Molecular dissection of reactive astrogliosis and glial scar formation.

doi:10.1016/J.TINS.2009.08.002

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Molecular dissection of reactive astrogliosis and glial scar formation.

Journal Article•DOI•

Molecular dissection of reactive astrogliosis and glial scar formation.

Michael V. Sofroniew¹•Institutions (1)

University of California, Los Angeles¹

01 Dec 2009-Trends in Neurosciences (Elsevier)-Vol. 32, Iss: 12, pp 638-647

TL;DR: Developments in the signaling mechanisms that regulate specific aspects of reactive astrogliosis are reviewed and the potential to identify novel therapeutic molecular targets for diverse neurological disorders is highlighted.

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About: This article is published in Trends in Neurosciences.The article was published on 2009-12-01 and is currently open access. It has received 2213 citations till now. The article focuses on the topics: Astrogliosis & Glial scar.

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Journal Article•DOI•

Astrocytes: biology and pathology

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Michael V. Sofroniew¹, Harry V. Vinters¹•Institutions (1)

University of California, Los Angeles¹

01 Jan 2010-Acta Neuropathologica

TL;DR: Astrocyte functions in healthy CNS, mechanisms and functions of reactive astrogliosis and glial scar formation, and ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions are reviewed.

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Abstract: Astrocytes are specialized glial cells that outnumber neurons by over fivefold. They contiguously tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS. Astrocytes respond to all forms of CNS insults through a process referred to as reactive astrogliosis, which has become a pathological hallmark of CNS structural lesions. Substantial progress has been made recently in determining functions and mechanisms of reactive astrogliosis and in identifying roles of astrocytes in CNS disorders and pathologies. A vast molecular arsenal at the disposal of reactive astrocytes is being defined. Transgenic mouse models are dissecting specific aspects of reactive astrocytosis and glial scar formation in vivo. Astrocyte involvement in specific clinicopathological entities is being defined. It is now clear that reactive astrogliosis is not a simple all-or-none phenomenon but is a finely gradated continuum of changes that occur in context-dependent manners regulated by specific signaling events. These changes range from reversible alterations in gene expression and cell hypertrophy with preservation of cellular domains and tissue structure, to long-lasting scar formation with rearrangement of tissue structure. Increasing evidence points towards the potential of reactive astrogliosis to play either primary or contributing roles in CNS disorders via loss of normal astrocyte functions or gain of abnormal effects. This article reviews (1) astrocyte functions in healthy CNS, (2) mechanisms and functions of reactive astrogliosis and glial scar formation, and (3) ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions.

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4,075 citations

Cites background from "Molecular dissection of reactive as..."

...As reviewed in detail elsewhere [226], many studies using transgenic and experimental animal models provide compelling evidence that reactive astrocytes protect CNS cells and tissue by (1) uptake of potentially excitotoxic glutamate [33, 198, 234], (2) protection from oxidative stress via glutathione production [42, 216, 234, 245], (3) neuroprotection via adenosine release [125], (4) protection from NH4 ? toxicity [193], (5) neuroprotection by degradation of amyloid-beta peptides [113], (6) facilitating blood brain barrier repair [33], (7) reducing vasogenic edema after trauma, stroke or obstructive hydrocephalus [33, 264], (8) stabilizing extracellular fluid and ion balance and reducing seizure threshold [264], and (9) limiting the spread of inflammatory cells or infectious agents from areas of damage or disease into healthy CNS parenchyma [33, 59, 68, 95, 123, 156, 175, 251]....
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...Because there is little or no reorganization of tissue architecture, if the triggering mechanism is able to resolve, then mild or moderate reactive astrogliosis exhibits the potential for resolution in which the astrocytes return to an appearance similar to that in healthy tissue [226]....
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...Experimental analysis of cell proliferation indicates that GFAP up regulation and hypertrophy can occur in mild or moderate astrogliosis in the absence of proliferation and increase in cell number [226]....
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...Based on a large body of observations in experimental animals, a definition of reactive astrogliosis has recently been proposed [226] that encompasses four key features: (1) reactive astrogliosis is a spectrum of potential molecular, cellular and functional changes in astrocytes that occur in response to all forms and severities of CNS injury and disease including subtle perturbations, (2) the changes undergone by reactive astrocytes vary with severity of the insult along a gradated continuum of progressive alterations in molecular expression, progressive cellular hypertrophy, and in severe cases, proliferation and scar formation, (3) the changes of reactive astrogliosis are regulated in a context-specific manner by inter- and intracellular signaling molecules, (4) the changes undergone during reactive astrogliosis have the potential to alter astrocyte activities both through gain and loss of functions that can impact both beneficially and detrimentally on surrounding neural and non-neural cells [226]....
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...In mild or moderate reactive astrogliosis there is variable up regulation of expression of GFAP and other genes [226], as well as hypertrophy of cell body and processes that can vary in degree but that occurs within the domains of individual astrocytes [257] without substantive inter-...
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Journal Article•DOI•

