Reactive astrocyte nomenclature, definitions, and future directions

doi:10.1038/s41593-020-00783-4

Review

. 2021 Mar;24(3):312-325.

doi: 10.1038/s41593-020-00783-4. Epub 2021 Feb 15.

Reactive astrocyte nomenclature, definitions, and future directions

Carole Escartin¹, Elena Galea^{2

3}, András Lakatos^#^{4

5}, James P O'Callaghan^#⁶, Gabor C Petzold^#^{7

8}, Alberto Serrano-Pozo^#^{9

10}, Christian Steinhäuser^#¹¹, Andrea Volterra^#¹², Giorgio Carmignoto^#^{13

14}, Amit Agarwal¹⁵, Nicola J Allen¹⁶, Alfonso Araque¹⁷, Luis Barbeito¹⁸, Ari Barzilai¹⁹, Dwight E Bergles²⁰, Gilles Bonvento²¹, Arthur M Butt²², Wei-Ting Chen²³, Martine Cohen-Salmon²⁴, Colm Cunningham²⁵, Benjamin Deneen²⁶, Bart De Strooper^{23

27}, Blanca Díaz-Castro²⁸, Cinthia Farina²⁹, Marc Freeman³⁰, Vittorio Gallo³¹, James E Goldman³², Steven A Goldman^{33

34}, Magdalena Götz^{35

36}, Antonia Gutiérrez^{37

38}, Philip G Haydon³⁹, Dieter H Heiland^{40

41}, Elly M Hol⁴², Matthew G Holt⁴³, Masamitsu Iino⁴⁴, Ksenia V Kastanenka⁴⁵, Helmut Kettenmann⁴⁶, Baljit S Khakh⁴⁷, Schuichi Koizumi⁴⁸, C Justin Lee⁴⁹, Shane A Liddelow⁵⁰, Brian A MacVicar⁵¹, Pierre Magistretti^{52

53}, Albee Messing⁵⁴, Anusha Mishra⁵⁵, Anna V Molofsky⁵⁶, Keith K Murai⁵⁷, Christopher M Norris⁵⁸, Seiji Okada⁵⁹, Stéphane H R Oliet⁶⁰, João F Oliveira^{61

62

63}, Aude Panatier⁶⁰, Vladimir Parpura⁶⁴, Marcela Pekna⁶⁵, Milos Pekny⁶⁶, Luc Pellerin⁶⁷, Gertrudis Perea⁶⁸, Beatriz G Pérez-Nievas⁶⁹, Frank W Pfrieger⁷⁰, Kira E Poskanzer⁷¹, Francisco J Quintana⁷², Richard M Ransohoff⁷³, Miriam Riquelme-Perez²¹, Stefanie Robel⁷⁴, Christine R Rose⁷⁵, Jeffrey D Rothstein⁷⁶, Nathalie Rouach⁷⁷, David H Rowitch⁵, Alexey Semyanov^{78

79}, Swetlana Sirko^{80

81}, Harald Sontheimer⁸², Raymond A Swanson⁸³, Javier Vitorica^{38

84}, Ina-Beate Wanner⁸⁵, Levi B Wood⁸⁶, Jiaqian Wu⁸⁷, Binhai Zheng⁸⁸, Eduardo R Zimmer⁸⁹, Robert Zorec^{90

