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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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Pathologic Potential of Astrocytic Vesicle Traffic: New Targets to Treat Neurologic Diseases?
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Astrocytes: From the Physiology to the Disease
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BackgroundLuijerink, L., Rodriguez, M. L., & Machaalani, R. (2023) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2023.110025 · Cited by 29
Bandara, E. M. S., Asih, P. R., Pedrini, S., Hone, E., Fernando, W. M. A. D. B., & Martins, R. N. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-05219-3 · Cited by 37
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Bharne, A. P., Upadhya, M. A., Shelkar, G. P., Singru, P. S., Subhedar, N. K., & Kokare, D. M. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.10.028 · Cited by 29
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BackgroundWang, Y., Liu, Y., Nham, A., Sherbaf, A., Quach, D., Yahya, E., Ranburger, D., Bi, X., & Baudry, M. (2020) · Science Advances · doi:10.1126/sciadv.aba5547 · Cited by 29
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Rapamycin Attenuates Acute Seizure-induced Astrocyte Injury in Mice in Vivo
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Microglial and Astrocytic Responses in the Human Midcingulate Cortex in Huntington's Disease
Palpagama, T. H., Mills, A., Ferguson, M. W., Anekal, P. V., Turner, C. P., Tippett, L. J., van der Werf, B., Waldvogel, H. J., Faull, R. L. M., & Kwakowsky, A. (2023) · Annals of Neurology · doi:10.1002/ana.26753 · Cited by 29
“18,19 The middle cingulate cortex (MCC) is a brain area that presents extensive connectivity to regions associated with motor and cognitive functioning.”
BackgroundLiu, L., Su, Y., Yang, W., Xiao, M., Gao, J., & Hu, G. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2010.05.028 · Cited by 28
Using biomaterials to promote pro-regenerative glial phenotypes after nervous system injuries
Thompson, R., & Sakiyama‐Elbert, S. E. (2017) · Biomedical Materials · doi:10.1088/1748-605x/aa9e23 · Cited by 28
“In contrast to this, filling studies performed on resting and reactive protoplasmic astrocytes show that reactive protoplasmic astrocytes exhibit some process hypertrophy, but they do not have increased overlap between adjacent astrocytes [33].”
ResultImmunolocalization of muscarinic M1 receptor in the rat medial prefrontal cortex
Oda, S., Tsuneoka, Y., Yoshida, S., Adachi‐Akahane, S., Ito, M., Kuroda, M., & Funato, H. (2018) · Journal of Comparative Neurology · doi:10.1002/cne.24409 · Cited by 27
“Interestingly, each domain only slightly overlaps with other domains (Wilhelmsson et al., 2006).”
BackgroundMechanobiological Modulation of In Vitro Astrocyte Reactivity Using Variable Gel Stiffness
Benincasa, J. C., Madias, M. I., Kandell, R. M., Delgado‐García, L. M., Engler, A. J., Kwon, E. J., & Porcionatto, M. A. (2024) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.4c00229 · Cited by 26
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Musashi1 as a marker of reactive astrocytes after transient focal brain ischemia
Oki, K., Kaneko, N., Kanki, H., Imai, T., Suzuki, N., Sawamoto, K., & Okano, H. (2009) · Neuroscience Research · doi:10.1016/j.neures.2009.12.013 · Cited by 27
“Among them, astrocytes react to brain injury by undergoing hypertrophy of their somata and processes (Wilhelmsson et al., 2006), increased synthesis of glial-fibrillary acidic protein (GFAP), or the re-expression of proteins, such as Vimentin and Nestin, that are markers for progenitor cells…”
BackgroundMême, S., Calas, A.-G., Montécot, C., Richard, O., Gautier, H. O. B., Gefflaut, T., Doan, B., Même, W., Pichon, J., & Belœil, J. (2009) · Toxicological Sciences · doi:10.1093/toxsci/kfp174 · Cited by 27
“Reactive astrocytes are characterized by a high-level expression of glial fibrillary acidic protein (GFAP) (Wilhelmsson et al., 2006).”
