Trends in Neurosciences
ReviewMolecular dissection of reactive astrogliosis and glial scar formation
Introduction
Astrocytes (Figure 1a) are complex, highly differentiated cells that tile the entire central nervous system (CNS) in a contiguous fashion and make numerous essential contributions to normal function in the healthy CNS, including regulation of blood flow, provision of energy metabolites to neurons, participation in synaptic function and plasticity, and maintenance of the extracellular balance of ions, fluid balance and transmitters 1, 2, 3, 4. In addition, astrocytes respond to all forms of CNS insults such as infection, trauma, ischemia and neurodegenerative disease by a process commonly referred to as reactive astrogliosis, which involves changes in their molecular expression and morphology (Figure 1b), and in severe cases, scar formation (Figure 1c) 5, 6, 7, 8, 9. In spite of the long-standing recognition that astrocytes have the potential to undergo these changes after CNS insults, and in spite of the ubiquitous presence of reactive astrocytes at all sites of CNS pathology, the functions and effects of reactive astrocytes are surprisingly poorly understood and their roles in specific disease processes are largely uncertain.
Perhaps the most well known aspect of reactive astrogliosis is that of scar formation. The ability of astrocytes to form scars that inhibit axon regeneration has been recognized for over 100 years and has led to an overall negative connotation that has long dominated concepts about the ramifications of reactive astrogliosis. Nevertheless, a growing body of information indicates that reactive astrocytes exert numerous essential beneficial functions and that astrocytes have a wide spectrum of potential, and often subtle, responses to CNS insults, of which scar formation is only one and lies at the extreme end in terms of its severity. This article summarizes recent advances in the molecular dissection of the functions and mechanisms of reactive astrogliosis, with the main focus on deletion experiments using transgenic mouse models that allow either cellular ablation or molecular deletion in combination with different types of injury or disease paradigms in vivo. This article begins with a definition and model of astrogliosis that includes surveys of molecules produced by reactive astrocytes and of triggering mechanisms and signaling pathways that regulate astrogliosis. It concludes with surveys of the functions of astrogliosis, the potential for dysfunction to contribute to disease mechanisms and the identification of novel therapeutic targets. Space constraints prevent exhaustive review of all topics and limit discussion to a cross-section of recent advances.
Section snippets
Defining reactive astrogliosis
What is astrogliosis? What features distinguish a reactive astrocyte from one that is non-reactive? Is astrogliosis an all-or-none process or a gradated one? Is it a good thing or bad? What are its molecular triggers or its functional consequences? Is astrogliosis synonymous with scar formation? Perhaps a majority of well-informed neurobiologists would be hard pressed to answer such questions. In spite of the increasing recognition that astrocytes play central roles in normal CNS function and
Extensive molecular repertoire of reactive astrocytes
A detailed catalog of information is now available regarding the many different molecules that can be produced by astrocytes under different stimulation conditions, enabling the development of hypotheses regarding potential functions or effects of reactive astrogliosis. This information is available from several decades of in vitro studies investigating biochemical measures of molecular expression in primary astrocyte cell cultures and from recent studies using gene array and proteomic analyses
Triggers and signaling mechanisms of reactive astrogliosis
Many different types of molecules that can be generated through a wide variety of different mechanisms are able to trigger aspects of reactive astrogliosis and are summarized in Table 2. Molecular mediators of reactive astrogliosis can be released by any cell type in CNS tissue, including neurons, microglia, oligodendrocyte lineage cells, endothelia, leukocytes and other astrocytes, in response to CNS insults ranging from subtle cellular perturbations to intense tissue injury and cell death.
Dissecting the functions and mechanisms of reactive astrogliosis
Transgenic manipulations and other molecular techniques provide powerful tools with which to test hypotheses regarding functions and effects of reactive astrogliosis in vivo using experimental models of specific CNS insults. Techniques that are able to target genetic manipulations specifically to astrocytes (Box 1), in combination with techniques that enable either ablating specific cell types or the knockout or knockdown of specific molecules [7] are enabling the molecular dissection of
‘Big picture’ functions of reactive astrogliosis and glial scar formation
Our understanding about the functions and effects of reactive astrogliosis and scar formation and their impact on neural function is at an early stage. The over 100-year long emphasis on glial scar formation as an inhibitor of axon regeneration has led to a widespread negative view of reactive astrogliosis per se. In this regard, it is important to emphasize that many new lines of evidence point towards numerous essential beneficial functions of reactive astrogliosis and scar formation,
Dysfunctions or effects of reactive astrogliosis as potential disease mechanisms
The studies described above provide compelling evidence that reactive astrogliosis is a ubiquitous, complex and essential part of the response to all CNS insults. In addition, there is also a growing realization that dysfunctions or effects of reactive astrogliosis can contribute to or can be primary sources of CNS disease mechanisms either through loss of essential functions performed by astrocytes or by reactive astrocytes, or through gain of detrimental effects.