91}, Michael V Sofroniew⁹², Alexei Verkhratsky^{93

94}

Affiliations

¹ Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives, Fontenay-aux-Roses, France. carole.escartin@cea.fr.
² Institut de Neurociències and Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain. Elena.Galea@uab.es.
³ ICREA, Barcelona, Spain. Elena.Galea@uab.es.
⁴ John van Geest Centre for Brain Repair and Division of Stem Cell Neurobiology, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
⁵ Wellcome Trust-MRC Cambridge Stem Cell Institute, Cambridge Biomedical Campus, Cambridge, UK.
⁶ Health Effects Laboratory Division, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, West Virginia, USA.
⁷ German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
⁸ Division of Vascular Neurology, Department of Neurology, University Hospital Bonn, Bonn, Germany.
⁹ Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
¹⁰ Harvard Medical School, Boston, Massachusetts, USA.
¹¹ Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, Bonn, Germany.
¹² Department of Fundamental Neuroscience, University of Lausanne, Lausanne, Switzerland.
¹³ Neuroscience Institute, Italian National Research Council (CNR), Padua, Italy.
¹⁴ Department of Biomedical Sciences, University of Padua, Padua, Italy.
¹⁵ The Chica and Heinz Schaller Research Group, Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany.
¹⁶ Salk Institute for Biological Studies, Molecular Neurobiology Laboratory, La Jolla, California, USA.
¹⁷ Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota, USA.
¹⁸ Institut Pasteur de Montevideo, Montevideo, Uruguay.
¹⁹ Department of Neurobiology, George S. Wise, Faculty of Life Sciences and Sagol School of Neuroscience, Tel Aviv University, Ramat Aviv Tel Aviv, Israel.
²⁰ The Solomon H. Snyder Department of Neuroscience, Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
²¹ Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives, Fontenay-aux-Roses, France.
²² School of Pharmacy and Biomedical Science, University of Portsmouth, Portsmouth, UK.
²³ Center for Brain and Disease Research, VIB and University of Leuven, Leuven, Belgium.
²⁴ 'Physiology and Physiopathology of the Gliovascular Unit' Research Group, Center for Interdisciplinary Research in Biology (CIRB), College de France, Unité Mixte de Recherche 7241 CNRS, Unité1050 INSERM, PSL Research University, Paris, France.
²⁵ Trinity Biomedical Sciences Institute & Trinity College Institute of Neuroscience, School of Biochemistry & Immunology, Trinity College Dublin, Dublin, Republic of Ireland.
²⁶ Center for Cell and Gene Therapy, Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, USA.
²⁷ UK Dementia Research Institute at the University College London, London, UK.
²⁸ UK Dementia Research Institute at the University of Edinburgh, Centre for Discovery Brain Sciences, Edinburgh, UK.
²⁹ Institute of Experimental Neurology (INSpe) and Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
³⁰ Vollum Institute, OHSU, Portland, Oregon, USA.
³¹ Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington DC, USA.
³² Department of Pathology & Cell Biology, Columbia University, New York, New York, USA.
³³ University of Rochester Medical Center, Rochester, New York, USA.
³⁴ Center for Translational Neuromedicine, University of Copenhagen Faculty of Health and Medical Science and Rigshospitalet, Kobenhavn N, Denmark.
³⁵ Physiological Genomics, Biomedical Center, Ludwig-Maximilians-Universitaet & Institute of Stem Cell Research, Helmholtz Center Munich, Munich, Germany.
³⁶ Synergy, Excellence Cluster of Systems Neurology, Biomedical Center, Munich, Germany.
³⁷ Dpto. Biología Celular, Genética y Fisiología, Instituto de Investigación Biomédica de Málaga-IBIMA, Facultad de Ciencias, Universidad de Málaga, Málaga, Spain.
³⁸ Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
³⁹ Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts, USA.
⁴⁰ Microenvironment and Immunology Research Laboratory, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
⁴¹ Department of Neurosurgery, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany.
⁴² Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.
⁴³ Laboratory of Glia Biology, VIB-KU Leuven Center for Brain and Disease Research, Leuven, Belgium.
⁴⁴ Division of Cellular and Molecular Pharmacology, Nihon University School of Medicine, Tokyo, Japan.
⁴⁵ Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
⁴⁶ Cellular Neurosciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
⁴⁷ Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
⁴⁸ Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi, Japan.
⁴⁹ Center for Cognition and Sociality, Institute for Basic Science 55, Expo-ro, Yuseong-gu, Daejeon, Korea.
⁵⁰ Neuroscience Institute, Department of Neuroscience and Physiology, Department of Ophthalmology, NYU School of Medicine, New York, USA.