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“The GFAP-positive astrocytes displayed highly reactive morphologies (Figure 4b,c), with abundant cytoplasm and processes (Pekny et al., 2014; Wilhelmsson et al., 2006) at 3 and 7 days after TBI in both the WT and Grn KO groups, then transformed into having a less reactive appearance (Figure 4d) in…”
BackgroundNguyen, W., Gyawali, N., Stewart, R., Tang, B., Cox, A. L., Yan, K., Larcher, T., Bishop, C., Wood, N., Devine, G. J., et al. (2024) · npj Viruses · doi:10.1038/s44298-024-00025-5 · Cited by 27
“Reactive astrocytes are characterized by the upregulated expression of glial fi brillary acidic protein (GFAP) and the growth/extension of cellular processes 53 .”
Lim, H.-W., Park, J.-I., More, S. V., Park, J., Kim, B.-W., Jeon, S., Yun, Y.-S., Park, E., Yoon, S., & Choi, D. (2015) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2015.01.004 · Cited by 27
Astrocyte precursor response to embryonic brain injury
Domowicz, M. S., Henry, J. G., Wadlington, N. L., Navarro, A., Kraig, R. P., & Schwartz, N. B. (2011) · Brain Research · doi:10.1016/j.brainres.2011.03.006 · Cited by 26
“The GFAP-positive cells in the injured side exhibited radial glial morphology, while astrocytes with reactive/hypertrophic morphology (Wilhelmsson et al., 2006) were identified in areas where pyknotic nuclei were observed (Fig 8C and D).”
BackgroundGFAPδ immunostaining improves visualization of normal and pathologic astrocytic heterogeneity
Andreiuolo, F. D. M., Junier, M., Hol, E. M., Miquel, C., Chimelli, L. M. C., Léonard, N., Chneiweiss, H., Daumas‐Duport, C., & Varlet, P. (2008) · Neuropathology · doi:10.1111/j.1440-1789.2008.00936.x · Cited by 27
“This pattern of immunostaining likely reflects a lower density of the gliofilament network in the distal processes.(29) Interestingly this is not the case with piloid gliosis, where the robust GFAPd and vimentin label-”
BackgroundAltered structure and function of astrocytes following status epilepticus
Wilcox, K. S., Gee, J. M., Gibbons, M. B., Tvrdík, P., & White, J. A. (2015) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2015.05.002 · Cited by 29
“Reactive astrogliosis is characterized by hypertrophy of primary processes, a dramatic increase in the expression of intermediate filament proteins such as glial fibrillary acidic protein (GFAP), a decrease in expression of glutamine synthetase [8–10] and, in some cases, a disruption in domain organization [11].”
BackgroundAstrocyte-mediated metaplasticity in the hippocampus: Help or hindrance?
Jones, O. D. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.08.035 · Cited by 30
Studying neurons and glia non-invasively via anomalous subdiffusion of intracellular metabolites
Ingo, C., Brink, W. M., Ercan, E., WEBB, A. G., & Ronen, I. (2018) · Brain Structure and Function · doi:10.1007/s00429-018-1719-9 · Cited by 27
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Villarreal, A., & Vogel, T. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22136867 · Cited by 27
“Acidic Protein (GFAP), several features of the phenotype are shared between different insults, including hypertrophy and overlapping of astrocyte 3D domains [31].”
BackgroundEbrahim, H. A., El‐Gamal, R., & Sherif, R. (2021) · Cells Tissues Organs · doi:10.1159/000519088 · Cited by 28
“Morphological changes with a considerable increase in the number and extent of astrocyte processes are associated with the upregulation of GFAP expression displayed in the quantitative morphological analysis [Wilhelmsson et al., 2006].”
BackgroundBaer, M. L., Henderson, S. C., & Colello, R. J. (2015) · PLoS ONE · doi:10.1371/journal.pone.0142740 · Cited by 26
“Following an injury, astrocytes in non-regenerating animals characteristically up-regulate the expression of the intermediate filament GFAP, relative to the intermediate filaments vimentin and nestin, while astrocytes in regenerating animals do not undergo this hypertrophic change [4,5,7,10,13,16].”
