Collection |

Glial Cells in Health and Disease

Glial cells – traditionally thought as simply the “glue” of the nervous system – are increasingly recognized to play a critical role in the development and function of the brain. Importantly, glial cell dysfunction has recently been shown to contribute to various neurological disorders, such as autism, schizophrenia, pain, and neurodegeneration. Understanding the function of glial cells under normal, physiological conditions, as well as how it goes awry in disease, has the potential to revolutionize how we think about the function and dysfunction of the nervous system, and inspire the development of new therapies to treat these devastating disorders.

In this Collection, we highlight the best research articles, reviews, and commentaries in the area of glial biology, published in the Nature Research journals, including Nature, Nature CommunicationsNature MedicineNature Neuroscience, Nature ImmunologyNature Methods, Nature Reviews Immunology, Nature Reviews Neuroscience, and Nature Reviews Neurology, during 2016 and 2017. Findings in these papers will not only be valuable to the basic science community, but would also lay the groundwork for future translational research that aims to restore glial function and treat disorders of the nervous system.

Research

  • Nature | Article

    A reactive astrocyte subtype termed A1 is induced after injury or disease of the central nervous system and subsequently promotes the death of neurons and oligodendrocytes.

    • Shane A. Liddelow
    • , Kevin A. Guttenplan
    • , Laura E. Clarke
    • , Frederick C. Bennett
    • , Christopher J. Bohlen
    • , Lucas Schirmer
    • , Mariko L. Bennett
    • , Alexandra E. Münch
    • , Won-Suk Chung
    • , Todd C. Peterson
    • , Daniel K. Wilton
    • , Arnaud Frouin
    • , Brooke A. Napier
    • , Nikhil Panicker
    • , Manoj Kumar
    • , Marion S. Buckwalter
    • , David H. Rowitch
    • , Valina L. Dawson
    • , Ted M. Dawson
    • , Beth Stevens
    •  &  Ben A. Barres
  • Nature Neuroscience | Resource

    Microglia are the macrophages of the CNS, with innate neuroimmune function, and play important roles in tissue homeostasis, CNS development and neurodegeneration. Here human microglial gene expression profiles were generated. Human and mouse microglia were highly similar, except for aging-regulated genes, indicating that microglial aging differs between humans and mice.

    • Thais F Galatro
    • , Inge R Holtman
    • , Antonio M Lerario
    • , Ilia D Vainchtein
    • , Nieske Brouwer
    • , Paula R Sola
    • , Mariana M Veras
    • , Tulio F Pereira
    • , Renata E P Leite
    • , Thomas Möller
    • , Paul D Wes
    • , Mari C Sogayar
    • , Jon D Laman
    • , Wilfred den Dunnen
    • , Carlos A Pasqualucci
    • , Sueli M Oba-Shinjo
    • , Erik W G M Boddeke
    • , Suely K N Marie
    •  &  Bart J L Eggen
  • Nature Immunology | Article

    Microglia are CNS-resident macrophages, but studying their functions in health and disease has been challenging due to a lack of specific markers. Greter and colleagues identify the transcription factor Sall1 as being uniquely associated with microglia in the CNS, where it is important for defining their fate and homeostatic function.

    • Anne Buttgereit
    • , Iva Lelios
    • , Xueyang Yu
    • , Melissa Vrohlings
    • , Natalie R Krakoski
    • , Emmanuel L Gautier
    • , Ryuichi Nishinakamura
    • , Burkhard Becher
    •  &  Melanie Greter
  • Nature Medicine | Article

    μ opioid receptors (MORs) expressed on primary afferent nociceptor neurons are responsible for two maladaptive side-effects of chronic opioid use: opioid tolerance and opioid-induced hyperalgesia (pain). A combination therapy of opioid receptor agonism plus peripheral-restricted MOR antagonism abrogates these side-effects while preserving opioid analgesia in rodent models of peri-operative and chronic pain.