⁵¹ Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.
⁵² Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.
⁵³ Centre de Neurosciences Psychiatriques, University of Lausanne and CHUV, Site de Cery, Prilly-Lausanne, Lausanne, Switzerland.
⁵⁴ Waisman Center and School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.
⁵⁵ Department of Neurology Jungers Center for Neurosciences Research and Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon, USA.
⁵⁶ Departments of Psychiatry/Weill Institute for Neuroscience University of California, San Francisco, California, USA.
⁵⁷ Centre for Research in Neuroscience, Department of Neurology & Neurosurgery, Brain Repair and Integrative Neuroscience Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
⁵⁸ Sanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, Kentucky, USA.
⁵⁹ Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
⁶⁰ Université de Bordeaux, Inserm, Neurocentre Magendie, U1215, Bordeaux, France.
⁶¹ Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.
⁶² ICVS/3B's -PT Government Associate Laboratory, Braga/Guimarães, Portugal.
⁶³ IPCA-EST-2Ai, Polytechnic Institute of Cávado and Ave, Applied Artificial Intelligence Laboratory, Campus of IPCA, Barcelos, Portugal.
⁶⁴ Department of Neurobiology, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
⁶⁵ Laboratory of Regenerative Neuroimmunology, Center for Brain Repair, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
⁶⁶ Laboratory of Astrocyte Biology and CNS Regeneration, Center for Brain Repair, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
⁶⁷ INSERM U1082, Université de Poitiers, Poitiers, France.
⁶⁸ Department of Functional and Systems Neurobiology, Cajal Institute, CSIC, Madrid, Spain.
⁶⁹ Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁷⁰ Centre National de la Recherche Scientifique, Université de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, Strasbourg, France.
⁷¹ Department of Biochemistry & Biophysics, Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, California, USA.
⁷² Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School. Associate Member, The Broad Institute, Boston, Massachusetts, USA.
⁷³ Third Rock Ventures, Boston, Massachusetts, USA.
⁷⁴ Fralin Biomedical Research Institute at Virginia Tech Carilion, School of Neuroscience Virginia Tech, Riverside Circle, Roanoke, Virginia, USA.
⁷⁵ Institute of Neurobiology, Heinrich Heine University, Düsseldorf, Germany.
⁷⁶ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
⁷⁷ Neuroglial Interactions in Cerebral Physiology and Pathologies, Center for Interdisciplinary Research in Biology, Collège de France, CNRS UMR 7241, INSERM U1050, Labex Memolife, PSL Research University Paris, Paris, France.
⁷⁸ Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.
⁷⁹ Sechenov First Moscow State Medical University, Moscow, Russia.
⁸⁰ Physiological Genomics, Biomedical Center, LMU Munich, Munich, Germany.
⁸¹ Institute for Stem Cell Research, Helmholtz Zentrum Munich, Neuherberg, Germany.
⁸² Virginia Tech School of Neuroscience and Center for Glial Biology in Health, Disease and Cancer, Virginia Tech at the Fralin Biomedical Research Institute, Roanoke, Virginia, USA.
⁸³ Dept. of Neurology, University of California San Francisco and San Francisco Veterans Affairs Health Care System, San Francisco, California, USA.
⁸⁴ Dept. Bioquímica y Biología Molecular, Instituto de Biomedicina de Sevilla, Universidad de Sevilla, Hospital Virgen del Rocío/CSIC, Sevilla, Spain.
⁸⁵ Semel Institute for Neuroscience & Human Behavior, IDDRC, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
⁸⁶ George W. Woodruff School of Mechanical Engineering, Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory, and Parker H. Petit Institute for Bioengineering & Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA.
⁸⁷ The Vivian L. Smith Department of Neurosurgery, Center for Stem Cell and Regenerative Medicine, MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, McGovern Medical School, UTHealth, University of Texas Health Science Center at Houston, Houston, TX, USA.
⁸⁸ Department of Neurosciences, UC San Diego School of Medicine, La Jolla; VA San Diego Research Service, San Diego, CA, USA.
⁸⁹ Department of Pharmacology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
⁹⁰ Laboratory of Neuroendocrinology, Molecular Cell Physiology, Institute of Pathophysiology, University of Ljubljana, Faculty of Medicine, Ljubljana, Slovenia.
⁹¹ Celica Biomedical, 1000, Ljubljana, Slovenia.
⁹² Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, California, USA. sofroniew@mednet.ucla.edu.
⁹³ Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK. alexej.verkhratsky@manchester.ac.uk.
⁹⁴ Achúcarro Basque Center for Neuroscience, IKERBASQUE, Basque Foundation for Science, Bilbao, Spain. alexej.verkhratsky@manchester.ac.uk.