BackgroundAstrocytes: inexplicable cells in neurodegeneration
Singh, S., & Joshi, N. (2016) · International Journal of Neuroscience · doi:10.3109/00207454.2016.1173692 · Cited by 26
“Reactive astrogliosis is not only a marker of neuropathological conditions, but plays an essential role in coordinating the pathological responses as well as in regulating inflammation and repair in the brain [32,33].”
BackgroundGlial Patchwork: Oligodendrocyte Progenitor Cells and Astrocytes Blanket the Central Nervous System
Barber, H. M., Ali, M., & Kucenas, S. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.803057 · Cited by 20
“Astrocyte Networks Under physiological conditions, there is a small amount of overlap between astrocytic domains, somewhere between 2 and 5% (Ogata and Kosaka, 2002; Wilhelmsson et al., 2006).”
BackgroundRetinal astrocyte morphology predicts integration of vascular and neuronal architecture
Holden, J. M., Wareham, L. K., & Calkins, D. J. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1244679 · Cited by 27
“Morphological changes, such as overall cytoskeletal hypertrophy, are largely assessed as a population, rather than for individual cells and their microstructures (Chen et al., 1993; Wilhelmsson et al., 2006).”
BackgroundRegulation and dysregulation of astrocyte activation and implications in tumor formation
Yang, C.-Z., Rahimpour, S., Yu, A., Lonser, R., & Zhuang, Z. (2013) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-013-1274-8 · Cited by 32
“Minimal astrocytic activation does not interfere with the established astrocytic territories or their metabolic functions, physiologic functions of astrocytes can be largely preserved during activation after mild injury [21].”
BackgroundSasaki, K., Fujita, H., Sato, T. K., Kato, S., Takahashi, Y., Takeshita, Y., Kanda, T., Saito, T., Saido, T., Hattori, S., et al. (2024) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2024.151016 · Cited by 25
Soung, A., Davé, V. A., Garber, C., Tycksen, E., Vollmer, L. L., & Klein, R. S. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.10.010 · Cited by 22
“Instead, astrocytes remain in their tileddomain and become hypertrophic (Wilhelmsson, 2006).”
Neuroprotection Induced by Transplanted CDK5 Knockdown Astrocytes in Global Cerebral Ischemic Rats
Becerra-Calixto, A., & Cardona‐Gómez, G. P. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-0162-2 · Cited by 25
Singh, K., Trivedi, R., Verma, A. M., D'Souza, M. M., Koundal, S., Rana, P., Baishya, B., & Khushu, S. (2017) · NMR in Biomedicine · doi:10.1002/nbm.3764 · Cited by 23
“Recent studies on graded insult to the brain have shown different patterns and manifestations of gliosis.(45,46) A milder form of injury may lead to reversible changes in astrocyte level and domains; however, severe injury may lead to irreversible changes in astrocytes, which may also affect glutamine synthesis activi…”
BackgroundSantos‐Galdiano, M., Pérez‐Rodríguez, D., Soto, B. A., Font-Belmonte, E., Ugidos, I. F., Pérez-García, C. C., & Fernández‐López, A. (2018) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.118.251264 · Cited by 23
“Thus, glial fibrillary acidic protein (GFAP) and astrocyte swelling have been reported to increase after stroke (Wilhelmsson et al., 2006; Barreto et al., 2011).”
