimental Ophthalmology, 2007Co-Authors: Andreas Reichenbach, Ianors Iandiev, Thomas Pannicke, Antje Wurm, Peter Wiedemann, Andreas BringmannAbstract:Under normal conditions, Muller cells support neuronal activity and the integrity of the blood-retinal barrier, whereas gliotic alterations of Muller cells under pathological conditions may contribute to retinal degeneration and edema formation. A major function of Muller cells is the fluid absorption from the retinal tissue, which is mediated by transcellular water transport coupled to currents through potassium channels. Alterations of retinal Muller cells under pathological conditions were investigated by immunohistochemistry and recording their behavior under osmotic stress. In animal models of various retinopathies, e.g., retinal ischemia, ocular inflammation, retinal detachment, and diabetes, it was found that Muller cells decrease the expression of their major potassium channel (Kir4.1). This alteration is associated with an impairment of the rapid water transport across Muller cell membranes, as recognizable in the induction of cellular swelling under hypoosmolar conditions. Osmotic swelling of Muller cells is also induced by oxidative stress and by inflammatory mediators such as arachidonic acid and prostaglandins. The data suggest that a disturbed fluid transport through Muller cells is (in addition to vascular leakage) a pathogenic factor contributing to the development of retinal edema. Pharmacological re-activation of the retinal water clearance by Muller cells may represent an approach to the development of new edema-resolving drugs. Triamcinolone acetonide, which is clinically used to resolve edema, prevents osmotic swelling of Muller cells as it induces the release of endogenous adenosine and subsequent A1 receptor activation which results in the opening of ion channels. Apparently, triamcinolone resolves edema by both inhibition of vascular leakage and stimulation of retinal fluid clearance by Muller cells.
Andreas Bringmann - One of the best experts on this subject based on the ideXlab platform.
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new functions of Muller cells
Glia, 2013Co-Authors: Andreas Reichenbach, Andreas BringmannAbstract:Muller cells, the major type of glial cells in the retina, are responsible for the homeostatic and metabolic support of retinal neurons. By mediating transcellular ion, water, and bicarbonate transport, Muller cells control the composition of the extracellular space fluid. Muller cells provide trophic and anti-oxidative support of photoreceptors and neurons and regulate the tightness of the blood-retinal barrier. By the uptake of glutamate, Muller cells are more directly involved in the regulation of the synaptic activity in the inner retina. This review gives a survey of recently discoved new functions of Muller cells. Muller cells are living optical fibers that guide light through the inner retinal tissue. Thereby they enhance the signal/noise ratio by minimizing intraretinal light scattering and conserve the spatial distribution of light patterns in the propagating image. Muller cells act as soft, compliant embedding for neurons, protecting them in case of mechanical trauma, and also as soft substrate required for neurite growth and neuronal plasticity. Muller cells release neuroactive signaling molecules which modulate neuronal activity, are implicated in the mediation of neurovascular coupling, and mediate the homeostasis of the extracellular space volume under hypoosmotic conditions which are a characteristic of intense neuronal activity. Under pathological conditions, a subset of Muller cells may differentiate to neural progenitor/stem cells which regenerate lost photoreceptors and neurons. Increasing knowledge of Muller cell function and responses in the normal and diseased retina will have great impact for the development of new therapeutic approaches for retinal diseases.
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effects of ischemia reperfusion on physiological properties of Muller glial cells in the porcine retina
Investigative Ophthalmology & Visual Science, 2011Co-Authors: Antje Wurm, Andreas Bringmann, Ianors Iandiev, Peter Wiedemann, Andreas Reichenbach, Susann Uhlmann, Thomas PannickeAbstract:Purpose Transient retinal ischemia-reperfusion is associated with neuronal degeneration and activation of Muller glial cells. Reactive gliosis may impede the homeostatic functions of Muller cells. A viable animal model for human ischemic events should display similarities in eye size and retinal blood supply. Therefore, pigs were used in this investigation of physiological alterations in Muller cells after ischemia-reperfusion. Methods Transient retinal ischemia was induced in young adult pigs by high intraocular pressure in one eye for 1 hour. After 3 days of reperfusion, the retinal tissue and isolated Muller cells were used for osmotic swelling recordings, whole-cell patch-clamp experiments, Ca(2+) microfluorimetry, and immunohistochemistry. Results Muller cells in retinal slices from postischemic eyes but not control cells displayed a significant swelling of the somata when osmotic stress was applied by hypotonic extracellular solution. The amplitude of K(+) inward currents was significantly reduced (∼60% of the control value). This decrease was accompanied by a depolarization of the cell membrane. The number of Muller cell end feet displaying a Ca(2+) increase after application of adenosine 5'-triphosphate was increased in the ischemic retina. Moreover, reactive Muller cell gliosis was characterized by an (increased) expression of vimentin, glial fibrillary acidic protein, the phosphorylated mitogen-activated protein kinases extracellular signal-related kinase (ERK) 1 and 2, and the transcription factor c-fos. Conclusions The alterations of reactive Muller cells after transient ischemia of the pig eye were similar to those found in rat and rabbit models, demonstrating that the porcine retina is a suitable model for the investigation of ischemic injury.
