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Graefe's Archive For Clinical and... Feb 2020Diabetic retinopathy (DR) is a sight-threatening complication associated with the highly prevalent diabetes disorder. Both the microvascular damage and neurodegeneration... (Review)
Review
Diabetic retinopathy (DR) is a sight-threatening complication associated with the highly prevalent diabetes disorder. Both the microvascular damage and neurodegeneration detected in the retina caused by chronic hyperglycemia have brought special attention to Müller cells, the major macroglia of the retina that are responsible for retinal homeostasis. Given the role of glucocorticoid signaling in anti-inflammatory responses and the almost exclusive expression of glucocorticoid receptors (GRs) in retinal Müller cells, administration of corticosteroid agonists as a potential treatment option has been widely studied. Although these approaches have been moderately efficacious in treating or de-escalating DR pathomechanisms, there are various side effects and gaps of knowledge with regard to introducing exogenous glucocorticoids to the diseased retina. In this paper, we provide a review of the literature concerning the available evidence for the role of Müller cell glucocorticoid signaling in DR and we discuss previously investigated approaches in modulating this system as possible treatment options. Furthermore, we propose a novel alternative to the available choices of treatment by using gene therapy as a tool to regulate the expression of GR in retinal Müller cells. Upregulating GR expression allows for induced glucocorticoid signaling with more enduring effects compared to injection of agonists. Hence, repetitive injections would no longer be required. Lastly, side effects of glucocorticoid therapy such as glucocorticoid resistance of GR following chronic exposure to excess ligands or agonists can be avoided.
Topics: Animals; Diabetic Retinopathy; Ependymoglial Cells; Humans; Receptors, Glucocorticoid; Retina; Signal Transduction
PubMed: 31734719
DOI: 10.1007/s00417-019-04521-w -
ASN Neuro 2022Müller glial cells exert multiple essential functions in retinal physiology and retinopathies reflecting perhaps the existence of distinct Müller cellular...
Müller glial cells exert multiple essential functions in retinal physiology and retinopathies reflecting perhaps the existence of distinct Müller cellular subpopulations. Harnessing Müller cell heterogeneity may serve to enhance new therapeutic approaches for retinal disease.
Topics: Ependymoglial Cells; Neuroglia; Retina
PubMed: 35673270
DOI: 10.1177/17590914221106903 -
BioMed Research International 2016Due to their permanent and close proximity to neurons, glial cells perform essential tasks for the normal physiology of the retina. Astrocytes and Müller cells (retinal... (Review)
Review
Due to their permanent and close proximity to neurons, glial cells perform essential tasks for the normal physiology of the retina. Astrocytes and Müller cells (retinal macroglia) provide physical support to neurons and supplement them with several metabolites and growth factors. Macroglia are involved in maintaining the homeostasis of extracellular ions and neurotransmitters, are essential for information processing in neural circuits, participate in retinal glucose metabolism and in removing metabolic waste products, regulate local blood flow, induce the blood-retinal barrier (BRB), play fundamental roles in local immune response, and protect neurons from oxidative damage. In response to polyetiological insults, glia cells react with a process called reactive gliosis, seeking to maintain retinal homeostasis. When malfunctioning, macroglial cells can become primary pathogenic elements. A reactive gliosis has been described in different retinal pathologies, including age-related macular degeneration (AMD), diabetes, glaucoma, retinal detachment, or retinitis pigmentosa. A better understanding of the dual, neuroprotective, or cytotoxic effect of macroglial involvement in retinal pathologies would help in treating the physiopathology of these diseases. The extensive participation of the macroglia in retinal diseases points to these cells as innovative targets for new drug therapies.
Topics: Astrocytes; Blood-Retinal Barrier; Ependymoglial Cells; Gliosis; Glucose; Homeostasis; Humans; Immunity, Cellular; Neurons; Oxidative Stress; Retina
PubMed: 27294114
DOI: 10.1155/2016/2954721 -
Development (Cambridge, England) Dec 2019As with all glial cells, the major role of retinal Müller glia (MG) is to provide essential neuronal support. However, the MG of some non-mammalian species have the... (Review)
Review
As with all glial cells, the major role of retinal Müller glia (MG) is to provide essential neuronal support. However, the MG of some non-mammalian species have the additional ability to generate new retinal neurons capable of sight restoration. Unfortunately, mammalian MG do not possess this ability. However, if we could understand the reasons why, we may be able to devise strategies to confer regenerative potential. The recent discovery that the Hippo signaling pathway acts as an intrinsic block to mammalian MG proliferation, along with reports of adeno-associated virus (AAV)-based MG reprogramming and functional photoreceptor differentiation, may indicate a watershed moment in the field of mammalian retinal regeneration. However, as researchers delve deeper into the cellular and molecular mechanisms, and further refine MG reprogramming strategies, we should recall past misinterpretations of data in this field and proceed with caution. Here, we provide a summary of these emerging data and a discussion of technical concerns specific to AAV-mediated reprogramming experiments that must be addressed in order for the field to move forward.