BackgroundModern approaches to investigating non‐neuronal aspects of Alzheimer's disease
Liddelow, S. A. (2019) · The FASEB Journal · doi:10.1096/fj.201802592 · Cited by 26
On astrocyte-neuron interactions: broad insights from the striatum
Khakh, B. S. (2025) · Neuron · doi:10.1016/j.neuron.2025.08.009 · Cited by 23
Imaging the microanatomy of astrocyte–T-cell interactions in immune-mediated inflammation
Barcia, C., Mitxitorena, I., Sauvage, M.-A. C.-D., Gallego, J. M., Pérez‐Vallés, A., & Barcia, C. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00058 · Cited by 23
“…allows a fine and detailed analysis of the entire astrocytic cell is the dye-filling method, which has the advantage of inoculating specific dyes within fixed brain tissue after extraction and fixation (Wilhelmsson et al., 2006); thus, this technique can be used in fixed tissue from human biopsies.”
Astrocytes in the Optic Nerve Are Heterogeneous in Their Reactivity to Glaucomatous Injury
Zhu, Y., Wang, R., Pappas, A. C., Seifert, P. A., Savol, A. J., Sadreyev, R. I., Sun, D., & Jakobs, T. (2023) · Cells · doi:10.3390/cells12172131 · Cited by 23
“In contrast to protoplasmic astrocytes in the grey matter of the CNS, which occupy spatially separated domains [80,81], the astrocytes in the optic nerve head often span the whole diameter of the nerve and their processes overlap considerably forming the sieve-like meshwork of the glial lamina [8].”
BackgroundSelf-supporting carbon nanotube films as flexible neural interfaces
Krukiewicz, K., Janas, D. W., Vallejo‐Giraldo, C., & Biggs, M. J. P. (2018) · Electrochimica Acta · doi:10.1016/j.electacta.2018.10.157 · Cited by 23
“This difference was significant as an increased cell area is characteristic of astrocyte activation, as seen with reactive gliosis and other neuropathologies [83].”
BackgroundDifferent expression patterns of Phactr family members in normal and injured mouse brain
Kim, J. Y., Choi, S. Y., Moon, Y., Kim, H. J., Chin, J. H., Kim, H., & Sun, W. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2012.06.059 · Cited by 23
Watanabe, H., Murakami, R., Tsumagari, K., Morimoto, S., Hashimoto, T., Imaizumi, K., Sonn, I., Yamada, K., Saito, Y., Murayama, S., et al. (2023) · Stem Cell Reports · doi:10.1016/j.stemcr.2023.08.002 · Cited by 24
“APOE3/3 and APOE4/4 iPSC-derived astrocytes (iPasts) were successfully differentiated from their respective iPSCs, but their soma size was significantly enlarged in APOE4/4 iPasts compared with APOE3/3 iPasts (Figure 1B), suggesting a subtle reactive state of APOE4/4 astrocytes (Wilhelmsson et al., 2006).”
The Diverse Roles of Reactive Astrocytes in the Pathogenesis of Amyotrophic Lateral Sclerosis
Yang, K., Liu, Y., & Zhang, M. (2024) · Brain Sciences · doi:10.3390/brainsci14020158 · Cited by 29
“This can be observed in tissue regions distant from focal lesions resulting from stroke, trauma, autoimmune attack, neurodegenerative changes, or diffuse neuroinflammation induced by peripheral exposure to microbial antigens such as lipopolysaccharide (LPS) [27–30].”
BackgroundInvolvement of the molecular chaperone Hspa5 in copper homeostasis in astrocytes
Qian, Y., Zheng, Y., Taylor, R., & Tiffany‐Castiglioni, E. (2012) · Brain Research · doi:10.1016/j.brainres.2012.01.065 · Cited by 22
Ando, T., Sato, S., Toyooka, T., Kobayashi, H., Nawashiro, H., Ashida, H., & Obara, M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0051744 · Cited by 22
“On the other hand, they also show morphological modifications involving hyperplasia and hypertrophy [11,13] and express various kinds of molecules associated with growth inhibitory properties [14–16].”
BackgroundRamadan, W. S., Abdel-Hamid, G. A., Alkarim, S., & Abbas, A. T. (2017) · Folia Histochemica et Cytobiologica · doi:10.5603/fhc.a2017.0001 · Cited by 22
“In accordance with these findings, previous studies have found that after SCI astrocytes, the most abundant glial cells in the CNS, transform into reactive astrocytes and undergo dramatic morphological changes [23].”
