Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse
Open accessAbstract
The functional and molecular similarities and distinctions between human and murine astrocytes are poorly understood. Here, we report the development of an immunopanning method to acutely purify astrocytes from fetal, juvenile, and adult human brains and to maintain these cells in serum-free cultures. We found that human astrocytes have abilities similar to those of murine astrocytes in promoting neuronal survival, inducing functional synapse formation, and engulfing synaptosomes. In contrast to existing observations in mice, we found that mature human astrocytes respond robustly to glutamate. Next, we performed RNA sequencing of healthy human astrocytes along with astrocytes from epileptic and tumor foci and compared these to human neurons, oligodendrocytes, microglia, and endothelial cells (available at http://www.brainrnaseq.org). With these profiles, we identified novel human-specific astrocyte genes and discovered a transcriptome-wide transformation between astrocyte precursor cells and mature post-mitotic astrocytes. These data represent some of the first cell-type-specific molecular profiles of the healthy and diseased human brain.
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Cldn5 is an endothelial cell-specific tight junction protein and is enriched in blood vessels.
“Cldn5 is an endothelial cell-specific tight junction protein (Supplementary Fig. 2D)29, 30, which we confirmed to be enriched in blood vessels using a brain capillary extraction method”
From Social stress induces neurovascular pathology promoting depression (2017) · cites this paper as [30]
The Results section on purified human cell transcriptomes identifies CLDN5 as an endothelial cell-specific marker and reports selective expression in endothelial cells. Our copy does not identify CLDN5 as a tight junction protein. The blood-vessel enrichment is presented in the citing sentence as the citing authors’ own confirmation, not a finding attributed to this source. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPlexin-B1 is predominantly expressed in astrocytes as compared to other cell types in both mouse and human CNS.
“a survey of gene expression databases (brainrnaseq.org)31, 32 revealed a predominant expression of Plexin-B1 in astrocytes as compared to other cell types in both mouse and human CNS (Fig. 2A).”
From Regulation of cell distancing in peri-plaque glial nets by Plexin-B1 affects glial activation and amyloid compaction in Alzheimer’s disease (2024) · cites this paper as [31]
Morphological and transcriptomic comparisons have revealed prominent differences between mice and humans.
“morphological and transcriptomic comparisons have revealed prominent differences between mice and humans101–103”
From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [101]
RNA-seq data for MCT8 gene expression in human brain demonstrated similar levels in purified human endothelial cells, astrocytes, and neurons, and to a lesser extent in mature oligodendrocytes, and it was not detected in microglia.
“Analyzing RNA-seq data for MCT8 gene expression in the human brain (Zhang et al., 2016) demonstrated similar levels in purified human endothelial cells, astrocytes, and neurons, and to a lesser extent in mature oligodendrocytes, and it was not detected in microglia (Figure 3A).”
From Modeling Psychomotor Retardation using iPSCs from MCT8-Deficient Patients Indicates a Prominent Role for the Blood-Brain Barrier (2017) · cites this paper as Zhang et al., 2016
The chr3q28 region proteins showed significant enrichment in neurons.
“For each of the 208 proteins, we analyzed brain-relevant cell-type expression data34 (Supp. Table S28) to determine cell specificity and observed a significant enrichment in neurons (Fig. 3B, Supp. Fig. 13, Supp. Table S29), supporting relevance of this region for brain-related traits.”
From Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer’s disease (2024) · cites this paper as [34]
Monocyte eQTL findings in the Cardiogenics dataset were validated by querying statistics from Fairfax et al.
“For additional monocyte eQTL analysis, we queried statistics from Fairfax et al.28 to validate findings in the Cardiogenics dataset.”
From A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease (2017) · cites this paper as [28]
The Results section, “Validation of genes differentially expressed by human and mouse” (page unavailable), describes PCR and qPCR validation of astrocyte gene-expression findings, not monocyte eQTLs. Searches for Fairfax, Cardiogenics, and monocyte eQTL validation found no passage addressing the attributed claim. (LLM, conf=0.77)
Experimental — accuracy not yet measuredH3K27ac at promoters tracked gene expression in the matching cell type better than ATAC-seq or H3K4me3 ChIP-seq did.