Topics: Animals; Cell Proliferation; Cellular Reprogramming; Cellular Reprogramming Techniques; Dependovirus; Ependymoglial Cells; Genetic Vectors; Humans; Photoreceptor Cells, Vertebrate; Regeneration
PubMed: 31792065
DOI: 10.1242/dev.182642 -
Glia Jun 2018Studies from a number of areas of neuroendocrinology indicate that hypothalamic tanycytes play a key role in control of energy metabolism. First, profound annual changes... (Review)
Review
Studies from a number of areas of neuroendocrinology indicate that hypothalamic tanycytes play a key role in control of energy metabolism. First, profound annual changes in gene expression have been identified in these unusual glial cells in seasonal mammals, for example in genes relating to the transport and metabolism of thyroid hormone into the hypothalamus. The consequent changes in local thyroid hormone availability in the hypothalamus have been shown experimentally to regulate annual cycles in energy intake, storage and expenditure in seasonal species. This is reflected in overt seasonal changes in appetite, body fat composition and torpor. Second, studies in laboratory rodents demonstrate that hypothalamic tanycytes possess transport mechanisms and receptors that indicate they have a cellular function as nutrient sensors. Ex vivo studies with organotypic tanycyte cultures confirm that acute changes in nutrient availability alter calcium and purinergic signalling within and between tanycytes. Finally, tanycytes are components of a stem cell niche in the hypothalamus whose activity can be regulated by the nutritional environment. Experimental depletion of cell division in the hypothalamus alters the homeostatic response to nutrient excess in mice raised in high fat diets. These convergent lines of evidence suggest that tanycytes are nutrient and metabolite sensors that impact upon plasticity and neuronal function in the surrounding hypothalamus, and consequently have an important role in energy intake and expenditure.
Topics: Animals; Energy Metabolism; Ependymoglial Cells; Humans; Hypothalamus
PubMed: 29411421
DOI: 10.1002/glia.23303 -
Cellular Physiology and Biochemistry :... 2019Hypoxia of the retina is a common pathogenic drive leading to vision loss as a result of tissue ischemia, increased vascular permeability and ultimately retinal...
BACKGROUND/AIMS
Hypoxia of the retina is a common pathogenic drive leading to vision loss as a result of tissue ischemia, increased vascular permeability and ultimately retinal neovascularisation. Here we tested the hypothesis that Müller cells stabilize the neurovascular unit, microvasculature by suppression of HIF-1α activation as a result of hypoxic preconditioning.
METHODS
Tube Formation Assay and In vitro Vascular Permeability Image Assay were used to analyze angiogenesis and vascular integrity. Seahorse XF Cell Mito Stress Test was used to measure mitochondrial respiration. Gene and protein expression were examined by qRTPCR, ELISA and western blot.
RESULTS
Hypoxic insult induces a significant induction of proangiogenic factors including vascular endothelial growth factor (VEGF) and angiopoietinlike 4 (ANGPTL-4) resulting in angiogenesis and increased vascular permeability of vascular endothelial cells. Hypoxic preconditioning of a human retinal Müller glia cell line significantly attenuates HIF-1α activation through the inhibition of mTOR and concomitant induction of aerobic glycolysis, stabilizing endothelial cells.
CONCLUSION
Hypoxic preconditioning of Müller cells confers a robust protection to endothelial cells, through the suppression of HIF1α activation and its downstream regulation of VEGF and ANGPTL-4.
Topics: Angiopoietin-Like Protein 4; Cell Hypoxia; Cell Line; Cell Proliferation; Cell Survival; Culture Media, Conditioned; Ependymoglial Cells; Glycolysis; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Microvessels; Mitochondria; Neovascularization, Physiologic; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A
PubMed: 30921506
DOI: 10.33594/000000047 -
Biochemical and Biophysical Research... Oct 2020Tumor necrosis factor-alpha (TNF-α), a major inflammatory factor released from activated retinal glial cells, is implicated in the pathogenesis of glaucoma. In this...
Tumor necrosis factor-alpha (TNF-α), a major inflammatory factor released from activated retinal glial cells, is implicated in the pathogenesis of glaucoma. In this study, we investigated whether and how TNF-α may affect functional conditions of activated retinal Müller cells. Our results showed that in the group I metabotropic glutamate receptor (mGluR I) agonist DHPG-activated cultured Müller cells, TNF-α treatment aggravated cell gliosis, as evidenced by significantly increased expression of glial fibrillary acidic protein (GFAP). TNF-α treatment of the DHPG-activated Müller cells decreased cell proliferation and induced cell apoptosis. In normal Müller cells, TNF-α treatment increased the mRNA levels of leukocyte inhibitory factor (LIF), intercellular cell adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM), and chemokine C-C-motif ligand 2 (CCL2), which could be significantly attenuated when Müller cells were pre-activated. However, TNF-α-induced elevation in mRNA levels of inflammatory factors, such as TNF-α, inducible nitric oxide synthase (iNOS), and interleukin-6 (IL-6), in normal Müller cells still kept higher levels when Müller cells were pre-activated. Furthermore, the TNF-α-induced changes of cytokines were partially mediated by NF-κB signaling pathway. Our results suggest that TNF-α may promote gliosis and inflammatory response of activated Müller cells, thus aggravating RGC injury in glaucoma.