Neuroinflammation in Alzheimer's disease

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Michael T. Heneka¹, Monica J. Carson², Joseph El Khoury³, Gary E. Landreth⁴, Frederic Brosseron, Douglas L. Feinstein⁵, Andreas H. Jacobs⁶, Tony Wyss-Coray⁷, Tony Wyss-Coray⁸, Javier Vitorica⁹, Richard M. Ransohoff¹⁰, Karl Herrup¹¹, Sally A. Frautschy¹², Bente Finsen¹³, Guy C. Brown¹⁴, Alexei Verkhratsky¹⁵, Alexei Verkhratsky¹⁶, Alexei Verkhratsky¹⁷, Koji Yamanaka¹⁸, Jari Koistinaho¹⁹, Eicke Latz²⁰, Eicke Latz²¹, Annett Halle²², Gabor C. Petzold¹, Terrence Town²³, Dave Morgan²⁴, Mari L. Shinohara²⁵, V. Hugh Perry²⁶, Clive Holmes²⁷, Clive Holmes²⁸, Nicolas G. Bazan²⁹, David J. Brooks³⁰, Stéphane Hunot³¹, Bertrand Joseph³², Nikolaus Deigendesch³³, Olga Garaschuk³⁴, Erik Boddeke³⁵, Charles A. Dinarello³⁶, John C.S. Breitner³⁷, Greg M. Cole¹², Douglas T. Golenbock²¹, Markus P. Kummer¹ - Show less +38 more•Institutions (37)

University Hospital Bonn¹, University of California, Riverside², Harvard University³, Case Western Reserve University⁴, University of Illinois at Chicago⁵, European Institute⁶, VA Palo Alto Healthcare System⁷, Stanford University⁸, Spanish National Research Council⁹, Cleveland Clinic Lerner Research Institute¹⁰, Hong Kong University of Science and Technology¹¹, University of California, Los Angeles¹², University of Southern Denmark¹³, University of Cambridge¹⁴, University of the Basque Country¹⁵, Ikerbasque¹⁶, University of Manchester¹⁷, RIKEN Brain Science Institute¹⁸, University of Eastern Finland¹⁹, University of Bonn²⁰, University of Massachusetts Medical School²¹, Center of Advanced European Studies and Research²², University of Southern California²³, University of South Florida²⁴, Duke University²⁵, Southampton General Hospital²⁶, Moorgreen Hospital²⁷, University of Southampton²⁸, Louisiana State University²⁹, Imperial College London³⁰, Centre national de la recherche scientifique³¹, Karolinska Institutet³², Max Planck Society³³, University of Tübingen³⁴, University of Groningen³⁵, University of Colorado Denver³⁶, Douglas Mental Health University Institute³⁷

01 Apr 2015-Lancet Neurology

TL;DR: Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction.

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Abstract: Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease.