^# Contributed equally.

PMID: 33589835
PMCID: PMC8007081
DOI: 10.1038/s41593-020-00783-4

Review

Reactive astrocyte nomenclature, definitions, and future directions

Carole Escartin et al. Nat Neurosci. 2021 Mar.

. 2021 Mar;24(3):312-325.

doi: 10.1038/s41593-020-00783-4. Epub 2021 Feb 15.

Authors

Affiliations

¹ Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives, Fontenay-aux-Roses, France. carole.escartin@cea.fr.
² Institut de Neurociències and Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain. Elena.Galea@uab.es.
³ ICREA, Barcelona, Spain. Elena.Galea@uab.es.
⁴ John van Geest Centre for Brain Repair and Division of Stem Cell Neurobiology, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
⁵ Wellcome Trust-MRC Cambridge Stem Cell Institute, Cambridge Biomedical Campus, Cambridge, UK.
⁶ Health Effects Laboratory Division, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, West Virginia, USA.
⁷ German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
⁸ Division of Vascular Neurology, Department of Neurology, University Hospital Bonn, Bonn, Germany.
⁹ Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
¹⁰ Harvard Medical School, Boston, Massachusetts, USA.
¹¹ Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, Bonn, Germany.
¹² Department of Fundamental Neuroscience, University of Lausanne, Lausanne, Switzerland.
¹³ Neuroscience Institute, Italian National Research Council (CNR), Padua, Italy.
¹⁴ Department of Biomedical Sciences, University of Padua, Padua, Italy.
¹⁵ The Chica and Heinz Schaller Research Group, Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany.
¹⁶ Salk Institute for Biological Studies, Molecular Neurobiology Laboratory, La Jolla, California, USA.
¹⁷ Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota, USA.
¹⁸ Institut Pasteur de Montevideo, Montevideo, Uruguay.
¹⁹ Department of Neurobiology, George S. Wise, Faculty of Life Sciences and Sagol School of Neuroscience, Tel Aviv University, Ramat Aviv Tel Aviv, Israel.
²⁰ The Solomon H. Snyder Department of Neuroscience, Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
²¹ Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives, Fontenay-aux-Roses, France.
²² School of Pharmacy and Biomedical Science, University of Portsmouth, Portsmouth, UK.
²³ Center for Brain and Disease Research, VIB and University of Leuven, Leuven, Belgium.
²⁴ 'Physiology and Physiopathology of the Gliovascular Unit' Research Group, Center for Interdisciplinary Research in Biology (CIRB), College de France, Unité Mixte de Recherche 7241 CNRS, Unité1050 INSERM, PSL Research University, Paris, France.
²⁵ Trinity Biomedical Sciences Institute & Trinity College Institute of Neuroscience, School of Biochemistry & Immunology, Trinity College Dublin, Dublin, Republic of Ireland.
²⁶ Center for Cell and Gene Therapy, Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, USA.
²⁷ UK Dementia Research Institute at the University College London, London, UK.
²⁸ UK Dementia Research Institute at the University of Edinburgh, Centre for Discovery Brain Sciences, Edinburgh, UK.
²⁹ Institute of Experimental Neurology (INSpe) and Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
³⁰ Vollum Institute, OHSU, Portland, Oregon, USA.
³¹ Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington DC, USA.
³² Department of Pathology & Cell Biology, Columbia University, New York, New York, USA.
³³ University of Rochester Medical Center, Rochester, New York, USA.
³⁴ Center for Translational Neuromedicine, University of Copenhagen Faculty of Health and Medical Science and Rigshospitalet, Kobenhavn N, Denmark.
³⁵ Physiological Genomics, Biomedical Center, Ludwig-Maximilians-Universitaet & Institute of Stem Cell Research, Helmholtz Center Munich, Munich, Germany.
³⁶ Synergy, Excellence Cluster of Systems Neurology, Biomedical Center, Munich, Germany.
³⁷ Dpto. Biología Celular, Genética y Fisiología, Instituto de Investigación Biomédica de Málaga-IBIMA, Facultad de Ciencias, Universidad de Málaga, Málaga, Spain.
³⁸ Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
³⁹ Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts, USA.
⁴⁰ Microenvironment and Immunology Research Laboratory, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
⁴¹ Department of Neurosurgery, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany.
⁴² Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.
⁴³ Laboratory of Glia Biology, VIB-KU Leuven Center for Brain and Disease Research, Leuven, Belgium.
⁴⁴ Division of Cellular and Molecular Pharmacology, Nihon University School of Medicine, Tokyo, Japan.
⁴⁵ Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
⁴⁶ Cellular Neurosciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
⁴⁷ Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
⁴⁸ Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi, Japan.
⁴⁹ Center for Cognition and Sociality, Institute for Basic Science 55, Expo-ro, Yuseong-gu, Daejeon, Korea.