ResultAbsence of the neurogenesis-dependent nuclear receptor TLX induces inflammation in the hippocampus
Kozareva, D. A., Hueston, C. M., Ó’Léime, C. S., Crotty, S., Dockery, P., Cryan, J. F., & Nolan, Y. M. (2017) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2017.08.008 · Cited by 22
Primary astrocytes as a cellular depot of polystyrene nanoparticles
Adamiak, K., Sidoryk‐Wȩgrzynowicz, M., Dąbrowska‐Bouta, B., Sułkowski, G., & Strużyńska, L. (2025) · Scientific Reports · doi:10.1038/s41598-025-91248-w · Cited by 22
The Effects of Modified Curcumin Preparations on Glial Morphology in Aging and Neuroinflammation
Ullah, F., Gamage, R. V., Sen, M. K., & Gyengési, E. (2022) · Neurochemical Research · doi:10.1007/s11064-021-03499-4 · Cited by 21
Principles of Astrogliopathology
Verkhratsky, A., Li, B., Scuderi, C., & Parpura, V. (2021) · Advances in Neurobiology · doi:10.1007/978-3-030-77375-5_3 · Cited by 21
“In isomorphic astrogliosis, astrocytes become hypertrophic; however, they do not move and do not proliferate and the reach of their individual territorial domains remains unchanged (Escartin et al. 2021; Wilhelmsson et al. 2006).”
BackgroundWatanabe, S., Omran, A. J. A., Shao, A. S., Chen, X., Zhang, Z., Zhang, J., Davies, D. L., Shao, X. M., Watanabe, J., & Liang, J. (2022) · Scientific Reports · doi:10.1038/s41598-022-09814-5 · Cited by 23
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Simulated blast overpressure induces specific astrocyte injury in an ex vivo brain slice model
Canchi, S., Sarntinoranont, M., Hong, Y., Flint, J. J., Subhash, G., & King, M. A. (2017) · PLoS ONE · doi:10.1371/journal.pone.0175396 · Cited by 21
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Alzheimer’s Disease, Sleep Disordered Breathing, and Microglia: Puzzling out a Common Link
Ulland, T. K., Ewald, A. C., Knutson, A. O., Marino, K. M., Smith, S. M. C., & Watters, J. J. (2021) · Cells · doi:10.3390/cells10112907 · Cited by 21
Mao, X., Zhang, D., Tao, T., Liu, X., Sun, X., Wang, Y., & Shen, A. (2015) · Experimental Cell Research · doi:10.1016/j.yexcr.2015.11.007 · Cited by 21
Jiang, N., Cupolillo, D., Grosjean, N., Muller, E., Deforges, S., Mulle, C., & Amédée, T. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105345 · Cited by 17
“While, astrocytes showed elongated bodies with long and fine processes in WT mice, they showed rounded cell bodies with shortened and enlarged processes, a morphological hallmark of activated astrocytes (Wilhelmsson et al., 2006; for review see Schiweck et al., 2018) in APP/PS1 mice (Fig.”
BackgroundYeh, C., Wu, K., Huang, G., & Verkhratsky, A. (2023) · Acta Physiologica · doi:10.1111/apha.13967 · Cited by 20
Lu, L., Armstrong, E. A., Yager, J. Y., & Unsworth, L. D. (2019) · Advanced Healthcare Materials · doi:10.1002/adhm.201900083 · Cited by 20
Kim, S. J., Ryu, M. J., Han, J., Jang, Y., Lee, M. J., Ju, X., Ryu, I., Lee, Y. L., Oh, E., Chung, W., et al. (2019) · Laboratory Investigation · doi:10.1038/s41374-019-0254-5 · Cited by 20
Hara, T., Umaru, B. A., Sharifi, K., Yoshikawa, T., Owada, Y., & Kagawa, Y. (2020) · ACTA HISTOCHEMICA ET CYTOCHEMICA · doi:10.1267/ahc.20001 · Cited by 20
Visualizing Astrocyte Morphology Using Lucifer Yellow Iontophoresis
Moye, S. L., Castro, B. D., Gangwani, M. R., & Khakh, B. S. (2019) · Journal of Visualized Experiments · doi:10.3791/60225 · Cited by 21
Guo, Y., Liu, S., Wang, P., Zhang, H., Wang, F., Bing, L., Gao, J., Yang, J., & Hao, A. (2014) · Journal of Neuroscience Research · doi:10.1002/jnr.23362 · Cited by 19
“This initial injury instigates a progressive cascade of secondary injury, which exacerbates the spinal cord injury (Crowe et al., 1997; Horner et al., 2000; Guest et al., 2005; Wilhelmsson et al., 2006).”
