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Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury
Open accessAbstract
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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“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]
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“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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“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.”
From Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice (2013) · cites this paper as [16]
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“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.”
From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [23]
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“Regarding the form of astrocytes, reactive astrocytes are an activated form of astrocytes in response to toxic materials [49].”
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Can Serum GFAP and UCH-L1 Replace CT in Assessing Acute Ischemic Stroke Severity?
Kraljević, I., Guić, M. M., Mršić, D. B., Dolić, K., Čaljkušić, K., Benzon, B., Šupe‐Domić, D., & Kojundžić, S. L. (2025) · Life · doi:10.3390/life15030495 · Cited by 6
“In this process, reactive astrocytes show altered expression of many genes, mainly upregulation of GFAP, which is later also detectable in serum [40].”
Mitchener, V. F. T., Thackray, M. J., & Arancibia‐Cárcamo, I. L. (2025) · The Journal of Physiology · doi:10.1113/jp287015 · Cited by 8
“A hallmark of AD is reactive astrocytes, observed early in disease (Fontana et al., 2023); interestingly reactive astrocytes are said to antigenically resemble immature astrocytes observed in development (Wilhelmsson et al., 2006).”
Benkovic, S. A., O'Callaghan, J. P., & Miller, D. B. (2009) · NeuroToxicology · doi:10.1016/j.neuro.2009.07.005 · Cited by 6
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“14-16 However, immunofluorescent labeling has several practical disadvantages, such as different tissue processing techniques, need for specific equipment and bleaching.”
BackgroundThe Role of Astrocytes in the Pathophysiology of Schizophrenia.
Steffek, A. E. (2007) · Deep Blue (University of Michigan) · Cited by 6
Pekny, M., Porritt, M. J., de Pablo, Y., Pekna, M., & Wilhelmsson, U. (2012) · Neuromethods · doi:10.1007/978-1-62703-266-7_13 · Cited by 6
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“Within chronic SCI, astrocytes proliferated, promoted inhibitory chondroitin sulfate proteoglycan production, and enhanced the formation of astroglia scars which could inhibit axon regrowth [19, 20].”
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Dwamena, A., Asadi, Y., Gilstrap, E., & Wang, H. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.11.13.623442 · Cited by 6
Zhou, N., Fan, Z., Tong, Y., Xiao, X., Xie, Y., Qi, Z., & Chen, L. (2023) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12913 · Cited by 5
“Variable increases in GFAP expression along with cell body and process hypertrophy have been observed in the hippocampus in epilepsy [7, 8].”
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“Reactive astrogliosis, exemplified by an upregulation of Gfap, can also be seen [179] and an increased understanding of astrocytes has highlighted their integral role in maintaining homeostatic functions within the CNS [180-184].”
BackgroundInflammation: Role in Parkinson's Disease and Target for Therapy
Flood, P. M., Arbabzada, N., & Sharma, M. (2016) · InTech eBooks · doi:10.5772/63164 · Cited by 5
“GFAP is an intermediate filament needed by astrocytes to synthesize cytoskeletal structures and is a well‐established biomarker for astrocytosis [8].”
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de Fraga, L. S., Tassinari, I. D., Jantsch, J., Guedes, R. P., & Bambini-Júnior, V. (2021) · Clinical & Experimental Immunology · doi:10.1111/cei.13669 · Cited by 5
“It has already been demonstrated that despite the various structural modifications, even when reactive, astrocytes did not present alterations in the total area occupied [84] or in the cellular division process of mature astrocytes, except for a specific subpopulation of these reactive astrocytes identified by the GFA…”
BackgroundExtracellular Vesicles Derived from Young Neural Cultures Attenuate Astrocytic Reactivity In Vitro
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“The two main hallmarks of astrocytic reactivity are cell hypertrophy and overexpression of the glial fibrillary acidic protein (GFAP) [23,24].”
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Mechanisms of Focal Epileptogenesis
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Astrocyte alterations in α-synucleinopathies
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Astrocyte cell volume dynamics across cortical states and transitions
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“88,89 Each protoplasmic astrocyte extends processes to ensheathe synapses (perisynaptic processes), 90 contact blood vessels (forming a specialized structure called a perivascular endfoot), and sometimes the pial surface (subpial endfeet, collectively forming the glia limitans ).”
Verkhratsky, A., & Butt, A. M. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-821565-4.00009-2 · Cited by 5
Augustin, E., Vinasco‐Sandoval, T., Riquelme‐Perez, M., Plassard, D., Gaudin, M., Aurégan, G., Mitja, J., Bernier, S., Joséphine, C., Petit, F., et al. (2025) · Glia · doi:10.1002/glia.70019 · Cited by 4
“There is some evidence of plasticity of perivascular astrocytes in vivo (Bardehle et al. 2013) or in neurotrauma, stroke, or neurodegeneration with hypertrophy of reactive astrocytes (Wilhelmsson et al. 2006).”
Comparative Anatomy of Glial Cells in Mammals
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Astrocytes réactifs et maladies cérébrales
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Blocking interleukin-1 signalling in the brain - structural and functional outcomes
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Nguyen, W., Gyawali, N., Stewart, R., Tang, B., Cox, A. L., Yan, K., Larcher, T., Bishop, C., Wood, N., Devine, G. J., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.04.26.538504 · Cited by 4
“Reactive astrocytes are characterized by the upregulated expression 425 of glial fibrillary acidic protein (GFAP) and the growth/extension of cellular processes (48).”
BackgroundAstrocytic G Protein-Coupled Receptors in Drug Addiction
Zinsmaier, A. K., Nestler, E. J., & Dong, Y. (2024) · Engineering · doi:10.1016/j.eng.2024.12.016 · Cited by 3
“%) with the territory of neighboring astrocytes [70–72], resulting in a highly complex, tiling arrangement in which astrocyte processes extend and cover the entire CNS while minimizing overlap [73].”
Identification of disulfidptosis-related genes and subgroups in spinal cord injury
Ye, T., Wang, S., Li, X., Jin, L., Liu, C., Jiao, K., Li, X., Cheng, Y., Xu, K., Zhou, X., et al. (2025) · Spinal Cord · doi:10.1038/s41393-025-01081-1 · Cited by 3
“However, astrocytes eventually form glial scars, which hinder axonal regeneration and neural repair [7].”
Moderating effects of plasma glial fibrillary acidic protein along the Alzheimer's disease continuum
Lee, S. Y., Diaz, V. E., Emanuel, O. M., Matusz, E. F., Webb, J. D., Chan, B., Lago, A. L., Wang, W., DeSimone, J. C., Rojas, J. C., et al. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70626 · Cited by 4
Metadata
- 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
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-11-14
- Volume
- 103
- Issue
- 46
- Pages
- 17513-17518
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1859960
- 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
- green
- www.ncbi.nlm.nih.gov
- 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 › Clinical 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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