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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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“…overlap of astrocytes back-bones was observed, suggesting that the non-overlapping (tiled) astrocytic territories described previously in CA1 Rad (Bushong et al., 2002; Livet et al., 2007; Wilhelmsson et al., 2006) are maintained across the subfields of the hippocampus, along the dorsoventral axis.”
Astrocytosis in parkinsonism: considering tripartite striatal synapses in physiopathology?
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“Such result contradicts previous observations collected in the denervated hippocampal region and the electrically-injured cerebral cortex (Wilhelmsson et al., 2006) suggesting that despite the increased thickness of astrocytic cellular processes in those two areas, astrocytes did not occupy a greater volume of tissue…”
ResultWaknine-Grinberg, J. H., Even‐Chen, S., Avichzer, J., Turjeman, K., Bentura-Marciano, A., Haynes, R. K., Weiss, L., Allon, N., Ovadia, H., Golenser, J., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0072722 · Cited by 53
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“In the context of brain inflammation, or remote from focal lesions, astrocytes show mild to moderate responses characterized by hypertrophy of cell soma and processes and an upregulation of intermediary filaments, but preserved individual domains (Wilhelmsson et al. 2006).”
BackgroundAstrocyte structural reactivity and plasticity in models of retinal detachment
Luna, G., Keeley, P. W., Reese, B. E., Linberg, K. A., Lewis, G. P., & Fisher, S. K. (2016) · Experimental Eye Research · doi:10.1016/j.exer.2016.03.027 · Cited by 53
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Syncytial isopotentiality: A system‐wide electrical feature of astrocytic networks in the brain
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“Dye filling and 3D reconstruction techniques have demonstrated that hypertrophy in reactive astrocytes is confined to IF-rich processes while the overall astrocyte domain remains unchanged (Wilhelmsson et al., 2006).”
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White matter activated glial cells produce BDNF in a stroke model of monkeys
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“…regeneration through the expression of inflammatory cytokines (Popko et al., 1997; Popko and Baerwald, 1999), yet recent studies have indicated beneficial aspects of activated astrocytes (Bush et al., 1999; Faulkner et al., 2004; Okada et al., 2006; Wilhelmsson et al., 2006; Li et al., 2008).”
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“Whereas this can persist in mild-to-moderate astro-gliosis, 12,13 substantial intermingling of processes occurs during instances of severe astrogliosis.”
Region-Restrict Astrocytes Exhibit Heterogeneous Susceptibility to Neuronal Reprogramming
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Toy, D., & Namgung, U. (2013) · Experimental Neurobiology · doi:10.5607/en.2013.22.2.68 · Cited by 53
“In mild-to-moderate reactive astrogliosis, astrocytes occupy non-overlapping domains in a similar manner to non-injured tissue [48, 49].”
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In vivo spatiotemporal dynamics of astrocyte reactivity following neural electrode implantation
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“Keywords High-fat diet nNOS Astrocyte Microglia Hippocampus Sholl analysis”
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Impaired astrocytic Ca2+ signaling in awake-behaving Alzheimer’s disease transgenic mice
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“extent these small processes are altered in reactive astrogliosis is unknown, although the astrocytic territories are known to be preserved (Wilhelmsson et al., 2006).”
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Hasan‐Olive, M. M., Hansson, H., Enger, R., Nagelhus, E. A., & Eide, P. K. (2019) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlz063 · Cited by 46
Role of astrocytes in major neurological disorders: The evidence and implications
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ResultHeterogeneity of Notch signaling in astrocytes and the effects of GFAP and vimentin deficiency
Lebkuechner, I., Wilhelmsson, U., Möllerström, E., Pekna, M., & Pekny, M. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13213 · Cited by 45
“Unilateral entorhinal cortex lesion (ECL) was performed as previously described (Wilhelmsson et al. 2006; Pekny et al. 2013).”
MethodAstrocytic contributions to Huntington's disease pathophysiology
Khakh, B. S., & Goldman, S. A. (2023) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.14977 · Cited by 49
Structural plasticity in the dentate gyrus- revisiting a classic injury model
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“For example, during mild insults to the CNS, such as the immune reaction that follows a viral infection or as occurs in areas distant to a lesion site, astrocytes hypertrophy but remain tiled (Figure 2B; Wilhelmsson et al., 2006).”
BackgroundTopological analyses in APP/PS1 mice reveal that astrocytes do not migrate to amyloid-β plaques
Galea, E., Morrison, W., Hudry, E., Arbel‐Ornath, M., Bacskai, B. J., Gómez‐Isla, T., Stanley, E., & Hyman, B. T. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1516779112 · Cited by 45
“(8) observed an average domain diameter of 43.”