⁵⁰ Neuroscience Institute, Department of Neuroscience and Physiology, Department of Ophthalmology, NYU School of Medicine, New York, USA.
⁵¹ Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.
⁵² Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.
⁵³ Centre de Neurosciences Psychiatriques, University of Lausanne and CHUV, Site de Cery, Prilly-Lausanne, Lausanne, Switzerland.
⁵⁴ Waisman Center and School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.
⁵⁵ Department of Neurology Jungers Center for Neurosciences Research and Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon, USA.
⁵⁶ Departments of Psychiatry/Weill Institute for Neuroscience University of California, San Francisco, California, USA.
⁵⁷ Centre for Research in Neuroscience, Department of Neurology & Neurosurgery, Brain Repair and Integrative Neuroscience Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
⁵⁸ Sanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, Kentucky, USA.
⁵⁹ Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
⁶⁰ Université de Bordeaux, Inserm, Neurocentre Magendie, U1215, Bordeaux, France.
⁶¹ Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.
⁶² ICVS/3B's -PT Government Associate Laboratory, Braga/Guimarães, Portugal.
⁶³ IPCA-EST-2Ai, Polytechnic Institute of Cávado and Ave, Applied Artificial Intelligence Laboratory, Campus of IPCA, Barcelos, Portugal.
⁶⁴ Department of Neurobiology, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
⁶⁵ Laboratory of Regenerative Neuroimmunology, Center for Brain Repair, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
⁶⁶ Laboratory of Astrocyte Biology and CNS Regeneration, Center for Brain Repair, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
⁶⁷ INSERM U1082, Université de Poitiers, Poitiers, France.
⁶⁸ Department of Functional and Systems Neurobiology, Cajal Institute, CSIC, Madrid, Spain.
⁶⁹ Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁷⁰ Centre National de la Recherche Scientifique, Université de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, Strasbourg, France.
⁷¹ Department of Biochemistry & Biophysics, Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, California, USA.
⁷² Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School. Associate Member, The Broad Institute, Boston, Massachusetts, USA.
⁷³ Third Rock Ventures, Boston, Massachusetts, USA.
⁷⁴ Fralin Biomedical Research Institute at Virginia Tech Carilion, School of Neuroscience Virginia Tech, Riverside Circle, Roanoke, Virginia, USA.
⁷⁵ Institute of Neurobiology, Heinrich Heine University, Düsseldorf, Germany.
⁷⁶ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
⁷⁷ Neuroglial Interactions in Cerebral Physiology and Pathologies, Center for Interdisciplinary Research in Biology, Collège de France, CNRS UMR 7241, INSERM U1050, Labex Memolife, PSL Research University Paris, Paris, France.
⁷⁸ Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.
⁷⁹ Sechenov First Moscow State Medical University, Moscow, Russia.
⁸⁰ Physiological Genomics, Biomedical Center, LMU Munich, Munich, Germany.
⁸¹ Institute for Stem Cell Research, Helmholtz Zentrum Munich, Neuherberg, Germany.
⁸² Virginia Tech School of Neuroscience and Center for Glial Biology in Health, Disease and Cancer, Virginia Tech at the Fralin Biomedical Research Institute, Roanoke, Virginia, USA.
⁸³ Dept. of Neurology, University of California San Francisco and San Francisco Veterans Affairs Health Care System, San Francisco, California, USA.
⁸⁴ Dept. Bioquímica y Biología Molecular, Instituto de Biomedicina de Sevilla, Universidad de Sevilla, Hospital Virgen del Rocío/CSIC, Sevilla, Spain.
⁸⁵ Semel Institute for Neuroscience & Human Behavior, IDDRC, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
⁸⁶ George W. Woodruff School of Mechanical Engineering, Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory, and Parker H. Petit Institute for Bioengineering & Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA.
⁸⁷ The Vivian L. Smith Department of Neurosurgery, Center for Stem Cell and Regenerative Medicine, MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, McGovern Medical School, UTHealth, University of Texas Health Science Center at Houston, Houston, TX, USA.
⁸⁸ Department of Neurosciences, UC San Diego School of Medicine, La Jolla; VA San Diego Research Service, San Diego, CA, USA.
⁸⁹ Department of Pharmacology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
⁹⁰ Laboratory of Neuroendocrinology, Molecular Cell Physiology, Institute of Pathophysiology, University of Ljubljana, Faculty of Medicine, Ljubljana, Slovenia.
⁹¹ Celica Biomedical, 1000, Ljubljana, Slovenia.
⁹² Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, California, USA. sofroniew@mednet.ucla.edu.
⁹³ Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK. alexej.verkhratsky@manchester.ac.uk.
⁹⁴ Achúcarro Basque Center for Neuroscience, IKERBASQUE, Basque Foundation for Science, Bilbao, Spain. alexej.verkhratsky@manchester.ac.uk.

