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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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Reactive astrogliosis in stroke: Contributions of astrocytes to recovery of neurological function
Sims, N. R., & Yew, W. P. (2017) · Neurochemistry International · doi:10.1016/j.neuint.2016.12.016 · Cited by 149
“In mice lacking GFAP and vimentin expression, the astrocytes in the hippocampus show a more limited hypertrophy that is initially associated with a greater loss of synapses but leads to increased synaptogenesis that greatly exceeds that of wild-type mice (Wilhelmsson et al., 2006).”
Astrocytes Negatively Regulate Neurogenesis Through the Jagged1‐Mediated Notch Pathway
Wilhelmsson, U., Faiz, M., de Pablo, Y., Sjöqvist, M., Andersson, D., Widestrand, Å., Potokar, M., Stenovec, M., Smith, P. L. P., Shinjyo, N., et al. (2012) · STEM CELLS · doi:10.1002/stem.1196 · Cited by 145
Physiology of neuronal–glial networking
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“The protoplasmic astrocytes occupy their own territory and create the micro-anatomical domains within the limits of their processes; such a domain organisation exists in both rodents and humans (Bushong et al., 2002; Nedergaard et al., 2003; Oberheim et al., 2009; Wilhelmsson et al., 2006).”
BackgroundStructure and Functions of Aquaporin-4-Based Orthogonal Arrays of Particles
Wolburg, H., Wolburg‐Buchholz, K., Fallier‐Becker, P., Noell, S., & Mack, A. F. (2011) · International review of cytology · doi:10.1016/b978-0-12-386043-9.00001-3 · Cited by 137
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“by the marked upregulation of GFAP immunoreactivity along with hypertrophic astrocytes, which are events associated with CNS injury [39–41].”
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Reactive Astrogliosis: Implications in Spinal Cord Injury Progression and Therapy
Li, X., Li, M., Tian, L., Chen, J., Liu, R., & Ning, B. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/9494352 · Cited by 138
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Neurons control the expression of connexin 30 and connexin 43 in mouse cortical astrocytes
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“Indeed, the morphology and the molecular profile of proximal astrocytes located in the immediate vicinity of the injury, also called anisotropic astrocytes, differ strongly from those of distal astrocytes (isotropic astrocytes) located in a less disturbed environment, in which only moderate modifications were describe…”
BackgroundLacroix, A., Toussay, X., Anenberg, E., Lecrux, C., Ferreirós, N., Karagiannis, A., Plaisier, F., Chausson, P., Jarlier, F., Burgess, S. A., et al. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.0651-15.2015 · Cited by 141
“Consistent with a low level of GFAP in quiescent cortical astrocytes (Wilhelmsson et al., 2006; Houades et al., 2008), GFAP was detected in one-half of the astrocytes, whereas S100 was expressed in most astrocytes (98%, n 43 of 44 cells).”
BackgroundGastrodin Protects Apoptotic Dopaminergic Neurons in a Toxin-Induced Parkinson’s Disease Model
Kumar, H., Kim, I., More, S. V., Kim, B.-W., Bahk, Y.-Y., & Choi, D. (2013) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2013/514095 · Cited by 129
“Astrocytes respond to brain injury through a process termed “reactive gliosis,” in which GFAP regulates the microenvironment, increases neuron survival, and promotes regeneration of neurites and functional recovery of the nervous system [55, 56].”
The Role of Astrocytes in the Neurorepair Process
Chiareli, R. A., Carvalho, G. A., Marques, B. L., Mota, L. S., Oliveira‐Lima, O. C., Gomes, R. M., Birbrair, A., Gomez, R. S., Simão, F., Klempin, F., et al. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.665795 · Cited by 130
Targeting innate immunity for neurodegenerative disorders of the central nervous system
Andreasson, K. I., Bachstetter, A. D., Colonna, M., Ginhoux, F., Holmes, C., Lamb, B., Landreth, G., Lee, D. C., Low, D., Lynch, M. A., et al. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13667 · Cited by 126
Abnormal Reactivity of Müller Cells after Retinal Detachment in Mice Deficient in GFAP and Vimentin
Verardo, M. R., Lewis, G. P., Takeda, M., Linberg, K. A., Byun, J., Luna, G., Wilhelmsson, U., Pekny, M., Chen, D., & Fisher, S. K. (2008) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.07-1474 · Cited by 129
Structural Remodeling of Fibrous Astrocytes after Axonal Injury
Sun, D., Lye‐Barthel, M., Masland, R. H., & Jakobs, T. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.3605-10.2010 · Cited by 136
“7A) (Bushong et al., 2002; Ogata and Kosaka, 2002; Wilhelmsson et al., 2006).”