“Promoter H3K27ac signal correlated with gene expression of the corresponding cell type more closely than ATAC-seq and H3K4me3 ChIP-seq”
From Brain cell type–specific enhancer–promoter interactome maps and disease <b>-</b> risk association (2019) · cites this paper as [12]
The Results section on cell-type transcriptomes reports RNA-seq expression profiles and correlations between samples, not correlations between promoter marks and expression. Searches for H3K27ac, ATAC-seq, H3K4me3, and chromatin accessibility found no passage in our copy comparing those signals. (LLM, conf=0.72)
Experimental — accuracy not yet measuredTREM2, ABI3 and PLCG2 have a common expression pattern in human brain cortex, with high expression in microglia and limited expression in neurons, oligodendrocytes, astrocytes and endothelial cells.
“TREM2, ABI3 and PLCG2 have a common expression pattern in human brain cortex, with high expression in microglia cells and limited expression in neurons, oligodendrocytes, astrocytes and endothelial cells (Supplementary Figure 12)38.”
From Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease (2017) · cites this paper as [38]
The Results section, “Transcriptomes of acutely purified human neurons, astrocytes, oligodendrocytes, microglia, and endothelial cells” (page unavailable), describes cortical cell-type RNA-seq data. But neither that passage nor searches for TREM2, ABI3, and PLCG2 yielded a passage reporting their relative expression across those cells, so the claimed pattern cannot be verified from our copy. (LLM, conf=0.74)
Experimental — accuracy not yet measuredNilvadipine, an anti-hypertensive drug in a phase III Alzheimer's disease trial, targets SYK and TYROBP, a hub gene in an Alzheimer's disease-related brain expression network that encodes the TREM2 complex protein DAP12.
“Notably, the anti-hypertensive drug Nilvadipine, currently in a phase III AD clinical trial, targets SYK as well as TYROBP, a hub gene in an AD-related brain expression network38, that encodes the TREM2 complex protein DAP12.”
From Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease (2017) · cites this paper as [38]
The Results sections discuss human astrocyte gene expression, and the supplied References do not establish the claimed Alzheimer’s disease-related network. Searches for Nilvadipine, SYK, TYROBP, TREM2 and DAP12 found no passage in our copy addressing the drug targets or TYROBP’s claimed network role. No page numbers were available for these passages. (LLM, conf=0.76)
Experimental — accuracy not yet measuredMultiple approaches have highlighted INPP5D as an Alzheimer's disease risk gene.
“Multiple approaches have highlighted inositol polyphosphate-5-phosphatase D (INPP5D) as an AD risk gene, and its expression in the brain is restricted to microglia.4–6”
From Microglial <i>INPP5D</i> limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [5]
The Results sections describe astrocyte and other brain-cell transcriptomes, but the retrieved passages do not identify INPP5D as an Alzheimer’s disease risk gene. Searches for INPP5D and Alzheimer’s genetic susceptibility found no passage in our copy addressing that attribution. (LLM, conf=0.77)
Experimental — accuracy not yet measuredINPP5D expression in the brain is restricted to microglia.
“Multiple approaches have highlighted inositol polyphosphate-5-phosphatase D (INPP5D) as an AD risk gene, and its expression in the brain is restricted to microglia.4–6”
From Microglial <i>INPP5D</i> limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [5]
The Results section, “Transcriptomes of acutely purified human neurons, astrocytes, oligodendrocytes, microglia, and endothelial cells” (page unavailable), describes a cell-type expression database. Searches for INPP5D, SHIP1, and microglial expression found no passage stating that INPP5D expression is restricted to microglia. (LLM, conf=0.73)
Experimental — accuracy not yet measuredSREBF2 is most highly expressed in astrocytes in the brain.
“In line with ABCA1 and APOE expression, SREBF2 is most highly expressed in astrocytes in the brain. 50 , 51”
From Deletion of miR-33, a regulator of the ABCA1–APOE pathway, ameliorates neuropathological phenotypes in APP/PS1 mice (2024) · cites this paper as [51]
The Results section on validation of differentially expressed genes names several astrocyte-enriched genes, but not SREBF2. Searches for SREBF2 and its expanded name found no passage in our copy comparing its expression across brain cell types, so the claimed ranking cannot be verified from this source. (LLM, conf=0.72)
Experimental — accuracy not yet measuredThe process by which ABCA1 lipidates apoE is mediated mainly by astrocytes.