Topics: Animals; Apoptosis; Cell Proliferation; Cell Survival; Cells, Cultured; Cytokines; Ependymoglial Cells; Glial Fibrillary Acidic Protein; Gliosis; Inflammation; Methoxyhydroxyphenylglycol; Mice, Inbred C57BL; NF-kappa B; RNA, Messenger; Signal Transduction; Tumor Necrosis Factor-alpha
PubMed: 32800547
DOI: 10.1016/j.bbrc.2020.07.102 -
Advances in Experimental Medicine and... 2023In recent years, reprogramming Müller glia by overexpressing Ascl1 and other transcription factors has shown promise for the regeneration of postmitotic retinal... (Review)
Review
In recent years, reprogramming Müller glia by overexpressing Ascl1 and other transcription factors has shown promise for the regeneration of postmitotic retinal neurons, primarily bipolar cells, following injury. Müller glial proliferation and efficiency of neuronal differentiation can be modified by the use of small molecules in various systems. The molecules and pathways studied thus far share remarkable consistency with astrocytes. In this mini review, we provide an overview on the modulation of Müller glial proliferation and cell fate using small molecules in injury and reprogramming. We also compare these observations to what has been observed in astrocytes.
Topics: Ependymoglial Cells; Neuroglia; Cell Differentiation; Neurogenesis; Cell Proliferation; Retina
PubMed: 37440074
DOI: 10.1007/978-3-031-27681-1_69 -
Development (Cambridge, England) May 2020Neurovascular pathologies of the central nervous system (CNS), which are associated with barrier dysfunction, are leading causes of death and disability. The roles that... (Review)
Review
Neurovascular pathologies of the central nervous system (CNS), which are associated with barrier dysfunction, are leading causes of death and disability. The roles that neuronal and glial progenitors and mature cells play in CNS angiogenesis and neurovascular barrier maturation have been elucidated in recent years. Yet how neuronal activity influences these processes remains largely unexplored. Here, we discuss our current understanding of how neuronal and glial development affects CNS angiogenesis and barriergenesis, and outline future directions to elucidate how neuronal activity might influence these processes. An understanding of these mechanisms is crucial for developing new interventions to treat neurovascular pathologies.
Topics: Animals; Astrocytes; Blood-Brain Barrier; Central Nervous System; Ependymoglial Cells; Female; Humans; Male; Models, Biological; Neovascularization, Physiologic
PubMed: 32358096
DOI: 10.1242/dev.182279 -
Archivos de La Sociedad Espanola de... Nov 2015Retinal ganglion cells (RGCs) are the first affected cells in neuropathies like glaucoma, for that reason it is very important to explore new methods to neuroprotect...
OBJECTIVE
Retinal ganglion cells (RGCs) are the first affected cells in neuropathies like glaucoma, for that reason it is very important to explore new methods to neuroprotect these neurons. Müller cells are glial cells that provide the neurons with trophic factors and scaffold. The purpose of this study was to analyze the effect of Müller cells on survival and neurite formation in RGCs.
METHOD
Rat Müller cells were grown until a confluent culture on which rat RGCs were added, using pure culture of rat RGCs as controls. RGCs were labeled with βIII-tubulin, and Müller cells with glutamine synthetase antibodies. In addition, nuclei were stained with DAPI. The number of RGCs and number and neurite length were measured.
RESULTS
No differences were found in the number of RGCs between control and cells grown on the substrate of Müller cells. The proportion of RGCs with neurites increased when they grew on Müller (RGCs with 1-3 neurites increased from 19% to 43%. The length of neurites also increased in RGCs grown on Müller cells, with the number of RGCs with neurites from 50 to 200μm increasing from 21% to 41%, and with neurites of more than 200μm the increase was from 6% to 20%.
CONCLUSIONS
Müller cells support the survival of RGCs and induced an increase in the number and length of neurites of RGCs.
Topics: Animals; Cell Count; Cell Survival; Cells, Cultured; Coculture Techniques; Ependymoglial Cells; Female; Intercellular Signaling Peptides and Proteins; Neurites; Rats; Rats, Sprague-Dawley; Retinal Ganglion Cells
PubMed: 26008927
DOI: 10.1016/j.oftal.2015.03.009