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Dysfunction of Optineurin in Amyotrophic Lateral Sclerosis and Glaucoma
Toth, R. P., & Atkin, J. D. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01017 · Cited by 114
“Astrocytes (71) are specialized glial cells that are highly abundant in the CNS and they possess a wide range of essential functions.”
BackgroundThe Time Course of Gene Expression during Reactive Gliosis in the Optic Nerve
Qu, J., & Jakobs, T. (2013) · PLoS ONE · doi:10.1371/journal.pone.0067094 · Cited by 116
“They lose their domain organization upon some injuries, but maintain it upon others [4,5].”
BackgroundTargeted Activation of Astrocytes: A Potential Neuroprotective Strategy
Escartin, C., & Bonvento, G. (2008) · Molecular Neurobiology · doi:10.1007/s12035-008-8043-y · Cited by 118
“This definition was recently refined by studies using dye-filling [23] or diolistic labeling [24] of reactive astrocytes and three-dimensional reconstruction of confocal images.”
BackgroundMethodThe glial perspective of autism spectrum disorders
Zeidán‐Chuliá, F., Salmina, A. B., Malinovskaya, N. A., Noda, M., Verkhratsky, A., & Moreira, J. C. F. (2013) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2013.11.008 · Cited by 116
“Reactive astrocytes are characterized by high-level expression f GFAP and by up-regulation of intermediate filaments in the ytoplasm (Wilhelmsson et al., 2006).”
Diffusion MRI and the detection of alterations following traumatic brain injury
Hutchinson, E. B., Schwerin, S. C., Avram, A., Juliano, S. L., & Pierpaoli, C. M. (2017) · Journal of Neuroscience Research · doi:10.1002/jnr.24065 · Cited by 113
“…or directional increased or decreased anisotropy, decreased diffusivity Norton et al., 1992; Sofroniew, 2005, 2009; Sofroniew & Vinters, 2010; Wilhelmsson et al., 2006; Suzuki et al., 2012; Sun & Jakobs, 2012; Pekny et al., 2014; Burda et al., 2016 Budde et al., 2011; Zhuo et al., 2012; Mac…”
BackgroundInfluentialVerkhratsky, A., Augusto‐Oliveira, M., Pivoriūnas, A., Popov, A., Brazhe, A., & Semyanov, A. V. (2020) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-020-02465-3 · Cited by 110
de Pablo, Y., Nilsson, M., Pekna, M., & Pekny, M. (2013) · Histochemistry and Cell Biology · doi:10.1007/s00418-013-1110-0 · Cited by 111
“…proteins glial fibrillary acidic protein (GFAP), vimentin, nestin, and synemin, increased cell proliferation, and release of molecules modulating inflammation and post-traumatic remodeling (Jing et al. 2007; Parpura et al. 2012; Pekny and Nilsson 2005; Sofroniew 2009; Wilhelmsson et al. 2006).”
Microglia-mediated synaptic pruning is impaired in sleep-deprived adolescent mice
Tuan, L., & Lee, L. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104517 · Cited by 107
Velasco‐Estevez, M., Mampay, M., Boutin, H., Chaney, A. M., Warn, P. A., Sharp, J., Burgess, E., Moeendarbary, E., Dev, K. K., & Sheridan, G. K. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00332 · Cited by 105
“, GFAP (Wilhelmsson et al., 2006; Sofroniew, 2009), and synthesis of proinflammatory cytokines (Buffo et al.”
BackgroundTransient Inflammation in Neurogenic Regions after Irradiation of the Developing Brain
Kalm, M., Fukuda, A., Fukuda, H., Öhrfelt, A., Lannering, B., Björk‐Eriksson, T., Blennow, K., Márky, I., & Blomgren, K. (2008) · Radiation Research · doi:10.1667/rr1269.1 · Cited by 102
Topper, L. A., Baculis, B. C., & Valenzuela, C. F. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0382-9 · Cited by 107
Bernal, G. M., & Peterson, D. A. (2011) · Aging Cell · doi:10.1111/j.1474-9726.2011.00694.x · Cited by 109
“…2011 The Authors Aging Cell ª 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland Aging Cell (2011) 10, pp466–482 Doi: 10.1111/j.1474-9726.2011.00694.x Ag in g Ce ll reactive hypertrophy (Wilhelmsson et al., 2006), have the potential to revert back to a nonreactive state.”