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Cholesterol Dysmetabolism in Alzheimer’s Disease: A Starring Role for Astrocytes?
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“Changes in astrocyte morphology are due to cytoskeletal reorganization; they range from soma and process hypertrophy to ramification or polarization of processes toward a lesion or glial scar formation [35,36].”
BackgroundLeukemia-derived exosomes and cytokines pave the way for entry into the brain
Kinjyo, I., Евгеньевич, Б. Д., Grattan, R. M., Winter, S. S., & Wilson, B. S. (2019) · Journal of Leukocyte Biology · doi:10.1002/jlb.3a0218-054r · Cited by 43
Semaphorin 4D is upregulated in neurons of diseased brains and triggers astrocyte reactivity
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“Similar cytoskeletal changes, together with significant changes in gene expression and function, are characteristic of reactive astrocytes [49, 50].”
BackgroundA role for ErbB signaling in the induction of reactive astrogliosis
Chen, J., He, W., Hu, X., Shen, Y., Cao, J., Wei, Z., Luan, Y., He, L., Jiang, F., & Tao, Y. (2017) · Cell Discovery · doi:10.1038/celldisc.2017.44 · Cited by 42
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“Despite the hypertrophy of GFAP-containing cellular processes, the interdigitation of adjacent reactive astrocytes in denervated hippocampus is minimal (73) (Fig.”
BackgroundRole of Astrocytes in Post-traumatic Epilepsy
Xu, S., Sun, Q., Fan, J., Jiang, Y., Yang, W., Cui, Y., Yu, Z., Jiang, H., & Li, B. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.01149 · Cited by 44
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“This finding was later replicated both in the hippocampus (Bushong et al., 2003, 2004; Livet et al., 2007; Ogata and Kosaka, 2002; Wilhelmsson et al., 2006; Xu et al., 2014) and in the cortex (Grosche et al.”
BackgroundMethodResultInfluentialStructural remodeling of gray matter astrocytes in the neonatal pig brain after hypoxia/ischemia
Sullivan, S. M., Bjorkman, S. T., Miller, S. M., Colditz, P. B., & Pow, D. V. (2009) · Glia · doi:10.1002/glia.20911 · Cited by 41
“In the mouse brain, astrocyte territories or domains typically overlap by 0.6–12.9% (Wilhelmsson et al., 2006).”
BackgroundInfluentialRegulatory T cells decrease C3-positive reactive astrocytes in Alzheimer-like pathology
Stym‐Popper, G., Matta, K., Chaigneau, T., Rupra, R., Demetriou, A., Fouquet, S., Dansokho, C., Toly‐Ndour, C., & Dorothée, G. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02702-3 · Cited by 45
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“Following an injury, reactive astrocytes increased in number and show altered morphology with hypertrophy of cellular processes [126, 127].”
BackgroundGibbons, M. B., Smeal, R. M., Takahashi, D. K., Vargas, J. R., & Wilcox, K. S. (2012) · Neurochemistry International · doi:10.1016/j.neuint.2012.12.008 · Cited by 40
“Wilhelmsson et al. (2006) dye filled astrocytes in the hippocampus following disruption of the perforant path from the entorhinal cortex.”
Li, G., Cao, Y., Shen, F., Wang, Y., Bai, L., Guo, W., Bi, Y., Lv, G., & Fan, Z. (2016) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2016.00241 · Cited by 40
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Essential Role of Astrocytes in Learning and Memory
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“They wrap around numerous synapses and can form networks through gap junctions, creating well-organized anatomical domains with minimal overlap between neighbouring cells [3–7].”
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Trivedi, R., Khan, A. R., Rana, P., Haridas, S., Kumar, B. S. H., Manda, K., Rathore, R. K. S., Tripathi, R. P., & Khushu, S. (2012) · Journal of Neuroscience Research · doi:10.1002/jnr.23073 · Cited by 43
“In mild-to-moderate reactive astrogliosis, there appears to be preservation of the individual nonoverlapping domains of reactive astrocytes in spite of the hypertrophy of the cell body and processes (Wilhelmsson et al., 2006).”
BackgroundEnvironmental cues determine the fate of astrocytes after spinal cord injury
Li, S., & Nathan, F. M. (2017) · Neural Regeneration Research · doi:10.4103/1673-5374.221144 · Cited by 39
“In response to injury, local naïve astrocytes (NAs) display sequential changes in phenotypes, initially as RAs and then as scar-forming astrocytes (SAs) (Bushong et al., 2002; Wilhelmsson et al., 2006).”
BackgroundUllah, F., Asgarov, R., Venigalla, M., Liang, H., Niedermayer, G., Münch, G. W., & Gyengési, E. (2020) · Scientific Reports · doi:10.1038/s41598-020-58838-2 · Cited by 41
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Astrocytes: The Stars in Neurodegeneration?
