Trends in Neurosciences
Volume 32, Issue 12, December 2009, Pages 638-647
Journal home page for Trends in Neurosciences

Review
Molecular dissection of reactive astrogliosis and glial scar formation

https://doi.org/10.1016/j.tins.2009.08.002Get rights and content

Reactive astrogliosis, whereby astrocytes undergo varying molecular and morphological changes, is a ubiquitous but poorly understood hallmark of all central nervous system pathologies. Genetic tools are now enabling the molecular dissection of the functions and mechanisms of reactive astrogliosis in vivo. Recent studies provide compelling evidence that reactive astrogliosis can exert both beneficial and detrimental effects in a context-dependent manner determined by specific molecular signaling cascades. Reactive astrocytes can have both loss of normal functions and gain of abnormal effects that could feature prominently in a variety of disease processes. This article reviews developments in the signaling mechanisms that regulate specific aspects of reactive astrogliosis and highlights the potential to identify novel therapeutic molecular targets for diverse neurological disorders.

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.

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