BackgroundInfluentialThompson, R. E., Pardieck, J., Smith, L. J., Kenny, P., Crawford, L., Shoichet, M. S., & Sakiyama‐Elbert, S. E. (2018) · Biomaterials · doi:10.1016/j.biomaterials.2018.02.013 · Cited by 106
“Injury to fibrous (white matter) astrocytes has been found to cause process hypertrophy and overlap reminiscent of the glial scar [12], while protoplasmic (grey matter) astrocytes exhibit minimal process overlap following injury [13].”
InfluentialDynamics of β‐adrenergic/cAMP signaling and morphological changes in cultured astrocytes
Vardjan, N., Kreft, M., & Zorec, R. (2014) · Glia · doi:10.1002/glia.22626 · Cited by 101
“In this state astrocytes, also termed reactive astrocytes, exhibit hypertrophic morphology with prominent processes (Wilhelmsson et al., 2006).”
BackgroundWierońska, J. M., Cieślik, P., & Kalinowski, L. (2021) · Biomolecules · doi:10.3390/biom11081097 · Cited by 105
“In response to pathological situations in surrounding tissue such as ischemic injury astrocytes undergo morphological, molecular and functional changes and become reactive astrocytes [54] The changes associated with the reactive state can directly impact synaptic transmission and neuronal circuit activity, thereby pot…”
BackgroundStress-Induced Depression and Alzheimer’s Disease: Focus on Astrocytes
Dolotov, O. V., Inozemtseva, L. S., Myasoedov, N. F., & Grivennikov, I. A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23094999 · Cited by 104
“Such astrocytes have an increased thickness of processes and begin to express nestin, which is a marker of nerve progenitor cells, and overexpress two other protein components of the astrocyte cytoskeleton, GFAP and vimentin [133].”
BackgroundYue, N., Li, B., Yang, L., Han, Q.-Q., Huang, H.-J., Wang, Y.-L., Wang, J., Yu, R., Wu, G.-C., Liu, Q., et al. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00149 · Cited by 100
Keller, A. F., Gravel, M., & Križ, J. (2010) · Experimental Neurology · doi:10.1016/j.expneurol.2010.12.010 · Cited by 103
“Because changes in GFAP levels reflect the state of astrocyte activation (Pekny and Nilsson, 2005;Wilhelmsson et al., 2006) we next analyzed the expression level of connexin43 (one of the measures of functional reactivity of astrocytes and a major component of gap junctions) (Kielian, 2008).”
BackgroundRana, A. K., & Singh, D. (2018) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.07.006 · Cited by 101
“The astrocytes far from the injured site also become hypertrophied but do not form bundles, andmaintain their original non overlapping domain as such (Wilhelmsson et al., 2006; Sun et al., 2013).”
Jinno, S., Fleischer, F., Eckel, S., Schmidt, V., & Kosaka, T. (2007) · Glia · doi:10.1002/glia.20552 · Cited by 98
“(Bushong et al., 2002; Ogata and Kosaka, 2002; Wilhelmsson et al., 2006).”
ResultImmune responses in the Parkinson's disease brain
Weiss, F. C., Labrador‐Garrido, A., Dzamko, N. L., & Halliday, G. M. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105700 · Cited by 100
Hewett, J. A. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06288.x · Cited by 100
“…in certain astrocyte populations under physiological conditions (Mathewson and Berry 1985; Takamiya et al. 1988; Vijayan et al. 1990; Kozlova and Lukanidin 1999; Aberg and Kozlova 2000; Pringle et al. 2003; Scotti Campos 2003; Hirrlinger et al. 2006; Wilhelmsson et al. 2006; Tanaka et al. 2007).”
BackgroundInfluentialRoles of glial cells in synapse development
Pfrieger, F. W. (2009) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-009-0005-7 · Cited by 97
Employing an open-source tool to assess astrocyte tridimensional structure
Tavares, G., Martins, M., Correia, J. S., Sardinha, V. M., Guerra‐Gomes, S., das Neves, S. P., Marques, F., Sousa, N., & Oliveira, J. F. (2016) · Brain Structure and Function · doi:10.1007/s00429-016-1316-8 · Cited by 93
“…the intermediate filament protein that is used extensively as a specific marker for astrocyte main processes, whose expression is tightly related to morphological alterations (Wilhelmsson et al. 2006; Oberheim et al. 2012; Hol and Pekny 2015; Sofroniew 2015; Kulkarni et al. 2015; Yang and Wang 2015).”