Dittlau, K. S., & Freude, K. (2024) · Biomolecules · doi:10.3390/biom14030289 · Cited by 39
“This notion is based on the observation that other astrocytes from different brain or spinal cord regions are unable to compensate in case of astrocyte domain loss in rodents [7,8].”
Wilhelmsson, U., Andersson, D., de Pablo, Y., Pekny, R., Ståhlberg, A., Mulder, J., Mitsios, N., Hortobágyi, T., Pekny, M., & Pekna, M. (2017) · Cerebral Cortex · doi:10.1093/cercor/bhx069 · Cited by 38
“Unilateral entorhinal cortex lesion was performed as described (Wilhelmsson et al. 2006; Pekny et al. 2013).”
MethodNeurotherapeutic capacity of P7C3 agents for the treatment of Traumatic Brain Injury
Blaya, M. O., Wasserman, J. M., Pieper, A. A., Sick, T. J., Bramlett, H. M., & Dietrich, W. D. (2018) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.09.024 · Cited by 39
Transcriptional and epigenetic mechanisms underlying astrocyte identity
Pavlou, M. A. S., Grandbarbe, L., Buckley, N. J., Niclou, S. P., & Michelucci, A. (2018) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2018.12.007 · Cited by 37
“Another distinctive attribute of reactive astrocytes reported by early neuropathologists was hypertrophy as evidenced by enlarged cell body and processes (Wilhelmsson et al., 2006).”
BackgroundUllah, F., Liang, H., Niedermayer, G., Münch, G. W., & Gyengési, E. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00170 · Cited by 39
Yang, R., Zhang, Y., Kang, J., Zhang, C., & Ning, B. (2024) · Aging and Disease · doi:10.14336/ad.2023.0512 · Cited by 38
“Non-proliferative RAs are located in spared but reactive neural tissue and interact with various cellular components, including neurons, synapses, and blood vessels [42].”
BackgroundLana, D., Ugolini, F., Nosi, D., Wenk, G. L., & Giovannini, M. G. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00296 · Cited by 39
“In moderate astrogliosis, astrocytes have hypertrophic bodies and processes (Wilhelmsson et al., 2006), are distributed in contiguous, non-overlapping domains (Bushong et al.”
BackgroundOh, J., Lee, J., Piao, C., Jeong, J. H., & Lee, M. (2019) · Biomaterials Science · doi:10.1039/c8bm01621f · Cited by 37
Glial Scar—a Promising Target for Improving Outcomes After CNS Injury
He, Y., Liu, X., & Chen, Z. (2019) · Journal of Molecular Neuroscience · doi:10.1007/s12031-019-01417-6 · Cited by 40
Amro, Z., Yool, A. J., & Collins‐Praino, L. E. (2021) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2021.100242 · Cited by 39
Notch1 and Galectin-3 Modulate Cortical Reactive Astrocyte Response After Brain Injury
Ribeiro, T. N., Delgado‐García, L. M., & Porcionatto, M. A. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.649854 · Cited by 37
“It was previously shown that reactive astrocytes from the cerebral cortex do not overlap domains, but rather show hypertrophy after electrical lesion (Wilhelmsson et al., 2006; Pekny et al., 2019).”
BackgroundFlavonoids and Astrocytes Crosstalking: Implications for Brain Development and Pathology
Nones, J., Stipursky, J., Costa, S., & Gomes, F. (2010) · Neurochemical Research · doi:10.1007/s11064-010-0144-0 · Cited by 37
“This evidence, together with the emerging characterization of gliotransmitters [47] and several neurotransmitter receptors in astrocytes, supports the argument that astrocytes are active partners of neurons, not only in synapse development but in function as well.”
ResultNeurogenesis in the enteric nervous system.
Metzger, M. (2010) · PubMed · Cited by 34
Makri, G., Lavdas, A. Α., Katsimpardi, L., Charneau, P., Thomaidou, D., & Matsas, R. (2009) · Stem Cells · doi:10.1002/stem.258 · Cited by 36
A central role for anterior cingulate cortex in the control of pathological aggression
van Heukelum, S., Tulva, K., Geers, F. E., van Dulm, S., Ruisch, I. H., Mill, J., Viana, J. F., Beckmann, C. F., Buitelaar, J. K., Poelmans, G., et al. (2021) · Current Biology · doi:10.1016/j.cub.2021.03.062 · Cited by 35
Morphological plasticity of rodent astroglia
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“Dye-filled astrocytes observed by optical imaging techniques and analyzed by 3D reconstruction programs show that the fine processes arise as lateral filopodium-like appendages to highly ramified branches of the stem processes (Wilhelmsson et al. 2006).”
