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      Identification of epiretinal proliferation in various retinal diseases and vitreoretinal interface disorders

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          Abstract

          Background

          To describe the presence of epiretinal proliferation in eyes with various retinal and vitreoretinal interface conditions.

          Methods

          Consecutive patients seen at the Stein Eye Institute, by one retina specialist, from December 2018 to March 2019, and demonstrating epiretinal proliferation on optical coherence tomography (OCT) were enrolled in this cross-sectional study. Included patients were divided into two groups: vitreoretinal interface pathologies group or retinal diseases group. Presence of epiretinal proliferation and its localization within the 9 macular sectors, as defined by the Early Treatment Diabetic Retinopathy Study (ETDRS), were assessed on OCT.

          Results

          77 eyes from 69 patients demonstrated epiretinal proliferation on OCT. The most frequently involved ETDRS sector was the 1-mm central subfield, followed by inner temporal and inner nasal sectors. Localization of epiretinal proliferation correlated with the presence of any retinal abnormalities in the same quadrant (r = 0.962; P < 0.0001). 31 eyes (40.3%) demonstrated symptomatic vitreoretinal interface pathologies including lamellar macular hole, full-thickness macular hole, epiretinal membrane and history of macular peeling. 46 eyes (59.7%) manifested various retinal diseases, including age-related macular degeneration, diabetic retinopathy, refractory macular edema, vein occlusion and high myopia.

          Conclusions

          Epiretinal proliferation was noted in several retinal conditions and not limited only to full-thickness and lamellar macular holes. Different mechanisms affecting retinal homeostasis might trigger Müller cells dysregulation, potentially leading to abnormal retinal remodeling.

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          Most cited references23

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          Müller glia: Stem cells for generation and regeneration of retinal neurons in teleost fish.

          Adult zebrafish generate new neurons in the brain and retina throughout life. Growth-related neurogenesis allows a vigorous regenerative response to damage, and fish can regenerate retinal neurons, including photoreceptors, and restore functional vision following photic, chemical, or mechanical destruction of the retina. Müller glial cells in fish function as radial-glial-like neural stem cells. During adult growth, Müller glial nuclei undergo sporadic, asymmetric, self-renewing mitotic divisions in the inner nuclear layer to generate a rod progenitor that migrates along the radial fiber of the Müller glia into the outer nuclear layer, proliferates, and differentiates exclusively into rod photoreceptors. When retinal neurons are destroyed, Müller glia in the immediate vicinity of the damage partially and transiently dedifferentiate, re-express retinal progenitor and stem cell markers, re-enter the cell cycle, undergo interkinetic nuclear migration (characteristic of neuroepithelial cells), and divide once in an asymmetric, self-renewing division to generate a retinal progenitor. This daughter cell proliferates rapidly to form a compact neurogenic cluster surrounding the Müller glia; these multipotent retinal progenitors then migrate along the radial fiber to the appropriate lamina to replace missing retinal neurons. Some aspects of the injury-response in fish Müller glia resemble gliosis as observed in mammals, and mammalian Müller glia exhibit some neurogenic properties, indicative of a latent ability to regenerate retinal neurons. Understanding the specific properties of fish Müller glia that facilitate their robust capacity to generate retinal neurons will inform and inspire new clinical approaches for treating blindness and visual loss with regenerative medicine. Copyright © 2014. Published by Elsevier Ltd.
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            Müller Glial Cells in Retinal Disease