Identifying novel therapeutic targets
Molecular dissection of reactive astrocytes is beginning to identify molecules whose functions might be enhanced or blocked in specific disease contexts as potential therapeutic strategies. For example, augmenting the function of the astrocyte glutamate transporter EAAT2 with parawexin 1, a molecule isolated from spider venom, has been shown to protect retinal neurons from ischemic degeneration by enhancing glutamate uptake and thereby reducing the potential for glutamate excitotoxicity [76]. A
Concluding remarks
Studies using molecular dissection techniques provide compelling evidence that reactive astrogliosis is not a single all-or-none response but is a complex and multifaceted process that can involve a finely gradated continuum of changes ranging from subtle and reversible alterations in gene expression and morphology up to the pronounced and long-lasting changes associated with scar formation. Accumulating evidence shows that the responses of reactive astrocytes to CNS insults are controlled in a
Acknowledgements
This work is supported by NIH NINDS (NS057624) and the Roman Reed Spinal Cord Injury Initiative of California. The author thanks Donna Crandal for artwork.
References (99)
The mystery and magic of glia: a perspective on their roles in health and disease
Neuron
(2008)New roles for astrocytes: redefining the functional architecture of the brain
Trends Neurosci.
(2003)- et al.
Molecular profile of reactive astrocytes – implications for their role in neurological disease
Neuroscience
(1993) Leukocyte infiltration, neuronal degeneration and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice
Neuron
(1999)Expression profiling identifies a molecular signature of reactive astrocytes stimulated by cyclic AMP or proinflammatory cytokines
Exp. Neurol.
(2008)- et al.
Trophic functions of nucleotides in the central nervous system
Trends Neurosci.
(2009) Fulminant jejuno-ileitis following ablation of enteric glia in adult transgenic mice
Cell
(1998)Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate
Neuron
(1996)Astrocytes are active players in cerebral innate immunity
Trends Immunol.
(2007)- et al.
The neurobiology of glia in the context of water and ion homeostasis
Neuroscience
(2004)
Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis
Cell
The classical complement cascade mediates CNS synapse elimination
Cell
Dysfunctional astrocytes as key players in the pathogenesis of central nervous system disorders
J. Neurol. Sci.
Neuronal or glial progeny: regional differences in radial glia fate
Neuron
Egr-1 regulates expression of the glial scar component phosphacan in astrocytes after experimental stroke
Am. J. Pathol.
Regulation of glial glutamate transporter expression by growth factors
Exp. Neurol.
Activity-dependent regulation of energy metabolism by astrocytes: an update
Glia
Astrocyte dysfunction in neurological disorders: a molecular perspective
Nat. Rev. Neurosci.
Astrocyte activation and reactive gliosis
Glia
Reactive astrocytes in neural repair and protection
Neuroscientist
Mechanisms of disease: astrocytes in neurodegenerative disease
Nat. Clin. Pract. Neurol.
Molecular mechanisms of astrogliosis: new approaches with mouse genetics
J. Neuropathol. Exp. Neurol.
Protoplasmic astrocytes in CA1 atratum radiatum occupy separate anatomical domains
J. Neurosci.
Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury
Proc. Natl. Acad. Sci. USA
Reactive astrocytes protect tissue and preserve function after spinal cord injury
J. Neurosci.
STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury
J. Neurosci.
Ephrin-B2 and EphB2 regulation of astrocyte-meningeal fibroblast interactions in response to spinal cord lesions in adult rats
J. Neurosci.
IL-1-regulated responses in astrocytes: relevance to injury and recovery
Glia
A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function
J. Neurosci.
The transcriptome and metabolic gene signature of protoplasmic astrocytes in the adult murine cortex
J. Neurosci.
Microarray analyses reveal regional astrocyte heterogeneity with implications for neurofibromatosis type 1 (NF1)-regulated glial proliferation
Glia
Phenotypic and functional heterogeneity of GFAP-expressing cells in vitro: differential expression of LeX/CD15 by GFAP-expressing multipotent neural stem cells and non-neurogenic astrocytes
Glia
Astrocyte gp130 expression is critical for the control of Toxoplasma encephalitis
J. Immunol.
Reactive astrocytes form scar-like barriers to leukocytes during adaptive immune inflammation of the central nervous system
J. Neurosci.
IL-6-type cytokines enhance epidermal growth factor-stimulated astrocyte proliferation
Glia
Endothelin-1 regulates astrocyte proliferation and reactive gliosis via a JNK/c-Jun signaling pathway
J. Neurosci.
Origin and progeny of reactive gliosis: a source of multipotent cells in the injured brain
Proc. Natl. Acad. Sci. USA
Adult glial precursor proliferation in mutant SOD1G93A mice
Glia
Spinal cord injury reveals multilineage differentiation of ependymal cells
PLoS Biol.
Forebrain ependymal cells are Notch-dependent and generate neuroblasts and astrocytes after stroke
Nat. Neurosci.
GFAP-expressing progenitors are the principle source of constitutive neurogenesis in adult mouse forebrain
Nat. Neurosci.
Poststroke neurogenesis: emerging principles of migration and localization of immature neurons
Neuroscientist
Essential protective roles of reactive astrocytes in traumatic brain injury
Brain
Experimental autoimmune encephalomyelitis in mice lacking glial fibrillary acidic protein is characterized by a more severe clinical course and an infiltrative central nervous system lesion
Am. J. Pathol.
Protective role of reactive astrocytes in brain ischemia
J. Cereb. Blood Flow Metab.
Absence of glial fibrillary acidic protein and vimentin prevents hypertrophy of astrocytic processes and improves post-traumatic regeneration
J. Neurosci.
Role of aquaporin-4 in cerebral edema and stroke
Handb. Exp. Pharmacol.
A central role of connexin 43 in hypoxic preconditioning
J. Neurosci.
Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury
Nat. Med.
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