^# Contributed equally.

PMID: 33589835
PMCID: PMC8007081
DOI: 10.1038/s41593-020-00783-4

Abstract

Reactive astrocytes are astrocytes undergoing morphological, molecular, and functional remodeling in response to injury, disease, or infection of the CNS. Although this remodeling was first described over a century ago, uncertainties and controversies remain regarding the contribution of reactive astrocytes to CNS diseases, repair, and aging. It is also unclear whether fixed categories of reactive astrocytes exist and, if so, how to identify them. We point out the shortcomings of binary divisions of reactive astrocytes into good-vs-bad, neurotoxic-vs-neuroprotective or A1-vs-A2. We advocate, instead, that research on reactive astrocytes include assessment of multiple molecular and functional parameters-preferably in vivo-plus multivariate statistics and determination of impact on pathological hallmarks in relevant models. These guidelines may spur the discovery of astrocyte-based biomarkers as well as astrocyte-targeting therapies that abrogate detrimental actions of reactive astrocytes, potentiate their neuro- and glioprotective actions, and restore or augment their homeostatic, modulatory, and defensive functions.

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Figures

**Fig. 1 |. Multivariate assessment of reactive astrocytes.**
a, Reactive astrocyte proliferation in the vicinity of blood vessels assessed by co-staining for BrdU (green; arrows), DAPI (blue), GFAP (white), and CD31 (red) after stab injury of the mouse cortex. Scale bar, 15 μm. Unpublished image from authors S.S. and M.G. b, Human cortical protoplasmic astrocytes in a surgical specimen injected with Lucifer yellow (arrow, injection site) that traverses the gap junctions into neighboring astrocytes. Scale bar, 45 μm. Courtesy of Drs. Xu, Sosunov, and McKhann, Columbia University Department of Neurosurgery. c, Event-based determination of Ca²⁺ responses in a GCaMP6-expressing astrocyte (surrounded by a dashed line) in mouse cortical slices using astrocyte quantitative analysis (AQuA). Colors indicate AQuA events occurring in a single 1-s frame of a 5-min movie. Scale bar, 10 μm. d, Activation of the transcription factor STAT3 (green) assessed by nuclear accumulation in GFAP+ reactive astrocytes (red) surrounding an amyloid plaque (blue, arrow) in a mouse AD model. Scale bar, 20 μm. Adapted from ref. , Society for Neuroscience. e, ScRNAseq in the remission phase of a mouse model of MS reveals several transcriptional astrocyte clusters. These astrocyte sub-populations may be validated with spatial transcriptomics, as shown in f in a model of AD. Adapted from ref. , Nature Publishing Group. f, Distribution of 87 astrocytic (green), neuronal (red), microglial (yellow), and oligodendroglial (blue) genes with in situ multiplex gene sequencing in a coronal section from a mouse model of AD. The method ‘reads’ barcodes of antisense DNA probes that simultaneously target numerous mRNAs. Scale bar, 800 μm. Boxed area is magnified in bottom image, showing 6E10⁺ amyloid-β plaques (white; arrows). Adapted from ref. , Cell Press.

