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Cited by 223Neuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration MechanismsNeurogenesis and neuroplasticity mechanisms

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Important Shapeshifter: Mechanisms Allowing Astrocytes to Respond to the Changing Nervous System During Development, Injury and Disease

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Schiweck, Juliane, Eickholt, Britta J., Murk, Kai·2018·Frontiers in Cellular Neuroscience
DOI 10.3389/fncel.2018.00261PMC PMC6111612
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Abstract

Astrocytes are the most prevalent glial cells in the brain. Historically considered as "merely supporting" neurons, recent research has shown that astrocytes actively participate in a large variety of central nervous system (CNS) functions including synaptogenesis, neuronal transmission and synaptic plasticity. During disease and injury, astrocytes efficiently protect neurons by various means, notably by sealing them off from neurotoxic factors and repairing the blood-brain barrier. Their ramified morphology allows them to perform diverse tasks by interacting with synapses, blood vessels and other glial cells. In this review article, we provide an overview of how astrocytes acquire their complex morphology during development. We then move from the developing to the mature brain, and review current research on perisynaptic astrocytic processes, with a particular focus on how astrocytes engage synapses and modulate their formation and activity. Comprehensive changes have been reported in astrocyte cell shape in many CNS pathologies. Factors influencing these morphological changes are summarized in the context of brain pathologies, such as traumatic injury and degenerative conditions. We provide insight into the molecular, cellular and cytoskeletal machinery behind these shape changes which drive the dynamic remodeling in astrocyte morphology during injury and the development of pathologies.