BackgroundCoincident Generation of Pyramidal Neurons and Protoplasmic Astrocytes in Neocortical Columns
Magavi, S. S. P., Friedmann, D., Banks, G. P., Stolfi, A., & Lois, C. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.3560-11.2012 · Cited by 94
“The GFP glial cells had typical morphologies of protoplasmic astrocytes and their processes appeared to occupy nonoverlapping domains, as has been previously described (Bushong et al., 2002; Wilhelmsson et al., 2006; Halassa et al., 2007).”
BackgroundGollihue, J. L., & Norris, C. M. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101039 · Cited by 93
“Reactive astrocytes are often morphologically distinct from “resting” astrocytes and are usually characterized as more ramified, larger, with elongated processes (Burda et al., 2016; Wilhelmsson et al., 2006).”
BackgroundGlia: victims or villains of the aging brain?
Salas, I. H., Burgado, J., & Allen, N. J. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.105008 · Cited by 99
“by an increased expression of the glial fibrillary acidic protein (GFAP) and changes in morphology and function (Wilhelmsson et al., 2006).”
BackgroundRobel, S., Bardehle, S., Lepier, A., Brakebusch, C., & Götz, M. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.2696-11.2011 · Cited by 95
Ischemic brain injury: New insights on the protective role of melatonin
Ramos, E., Patiño, P., Reiter, R. J., Gil‐Martín, E., Marco‐Contelles, J., Parada, E., Rı́os, C. D. L., Romero, A., & Egea, J. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.01.005 · Cited by 94
You, T., Bi, Y., li, J., Zhang, M., Chen, X., Zhang, K., & Li, J. (2017) · Scientific Reports · doi:10.1038/srep41779 · Cited by 92
Ionic Transporter Activity in Astrocytes, Microglia, and Oligodendrocytes During Brain Ischemia
Annunziato, L., Boscia, F., & Pignataro, G. (2013) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2013.44 · Cited by 92
Glial-Neuronal Interactions in Pathogenesis and Treatment of Spinal Cord Injury
Lukáčová, N., Kisucká, A., Bimbová, K., Bačová, M., Ileninová, M., Kuruc, T., & Gálik, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222413577 · Cited by 94
Friend, Foe or Both? Immune Activity in Alzheimer’s Disease
Frost, G. R., Jonas, L. A., & Li, Y. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00337 · Cited by 88
“Further, recent reports have indicated higher levels of AMPs and pathogen derived epitopes in post mortem AD brain tissue (Williams et al., 2013; Alonso et al., 2014).”
BackgroundAltay, M. F., Liu, A. K. L., Holton, J. L., Parkkinen, L., & Lashuel, H. A. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-022-01468-8 · Cited by 85
“Insults may activate astrocytes [46], which can in turn signal the microglia [47–49] and act as key determinants of microglial activation and neuroinflammation in disease progression [50].”
BackgroundDynamic reactive astrocytes after focal ischemia
Ding, S. (2014) · Neural Regeneration Research · doi:10.4103/1673-5374.147929 · Cited by 86
“In addition to their morphologic differences, the processes of protoplasmic astrocytes completely wrap or ensheath synapses as well as blood vessels (Bushong et al., 2002; Wilhelmsson et al., 2006; Halassa et al., 2007).”
BackgroundVersatile and Simple Approach to Determine Astrocyte Territories in Mouse Neocortex and Hippocampus
Grosche, A., Grosche, J., Tackenberg, M., Scheller, D., Gerstner, G., Gumprecht, A., Pannicke, T., Hirrlinger, P. G., Wilhelmsson, U., Hüttmann, K., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0069143 · Cited by 87
“Additionally, we compared the results of the present study with data from earlier dye filling experiments performed on adult mice ([29]; Table 1).”