BackgroundAstrocytic changes with aging and Alzheimer's disease‐type pathology in chimpanzees
Munger, E. L., Edler, M. K., Hopkins, W. D., Ely, J. J., ERWIN, J. M., Perl, D. P., Mufson, E. J., Hof, P. R., Sherwood, C. C., & Raghanti, M. A. (2018) · The Journal of Comparative Neurology · doi:10.1002/cne.24610 · Cited by 37
“…as a spectrum of molecular, cellular, and functional changes in astrocytes marked by upregulation of glial fibrillary acidic protein (GFAP), hypertrophy of the soma and cellular processes, and loss of domain organization (Pekny & Pekna, 2004; Sofroniew & Vinters, 2010; Wilhelmsson et al., 2006).”
BackgroundPhosphorylation of GFAP is Associated with Injury in the Neonatal Pig Hypoxic-Ischemic Brain
Sullivan, S. M., Sullivan, R., Miller, S. M., Ireland, Z., Bjorkman, S. T., Pow, D. V., & Colditz, P. B. (2012) · Neurochemical Research · doi:10.1007/s11064-012-0774-5 · Cited by 38
“4d) and did not exhibit the fine, bushy processes of a normal control astrocyte (see images contained within [6, 39]).”
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Rocamonde, B., Paradells, S., Barcia, J. M., Barcia, C., García‐Verdugo, J. M., Miranda, M., Gómez, F. J. R., & Soria, J. M. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2012.08.028 · Cited by 34
“In response to diverse brain injury astrocytes become hypertrophic; such astrocytes are also referred to as reactive and/or activated astrocytes (Bushong et al., 2004; Wilhelmsson et al., 2006; Chvatal et al., 2007).”
BackgroundXu, D., Omura, T., Masaki, N., Arima, H., Banno, T., Okamoto, A., Hanada, M., Takei, S., Matsushita, S., Sugiyama, E., et al. (2016) · Scientific Reports · doi:10.1038/srep26427 · Cited by 34
G-CSF promotes autophagy and reduces neural tissue damage after spinal cord injury in mice
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Deplete and repeat: microglial CSF1R inhibition and traumatic brain injury
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“In the current study, to further confirm the anti-n euroinflammation of 4b in vivo, we detected the expression of glial fibrillary acidic portein (GFAP ), a marker for activated astrocytes, using immunofluorescence [19].”
Kodidela, S., Gerth, K., Sinha, N., Kumar, A., Kumar, P., & Kumar, S. (2020) · Diagnostics · doi:10.3390/diagnostics10060349 · Cited by 30
“During neuroinflammation, when astrocytes are activated, they are characterized by an increase in size, number, and thickness of processes, as well as an increased level of GFAP expression [36].”
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Insertional effect following electrode implantation: an underreported but important phenomenon
Hamani, C., Davidson, B., Lipsman, N., Abrahão, A., Nestor, S. M., Rabin, J. S., Giacobbe, P., Pagano, R. L., & Campos, A. C. P. (2024) · Brain Communications · doi:10.1093/braincomms/fcae093 · Cited by 32
“19,20 Reactive astrocytes are characterized by hypertrophic so-mata and processes, 70 synthesize a higher than normal amount of glial-fibrillary acidic protein (GFAP) and express progenitor markers, such as vimentin, nestin and syne-min.”
BackgroundA Novel Method for Three-Dimensional Culture of Central Nervous System Neurons
Puschmann, T. B., de Pablo, Y., Zandén, C., Liu, J., & Pekny, M. (2013) · Tissue Engineering Part C Methods · doi:10.1089/ten.tec.2013.0445 · Cited by 31
“…reactive, a condition that is defined by increased cell proliferation and cell process hypertrophy, upregulation of stress proteins such as glial fibrillary acidic protein (GFAP), and release of various factors and cytokines, 9–11 which can be both supportive of and detrimental to neuronal survival.”
Asuni, A. A., Gray, B., Bailey, J., Skipp, P., Perry, V. H., & O'Connor, V. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.502690 · Cited by 31
“There is evidence showing that GFAP content is increased in astrocytes during reactive gliosis (37, 38) and also evidence astrocytes may proliferate in some disease states (39).”
BackgroundChen, Y., Chu, J. M. T., Wong, G. T. C., & Chang, R. C. (2024) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-024-10107-z · Cited by 32
“Astrocytic reactivity can also be induced by cytokines, aberrant proteins, or an imbalance in neurotrans-mitters and is initially characterized by hypertrophy and GFAP overexpression (Wilhelmsson et al. 2006; Ben Haim et al. 2015).”
Background
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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