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3,947 citations

Journal Article•DOI•

Genomic Analysis of Reactive Astrogliosis

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Jennifer L. Zamanian¹, Lijun Xu, Lynette C. Foo, Navid Nouri, Lu Zhou, Rona G. Giffard, Ben A. Barres - Show less +3 more•Institutions (1)

Stanford University¹

02 May 2012-The Journal of Neuroscience

TL;DR: The findings provide transcriptome databases for two subtypes of reactive astrocytes that will be highly useful in generating new and testable hypotheses of their function, as well as for providing new markers to detect different types of reactiveAstrocyte reactive gliosis in human neurological diseases.

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Abstract: Reactive astrogliosis is characterized by a profound change in astrocyte phenotype in response to all CNS injuries and diseases. To better understand the reactive astrocyte state, we used Affymetrix GeneChip arrays to profile gene expression in populations of reactive astrocytes isolated at various time points after induction using two mouse injury models, ischemic stroke and neuroinflammation. We find reactive gliosis consists of a rapid, but quickly attenuated, induction of gene expression after insult and identify induced Lcn2 and Serpina3n as strong markers of reactive astrocytes. Strikingly, reactive astrocyte phenotype strongly depended on the type of inducing injury. Although there is a core set of genes that is upregulated in reactive astrocytes from both injury models, at least 50% of the altered gene expression is specific to a given injury type. Reactive astrocytes in ischemia exhibited a molecular phenotype that suggests that they may be beneficial or protective, whereas reactive astrocytes induced by LPS exhibited a phenotype that suggests that they may be detrimental. These findings demonstrate that, despite well established commonalities, astrocyte reactive gliosis is a highly heterogeneous state in which astrocyte activities are altered to respond to the specific injury. This raises the question of how many subtypes of reactive astrocytes exist. Our findings provide transcriptome databases for two subtypes of reactive astrocytes that will be highly useful in generating new and testable hypotheses of their function, as well as for providing new markers to detect different types of reactive astrocytes in human neurological diseases.

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1,730 citations

Cites background from "Molecular dissection of reactive as..."

..., 2006), and various alterations in gene expression have been observed (Sofroniew, 2009)....
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...Most gene expression changes associated with reactive gliosis are transient Although prolonged GFAP expression is widely reported after injury, and particularly in scar-forming astrocytes (Sofroniew, 2009), it has not been clear to what extent the reactive astrocyte state is stable, transient, or represents multiple phenotypes....
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...The astrocytes’ abilities to help support neurons, regulate the blood– brain barrier, remodel the extracellular space, control immune cells, and control synapse formation and function may all be of great import in influencing how the brain fares during and following injury (Pekny and Nilsson, 2005; Sofroniew, 2009)....
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...Gene expression changes suggest a delayed and brief burst of astrocyte proliferation after injury Whether reactive astrocytes proliferate after injury or simply undergo hypertrophy has long been controversial (Sofroniew, 2009)....
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Journal Article•DOI•

Obesity is associated with hypothalamic injury in rodents and humans

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Joshua P. Thaler¹, Chun-Xia Yi², Ellen A. Schur¹, Stephan J. Guyenet¹, Bang H. Hwang, Marcelo O. Dietrich³, Xiaolin Zhao⁴, David A. Sarruf⁵, Vitaly Izgur¹, Kenneth R. Maravilla¹, Hong T. Nguyen¹, Jonathan D. Fischer¹, Miles E. Matsen¹, Brent E. Wisse¹, Gregory J. Morton¹, Tamas L. Horvath³, Denis G. Baskin, Matthias H. Tschöp², Michael W. Schwartz¹ - Show less +15 more•Institutions (5)

University of Washington¹, University of Cincinnati², Yale University³, Xi'an Jiaotong University⁴, Novo Nordisk⁵

03 Jan 2012-Journal of Clinical Investigation

TL;DR: Obesity is associated with neuronal injury in a brain area crucial for body weight control in both humans and rodent models, and evidence of increased gliosis in the mediobasal hypothalamus of obese humans is found.