    • Gregory Corder
    • , Vivianne L Tawfik
    • , Dong Wang
    • , Elizabeth I Sypek
    • , Sarah A Low
    • , Jasmine R Dickinson
    • , Chaudy Sotoudeh
    • , J David Clark
    • , Ben A Barres
    • , Christopher J Bohlen
    •  &  Grégory Scherrer
  • Nature Communications | Article | open

    The contribution of glia to Huntington's disease is unclear. The authors show that human glial progenitor cells (GPCs) expressing mutant huntingtin impair motor performance when engrafted into wild type mice, and wild type human GPCs ameliorate disease phenotypes when engrafted into an HD mouse model.

    • Abdellatif Benraiss
    • , Su Wang
    • , Stephanie Herrlinger
    • , Xiaojie Li
    • , Devin Chandler-Militello
    • , Joseph Mauceri
    • , Hayley B. Burm
    • , Michael Toner
    • , Mikhail Osipovitch
    • , Qiwu Jim Xu
    • , Fengfei Ding
    • , Fushun Wang
    • , Ning Kang
    • , Jian Kang
    • , Paul C. Curtin
    • , Daniela Brunner
    • , Martha S. Windrem
    • , Ignacio Munoz-Sanjuan
    • , Maiken Nedergaard
    •  &  Steven A. Goldman

Reviews and Perspectives

  • Nature Immunology | Review Article

    Microglia are by far the best-characterized macrophages in the CNS, but non-parenchymal populations, such as those found in the meninges, are being increasingly studied. Prinz et al. review the ontogeny and functions of both parenchymal macrophages and non-parenchymal macrophages the CNS.

    • Marco Prinz
    • , Daniel Erny
    •  &  Nora Hagemeyer
  • Nature Reviews Neuroscience | Review Article

    Emerging evidence suggests that astrocytes may be as diverse in their physiological and functional characteristics as neurons. Ben Haim and Rowitch describe astrocyte heterogeneity, consider the mechanisms by which such diversity may arise and discuss the consequences of its disruption in disease.

    • Lucile Ben Haim
    •  &  David H. Rowitch
  • Nature Reviews Neuroscience | Review Article

    Central and peripheral inflammation can be induced by psychological stress and is associated with depressive symptoms, suggesting a possible role for immune dysfunction in depression. Duman and colleagues examine the neuroimmune mechanisms influencing neuronal–microglial interactions, neuronal activity and synaptic plasticity in stress and depression.

    • Eric S. Wohleb
    • , Tina Franklin
    • , Masaaki Iwata
    •  &  Ronald S. Duman
  • Nature Neuroscience | Review Article

    Dynamic membrane transformations are not exclusively controlled by cytoskeletal rearrangement, but also by biophysical constraints, adhesive forces, membrane curvature and compaction. Recent technological advances have helped clarify longstanding controversies concerning myelination, from target selection to axon wrapping and membrane compaction. Chang et al. review these findings and discuss how understanding these processes provides insight into myelination-centered mechanisms of neural plasticity.

    • Kae-Jiun Chang
    • , Stephanie A Redmond
    •  &  Jonah R Chan
  • Nature Reviews Neurology | Review Article

    Effective drug treatments for intracerebral haemorrhage (ICH) are still lacking. However, therapies that target microglial phenotype switching might soon become available for affected patients. Here, Wang and colleagues summarize key advances in understanding of microglial function after ICH, including modulators of microglial function and interactions with other cells.

    • Xi Lan
    • , Xiaoning Han
    • , Qian Li
    • , Qing-Wu Yang
    •  &  Jian Wang
  • Nature Medicine | Review Article

    In this Review, Salter and Stevens discuss the role of microglia in CNS disorders such as autism, neurodegenerative disorders, Alzheimer’s disease, and chronic pain.

    • Michael W Salter
    •  &  Beth Stevens

Research Highlights

  • Nature Reviews Neuroscience | Research Highlight

    A new study shows that astrocytic scars facilitate the regrowth of axons following spinal cord injury in mice.

    • Darran Yates
  • Nature Reviews Neuroscience | Research Highlight

    In experimental autoimmune encephalitis (a mouse model of multiple sclerosis), type I interferons stimulate the production of aryl hydrocarbon receptor, which is activated by diet- and microbe-derived molecules and limits CNS inflammation.

    • Natasha Bray
  • Nature Reviews Neuroscience | Research Highlight

    Activated microglia induce a subtype of reactive astrocytes that is toxic to various neuronal types and oligodendrocytes and that is found in various neurological disorders.

