Cited by 644Neuroinflammation and Neurodegeneration MechanismsTraumatic Brain Injury and Neurovascular DisturbancesNeuroscience and Neuropharmacology Research

Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury

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Wilhelmsson, Ulrika, Bushong, Eric A., Price, Diana L., Smarr, Benjamin L., Phung, Van, Terada, Masako, Ellisman, Mark H., Pekny, Milos·2006·Proceedings of the National Academy of Sciences

Abstract

Reactive astrocytes in neurotrauma, stroke, or neurodegeneration are thought to undergo cellular hypertrophy, based on their morphological appearance revealed by immunohistochemical detection of glial fibrillary acidic protein, vimentin, or nestin, all of them forming intermediate filaments, a part of the cytoskeleton. Here, we used a recently established dye-filling method to reveal the full three-dimensional shape of astrocytes assessing the morphology of reactive astrocytes in two neurotrauma models. Both in the denervated hippocampal region and the lesioned cerebral cortex, reactive astrocytes increased the thickness of their main cellular processes but did not extend to occupy a greater volume of tissue than nonreactive astrocytes. Despite this hypertrophy of glial fibrillary acidic protein-containing cellular processes, interdigitation between adjacent hippocampal astrocytes remained minimal. This work helps to redefine the century-old concept of hypertrophy of reactive astrocytes.

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Crossref · 10.1073/pnas.0602841103

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  • Astrocytes are activated in response to acute or chronic central nervous system injury, characterized by hypertrophy of proximal processes and up-regulation of GFAP and Vim.

    “Astrocytes are activated in response to acute or chronic central nervous system injury. The activated state is characterized by hypertrophy of proximal processes and up-regulation of the intermediate filament (nanofilament) proteins glial fibrillary acid protein (GFAP) and vimentin (Vim) (15, 16).”

    From Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice (2013) · cites this paper as [16]

    The Results and Discussion report astrocyte activation after injury and thickening of the main GFAP-containing processes. The introductory passage (labeled Abstract in our copy; page unavailable) reports increased GFAP expression and intermediate filaments in reactive astrocytes, and names vimentin as an intermediate-filament marker, but does not specifically establish vimentin up-regulation. (LLM, conf=0.84)

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  • Increased GFAP immunoreactivity largely reflects changes in the astrocytic cytoskeleton and tends to exaggerate the degree of hypertrophy because, except for scar-border astrocytes, the volume accessed by reactive astrocytes does not change, as they remain in their territorial domains.

    “Increased GFAP immunoreactivity largely reflects changes in the astrocytic cytoskeleton and tends to exaggerate the degree of hypertrophy because, with the exception of scar-border astrocytes, the volume accessed by reactive astrocytes does not change, as they remain in their territorial domains23.”

    From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [23]

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  • Immunostaining with individual antibodies cannot reveal the full extent of astrocyte morphology.

    “Because immunostaining with individual antibodies cannot reveal the full extent of astrocyte morphology (16), we expressed GFP in astrocytes in vivo to observe the complete cellular profile of the cells.”
  • Dye-filling methods can visualize whole astrocytes in mice and in human brain samples from surgical resections.

    “Further, dye-filling methods can be used to visualize whole astrocytes in mice23, as well as in human brain samples from surgical resections (Fig. 1b)24.”
  • Reactive astrocytes are an activated form of astrocytes in response to toxic materials.

    “Regarding the form of astrocytes, reactive astrocytes are an activated form of astrocytes in response to toxic materials [49].”

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Cites

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1 of the 34 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. [21]Steward O, Vinsant SL. J Comp Neurol. 1983;214:370–386. [Google Scholar]
  2. [27]Rohlmann A, Wolff J. In: Gap Junctions in the Nervous System. Spray D, Dermietzel R, editors. New York: Landes; 1996. pp. 175–192. [Google Scholar]

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Authors
Wilhelmsson, U., Bushong, E. A., Price, D. L., Smarr, B. L., Phung, V., Terada, M., Ellisman, M. H., & Pekny, M.
Affiliations
  • University of Gothenburg (SE)
  • University of California San Diego (US)
Corresponding author
Pekny, Milos
Venue
Proceedings of the National Academy of Sciences
Published
2006-11-14
Volume
103
Issue
46
Pages
17513-17518
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W1969305530
Cited by
643
References
34
Citations by year
2026: 17 · 2025: 33 · 2024: 41 · 2023: 45 · 2022: 40 · 2021: 56 · 2020: 35 · 2019: 36 · 2018: 40 · 2017: 40 · 2016: 35 · 2015: 42 · 2014: 35 · 2013: 30 · 2012: 30
FWCI
10.99
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Cancer Institute (CA4084314)
  • National Institute of Neurological Disorders and Stroke (R01NS014718, NS046068, R01NS046068, NS014718)
  • National Center for Research Resources (P41RR004050, RR004050)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
reactive astrocytes, astrocyte hypertrophy, astrocyte morphology, glial fibrillary acidic protein, intermediate filaments, neurotrauma, cerebral cortex lesions
MeSH terms
Animals, Astrocytes, Brain Injuries, Female, Cell Shape, Mice

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