BackgroundMethodResultInfluentialAlterations of Astrocytes in the Context of Schizophrenic Dementia
Tarasov, V. V., Svistunov, A. А., Chubarev, V. N., Sologova, S. S., Мухортова, П. А., Levushkin, D., Somasundaram, S. G., Kirkland, C. E., Бачурин, С. О., & Aliev, G. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.01612 · Cited by 85
“…about the presence of changes in the morphology of astrocytes in schizophrenia is also different: despite the hypertrophy of glial fibrillary acidic protein-containing cellular processes, the volume of tissue accessed by individual astrocytes of mice remains unchanged (Wilhelmsson et al., 2006).”
Role of glutamate receptors and glial cells in the pathophysiology of treatment-resistant depression
Kim, Y.-K., & Na, K.-S. (2016) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2016.03.009 · Cited by 84
Ongnok, B., Khuanjing, T., Chunchai, T., Pantiya, P., Kerdphoo, S., Arunsak, B., Nawara, W., Jaiwongkam, T., Apaijai, N., Chattipakorn, N., et al. (2021) · Neurotherapeutics · doi:10.1007/s13311-021-01092-9 · Cited by 86
Zhang, Z., Bassam, B., Thomas, A. G., Williams, M., Liu, J., Nance, E., Rojas, C., Slusher, B. S., & Kannan, S. (2016) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.06.010 · Cited by 84
“…demonstrate that diffuse innate immune activation (e.g. system bacterial infections) can induce mild or moderate reactive astrogliosis, which results in variable GFAP upregulation (Sofroniew, 2009), variable hypertrophy of soma and processes in individual astrocytes (Wilhelmsson et al., 2006).”
Obesity Accelerates Alzheimer-Related Pathology inAPOE4but notAPOE3Mice
Moser, V. A., & Pike, C. J. (2017) · eNeuro · doi:10.1523/eneuro.0077-17.2017 · Cited by 85
“Each cell was categorized as either resting or reactive based on its morphology, as reported in previous studies (Ayoub and Salm, 2003; Wilhelmsson et al., 2006).”
ResultAstrocytes in the Optic Nerve Head of Glaucomatous Mice Display a Characteristic Reactive Phenotype
Wang, R., Seifert, P. A., & Jakobs, T. (2017) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.16-20571 · Cited by 82
“60,61 Nor is it observed after severe traumatic injury in the astrocytes of the glial lamina and the optic nerve proper.”
Asken, B. M., Elahi, F. M., Joie, R. L., Strom, A., Staffaroni, A. M., Lindbergh, C. A., Apple, A. C., You, M. Y., Weiner‐Light, S., Brathaban, N., et al. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-200755 · Cited by 81
Phenotypic Conversions of “Protoplasmic” to “Reactive” Astrocytes in Alexander Disease
Sosunov, A. A., Guilfoyle, E., Wu, X., McKhann, G. M., & Goldman, J. E. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.4506-12.2013 · Cited by 80
“The hypertrophic ap- pearance with thickening of astrocyte processes and increases in GFAP is a characteristic reactive change in astrocytes in response to many CNS pathologies (Eddleston and Mucke, 1993; Wilhelmsson et al., 2006).”
BackgroundWhere the thoughts dwell: The physiology of neuronal–glial “diffuse neural net”
Verkhratsky, A., Parpura, V., & Rodriguez, J. J. (2010) · Brain Research Reviews · doi:10.1016/j.brainresrev.2010.05.002 · Cited by 83
“The protoplasmic astrocytes occupy their own territory and create the microanatomical domains within the limits of their processes (Bushong et al., 2002; Halassa et al., 2007b; Nedergaard et al., 2003; Oberheim et al., 2009; Ogata and Kosaka, 2002;Wilhelmsson et al., 2006).”
BackgroundTaipa, R. J. F., Ferreira, V., Brochado, P., Robinson, A., Reis, I., Marques, F., Mann, D. M. A., Pires, M. M., & Sousa, N. (2017) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12445 · Cited by 83
Pekna, M., & Pekny, M. (2021) · Cells · doi:10.3390/cells10071812 · Cited by 82
“Indeed, reactive astrocytes are characterized by hypertrophy of their cellular processes and exhibit changes in the expression of many genes including the up-regulation of glial fibrillary acidic protein (GFAP), the main component of astrocyte cytoplasmic intermediate filaments (also known as nanofilaments) [39,70,71].”