BackgroundMoser, V. A., Christensen, A., Liu, J., Zhou, A. G., Yagi, S., Beam, C. R., Galea, L. A. M., & Pike, C. J. (2018) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2018.09.016 · Cited by 20
“50i (National Institutes of Health, Rockville, MD, USA) with the cell counter plugin to mark cells as having either a resting or a reactive morphological phenotype, as previously described (Moser and Pike, 2017; Wilhelmsson et al., 2006).”
MethodAbsence of BBSome function leads to astrocyte reactivity in the brain
Singh, M., Garrison, J. E., Wang, K., & Sheffield, V. C. (2019) · Molecular Brain · doi:10.1186/s13041-019-0466-z · Cited by 20
Astrocytes: Initiators of and Responders to Inflammation
Soung, A., & Klein, R. S. (2020) · IntechOpen eBooks · doi:10.5772/intechopen.89760 · Cited by 19
“Instead, astrocytes remain in their tileddomains and become hypertrophic [54, 55].”
BackgroundGlycan-Functionalized Collagen Hydrogels Modulate the Glycoenvironment of a Neuronal Primary Culture
Rebelo, A. L., Bizeau, J., Russo, L., & Pandit, A. S. (2020) · Biomacromolecules · doi:10.1021/acs.biomac.0c00387 · Cited by 19
Roles of Piezo1 in chronic inflammatory diseases and prospects for drug treatment (Review)
Yang, J. H., Xu, C.-M., Xie, X., Wang, J., & Shi, P. (2025) · Molecular Medicine Reports · doi:10.3892/mmr.2025.13565 · Cited by 19
“…cell type in the brain, exhibit a ‘reactive’ phenotype with increased intermediate fila‑ ment expression in response to amyloid plaque deposition (63). in the brains of ad patients, glial cells are the most abundant type of glial cell in the brain and astrocytes are more reactive and release…”
Xu, C., Li, M., LiZhao, Chen, W.-G., & Wang, J. (2021) · Aging · doi:10.18632/aging.203607 · Cited by 18
“Moreover, the IF staining results in Figure 4G also demonstrated hypertrophic astrocytes [31] and hypertrophic microglia [32] delineated by red boxes at day 21 compared to chow diet groups.”
BackgroundAbdel‐Aal, R. A., Hussein, O. A., Elsaady, R. G., & Abdelzaher, L. A. (2021) · Journal of Medical and Life Science · doi:10.21608/jmals.2021.210630 · Cited by 17
“limiting Aβ plaques build-up [121,122] through the expression of type III intermediate filament (IF) protein; GFAP (a marker for astrogliosis) [123,124].”
BackgroundAdenosinergic Signaling as a Key Modulator of the Glioma Microenvironment and Reactive Astrocytes
Debom, G. N., Rubenich, D. S., & Braganhol, E. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.648476 · Cited by 20
Eide, P. K. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.981399 · Cited by 18
“Furthermore, astrocytic glial cells were examined for the presence of astrogliosis, astrocyte hypertrophy and loss of astrocyte domains (Wilhelmsson et al., 2006; Oberheim et al., 2012).”