“The process by which ABCA1 lipidates apoE is mediated mainly by astrocytes. Indeed, both ABCA1 and APOE are highly expressed in astrocytes in the brain. 50 , 51”
From Deletion of miR-33, a regulator of the ABCA1–APOE pathway, ameliorates neuropathological phenotypes in APP/PS1 mice (2024) · cites this paper as [51]
The Results section on transcriptome differences reports increased fatty-acid-metabolism gene expression as human astrocytes mature, but does not address ABCA1-mediated apoE lipidation or whether astrocytes are its main mediators. Searches for ABCA1, APOE, and apoE lipidation found no passage establishing the claim (page numbers unavailable). (LLM, conf=0.74)
Experimental — accuracy not yet measuredPSAP is secreted by microglia and astrocytes in humans and predominantly by microglia in mice.
“PSAP is secreted by microglia and astrocytes in humans and predominantly by microglia in mice. 45 , 46”
From Loss of <i>Inpp5d</i> has disease‐relevant and sex‐specific effects on glial transcriptomes (2024) · cites this paper as [46]
The Results passages on human astrocyte transcriptomes and human–mouse functional differences do not address PSAP secretion or compare its cellular sources across species. Searches of our copy for “PSAP,” “prosaposin,” and secretion by microglia and astrocytes found no relevant passage; page numbers were not available. (LLM, conf=0.74)
Experimental — accuracy not yet measuredIn human brains, CFL1 is expressed across various cell types, including astrocytes, neurons, and microglia, while ACTR2 is predominately expressed in microglia and macrophages.
“Indeed, in human brains, CFL1 is expressed across various cell types, including astrocytes, neurons, and microglia, while ACTR2 is predominately expressed in microglia and macrophages [108].”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [108]
The Results section on acutely purified human brain cell transcriptomes describes expression profiles for these cell types, but does not report CFL1 or ACTR2 expression. Searches for both gene names and their proposed cell-type patterns found no passage in our copy that verifies the claim; no page numbers are available. (LLM, conf=0.72)
Experimental — accuracy not yet measuredLPL is predominantly expressed in microglia of the human and mouse brain.
“Recent RNA-seq data suggest that LPL is predominantly expressed in the microglia of the human and mouse brain [23,24].”
From Lipoprotein Lipase Regulates Microglial Lipid Droplet Accumulation (2021) · cites this paper as [23]
The Results section on transcriptomes of purified human brain cell types reports RNA-seq profiles and microglial markers, but does not identify LPL as one of them. Searches for “LPL” and “lipoprotein lipase” found no passage stating that it is predominantly expressed in microglia in either humans or mice. (LLM, conf=0.72)
Experimental — accuracy not yet measuredStudies using FACS or immunopanning to isolate astrocyte mRNA offer the ability to look at the whole transcriptome, including non-coding RNAs, but do not highlight mRNAs that are being functionally utilized and are restricted to RNAs present in the cell body.
“Studies using FACS (Cahoy et al., 2008) or immunopanning (Zhang et al., 2016) to isolate astrocyte mRNA offer the ability to look at the whole transcriptome, including non-coding RNAs, but do not highlight mRNAs that are being functionally utilized and are restricted to RNAs present in the cell body because of the isolation method.”
From The aging astrocyte transcriptome from multiple regions of the mouse brain. (2018) · cites this paper as Zhang et al., 2016
The majority of Alzheimer's disease-associated risk genes are expressed selectively or preferentially in microglia relative to other brain cell types.
“a striking feature of the identified risk genes is that the majority of them are expressed selectively or preferentially in microglia relative to other cell types in the brain (Fig. 1 A; Srinivasan et al., 2016; Zhang et al., 2016).”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Zhang et al., 2016
SORL1 is a sorting receptor located in neurons, astrocytes, and microglia and is known to direct APP toward non-amyloidogenic processing in the trans-Golgi network.
“SORL1, a sorting receptor located in neurons [152], astrocytes, and microglia [153] is known to direct APP toward non-amyloidogenic processing in the trans-Golgi network [148, 154].”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [153]
In microglia, ROS are generated primarily by NADPH oxidase 2 (NOX2).