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Muller cells in the healthy and diseased retina
2010Co-Authors: Andreas Bringmann, Thomas Pannicke, Peter Wiedemann, Neville N. Osborne, Jens Grosche, Mike Francke, Serguei N Skatchkov, Andreas ReichenbachAbstract:Muller glial cells span the entire thickness of the tissue, and ensheath all retinal neurons, in vertebrate retinae of all species. This morphological relationship is reflected by a multitude of functional interactions between neurons and Muller cells, including a 'metabolic symbiosis' and the processing of visual information. Muller cells are also responsible for the maintenance of the homeostasis of the retinal extracellular milieu (ions, water, neurotransmitter molecules, and pH). In vascularized retinae, Muller cells may also be involved in the control of angiogenesis, and the regulation of retinal blood flow. Virtually every disease of the retina is associated with a reactive Muller cell gliosis which, on the one hand, supports the survival of retinal neurons but, on the other hand, may accelerate the progress of neuronal degeneration: Muller cells protect neurons via a release of neurotrophic factors, the uptake and degradation of the excitotoxin, glutamate, and the secretion of the antioxidant, glutathione. However, gliotic Muller cells display a dysregulation of various neuron- supportive functions. This contributes to a disturbance of retinal glutamate metabolism and ion homeostasis, and causes the development of retinal edema and neuronal cell death. Moreover, there are diseases evoking a primary Muller cell insufficiency, such as hepatic retinopathy and certain forms of glaucoma. Any impairment of supportive functions of Muller cells, primary or secondary, must cause and/or aggravate a dysfunction and loss of neurons, by increasing the susceptibility of neurons to stressful stimuli in the diseased retina. On the contrary, Muller cells may be used in the future for novel therapeutic strategies to protect neurons against apoptosis (somatic gene therapy), or to differentiate retinal neurons from Muller/stem cells. Meanwhile, a proper understanding of the gliotic responses of Muller cells in the diseased retina, and of their protective vs. detrimental effects, is essential for the development of efficient therapeutic strategies that use and stimulate the neuron-supportive/protective—and prevent the destructive—mechanisms of gliosis.
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Cellular signaling and factors involved in Müller cell gliosis: neuroprotective and detrimental effects.
Progress in Retinal and Eye Research, 2009Co-Authors: Andreas Bringmann, Ianors Iandiev, Thomas Pannicke, Antje Wurm, Margrit Hollborn, Peter Wiedemann, Neville N. Osborne, Andreas ReichenbachAbstract:Muller cells are active players in normal retinal function and in virtually all forms of retinal injury and disease. Reactive Muller cells protect the tissue from further damage and preserve tissue function by the release of antioxidants and neurotrophic factors, and may contribute to retinal regeneration by the generation of neural progenitor/stem cells. However, Muller cell gliosis can also contribute to neurodegeneration and impedes regenerative processes in the retinal tissue by the formation of glial scars. This article provides an overview of the neuroprotective and detrimental effects of Muller cell gliosis, with accounts on the cellular signal transduction mechanisms and factors which are implicated in Muller cell-mediated neuroprotection, immunomodulation, regulation of Muller cell proliferation, upregulation of intermediate filaments, glial scar formation, and the generation of neural progenitor/stem cells. A proper understanding of the signaling mechanisms implicated in gliotic alterations of Muller cells is essential for the development of efficient therapeutic strategies that increase the supportive/protective and decrease the destructive roles of gliosis.
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Muller cells as players in retinal degeneration and edema
Graefes Archive for Clinical and Experimental Ophthalmology, 2007Co-Authors: Andreas Reichenbach, Ianors Iandiev, Thomas Pannicke, Antje Wurm, Peter Wiedemann, Andreas BringmannAbstract:Under normal conditions, Muller cells support neuronal activity and the integrity of the blood-retinal barrier, whereas gliotic alterations of Muller cells under pathological conditions may contribute to retinal degeneration and edema formation. A major function of Muller cells is the fluid absorption from the retinal tissue, which is mediated by transcellular water transport coupled to currents through potassium channels. Alterations of retinal Muller cells under pathological conditions were investigated by immunohistochemistry and recording their behavior under osmotic stress. In animal models of various retinopathies, e.g., retinal ischemia, ocular inflammation, retinal detachment, and diabetes, it was found that Muller cells decrease the expression of their major potassium channel (Kir4.1). This alteration is associated with an impairment of the rapid water transport across Muller cell membranes, as recognizable in the induction of cellular swelling under hypoosmolar conditions. Osmotic swelling of Muller cells is also induced by oxidative stress and by inflammatory mediators such as arachidonic acid and prostaglandins. The data suggest that a disturbed fluid transport through Muller cells is (in addition to vascular leakage) a pathogenic factor contributing to the development of retinal edema. Pharmacological re-activation of the retinal water clearance by Muller cells may represent an approach to the development of new edema-resolving drugs. Triamcinolone acetonide, which is clinically used to resolve edema, prevents osmotic swelling of Muller cells as it induces the release of endogenous adenosine and subsequent A1 receptor activation which results in the opening of ion channels. Apparently, triamcinolone resolves edema by both inhibition of vascular leakage and stimulation of retinal fluid clearance by Muller cells.
