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      Microglia regulate central nervous system myelin growth and integrity

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      1 , 2 , 3 , 1 , 4 , 5 , 6 , 7 , 8 , 1 , 2 , 3 , 1 , 2 , 3 , 9 , 10 , 11 , 1 , 2 , 3 , 2 , 12 , 13 , 13 , 14 , 5 , 1 , 2 , 1 , 2 , 15 , 16 , 1 , 2 , 15 , 16 , 1 , 2 , 14 , 2 , 7 , 8 , 17 , 18 , 19 , 6 , 1 , 5 , 1 , 4 , 20 , 21 , 1 , 2 , 3 , 9 , 10 , 11 ,
      Nature
      Nature Publishing Group UK
      Microglia, Oligodendrocyte

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          Abstract

          Myelin is required for the function of neuronal axons in the central nervous system, but the mechanisms that support myelin health are unclear. Although macrophages in the central nervous system have been implicated in myelin health 1 , it is unknown which macrophage populations are involved and which aspects they influence. Here we show that resident microglia are crucial for the maintenance of myelin health in adulthood in both mice and humans. We demonstrate that microglia are dispensable for developmental myelin ensheathment. However, they are required for subsequent regulation of myelin growth and associated cognitive function, and for preservation of myelin integrity by preventing its degeneration. We show that loss of myelin health due to the absence of microglia is associated with the appearance of a myelinating oligodendrocyte state with altered lipid metabolism. Moreover, this mechanism is regulated through disruption of the TGFβ1–TGFβR1 axis. Our findings highlight microglia as promising therapeutic targets for conditions in which myelin growth and integrity are dysregulated, such as in ageing and neurodegenerative disease 2, 3 .

          Abstract

          Resident microglia in the central nervous system are identified as the specific macrophage population that regulates myelin growth and integrity.

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          Most cited references52

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          Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes

          Microglia, the resident immune cells of the brain, rapidly change states in response to their environment, but we lack molecular and functional signatures of different microglial populations. Here, we analyzed the RNA expression patterns of more than 76,000 individual microglia in mice during development, in old age, and after brain injury. Our analysis uncovered at least nine transcriptionally distinct microglial states, which expressed unique sets of genes and were localized in the brain using specific markers. The greatest microglial heterogeneity was found at young ages; however, several states-including chemokine-enriched inflammatory microglia-persisted throughout the lifespan or increased in the aged brain. Multiple reactive microglial subtypes were also found following demyelinating injury in mice, at least one of which was also found in human multiple sclerosis lesions. These distinct microglia signatures can be used to better understand microglia function and to identify and manipulate specific subpopulations in health and disease.
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            Identification of a Unique TGF-β Dependent Molecular and Functional Signature in Microglia

            Microglia are myeloid cells of the central nervous system (CNS) that participate both in normal CNS function and disease. We investigated the molecular signature of microglia and identified 239 genes and 8 microRNAs that were uniquely or highly expressed in microglia vs. myeloid and other immune cells. Out of 239 genes, 106 were enriched in microglia as compared to astrocytes, oligodendrocytes and neurons. This microglia signature was not observed in microglial lines or in monocytes recruited to the CNS and was also observed in human microglia. Based on this signature, we found a crucial role for TGF-β in microglial biology that included: 1) the requirement of TGF-β for the in vitro development of microglia that express the microglial molecular signature characteristic of adult microglia; and 2) the absence of microglia in CNS TGF-β1 deficient mice. Our results identify a unique microglial signature that is dependent on TGF-β signaling which provides insights into microglial biology and the possibility of targeting microglia for the treatment of CNS disease.
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              Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution

              Microglia have critical roles not only in neural development and homeostasis, but also in neurodegenerative and neuroinflammatory diseases of the central nervous system1-4. These highly diverse and specialized functions may be executed by subsets of microglia that already exist in situ, or by specific subsets of microglia that develop from a homogeneous pool of cells on demand. However, little is known about the presence of spatially and temporally restricted subclasses of microglia in the central nervous system during development or disease. Here we combine massively parallel single-cell analysis, single-molecule fluorescence in situ hybridization, advanced immunohistochemistry and computational modelling to comprehensively characterize subclasses of microglia in multiple regions of the central nervous system during development and disease. Single-cell analysis of tissues of the central nervous system during homeostasis in mice revealed specific time- and region-dependent subtypes of microglia. Demyelinating and neurodegenerative diseases evoked context-dependent subtypes of microglia with distinct molecular hallmarks and diverse cellular kinetics. Corresponding clusters of microglia were also identified in healthy human brains, and the brains of patients with multiple sclerosis. Our data provide insights into the endogenous immune system of the central nervous system during development, homeostasis and disease, and may also provide new targets for the treatment of neurodegenerative and neuroinflammatory pathologies.
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                Author and article information