“In microglia, ROS are generated primarily by NADPH oxidase 2 (NOX2)”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [73]
The human microglial cell line clone 3 does not express NOX2, which calls into question the validity of the model since NOX2 is the most highly expressed isotype in both human and murine microglia.
“Interestingly, however, this particular cell line does not express NOX2; this calls into question the validity of the model since NOX2 is the most highly expressed isotype in both human and murine microglia [72,73].”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [73]
Robust and constitutive expression of NOX in microglia has been demonstrated.
“Robust and constitutive expression of NOX in microglia has been demonstrated and is the focus of this section.”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [73]
NOX4 has the second-highest transcript expression in microglia, albeit at a much lower level.
“NOX4 has the second-highest transcript expression in microglia, albeit at a much lower level [72,73].”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [73]
NOX2 (CYBB) is the most highly expressed NOX isotype transcript in human and mouse brain microglia.
“single-cell (sc)RNA-seq has determined that NOX2 (CYBB) is the most highly expressed NOX isotype transcript in human and mouse brain microglia, concurrent with expression in peripheral macrophages [71,72,73].”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [73]
All the cell types in the current study cluster with human cortex myeloid cells and not with cortical oligodendrocytes, astrocytes, neurons, or endothelial cells.
“Comparison with a previously published expression dataset for cells derived from human brain tissue (Zhang et al., 2016) showed that all the cell types in the current study cluster with human cortex myeloid cells and not with cortical oligodendrocytes, astrocytes, neurons, or endothelial cells (Figure 2B).”
From A highly efficient human pluripotent stem cell microglia model displays a neuronal-co-culture-specific expression profile and inflammatory response (2017) · cites this paper as Zhang et al., 2016
There was extensive overlap in gene expression between the human microglial core and the published human CD45+ microglial cell population; the median Δ percentile was 10.1.
“Overall, we observed an extensive overlap in gene expression between these data sets: the median ∆ percentile was 10.1, indicating most genes were similarly expressed in both data sets ( Fig. 2b ).”
From Transcriptomic analysis of purified human cortical microglia reveals age-associated changes (2017) · cites this paper as [15]
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Self-citation
- Authors
- Zhang, Y., Sloan, S. A., Clarke, L. E., Caneda, C., Plaza, C. A., Blumenthal, P. D., Vogel, H., Steinberg, G. K., Edwards, M. S. B., Li, G., Duncan, J. A., Cheshier, S. H., Shuer, L. M., Chang, E. F., Grant, G. A., Gephart, M. G. H., & Barres, B. A.
- Affiliations
- Stanford Medicine (US)
- Lucile Packard Children's Hospital (US)
- Kaiser Permanente Santa Clara Medical Center (US)
- University of California, San Francisco (US)
- Corresponding author
- Zhang, Ye
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2016-01
- Volume
- 89
- Issue
- 1
- Pages
- 37-53
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC4707064
- OpenAlex
- W2191292005
- Cited by
- 2,295
- References
- 47
- Citations by year
- 2026: 167 · 2025: 215 · 2024: 274 · 2023: 252 · 2022: 301 · 2021: 301 · 2020: 273 · 2019: 208 · 2018: 136 · 2017: 122 · 2016: 43 · 2012: 1
- FWCI
- 46.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- JPB Foundation
- National Institutes of Health
- National Institute on Aging (P50AG005131)
- National Institute of Mental Health (F30MH106261, R01MH099555, T32MH020016)
- National Cancer Institute (R01CA216054)
- National Institute of General Medical Sciences (T32GM007365)
- National Institute of Neurological Disorders and Stroke (R00NS089780, R01NS081703, K99NS089780)
- 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
- human astrocytes, immunopanning, human-mouse comparison, glutamate response, synaptogenesis, neuronal survival, astrocyte transcriptome, epileptic foci, tumor foci, cell type-specific gene expression, serum-free culture
- MeSH terms
- Animals, Astrocytes, Brain, Cell Differentiation, Cell Separation, Cell Survival, Cells, Cultured, Humans, Neurons, Oligodendroglia, Stem Cells, Microglia, Cell Culture Techniques, Mice, Transcriptome
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