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Figures

Figure 1 Astrogenesis and morphogenesis of astrocytes during development. (A) First wave of progenitor migration: asymmetric division of neural stem cells within the ventricular zones creates the first wave of astrocyte precursor cells (black and blue), which migrate along the processes of radial glial cells (gray) towards their final location in the central nervous system (CNS). (B) Clonal expansion of pioneering astrocytes and second wave of migrating astrocyte progenitor during late development: pioneering astrocytes of the first migration wave (blue) undergo symmetric cell division in the upper cortical layers, while a second wave of astrocyte progenitors emerges from the subventricular zone (SVZ; green), predominantly colonizing the lower cortical layers. Corpus callosum (CC). (C) Time course of astrocyte morphogenesis during postnatal development, demonstrated by two neighboring astrocytes (blue and black). Differentiating astrocytes possess long main processes at postnatal day (PND) 7, which invade the domains of neighboring astrocytes. At PND14, ramification into smaller processes has increased, whilst the extent of invasion into domains of neighboring astrocytes is reduced. Three weeks after birth, at PND21, astrocytes have acquired their complex morphologies within their distinct domains. At this stage, only very limited intermingling with neighboring astrocytes occurs.
Figure 1 Astrogenesis and morphogenesis of astrocytes during development. (A) First wave of progenitor migration: asymmetric division of neural stem cells within the ventricular zones creates the first wave of astrocyte precursor cells (black and blue), which migrate along the processes of radial glial cells (gray) towards their final location in the central nervous system (CNS). (B) Clonal expansion of pioneering astrocytes and second wave of migrating astrocyte progenitor during late development: pioneering astrocytes of the first migration wave (blue) undergo symmetric cell division in the upper cortical layers, while a second wave of astrocyte progenitors emerges from the subventricular zone (SVZ; green), predominantly colonizing the lower cortical layers. Corpus callosum (CC). (C) Time course of astrocyte morphogenesis during postnatal development, demonstrated by two neighboring astrocytes (blue and black). Differentiating astrocytes possess long main processes at postnatal day (PND) 7, which invade the domains of neighboring astrocytes. At PND14, ramification into smaller processes has increased, whilst the extent of invasion into domains of neighboring astrocytes is reduced. Three weeks after birth, at PND21, astrocytes have acquired their complex morphologies within their distinct domains. At this stage, only very limited intermingling with neighboring astrocytes occurs.CC BY · PubMed Central
Figure 2 Morphology of astrocytes in vivo and their dynamic association with synapses. (A) Z-projection of a cortical rat astrocyte (P14), stained for glial fibrillary acidic protein (GFAP; red) and S100β (green), by confocal microscopy after tissue clearance (left). Scale bars: 10 μm. 3D rendering and morphometric analyses show the restriction of the intermediate filament protein GFAP to main processes, which are decorated with myriads of fine S100β-positive processes (right; with permission from Murk et al., 2013). (B) Schematic of dendritic filopodia, with the precursors of dendritic spines, emerging from dendrites (magenta) in the absence (top) or presence of perisynaptic astrocytic processes (PAPs; green, bottom). Without the support of astrocytic processes, sprouting dendritic filopodia have a short lifespan and are likely to retract. Astrocytic processes contact filopodia-like protrusions, which then exhibit an increased stability and higher tendency to develop into mature dendritic spines. (C) Schematic of a mature tripartite synapse consisting of the pre-synapse (gray), post-synapse (magenta) and PAPs (green), which respond to long-term potentiation (LTP) with structural changes. Induction of LTP transiently enhances the motility and retraction of PAPs allowing growth of the postsynaptic dendritic spine to occur. Subsequent to dendritic spine remodeling, PAPs intensify their coverage of synapses.
Figure 2 Morphology of astrocytes in vivo and their dynamic association with synapses. (A) Z-projection of a cortical rat astrocyte (P14), stained for glial fibrillary acidic protein (GFAP; red) and S100β (green), by confocal microscopy after tissue clearance (left). Scale bars: 10 μm. 3D rendering and morphometric analyses show the restriction of the intermediate filament protein GFAP to main processes, which are decorated with myriads of fine S100β-positive processes (right; with permission from Murk et al., 2013). (B) Schematic of dendritic filopodia, with the precursors of dendritic spines, emerging from dendrites (magenta) in the absence (top) or presence of perisynaptic astrocytic processes (PAPs; green, bottom). Without the support of astrocytic processes, sprouting dendritic filopodia have a short lifespan and are likely to retract. Astrocytic processes contact filopodia-like protrusions, which then exhibit an increased stability and higher tendency to develop into mature dendritic spines. (C) Schematic of a mature tripartite synapse consisting of the pre-synapse (gray), post-synapse (magenta) and PAPs (green), which respond to long-term potentiation (LTP) with structural changes. Induction of LTP transiently enhances the motility and retraction of PAPs allowing growth of the postsynaptic dendritic spine to occur. Subsequent to dendritic spine remodeling, PAPs intensify their coverage of synapses.CC BY · PubMed Central
Figure 3 Morphological hallmarks of reactive astrocytes in traumatic brain injury. Typical distribution of reactive astrocytes after a cortical stab wound in the mouse cortex 7 days after injury. Schematic drawings show the main processes of astrocytes, which contain high levels of GFAP (gray) upon injury. GFAP-positive astrocytes exhibit different morphologies depending on their distance from the lesion site: in the immediate vicinity (magenta), astrocytes polarize and extend long “palisading” processes. In the second row, multiple processes of the hypertrophic astrocytes (yellow) are orientated towards the injury site; with increased distance, astrocytes possess hypertrophic cell bodies and primarily main processes (green). Finally, reactive astrocytes at the border of the unaffected parenchyma upregulate GFAP but show no signs of hypertrophy (blue). Note that cortical astrocytes in the uninjured contralateral hemisphere sparsely express GFAP, as indicated with silhouettes (bottom left image).
Figure 3 Morphological hallmarks of reactive astrocytes in traumatic brain injury. Typical distribution of reactive astrocytes after a cortical stab wound in the mouse cortex 7 days after injury. Schematic drawings show the main processes of astrocytes, which contain high levels of GFAP (gray) upon injury. GFAP-positive astrocytes exhibit different morphologies depending on their distance from the lesion site: in the immediate vicinity (magenta), astrocytes polarize and extend long “palisading” processes. In the second row, multiple processes of the hypertrophic astrocytes (yellow) are orientated towards the injury site; with increased distance, astrocytes possess hypertrophic cell bodies and primarily main processes (green). Finally, reactive astrocytes at the border of the unaffected parenchyma upregulate GFAP but show no signs of hypertrophy (blue). Note that cortical astrocytes in the uninjured contralateral hemisphere sparsely express GFAP, as indicated with silhouettes (bottom left image).CC BY · PubMed Central
Figure 4 The abuse of scarring astrocytes by glioma. Schematic drawings of how reactive astrocytes turn from initially tumor containing to cancer promoting cells. Astrocytes (black) form prominent palisading processes in response to growing glioma masses (gray rhomboid cells). Glioma derived signals force the reactive astrocytes to secret trophic factors (yellow), pro matrix metalloproteinase-2 (scissors) and microRNA containing exosomes (green, left). The uptake of microRNA containing exosomes evokes the epigenetical downregulation of tumor suppressing PTEN in glioma. PTEN depletion and astrocyte-derived trophic signals enhance the cell proliferation of the glioma cells. Expanding tumor cells use matrix metalloproteinases to degrade the surrounding extracellular matrix (blue stripped pattern) and begin to penetrate the glial scar (center). In the late phase, glioma have comprehensively degraded their adjacent extracellular matrix and seemingly consumed the originally tumor encompassing astrocytes (right).
Figure 4 The abuse of scarring astrocytes by glioma. Schematic drawings of how reactive astrocytes turn from initially tumor containing to cancer promoting cells. Astrocytes (black) form prominent palisading processes in response to growing glioma masses (gray rhomboid cells). Glioma derived signals force the reactive astrocytes to secret trophic factors (yellow), pro matrix metalloproteinase-2 (scissors) and microRNA containing exosomes (green, left). The uptake of microRNA containing exosomes evokes the epigenetical downregulation of tumor suppressing PTEN in glioma. PTEN depletion and astrocyte-derived trophic signals enhance the cell proliferation of the glioma cells. Expanding tumor cells use matrix metalloproteinases to degrade the surrounding extracellular matrix (blue stripped pattern) and begin to penetrate the glial scar (center). In the late phase, glioma have comprehensively degraded their adjacent extracellular matrix and seemingly consumed the originally tumor encompassing astrocytes (right).CC BY · PubMed Central
Figure 5 Roles of cytoskeletal systems during the Injury response of astrocytes in vitro. Summary in view of the localization and roles of microtubules, intermediate and actin filaments in cultured astrocytes upon injury. The schematic drawings depict the cytoskeletal systems and their major regulators involved in extension of astrocyte processes and cell body hypertrophy.
Figure 5 Roles of cytoskeletal systems during the Injury response of astrocytes in vitro. Summary in view of the localization and roles of microtubules, intermediate and actin filaments in cultured astrocytes upon injury. The schematic drawings depict the cytoskeletal systems and their major regulators involved in extension of astrocyte processes and cell body hypertrophy.CC BY · PubMed Central
Figure 6 Organization of the cytoskeleton in reactive astrocytes in comparison to fibroblasts and neurons in vitro. Schematic drawings of microtubules (green) and F-actin arrays and fibers (magenta) in cultured mouse astrocytes after injury (left), migrating fibroblasts (center) and in extending axonal growth cones of developing neurons (right). The dashed line indicates the injury border and the nucleus is shown in gray (N). Elongated polygonal astrocytes at the wound edge extend into the cell-free space and have actin filaments (magenta) that are organized around the cell body and in bundles reaching into the center of the processes, while the leading edge possesses only a narrow outer rim of filamentous actin within sparse ruffles (left). Microtubules are enriched throughout the processes and reach into the extreme tip. In contrast, both fibroblasts and neuronal growth cones exhibit prominent actin arrays and fibers in the periphery of their leading edge forming filopodia, lamellipodia or lamellipodia-like veils. Most of their microtubules are present behind the actin-rich periphery, where microtubules form dense parallel bundles in growth cones. Microtubules extending into the actin-rich periphery frequently associate with actin fibers of filopodia.
Figure 6 Organization of the cytoskeleton in reactive astrocytes in comparison to fibroblasts and neurons in vitro. Schematic drawings of microtubules (green) and F-actin arrays and fibers (magenta) in cultured mouse astrocytes after injury (left), migrating fibroblasts (center) and in extending axonal growth cones of developing neurons (right). The dashed line indicates the injury border and the nucleus is shown in gray (N). Elongated polygonal astrocytes at the wound edge extend into the cell-free space and have actin filaments (magenta) that are organized around the cell body and in bundles reaching into the center of the processes, while the leading edge possesses only a narrow outer rim of filamentous actin within sparse ruffles (left). Microtubules are enriched throughout the processes and reach into the extreme tip. In contrast, both fibroblasts and neuronal growth cones exhibit prominent actin arrays and fibers in the periphery of their leading edge forming filopodia, lamellipodia or lamellipodia-like veils. Most of their microtubules are present behind the actin-rich periphery, where microtubules form dense parallel bundles in growth cones. Microtubules extending into the actin-rich periphery frequently associate with actin fibers of filopodia.CC BY · PubMed Central