                Contributors
                Veronique.Miron@unityhealth.to
                Journal
                Nature
                Nature
                Nature
                Nature Publishing Group UK (London )
                0028-0836
                1476-4687
                14 December 2022
                14 December 2022
                2023
                : 613
                : 7942
                : 120-129
                Affiliations
                [1 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, UK Dementia Research Institute at The University of Edinburgh, ; Edinburgh, UK
                [2 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, Centre for Discovery Brain Sciences, Chancellor’s Building, , The University of Edinburgh, ; Edinburgh, UK
                [3 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, Medical Research Council Centre for Reproductive Health, The Queen’s Medical Research Institute, , The University of Edinburgh, ; Edinburgh, UK
                [4 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, Centre for Clinical Brain Sciences, Chancellor’s Building, , The University of Edinburgh, ; Edinburgh, UK
                [5 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, Centre for Regenerative Medicine, Institute for Regeneration and Repair, , The University of Edinburgh, ; Edinburgh, UK
                [6 ]GRID grid.419280.6, ISNI 0000 0004 1763 8916, Departments of Molecular Pharmacology, National Institute of Neuroscience, , National Center of Neurology and Psychiatry, ; Kodaira, Japan
                [7 ]GRID grid.12155.32, ISNI 0000 0001 0604 5662, Department of Immunology and Infection, Biomedical Research Institute, , Hasselt University, ; Hasselt, Belgium
                [8 ]GRID grid.12155.32, ISNI 0000 0001 0604 5662, University MS Centre, Hasselt University, ; Hasselt, Belgium
                [9 ]GRID grid.415502.7, Barlo Multiple Sclerosis Centre, , St Michael’s Hospital, ; Toronto, Ontario Canada
                [10 ]GRID grid.415502.7, Keenan Research Centre for Biomedical Science, , St Michael’s Hospital, ; Toronto, Ontario Canada
                [11 ]GRID grid.17063.33, ISNI 0000 0001 2157 2938, Department of Immunology, , The University of Toronto, ; Toronto, Ontario Canada
                [12 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, Wellcome Trust Centre for Cell Biology, King’s Buildings, , The University of Edinburgh, ; Edinburgh, UK
                [13 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, Biological and Veterinary Services, Chancellor’s Building, , The University of Edinburgh, ; Edinburgh, UK
                [14 ]GRID grid.6363.0, ISNI 0000 0001 2218 4662, Department of Neuropathology and Neurocure Clinical Research Center, , Charité-Universitätsmedizin Berlin, ; Berlin, Germany
                [15 ]GRID grid.5963.9, Institute of Neuropathology, Centre for Basics in NeuroModulation, Faculty of Medicine, , University of Freiburg, ; Freiburg, Germany
                [16 ]GRID grid.5963.9, Signalling Research Centres BIOSS and CIBSS, , University of Freiburg, ; Freiburg, Germany
                [17 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, Centre for Inflammation Research, The Queen’s Medical Research Institute, , The University of Edinburgh, ; Edinburgh, UK
                [18 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, , University of Edinburgh, ; Edinburgh, UK
                [19 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, Muir Maxwell Epilepsy Centre, , University of Edinburgh, ; Edinburgh, UK
                [20 ]GRID grid.6936.a, ISNI 0000000123222966, Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, School of Medicine, , Technical University of Munich, ; Munich, Germany
                [21 ]GRID grid.6363.0, ISNI 0000 0001 2218 4662, Neuropsychiatry and Laboratory of Molecular Psychiatry, , Charité-Universitätsmedizin Berlin and DZNE, ; Berlin, Germany
                Author information
                http://orcid.org/0000-0002-9769-367X
                http://orcid.org/0000-0002-9396-7776
                http://orcid.org/0000-0001-5966-0351
                http://orcid.org/0000-0002-8363-373X
                http://orcid.org/0000-0002-0521-9656
                http://orcid.org/0000-0002-0349-1955
                http://orcid.org/0000-0003-2530-0598
                http://orcid.org/0000-0002-7717-8582
                http://orcid.org/0000-0001-9423-557X
                http://orcid.org/0000-0001-5342-7823
                http://orcid.org/0000-0002-6329-382X
                http://orcid.org/0000-0003-1738-0647
                Article
                5534
                10.1038/s41586-022-05534-y
                9812791
                36517604
                a5b19a6c-d36b-40cd-99af-b981e007cf5a
                © The Author(s) 2022

                Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 9 June 2021
                : 5 November 2022
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                © The Author(s), under exclusive licence to Springer Nature Limited 2023

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                microglia,oligodendrocyte
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                microglia, oligodendrocyte

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