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Abstract: Rodent models of obesity induced by consuming high-fat diet (HFD) are characterized by inflammation both in peripheral tissues and in hypothalamic areas critical for energy homeostasis. Here we report that unlike inflammation in peripheral tissues, which develops as a consequence of obesity, hypothalamic inflammatory signaling was evident in both rats and mice within 1 to 3 days of HFD onset, prior to substantial weight gain. Furthermore, both reactive gliosis and markers suggestive of neuron injury were evident in the hypothalamic arcuate nucleus of rats and mice within the first week of HFD feeding. Although these responses temporarily subsided, suggesting that neuroprotective mechanisms may initially limit the damage, with continued HFD feeding, inflammation and gliosis returned permanently to the mediobasal hypothalamus. Consistent with these data in rodents, we found evidence of increased gliosis in the mediobasal hypothalamus of obese humans, as assessed by MRI. These findings collectively suggest that, in both humans and rodent models, obesity is associated with neuronal injury in a brain area crucial for body weight control.

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1,432 citations

Journal Article•DOI•

Reactive gliosis and the multicellular response to CNS damage and disease.

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Joshua E. Burda¹, Michael V. Sofroniew¹•Institutions (1)

University of California, Los Angeles¹

22 Jan 2014-Neuron

TL;DR: The contributions of diverse nonneuronal cell types to outcome after acute injury, or to the progression of chronic disease, are of increasing interest as the push toward understanding and ameliorating CNS afflictions accelerates.

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1,056 citations

Cites background from "Molecular dissection of reactive as..."

...This array includes not only molecules released by damaged or dead cells as just described, but alsomolecules entering via leaky BBB,molecules released by infiltrating leukocytes, and molecules released by local cells including reactive glia themselves (Figure 5A) (Sofroniew, 2009)....
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References

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Journal Article•DOI•

Regeneration beyond the glial scar

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Jerry Silver¹, Jared H. Miller¹•Institutions (1)

Case Western Reserve University¹

01 Feb 2004-Nature Reviews Neuroscience

TL;DR: Chondroitin and keratan sulphate proteoglycans are among the main inhibitory extracellular matrix molecules that are produced by reactive astrocytes in the glial scar, and they are believed to play a crucial part in regeneration failure.

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Abstract: After injury to the adult central nervous system (CNS), injured axons cannot regenerate past the lesion. In this review, we present evidence that this is due to the formation of a glial scar. Chondroitin and keratan sulphate proteoglycans are among the main inhibitory extracellular matrix molecules that are produced by reactive astrocytes in the glial scar, and they are believed to play a crucial part in regeneration failure. We will focus on this role, as well as considering the behaviour of regenerating neurons in the environment of CNS injury.

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2,838 citations

Journal Article•DOI•

A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function.

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John D. Cahoy¹, Ben Emery¹, Amit Kaushal¹, Lynette C. Foo¹, Jennifer L. Zamanian¹, Karen S. Christopherson¹, Yi Xing², Jane L. Lubischer³, Paul A. Krieg⁴, Sergey A. Krupenko⁵, Wesley J. Thompson⁶, Ben A. Barres¹ - Show less +8 more•Institutions (6)

Stanford University¹, University of Iowa², North Carolina State University³, University of Arizona⁴, Medical University of South Carolina⁵, University of Texas at Austin⁶

02 Jan 2008-The Journal of Neuroscience

TL;DR: These findings call into question the concept of a “glial” cell class as the gene profiles of astrocyte and oligodendrocytes are as dissimilar to each other as they are to neurons, for better understanding of neural development, function, and disease.