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  1. Ramón y Cajal, 1913, Un nuevo proceder para la impregnación de la neuroglía, Bol. Soc. Esp. Bio., 2, 104

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Metadata

Authors
Schiweck, J., Eickholt, B. J., & Murk, K.
Affiliations
Charité – Universitätsmedizin Berlin (DE)
Corresponding author
  • Eickholt, Britta J.
  • Murk, Kai
ORCID
Venue
Frontiers in Cellular Neuroscience
Publisher
Frontiers Media SA
Published
2018-08-21
Volume
12
Pages
261-261
ISSN
1662-5102 (ISSN-L)
DOI
10.3389/fncel.2018.00261
PMC
PMC6111612
OpenAlex
W2888094777
Cited by
223
References
169
Citations by year
2026: 14 · 2025: 28 · 2024: 25 · 2023: 23 · 2022: 38 · 2021: 44 · 2020: 33 · 2019: 18
FWCI
10.82
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Cellular Neuroscience (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Refubium (Universitätsbibliothek der Freien Universität Berlin) (submittedVersion, cc-by)
  • Universitätsbibliothek der FU Berlin Hochschulschriftenstelle u. Dokumentenserver (cc-by)
Funders
Deutsche Forschungsgemeinschaft (SFB958, TRR168, 285933818)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
astrocytes, astrocyte morphology, synaptogenesis, synaptic plasticity, neural transmission, astrocyte development, traumatic brain injury, neurodegenerative diseases, blood-brain barrier, cytoskeleton, glial cells

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