    • Darran Yates

Methods and Protocols

  • Nature Neuroscience | Article

    Microglia can expand and divide quickly in the context of CNS pathology, but little is known about the kinetics and clonality of microgliosis. Prinz and colleagues develop a new fate mapping system to monitor microglial dynamics. Microglial self-renewal is found to be a stochastic process under steady state conditions, whereas clonal expansion is observed during disease.

    • Tuan Leng Tay
    • , Dominic Mai
    • , Jana Dautzenberg
    • , Francisco Fernández-Klett
    • , Gen Lin
    • , Sagar
    • , Moumita Datta
    • , Anne Drougard
    • , Thomas Stempfl
    • , Alberto Ardura-Fabregat
    • , Ori Staszewski
    • , Anca Margineanu
    • , Anje Sporbert
    • , Lars M Steinmetz
    • , J Andrew Pospisilik
    • , Steffen Jung
    • , Josef Priller
    • , Dominic Grün
    • , Olaf Ronneberger
    •  &  Marco Prinz
  • Nature Methods | Brief Communication

    Adaptive optics can counteract optical aberrations within tissues, but the field of view is typically limited. Multi-pupil adaptive optics expands the area that can be imaged, and this is demonstrated by multiple applications in the mouse brain imaging.

    • Jung-Hoon Park
    • , Lingjie Kong
    • , Yifeng Zhou
    •  &  Meng Cui
  • Nature Medicine | Technical Report

    A protocol is developed to enable the differentiation of microglial-like cells from human pluripotent stem cells, which are shown to resemble primary human microglia, integrate into 3D neuronal cultures, and perform phagocytic and injury-response functions.

    • Julien Muffat
    • , Yun Li
    • , Bingbing Yuan
    • , Maisam Mitalipova
    • , Attya Omer
    • , Sean Corcoran
    • , Grisilda Bakiasi
    • , Li-Huei Tsai
    • , Patrick Aubourg
    • , Richard M Ransohoff
    •  &  Rudolf Jaenisch
  • Nature Neuroscience | Technical Report

    Pandya et al. describe a protocol to differentiate human and mouse iPSCs into cells with the phenotype, transcriptional profile and functional properties of microglia. The treatment of murine intracranial malignant gliomas with these cells demonstrates their potential clinical use. These microglia-like cells will enable further studies into the role of microglia in health and disease.

    • Hetal Pandya
    • , Michael J Shen
    • , David M Ichikawa
    • , Andrea B Sedlock
    • , Yong Choi
    • , Kory R Johnson
    • , Gloria Kim
    • , Mason A Brown
    • , Abdel G Elkahloun
    • , Dragan Maric
    • , Colin L Sweeney
    • , Selamawit Gossa
    • , Harry L Malech
    • , Dorian B McGavern
    •  &  John K Park
  • Nature Methods | Article

    A method for 3D differentiation of human pluripotent stem cells yields brain cortical spheroids with functional neurons and astrocytes. The spheroids can be sliced for imaging and electrophysiological studies.

    • Anca M Paşca
    • , Steven A Sloan
    • , Laura E Clarke
    • , Yuan Tian
    • , Christopher D Makinson
    • , Nina Huber
    • , Chul Hoon Kim
    • , Jin-Young Park
    • , Nancy A O'Rourke
    • , Khoa D Nguyen
    • , Stephen J Smith
    • , John R Huguenard
    • , Daniel H Geschwind
    • , Ben A Barres
    •  &  Sergiu P Paşca
  • Nature Methods | Article

    The Fixed and Recovered Intact Single-cell RNA (FRISCR) method enables robust RNA extraction and sequencing from fixed, stained and sorted single cells and allows unprecedented profiling of rare cell types, including two subpopulations of radial glial cells in the developing human cortex.

    • Elliot R Thomsen
    • , John K Mich
    • , Zizhen Yao
    • , Rebecca D Hodge
    • , Adele M Doyle
    • , Sumin Jang
    • , Soraya I Shehata
    • , Angelique M Nelson
    • , Nadiya V Shapovalova
    • , Boaz P Levi
    •  &  Sharad Ramanathan