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Abstract: Understanding the cell–cell interactions that control CNS development and function has long been limited by the lack of methods to cleanly separate neural cell types. Here we describe methods for the prospective isolation and purification of astrocytes, neurons, and oligodendrocytes from developing and mature mouse forebrain. We used FACS (fluorescent-activated cell sorting) to isolate astrocytes from transgenic mice that express enhanced green fluorescent protein (EGFP) under the control of an S100β promoter. Using Affymetrix GeneChip Arrays, we then created a transcriptome database of the expression levels of >20,000 genes by gene profiling these three main CNS neural cell types at various postnatal ages between postnatal day 1 (P1) and P30. This database provides a detailed global characterization and comparison of the genes expressed by acutely isolated astrocytes, neurons, and oligodendrocytes. We found that Aldh1L1 is a highly specific antigenic marker for astrocytes with a substantially broader pattern of astrocyte expression than the traditional astrocyte marker GFAP. Astrocytes were enriched in specific metabolic and lipid synthetic pathways, as well as the draper/Megf10 and Mertk/integrin αvβ5 phagocytic pathways suggesting that astrocytes are professional phagocytes. Our findings call into question the concept of a “glial” cell class as the gene profiles of astrocytes and oligodendrocytes are as dissimilar to each other as they are to neurons. This transcriptome database of acutely isolated purified astrocytes, neurons, and oligodendrocytes provides a resource to the neuroscience community by providing improved cell-type-specific markers and for better understanding of neural development, function, and disease.

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2,838 citations

Journal Article•DOI•

The classical complement cascade mediates CNS synapse elimination.

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Beth Stevens¹, Nicola J. Allen¹, Luis E. Vazquez¹, Gareth R. Howell², Karen S. Christopherson¹, Navid Nouri¹, Kristina D. Micheva¹, Adrienne K. Mehalow², Andrew D. Huberman¹, Benjamin K. Stafford³, Alexander Sher³, Alan Litke³, John D. Lambris⁴, Stephen J. Smith¹, Simon W. M. John², Ben A. Barres¹ - Show less +12 more•Institutions (4)

Stanford University¹, Howard Hughes Medical Institute², Santa Cruz Institute for Particle Physics³, University of Pennsylvania⁴

14 Dec 2007-Cell

TL;DR: It is shown that C1q, the initiating protein in the classical complement cascade, is expressed by postnatal neurons in response to immature astrocytes and is localized to synapses throughout the postnatal CNS and retina, supporting a model in which unwanted synapses are tagged by complement for elimination and suggesting that complement-mediated synapse elimination may become aberrantly reactivated in neurodegenerative disease.

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2,501 citations

Journal Article•DOI•

Knockout of Glutamate Transporters Reveals a Major Role for Astroglial Transport in Excitotoxicity and Clearance of Glutamate

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Jeffrey D. Rothstein¹, Margaret Dykes-Hoberg¹, Carlos A. Pardo¹, Lynn A. Bristol¹, Lin Jin¹, Ralph W. Kuncl¹, Yoshikatsu Kanai², Matthias A. Hediger³, Yanfeng Wang, Jerry P Schielke⁴, Devin Franklin Welty - Show less +7 more•Institutions (4)

Johns Hopkins University¹, Kyorin University², Harvard University³, Parke-Davis⁴

01 Mar 1996-Neuron

TL;DR: It is suggested that glial glutamate transporters provide the majority of functional glutamate transport and are essential for maintaining low extracellular glutamate and for preventing chronic glutamate neurotoxicity.

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2,482 citations

Journal Article•DOI•

IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel.

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Vanda A. Lennon¹, Thomas J. Kryzer¹, Sean J. Pittock¹, Alan S. Verkman², Shannon R. Hinson¹ - Show less +1 more•Institutions (2)

Mayo Clinic¹, University of California, San Francisco²

15 Aug 2005-Journal of Experimental Medicine

TL;DR: It is shown that NMO-IgG binds selectively to the aquaporin-4 water channel, a component of the dystroglycan protein complex located in astrocytic foot processes at the blood-brain barrier, which may represent the first example of a novel class of autoimmune channelopathy.

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Abstract: Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that selectively affects optic nerves and spinal cord. It is considered a severe variant of multiple sclerosis (MS), and frequently is misdiagnosed as MS, but prognosis and optimal treatments differ. A serum immunoglobulin G autoantibody (NMO-IgG) serves as a specific marker for NMO. Here we show that NMO-IgG binds selectively to the aquaporin-4 water channel, a component of the dystroglycan protein complex located in astrocytic foot processes at the blood-brain barrier. NMO may represent the first example of a novel class of autoimmune channelopathy.

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2,024 citations