BackgroundInfluenza vaccine is able to prevent neuroinflammation triggered by H7N7 IAV infection
Demuth, L., Ohm, M., Michaelsen‐Preusse, K., Schulze, K., Riese, P., Guzmán, C. A., Körte, M., & Hosseini, S. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1142639 · Cited by 17
“Previously, it was shown that reactive astrocytes exhibit a striking increase in GFAP immunoreactivity (astrogliosis) (Wilhelmsson et al., 2006).”
BackgroundRueda-Gensini, L., Serna, J. A., Rubio, D., Orozco, J. C., Bolaños, N. I., Cruz, J. C., & Muñoz-Camargo, C. (2023) · Biofabrication · doi:10.1088/1758-5090/ace21b · Cited by 20
“This is shown by the increased expression of the proinflammatory markers CCR7 and GFAP in differentiated THP-1 monocytes and NHA, respectively [77, 84, 85].”
BackgroundUtilizing human cerebral organoids to model breast cancer brain metastasis in culture
Wang, C., Nagayach, A., Patel, H., Dao, L., Zhu, H., Wasylishen, A. R., Fan, Y., Kendler, A., & Guo, Z. (2024) · Breast Cancer Research · doi:10.1186/s13058-024-01865-y · Cited by 20
“The astrocytes are hijacked by brain tumor cells to reactive with proliferation, hypertrophy, and enhanced expression of GFAP [52, 53].”
BackgroundDragić, M., Kontić, M. Z., Mitrović, N., Nedeljković, N., & Grković, I. (2019) · Neuroscience · doi:10.1016/j.neuroscience.2019.10.022 · Cited by 19
The role of neuroglial cells communication in ischemic stroke
Yu, Y., Liao, X., Xie, X., Qihua, L., Chen, X., & Liu, R. (2024) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2024.110910 · Cited by 20
“Therefore, the role of astrocytes in cell communication should not be underestimated.”
BackgroundAstrocyte Mitochondria in White-Matter Injury
Nguyen, H., Zerimech, S., & Baltan, S. (2021) · Neurochemical Research · doi:10.1007/s11064-021-03239-8 · Cited by 18
Costantini, C., Lorenzetto, E., Cellini, B., Buffelli, M., Rossi, F., & Bianca, V. D. (2009) · Journal of Molecular Neuroscience · doi:10.1007/s12031-009-9305-5 · Cited by 18
“It should be taken into account that during senescence of our primary neuronal cultures, astrocytes acquire a phenotype consistent with that of reactive astrocytes (Wilhelmsson et al. 2006).”
BackgroundTiryaki, V. M., Ayres, V. M., Ahmed, I., & Shreiber, D. I. (2014) · Nanomedicine · doi:10.2217/nnm.14.33 · Cited by 17
Lack of CAR impacts neuronal function and cerebrovascular integrity in vivo
Boussadia, B., Gangarossa, G., Mselli-Lakhal, L., Rousset, M.-C., de Bock, F., Lassere, F., Ghosh, C., Pascussi, J., Janigro, D., & Marchi, N. (2016) · Experimental Neurology · doi:10.1016/j.expneurol.2016.05.018 · Cited by 17
“Quantification of total GFAP fluorescence indicated no significant changes between WT and CAR−/− mice (data not shown) (Wilhelmsson et al., 2006).”
BackgroundThe neurobiology of brain injury.
Pekna, M., & Pekny, M. (2012) · Europe PMC (PubMed Central) · Cited by 17
Reinehr, S., Reinhard, J., Wiemann, S., Hesse, K., Voss, C., Gandej, M., Dick, H. B., Faissner, A., & Joachim, S. C. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20102563 · Cited by 17
“It is known that in response to an injury in the central nervous system, astrocytes become reactive [25,26].”