Donatella Macchia - One of the best experts on this subject based on the ideXlab platform.
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Vespa crabro immunotherapy versus Vespula-venom immunotherapy in Vespa crabro allergy: a comparison study in field re-stings
World Allergy Organization Journal, 2018Co-Authors: Donatella Macchia, Gabriele Cortellini, Marina Mauro, Elisa Meucci, Oliviero Quercia, Mariangela Manfredi, Alessandro Massolo, Maurizio Valentini, Maurizio Severino, Giovanni PassalacquaAbstract:Background In ascertained allergic sensitization to Vespa crabro (VC) venom, the European guidelines still consider venom immunotherapy (VIT) with Vespula (VE) venom sufficient to achieve an adequate protection against VC. However, antigen 5 immunoblotting studies showed that a genuine sensitization to VC venom may exist. In such cases, a specific VC venom would be preferable for VIT treatment. Since in the last few years, VC venom extracts became available for diagnosis and desensitization, we assessed the efficacy and safety of VIT with a VC-VIT, compared to VE extract. Methods Patients stung by VC, and carefully diagnosed for specific sensitization and indication to VIT underwent a 5-year course of immunotherapy with either VE or VC extracts . The severity of reactions at the first sting (pre-VIT) and after field re-stings (during VIT) were compared. Results Eighty-three patients, treated with VE extract and 130 patients treated with VC extract completed the 5-year course of VIT. Only a fraction of those patients (43,8%) were field-re-stung by VC: 64 patients on VC VIT and 69 on VE VIT. In the VC VIT group, reactions at re-sting were: 50 negative, 12 large local reactions, 4 systemic reactions (Muller grade I). In this group the VC VIT efficacy was 93,8%. In the VE VIT treated group the reactions at VC re-sting were: 51 negative, 10 large local reactions and 9 systemic reactions (5 Muller I, 3 Mueller III, 1 Muller IV). In this group the overall efficacy of VIT was 87,0%. The difference in efficacy between the two groups was not statistically significant, as previously reported in literature. Nonetheless, field sting systemic reactions Muller III and IV were recorded only in those patients receiving VE VIT. Conclusion This observation suggests that in patients with ascertained VC-induced allergic reactions a specific VC VIT, where available, would be more adequate, at least concerning the safety profile.
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Vespa crabro immunotherapy versus Vespula-venom immunotherapy in Vespa crabro allergy: a comparison study in field re-stings.
The World Allergy Organization journal, 2018Co-Authors: Donatella Macchia, Gabriele Cortellini, Marina Mauro, Elisa Meucci, Oliviero Quercia, Mariangela Manfredi, Alessandro Massolo, Maurizio Valentini, Maurizio Severino, Giovanni PassalacquaAbstract:In ascertained allergic sensitization to Vespa crabro (VC) venom, the European guidelines still consider venom immunotherapy (VIT) with Vespula (VE) venom sufficient to achieve an adequate protection against VC. However, antigen 5 immunoblotting studies showed that a genuine sensitization to VC venom may exist. In such cases, a specific VC venom would be preferable for VIT treatment. Since in the last few years, VC venom extracts became available for diagnosis and desensitization, we assessed the efficacy and safety of VIT with a VC-VIT, compared to VE extract. Patients stung by VC, and carefully diagnosed for specific sensitization and indication to VIT underwent a 5-year course of immunotherapy with either VE or VC extracts. The severity of reactions at the first sting (pre-VIT) and after field re-stings (during VIT) were compared. Eighty-three patients, treated with VE extract and 130 patients treated with VC extract completed the 5-year course of VIT. Only a fraction of those patients (43,8%) were field-re-stung by VC: 64 patients on VC VIT and 69 on VE VIT. In the VC VIT group, reactions at re-sting were: 50 negative, 12 large local reactions, 4 systemic reactions (Muller grade I). In this group the VC VIT efficacy was 93,8%. In the VE VIT treated group the reactions at VC re-sting were: 51 negative, 10 large local reactions and 9 systemic reactions (5 Muller I, 3 Mueller III, 1 Muller IV). In this group the overall efficacy of VIT was 87,0%. The difference in efficacy between the two groups was not statistically significant, as previously reported in literature. Nonetheless, field sting systemic reactions Muller III and IV were recorded only in those patients receiving VE VIT. This observation suggests that in patients with ascertained VC-induced allergic reactions a specific VC VIT, where available, would be more adequate, at least concerning the safety profile.