**Fig. 2 |. Workflow for the identification of key variables shaping astrocyte reactivity using multidimensional analyses.**
a, Variables to measure in individual experiments. Although at present it is unrealistic to measure all in the same experiment, it will in most cases be possible to measure at least two or three. b, Variables to record in individual experiments. In some experiments, all or most of these variables are kept constant and are not compared, but they should all be recorded to allow for future comparison across experiments and studies. c, Individual studies will generate multidimensional datasets of reactive astrocytes that can be organized in matrices containing all outcome measures of variables assessed in a (for example, -omics data, functional measurements). One matrix may be generated for each condition listed in b using data obtained in a. Determining whether such states are equivalent to fixed categories rather than temporary changes due to the dynamic nature of cell functioning requires cross-comparison among studies or longitudinal studies, paired with statistical analyses, as in d. d, Multidimensional data analysis and clustering statistics of weighted scores from datasets (a) across different contexts (b) represented in matrices (c) allow identification of functional vectors (V) driving astrocyte reactivity in different contexts. A high score and a low score in each vector represent gain and loss of function, respectively. The graph shows a hypothetical plot of simulated multivariate datasets from a (each dot represents one dataset or sample) obtained in different contexts (b), depicted in different colors. Astrocytes with shared features segregate together along three axes according to the predominance of the function represented in each vector. A state is defined by where the dataset(s) are placed in the V1–3 space. The analysis can be n-dimensional, but for visual clarity, we show a 3D scenario.

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References

1. Virchow R Cellular Pathology (De Witt Robert M., 1860).
1. Achucarro N Some pathological findings in the neuroglia and in the ganglion cells of the cortex in senile conditions. Bull. Gov. Hosp. Insane 2, 81–90 (1910).
1. Andriezen WL The neuroglia elements in the human brain. Brit. Med. J 2, 227–230 (1893).
  The first account of hypertrophic reactive astrocytes in pathology, although they were not called hypertrophic or reactive astrocytes.
1. Weigert C Beiträge zur Kenntnis der normalen menschlichen Neuroglia. in Zeitschrift für Psychologie und Physiologie der Sinnesorgane (Moritz Diesterweg, 1895).
1. Del Río-Hortega P & Penfield WG Cerebral cicatrix: The reaction of neuroglia and microglia to brain wounds. Bull. Johns Hopkins Hosp. 41, 278–303 (1927).

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[1] Virchow R Cellular Pathology (De Witt Robert M., 1860).

[2] Virchow R Cellular Pathology (De Witt Robert M., 1860).

[3] Achucarro N Some pathological findings in the neuroglia and in the ganglion cells of the cortex in senile conditions. Bull. Gov. Hosp. Insane 2, 81–90 (1910).

[4] Achucarro N Some pathological findings in the neuroglia and in the ganglion cells of the cortex in senile conditions. Bull. Gov. Hosp. Insane 2, 81–90 (1910).

[5] Andriezen WL The neuroglia elements in the human brain. Brit. Med. J 2, 227–230 (1893).
The first account of hypertrophic reactive astrocytes in pathology, although they were not called hypertrophic or reactive astrocytes.

[6] Andriezen WL The neuroglia elements in the human brain. Brit. Med. J 2, 227–230 (1893).
The first account of hypertrophic reactive astrocytes in pathology, although they were not called hypertrophic or reactive astrocytes.

[7] Weigert C Beiträge zur Kenntnis der normalen menschlichen Neuroglia. in Zeitschrift für Psychologie und Physiologie der Sinnesorgane (Moritz Diesterweg, 1895).

[8] Weigert C Beiträge zur Kenntnis der normalen menschlichen Neuroglia. in Zeitschrift für Psychologie und Physiologie der Sinnesorgane (Moritz Diesterweg, 1895).

[9] Del Río-Hortega P & Penfield WG Cerebral cicatrix: The reaction of neuroglia and microglia to brain wounds. Bull. Johns Hopkins Hosp. 41, 278–303 (1927).

[10] Del Río-Hortega P & Penfield WG Cerebral cicatrix: The reaction of neuroglia and microglia to brain wounds. Bull. Johns Hopkins Hosp. 41, 278–303 (1927).

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Reactive astrocyte nomenclature, definitions, and future directions

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Reactive astrocyte nomenclature, definitions, and future directions

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