            Virtually all pathogenic stimuli activate Müller cells. Reactive Müller cells exert protective and toxic effects on photoreceptors and neurons. They contribute to oxidative stress and glutamate toxicity due to malfunctions of glutamate uptake and glutathione synthesis. Downregulation of potassium conductance disrupts transcellular potassium and water transport, resulting in neuronal hyperexcitability and edema. Protective effects of reactive Müller cells include upregulation of adenosine 5′-triphosphate (ATP)-degrading ectoenzymes, which enhances the extracellular availability of the neuroprotectant adenosine, abrogation of the osmotic release of ATP, which might protect retinal ganglion cells from apoptosis, and the release of antioxidants and neurotrophic factors. The dedifferentiation of reactive Müller cells to progenitor-like cells might have an impact on future therapeutic approaches. A better understanding of the gliotic mechanisms will be helpful in developing efficient therapeutic strategies aiming at increased protective and regenerative properties and decreased toxicity of reactive Müller cells.
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              Restoration of vision after de novo genesis of rod photoreceptors in mammalian retinas

              In zebrafish, Müller glial cells (MGs) are a source of retinal stem cells that can replenish damaged retinal neurons and restore vision 1 . In mammals, however, MGs lack regenerative capability as they do not spontaneously re-enter the cell cycle to generate a population of stem/progenitor cells that differentiate into retinal neurons. The regenerative machinery may exist in the mammalian retina, however, as retinal injury can stimulate MG proliferation followed by limited neurogenesis 2–7 . The fundamental question remains whether MG-derived regeneration can be exploited to restore vision in mammalian retinas. Previously, we showed that gene transfer of β-catenin stimulates MG proliferation in the absence of injury in mouse retinas 8 . Here, we report that following gene transfer of β-catenin, cell-cycle-reactivated MGs can be reprogrammed into rod photoreceptors via a subsequent gene transfer of transcription factors that are essential for rod cell fate specification and determination. MG-derived rods restored visual responses in Gnat1rd17 :Gnat2cpfl3 double mutant mice, a model of congenital blindness 9,10 , throughout the visual pathway from the retina to the primary visual cortex. Together, our results provide evidence of vision restoration after de novo MG-derived genesis of rod photoreceptors in mammalian retinas.
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                Author and article information

                Contributors
                hubschman@jsei.ucla.edu
                Journal
                Int J Retina Vitreous
                Int J Retina Vitreous
                International Journal of Retina and Vitreous
                BioMed Central (London )
                2056-9920
                10 July 2020
                10 July 2020
                2020
                : 6
                : 31
                Affiliations
                [1 ]GRID grid.19006.3e, ISNI 0000 0000 9632 6718, Retina Division, Stein Eye Institute, , University of California Los Angeles, ; 100 Stein Plaza, Los Angeles, CA 90095 USA
                [2 ]GRID grid.411296.9, ISNI 0000 0000 9725 279X, Ophthalmology Department, AP-HP, Université de Paris, , Hôpital Lariboisière, ; 75010 Paris, France
                [3 ]GRID grid.414759.a, ISNI 0000 0004 1760 170X, Ophthalmology Department, , Fatebenefratelli-Oftalmico Hospital, ASST-Fatebenefratelli-Sacco, ; Milan, Italy
                [4 ]GRID grid.12136.37, ISNI 0000 0004 1937 0546, Department of Ophthalmology, Tel Aviv Sourasky Medical Center, Affiliated to the Sackler Faculty of Medicine, , Tel Aviv University, ; Tel Aviv, Israel
                [5 ]GRID grid.280881.b, ISNI 0000 0001 0097 5623, Doheny Image Reading Center, Doheny Eye Institute, ; Los Angeles, CA USA
                Author information
                http://orcid.org/0000-0002-8631-3467
                Article
                233
                10.1186/s40942-020-00233-0
                7350739
                32670614
                125d3047-8dfe-4d42-959a-3d5a45719dd2
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 22 April 2020
                : 29 June 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100001818, Research to Prevent Blindness;
                Funded by: Hess Foundation (US)
                Categories
                Original Article
                Custom metadata
                © The Author(s) 2020

                epiretinal membrane,epiretinal proliferation,full-thickness macular holes,lamellar hole-associated epiretinal proliferation,lamellar macular holes,macular edema,müller glial cells,spectral-domain optical coherence tomography

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