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      Reactive astrocytes in multiple sclerosis impair neuronal outgrowth through TRPM7‐mediated chondroitin sulfate proteoglycan production

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          Abstract

          Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS), characterized by inflammation‐mediated demyelination, axonal injury and neurodegeneration. The mechanisms underlying impaired neuronal function are not fully understood, but evidence is accumulating that the presence of the gliotic scar produced by reactive astrocytes play a critical role in these detrimental processes. Here, we identified astrocytic Transient Receptor Potential cation channel, subfamily M, member 7 (TRPM7), a Ca 2+‐permeable nonselective cation channel, as a novel player in the formation of a gliotic scar. TRPM7 was found to be highly expressed in reactive astrocytes within well‐characterized MS lesions and upregulated in primary astrocytes under chronic inflammatory conditions. TRPM7 overexpressing astrocytes impaired neuronal outgrowth in vitro by increasing the production of chondroitin sulfate proteoglycans, a key component of the gliotic scar. These findings indicate that astrocytic TRPM7 is a critical regulator of the formation of a gliotic scar and provide a novel mechanism by which reactive astrocytes affect neuronal outgrowth.

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          Most cited references36

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          The stem cell potential of glia: lessons from reactive gliosis.

          Astrocyte-like cells, which act as stem cells in the adult brain, reside in a few restricted stem cell niches. However, following brain injury, glia outside these niches acquire or reactivate stem cell potential as part of reactive gliosis. Recent studies have begun to uncover the molecular pathways involved in this process. A comparison of molecular pathways activated after injury with those involved in the normal neural stem cell niches highlights strategies that could overcome the inhibition of neurogenesis outside the stem cell niche and instruct parenchymal glia towards a neurogenic fate. This new view on reactive glia therefore suggests a widespread endogenous source of cells with stem cell potential, which might potentially be harnessed for local repair strategies.
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            Deletion of Trpm7 disrupts embryonic development and thymopoiesis without altering Mg2+ homeostasis.

            The gene transient receptor potential-melastatin-like 7 (Trpm7) encodes a protein that functions as an ion channel and a kinase. TRPM7 has been proposed to be required for cellular Mg2+ homeostasis in vertebrates. Deletion of mouse Trpm7 revealed that it is essential for embryonic development. Tissue-specific deletion of Trpm7 in the T cell lineage disrupted thymopoiesis, which led to a developmental block of thymocytes at the double-negative stage and a progressive depletion of thymic medullary cells. However, deletion of Trpm7 in T cells did not affect acute uptake of Mg2+ or the maintenance of total cellular Mg2+. Trpm7-deficient thymocytes exhibited dysregulated synthesis of many growth factors that are necessary for the differentiation and maintenance of thymic epithelial cells. The thymic medullary cells lost signal transducer and activator of transcription 3 activity, which accounts for their depletion when Trpm7 is disrupted in thymocytes.
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              The astrocyte in multiple sclerosis revisited.

              Among the constituent cell types of the multiple sclerosis (MS) plaque, the astrocyte has been the least considered as a player in the pathogenesis of the lesion. Traditionally, it has been assigned a secondary scarring role with little or no role in lesion formation or repair. However, the recent upsurge of interest in the demyelinating condition neuromyelitis optica (NMO) has resulted in NMO being identified as the first disease of myelin in which primary damage to astrocytes, resulting from a humoral immune response that forms against the water channel aquaporin-4, has been documented. This finding in NMO prompted us to re-examine data and material from cases of MS displaying active lesions. Our reappraisal revealed unambiguous early damage to perivascular astrocyte end-feet and to hypertrophic astrocytes in the adjacent parenchyma, but whether this was a primary event was difficult to evaluate due to concomitant edema and inflammation in these acute lesions. The astrocyte damage was long-lasting since resolving lesions displaying remyelination also showed defects in the integrity of the astrocytic covering around blood vessels. Analysis of our findings and of the astrocytic literature supports multiple roles for the astrocyte in the evolution of changes encountered in MS depending upon lesion stage and lesion topography. At variance with the somewhat inhibitory role of the astrocyte is the abundant and growing evidence for this cell to actively participate in both lesion development and repair. We propose that the unequivocal selective early involvement of the astrocyte in MS lesions may have therapeutic relevance Copyright © 2013 Wiley Periodicals, Inc.
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                Author and article information

                Contributors
                a.kamermans@vumc.nl
                Journal
                Glia
                Glia
                10.1002/(ISSN)1098-1136
                GLIA
                Glia
                John Wiley & Sons, Inc. (Hoboken, USA )
                0894-1491
                1098-1136
                19 November 2018
                January 2019
                : 67
                : 1 ( doiID: 10.1002/glia.v67.1 )
                : 68-77
                Affiliations
                [ 1 ] Department of Molecular Cell Biology and Immunology, Amsterdam Neuroscience, MS center Amsterdam, Amsterdam UMC Vrije Universiteit Amsterdam Amsterdam The Netherlands
                [ 2 ] Department of Cell Biology The Netherlands Cancer Institute Amsterdam the Netherlands
                Author notes
                [*] [* ] Correspondence

                Alwin Kamermans, Department of Molecular Cell Biology and Immunology, Amsterdam Neuroscience, MS center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

                Email: a.kamermans@ 123456vumc.nl

                [†]

                Jack van Horssen and Helga E. de Vries contributed equally to this study.

                Author information
                https://orcid.org/0000-0002-3601-395X
                Article
                GLIA23526
                10.1002/glia.23526
                6587975
                30453391
                7faf0cc3-1caa-4840-a1c0-f69b8f99bb0a
                © 2018 The Authors. Glia published by Wiley Periodicals, Inc.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 09 May 2018
                : 08 August 2018
                : 10 August 2018
                Page count
                Figures: 5, Tables: 3, Pages: 10, Words: 7859
                Funding
                Funded by: Dutch MS research Foundation
                Award ID: MS‐14‐358e, AK
                Categories
                Research Article
                Research Articles
                Custom metadata
                2.0
                glia23526
                January 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.4 mode:remove_FC converted:21.06.2019

                Neurosciences
                astrocytes,chondroitin sulfate proteoglycan,multiple sclerosis,neurodegeneration,trpm7

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