BackgroundThe roles of microglia and astrocytes in neuroinflammation of Alzheimer’s disease
Han, J., Zhang, Z., Zhang, P., Yu, Q., Cheng, Q., Lu, Z., & Zong, S. (2025) · Frontiers in Neuroscience · doi:10.3389/fnins.2025.1575453 · Cited by 97
Astrocytes in Memory Function: Pioneering Findings and Future Directions
Adamsky, A., & Goshen, I. (2017) · Neuroscience · doi:10.1016/j.neuroscience.2017.05.033 · Cited by 83
“They can be interconnected via gapjunctions (Houades et al., 2008), and form highly organized anatomical domains with very little overlap between adjacent cells (Bushong et al., 2002; Wilhelmsson et al., 2006; Oberheim et al., 2009).”
Astrocyte-secreted glypican-4 drives APOE4-dependent tau hyperphosphorylation
Saroja, S. R., Gorbachev, K., Julia, T., Goate, A. M., & Pereira, A. C. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2108870119 · Cited by 75
Yang, H., Reynaud, J. F., Lockwood, H., Williams, G. A., Hardin, C., Reyes, L., Stowell, C., Gardiner, S. K., & Burgoyne, C. F. (2017) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2017.03.001 · Cited by 74
“7, above, Ellisman has previously used EM (Berlanga et al., 2011; Mills et al., 2015; West et al., 2010; Wilhelmsson et al., 2006) to characterize astrocyte, axon and myelin interactions including phagocytosis of myelin (Nguyen et al.”
Up-regulation of Connexin43 in the glial scar following photothrombotic ischemic injury.
Haupt, C., Witte, O., & Frahm, C. (2007) · Molecular and cellular neurosciences · doi:10.1016/j.mcn.2007.02.005 · Cited by 76
“Neighboring astrocytes make their main contacts rather through fine processes (Wilhelmsson et al., 2006).”
BackgroundSeidel, J. L., Escartin, C., Ayata, C., Bonvento, G., & Shuttleworth, C. W. (2015) · Glia · doi:10.1002/glia.22824 · Cited by 77
“, the 3D maximal volume contacted by astrocytes) remains grossly unaffected, at least in models of axotomy or electrical lesions (Wilhelmsson et al., 2006).”
BackgroundInfluentialA Threshold Shear Force for Calcium Influx in an Astrocyte Model of Traumatic Brain Injury
Maneshi, M., Sachs, F., & Hua, S. Z. (2015) · Journal of Neurotrauma · doi:10.1089/neu.2014.3677 · Cited by 75
The prefrontal–limbic network in depression: A core pathology of synapse regression
Bennett, M. R. (2011) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2011.01.001 · Cited by 79
“Deafferentation of some nuclei leads to a substantial increase in glia, presumably due to an increase in the primary processes of astrocytes (Griph and Westman, 1977) as reactive astrocytes are known to increase the diameter of their primary processes without changes in the length of processes or in the extent of the…”
Reactive astrogliosis in the era of single-cell transcriptomics
Matusova, Z., Hol, E. M., Pekny, M., Kubista, M., & Valihrach, L. (2023) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.1173200 · Cited by 78
“Reactive astrocytes are classically identified by hypertrophy of cellular processes and increased expression of the glial fibrillary acidic protein (GFAP) (Wilhelmsson et al., 2006; Hol and Pekny, 2015; Escartin et al., 2021).”
BackgroundInfluentialNeuron-astrocyte omnidirectional signaling in neurological health and disease
Pathak, D., & Sriram, K. (2023) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2023.1169320 · Cited by 72
Goursaud, S., Kozlova, E. N., Maloteaux, J., & Hermans, E. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.05889.x · Cited by 71
“Indeed, reactive astrocytes increase the thickness of their cell processes (Wilhelmsson et al. 2006), and are packed with intracellular glial filaments such as GFAP, vimentin (Eng et al.”
BackgroundSelective estrogen receptor modulators regulate reactive microglia after penetrating brain injury
Barreto, G. E., Santos‐Galindo, M., & García‐Segura, L. M. (2014) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2014.00132 · Cited by 71
“The morphology can be analyzed in many ways, such as filling cells with Lucifer yellow dye (Wilhelmsson et al., 2006), or in”
BackgroundMethodThe complex morphology of reactive astrocytes controlled by fibroblast growth factor signaling
Kang, K., Lee, S.-W., Han, J. E., Choi, J. W., & Song, M. (2014) · Glia · doi:10.1002/glia.22684 · Cited by 72
“Astrocytes near the wound site are elongated, while those distant from the lesion are stellate, creating a morphological gradient over the distance from the injured site (Wanner et al., 2013; Wilhelmsson et al., 2006).”
