Phenotypic Heterogeneity and Plasticity of Isocortical and Hippocampal Astrocytes in the Human Brain
Open accessAbstract
To examine the diversity of astrocytes in the human brain, we immunostained surgical specimens of temporal cortex and hippocampus and autopsy brains for CD44, a plasma membrane protein and extracellular matrix receptor. CD44 antibodies outline the details of astrocyte morphology to a degree not possible with glial fibrillary acidic protein (GFAP) antibodies. CD44+ astrocytes could be subdivided into two groups. First, CD44+ astrocytes with long processes were consistently found in the subpial area (“interlaminar” astrocytes), the deep isocortical layers, and the hippocampus. Many of these processes ended on blood vessels. Some were also found adjacent to large blood vessels, from which they extended long processes. We observed these CD44+, long-process astrocytes in every brain we examined, from fetal to adult. These astrocytes generally displayed high immunostaining for GFAP, S100β, and CD44, but low immunostaining for glutamine synthetase, excitatory amino-acid transporter 1 (EAAT1), and EAAT2. Aquaporin 4 (AQP4) appeared distributed all over the cell bodies and processes of the CD44+ astrocytes, while, in contrast, AQP4 localized to perivascular end feet in the CD44− protoplasmic astrocytes. Second, there were CD44+ astrocytes without long processes in the cortex. These were not present during gestation or at birth, and in adult brains varied substantially in number, shape, and immunohistochemical phenotype. Many of these displayed a “mixed” morphological and immunocytochemical phenotype between protoplasmic and fibrous astrocytes. We conclude that the diversity of astrocyte populations in the isocortex and archicortex in the human brain reflects both intrinsic and acquired phenotypes, the latter perhaps representing a shift from CD44− “protoplasmic” to CD44+ “fibrous”-like astrocytes.
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VP-As are "individual-specific," meaning they are not present in all individuals within the same species, but only in some.
“Intriguingly, VP-As were found to be “individual-specific,” meaning they were not present in all the individuals within the same species, but only in some of them, enforcing the hypothesis of their origin as linked to specific brain conditions (Falcone et al., 2022; Pereira and Furlan, 2010; Sosunov et al., 2014).”
From Interlaminar and varicose-projection astrocytes: toward a new understanding of the primate brain (2024) · cites this paper as Sosunov et al., 2014
In “The adult human neocortex contains CD44+ astrocytes with long processes” (page unavailable), the paper identifies deep-layer long-process cells with “varicose projection astrocytes.” Its summary in “CD44+ astrocytes do not respect the borders of other astrocytes” says this long-process population was present in every specimen examined, regardless of age or pathology. The cells whose numbers varied markedly between individuals were a different, potentially acquired cortical population. (LLM, conf=0.87)
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Experimental — accuracy not yet measuredMembrane proteins EAAT1 and EAAT2 are not optimal candidates to assess complex astrocyte morphology because they tend to produce widespread and diffuse staining.
“Membrane proteins such as the glutamate transporters EAAT1 and EAAT2 are not optimal candidates to assess complex astrocyte morphology, as they tend to produce widespread and diffuse staining24.”
From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [24]
The section “Astrocyte domain localizations and microheterogeneity among astrocyte types” (page unavailable) reports that EAAT1- and EAAT2-positive processes from neighboring astrocytes penetrate CD44-positive astrocyte domains, supporting a limitation in using these markers to delineate individual cells. It does not say that EAAT1 or EAAT2 staining is generally widespread and diffuse, or explicitly conclude that they are unsuitable for assessing complex morphology. (LLM, conf=0.76)
Experimental — accuracy not yet measuredILAs interact with blood vessels, perivascular astrocytes, neurons, and protoplasmic astrocytes.
“These astrocytes interact with blood vessels, perivascular astrocytes, neurons, and protoplasmic astrocytes”
From Interlaminar and varicose-projection astrocytes: toward a new understanding of the primate brain (2024) · cites this paper as Sosunov et al., 2014
The section on the adult human neocortex reports interlaminar astrocyte processes ending on blood vessels, and the discussion reports coupling between pial-based long-process astrocytes and neighboring protoplasmic astrocytes. Figure 2 shows a long process touching another astrocyte’s process near a vessel. It depicts a different long-process astrocyte in a perineuronal position, but does not establish that interlaminar astrocytes interact with neurons. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPial-based GFAP+/CD44+ astrocytes are present at 26 weeks of gestation and in young brains of 2-year-old children.
“Sosunov et al. (2014), found pial-based, GFAP+/CD44+ astrocytes at 26 weeks of gestation and confirmed their presence also in young brains of 2-year-old children”
From Interlaminar and varicose-projection astrocytes: toward a new understanding of the primate brain (2024) · cites this paper as Sosunov et al., 2014
The developmental-results section (page unavailable) reports focal CD44 staining of pial-based astrocytes by 26 weeks of gestation and examination of brains from children aged 2–7 years. The paper describes long-process CD44+ astrocytes across ages as generally GFAP-positive, but these passages do not establish GFAP/CD44 co-positivity specifically in the 26-week specimen or document pial-based co-positive cells specifically in a 2-year-old. (LLM, conf=0.82)
Experimental — accuracy not yet measuredDye-filling methods can visualize whole astrocytes in mice and in human brain samples from surgical resections.
“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 [24]
Long ILA processes cross the domains of protoplasmic astrocytes they encounter, passing in close proximity to their perikaryal.
“they cross the domains of the protoplasmic astrocytes they encounter, passing in close proximity to their perikaryal”
From Interlaminar and varicose-projection astrocytes: toward a new understanding of the primate brain (2024) · cites this paper as Sosunov et al., 2014
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- Authors
- Sosunov, A. A., Wu, X., Tsankova, N. M., Guilfoyle, E., McKhann, G. M., & Goldman, J. E.
- Affiliations
- Columbia University Irving Medical Center (US)
- Columbia University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2014-02-05
- Volume
- 34
- Issue
- 6
- Pages
- 2285-2298
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3913872
- OpenAlex
- W2002962618
- Cited by
- 185
- References
- 28
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 16 · 2023: 16 · 2022: 18 · 2021: 26 · 2020: 19 · 2019: 11 · 2018: 13 · 2017: 13 · 2016: 9 · 2015: 19 · 2014: 9
- FWCI
- 7.61
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, public-domain)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Tuberous Sclerosis Alliance
- National Institutes of Health (NS42803)
- National Institute of Neurological Disorders and Stroke (NS-42803, P01NS042803)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- astrocyte heterogeneity, astrocyte plasticity, CD44, hippocampus, protoplasmic astrocyte, fibrous astrocytes, aquaporin-4, astrocyte morphology, extracellular matrix, temporal cortex, S100β, glutamine synthetase, glutamate transporters
- MeSH terms
- Adolescent, Adult, Aged, Astrocytes, Brain, Cerebral Cortex, Child, Child, Preschool, Female, Hippocampus, Humans, Male, Middle Aged, Neuronal Plasticity, Phenotype, Genetic Heterogeneity, Young Adult
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