BackgroundEnhanced wall shear stress prevents obstruction by astrocytes in ventricular catheters
Lee, S., Kwok, N., Holsapple, J. W., Heldt, T., & Bourouiba, L. (2020) · Journal of The Royal Society Interface · doi:10.1098/rsif.2019.0884 · Cited by 18
“Decrease of confluency and change in cell morphology upon long-term fluid shear stress Astrocytes in static culture exhibited a gradual increase of confluency andmaintained their star-shaped/stellate morphology that is the typical shape of physiological astrocytes; this stellate shape is commonly observed in both nonr…”
BackgroundChondroitin sulfate demarcates astrocytic territories in the mammalian cerebral cortex
Horii-Hayashi, N., Tatsumi, K., Matsusue, Y., Okuda, H., Okuda, A., Hayashi, M., Yano, H., Tsuboi, A., Nishi, M., Yoshikawa, M., et al. (2010) · Neuroscience Letters · doi:10.1016/j.neulet.2010.07.064 · Cited by 16
Chen, Y., Hunter, E., Arbabi, K., Guet-McCreight, A., Consens, M. E., Felsky, D., Sibille, E. L., & Tripathy, S. J. (2023) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2023.01.013 · Cited by 16
Applications and Considerations for Microfluidic Systems To Model the Blood–Brain Barrier
Floryanzia, S., & Nance, E. A. (2023) · ACS Applied Bio Materials · doi:10.1021/acsabm.3c00364 · Cited by 17
Blunted Respiratory Responses in the Streptozotocin-Induced Alzheimer’s Disease Rat Model
Ebel, D. L., Torkilsen, C. G., & Ostrowski, T. D. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-160974 · Cited by 16
Uccelli, N. A., Codagnone, M. G., Traetta, M. E., Levanovich, N., Rosato‐Siri, M. V., Urrutia, L., Falasco, G., Vázquez, S., Pasquini, J. M., & Reinés, A. G. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15444 · Cited by 17
“…when the morphological pattern of astrocytes and microglia is well known to correlate with their activation status (Fernández- Arjona et al., 2019; Wilhelmsson et al., 2006), further evaluation of their secretion profiles could provide new insights into the modulation of CC myelination in VPA…”
BackgroundIdentification and functional comparison of primary astrocytes and microglia.
Shi, J.-M., Liu, H., Cai, L., Guo, Y.-B., Ma, H., Li, Y.-S., Li, S.-D., Zhang, Z., Ma, Y., & Guo, C. (2022) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2022.109731 · Cited by 7
“Glia fibrillary acidic protein (GFAP) is commonly utilized as a specific marker for astrocytes (Wilhelmsson et al., 2006), whereas ionized calcium-binding adapter molecule1 (Iba1) is a widely employed microglia protein (Facci et al.”
Constantakis, J., Reed-McBain, C. A., & Famakin, B. M. (2022) · Neurochemistry International · doi:10.1016/j.neuint.2022.105456 · Cited by 15
Kontić, M. Z., Dragić, M., Martinović, J., Mihajlović, K., Brkic, Z., Mitrović, N., & Grković, I. (2023) · Pharmaceuticals · doi:10.3390/ph16030331 · Cited by 17
“Effect of 48-h ALP Treatment on GFAP Protein Expression In Vitro Since reactive astrocytes are characterized by high-level expression of glial fibrillary acidic protein (GFAP) [19], its protein expression was examined in primary astrocyte culture.”
BackgroundInfluentialAstrocytes in Spinal Cord Injury: Current Opportunities and Prospects for Directional Polarization
Bilalova, A., Tutova, O. N., Mukhamedshina, Y. O., & Rizvanov, A. A. (2024) · Frontiers in Bioscience-Landmark · doi:10.31083/j.fbl2903094 · Cited by 15
“In response to neurotrauma, neurodegeneration, or infection, astrocyte activation occurs, accompanied by changes in gene expression and consequent morphology and function of these cells [3,4].”
Blood biomarkers for clinical applications in Alzheimer's disease: A narrative review
Li, H., & Wang, Z. (2025) · NeuroMarkers. · doi:10.1016/j.neumar.2025.100078 · Cited by 16
Bačová, M., Bimbová, K., Fedorová, J., Lukáčová, N., & Gálik, J. (2018) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2018.10.020 · Cited by 15
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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