BackgroundSikorska, M., Lanthier, P., Miller, H., Beyers, M., Sodja, C., Zurakowski, B., Gangaraju, S., Pandey, S., & Sandhu, J. K. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.03.032 · Cited by 70
“Several studies published in recent years show protective role of reactive astrocytes in traumatic brain injury, spinal cord injury, brain ischemia, and cortical lesion innervation dentate gyrus in mice, highlighting the facts that their function is critical for the survival of neurons (Eng et al., 2000; Hertz and Zie…”
BackgroundNotch signaling in astrocytes mediates their morphological response to an inflammatory challenge
Acaz‐Fonseca, E., Ortiz‐Rodriguez, A., Azcoitia, Í., García‐Segura, L. M., & Arévalo, M. (2019) · Cell Death Discovery · doi:10.1038/s41420-019-0166-6 · Cited by 71
New advances on glial activation in health and disease
Lee, K. M. (2015) · World Journal of Virology · doi:10.5501/wjv.v4.i2.42 · Cited by 73
The Role of Glia in Alpha-Synucleinopathies
Fellner, L., & Stefanova, N. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8340-3 · Cited by 69
“microglia, also clearance of dead or damaged cells [30–34].”
BackgroundAstrocytic Ephrin-B1 Regulates Synapse Remodeling Following Traumatic Brain Injury
Nikolakopoulou, A. M., Koeppen, J., Garcia, M. L., Leish, J., Obenaus, A., & Ethell, I. M. (2016) · ASN NEURO · doi:10.1177/1759091416630220 · Cited by 72
“Astrocytes undergo substantial changes in response to brain and spinal cord injury (Sofroniew, 2009), including cell hypertrophy (Wilhelmsson et al., 2006), enhanced proliferation and scar formation, increased expression of glial-fibrillary acidic protein (GFAP), and reexpression of the progenitor…”
BackgroundHeterogeneous astrocytes: Active players in CNS
Hu, X., Yuan, Y., Wang, D., & Su, Z. (2016) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2016.03.017 · Cited by 73
“However, the recapitulative classification, mild, moderate and severe glial reaction, can be provided based on the structure, molecular expression and other indicators (Sofroniew 2009; Sofroniew MV 2010; Wilhelmsson et al. 2006).”
Astrocyte–synapse interactions and cell adhesion molecules
Saint‐Martin, M., & Goda, Y. (2022) · FEBS Journal · doi:10.1111/febs.16540 · Cited by 70
Large-scale recording of astrocyte activity
Nimmerjahn, A., & Bergles, D. E. (2015) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2015.01.015 · Cited by 69
Davis, N., Mota, B. C., Stead, L., Palmer, E. O. C., Lombardero, L., Rodríguez-Puertas, R., de Paola, V., Barnes, S. J., & Sastre, M. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02117-y · Cited by 65
D-serine mitigates cell loss associated with temporal lobe epilepsy
Beesley, S., Sullenberger, T., Crotty, K. M., Ailani, R., D’Orio, C. S., Evans, K., Ogunkunle, E. O., Roper, M. G., & Kumar, S. S. (2020) · Nature Communications · doi:10.1038/s41467-020-18757-2 · Cited by 64
Calsolaro, V., Matthews, P. M., Donat, C. K., Livingston, N. R., Femminella, G. D., Guedes, S. D. S., Myers, J., Fan, Z., Tyacke, R. J., Venkataraman, A. V., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01193-z · Cited by 63
“GFAP is significantly upregulated during astrocyte reactivity [46] as the protein is necessary to build intermediate filaments [47] required for the biological process of hypertrophy that is characteristic of astrocyte reactivity [48].”
BackgroundZhang, X., Li, L., Zhang, X., Xie, W., Li, L., Yang, D., Heng, X., Du, Y., Doody, R. S., & Le, W. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.06.012 · Cited by 65
“The reactive astrocytes exhibit striking increases in GFAP-immunoreactivity and in the number and length of GFAP-positive processes (Wilhelmsson et al., 2006).”
BackgroundCentral Nervous System Effects of Whole-Body Proton Irradiation
Sweet, T. B., Panda, N., Hein, A. M., Das, S. L., Hurley, S. D., Olschowka, J. A., Williams, J. P., & O’Banion, M. K. (2014) · Radiation Research · doi:10.1667/rr13699.1 · Cited by 64
Wang, Y., Li, W., Wang, M., Lin, C., Li, G., Zhou, X., Luo, J., & Jin, D.-D. (2017) · Journal of Cellular Biochemistry · doi:10.1002/jcb.26392 · Cited by 62
“In chronic SCI, astrocytes become proliferative, increased the production of inhibitory chondroitin sulfate proteoglycans, and promoted astroglial scar formation which can hamper axonal regeneration.(33,34) However, a lot of different studies showed that reactive astrocytes exert beneficial effects following SCI.”
BackgroundCrosstalk of Astrocytes and Other Cells during Ischemic Stroke
He, T., Yang, G., & Zhang, Z. (2022) · Life · doi:10.3390/life12060910 · Cited by 63
Lana, D., Melani, A., Pugliese, A. M., Cipriani, S., Nosi, D., Pedata, F., & Giovannini, M. G. (2014) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2014.00322 · Cited by 63
“In moderate forms of reactive astrogliosis, astrocyte proliferation is limited, astrocytes occupy contiguous non-overlapping domains (Bushong et al., 2002) but have hypertrophic bodies and processes (Wilhelmsson et al., 2006).”
BackgroundRuscher, K., Johannesson, E., Brugiere, E., Erickson, A., Rickhag, M., & Wieloch, T. W. (2009) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2009.96 · Cited by 63
“These cells showed a typical morphology for reactive astrocytes, but weak or no immunoreactivitiy for GFAP (Figure 3D) (Wilhelmsson et al, 2006).”
BackgroundNestin Regulates Neurogenesis in Mice Through Notch Signaling From Astrocytes to Neural Stem Cells
Wilhelmsson, U., Lebkuechner, I., Leke, R., Marášek, P., Yang, X., Antfolk, D., Chen, M., Mohseni, P., Lasič, E., Bobnar, S. T., et al. (2018) · Cerebral Cortex · doi:10.1093/cercor/bhy284 · Cited by 65
Mechanisms underlying AQP4 accumulation in astrocyte endfeet
Camassa, L. M. A., Lunde, L. K., Hoddevik, E. H., Stensland, M., Boldt, H. B., de Souza, G. A., Ottersen, O. P., & Amiry-Moghaddam, M. R. (2015) · Glia · doi:10.1002/glia.22878 · Cited by 62
“Astrocytes that populate grey matter typically show a rich complexity of processes that engage in contact with thousands of synapses in their respective domains (Bushong et al., 2004; Iadecola and Nedergaard, 2007; Pekny et al., 2007; Wilhelmsson et al., 2006).”
BackgroundXie, Y., Wang, T., Sun, G. Y., & Ding, S. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2010.08.034 · Cited by 60
GFAP isoforms control intermediate filament network dynamics, cell morphology, and focal adhesions
Moeton, M., Stassen, O. M. J. A., Sluijs, J. A., van der Meer, V. W. N., Kluivers, L. J., van Hoorn, H., Schmidt, T., Reits, E. A., van Strien, M. E., & Hol, E. M. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2239-5 · Cited by 67
Guzmán, B. C., Chaffey, T. E., Palpagama, T. H., Waters, S., Boix, J., Tate, W. P., Peppercorn, K., Dragunow, M., Waldvogel, H. J., Faull, R. L. M., et al. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.552073 · Cited by 63
“Cells with activated morphology tend to be larger, with more primary branches and an increased number of smaller processes (Glenn et al., 1992; Wilhelmsson et al., 2006; Boche et al., 2013; Palpagama et al., 2019b).”
BackgroundCellular Mechanisms Participating in Brain Repair of Adult Zebrafish and Mammals after Injury
Ghaddar, B., Lübke, L., Couret, D., Rastegar, S., & Diotel, N. (2021) · Cells · doi:10.3390/cells10020391 · Cited by 69
“GFAP upregulation after brain ischemia will be weak at 24h post-injury but will increase rapidly during the first week [152,153], while the number of GFAP-positive astrocytes increases within the first two weeks [154,155].”
BackgroundInfluentialKrishnasamy, S., Weng, Y.-C., Thammisetty, S. S., Phaneuf, D., Lalancette–Hébert, M., & Križ, J. (2017) · Journal of Neuroinflammation · doi:10.1186/s12974-017-0816-7 · Cited by 59
“Thus, our results suggest that the observed increase in the number of GFAP-positive cells after LPS, at the tested time point, is not due to proliferation [28].”
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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