Human iPSC-derived Down syndrome astrocytes display genome-wide perturbations in gene expression, an altered adhesion profile, and increased cellular dynamics
Open accessAbstract
Down syndrome (DS), caused by the triplication of human chromosome 21, leads to significant alterations in brain development and is a major genetic cause of intellectual disability. While much is known about changes to neurons in DS, the effects of trisomy 21 on non-neuronal cells such as astrocytes are poorly understood. Astrocytes are critical for brain development and function, and their alteration may contribute to DS pathophysiology. To better understand the impact of trisomy 21 on astrocytes, we performed RNA-sequencing on astrocytes from newly produced DS human induced pluripotent stem cells (hiPSCs). While chromosome 21 genes were upregulated in DS astrocytes, we found consistent up- and down-regulation of genes across the genome with a strong dysregulation of neurodevelopmental, cell adhesion and extracellular matrix molecules. ATAC (assay for transposase-accessible chromatin)-seq also revealed a global alteration in chromatin state in DS astrocytes, showing modified chromatin accessibility at promoters of cell adhesion and extracellular matrix genes. Along with these transcriptomic and epigenomic changes, DS astrocytes displayed perturbations in cell size and cell spreading as well as modifications to cell-cell and cell-substrate recognition/adhesion, and increases in cellular motility and dynamics. Thus, triplication of chromosome 21 is associated with genome-wide transcriptional, epigenomic and functional alterations in astrocytes that may contribute to altered brain development and function in DS.
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Co-culture with T21 iPSC-derived astrocytes reduces the intrinsic excitability of neurons and tends to have a consequent impact on synaptic development and transmission.
“Co-culture with T21 iPSC-derived astrocytes also reduces the intrinsic excitability of neurons and tends to have a consequent impact on synaptic development and transmission82,135,145.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [145]
The Introduction reports that Down syndrome astrocytes affect neuronal synaptic markers, and the discussion suggests that the observed adhesion changes may have implications for synaptogenesis. But this paper does not report that co-culture with its T21 iPSC-derived astrocytes reduces neurons’ intrinsic excitability or alters synaptic transmission. Reduced excitability appears only in the title of a different study listed in its References. (LLM, conf=0.82)
Experimental — accuracy not yet measuredDS iPSC-derived astrocytes have changes in cell adhesion and motility dynamics.
“Astrocytes differentiated from iPSCs derived from individuals with DS had changes in cell adhesion and motility dynamics compared to matched euploid controls (Bally et al., 2020).”
From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Bally et al., 2020
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Down Syndrome iPSC-Derived Astrocytes Impair Neuronal Synaptogenesis and the mTOR Pathway In Vitro
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Fibronectin and Laminin Increase in the Mouse Brain after Controlled Cortical Impact Injury
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Stem and progenitor cell dysfunction in human trisomies
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Down's syndrome astrocytes have greater antioxidant capacity than euploid astrocytes
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Flagged first, then by citations
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Down-syndrome-induced senescence disrupts the nuclear architecture of neural progenitors
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Astrocytic Factors Controlling Synaptogenesis: A Team Play
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Clustered Protocadherins Emerge as Novel Susceptibility Loci for Mental Disorders
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Astrocytes in Down Syndrome Across the Lifespan
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Self-citationDown syndrome is an oxidative phosphorylation disorder
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Choroid plexus defects in Down syndrome brain organoids enhance neurotropism of SARS-CoV-2
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Consequences of trisomy 21 for brain development in Down syndrome
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“Co-culture with T21 iPSC-derived astrocytes also reduces the intrinsic excitability of neurons and tends to have a consequent impact on synaptic development and transmission 82,135,145 .”
Astrocytes in rare neurological conditions: Morphological and functional considerations
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Robust induction of functional astrocytes using NGN2 expression in human pluripotent stem cells
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Rethinking intellectual disability from neuro- to astro-pathology.
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Cell models for Down syndrome-Alzheimer’s disease research
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Neural lineage differentiation of human pluripotent stem cells: Advances in disease modeling
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Consequences of trisomy syndromes – 21 and beyond
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Studying Abnormal Chromosomal Diseases Using Patient-Derived Induced Pluripotent Stem Cells
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Detection of Embryonic Trisomy 21 in the First Trimester Using Maternal Plasma Cell-Free RNA
Weiner, C. P., Weiss, M. L., Zhou, H. H., Syngelaki, A., Nicolaides, K. H., & Dong, Y. (2022) · Diagnostics · doi:10.3390/diagnostics12061410 · Cited by 8 · see citing works
DYRK1A in the physiology and pathology of the neuron-astrocyte axis
Cisternas, P., Kim, J.-Y., Ashfeld, B. L., & Zartman, J. J. (2025) · Frontiers in Neuroscience · doi:10.3389/fnins.2025.1626062 · Cited by 7 · see citing works
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Elucidation of the Pathogenesis of Autoinflammatory Diseases Using iPS Cells
Saito, M. K. (2021) · Children · doi:10.3390/children8020094 · Cited by 4 · see citing works
Silva, A. L. T. E., de Oliveira, P. H. P., Yokota-Moreno, B. Y., Fausto, J. D. S., Avila, J. P., Nakaya, H. I., Sertie, A. L., & Zampieri, B. L. (2025) · Acta Neuropathologica Communications · doi:10.1186/s40478-025-02090-0 · Cited by 5 · see citing works
Astrocytopathy Is Associated with CA1 Synaptic Dysfunction in a Mouse Model of Down Syndrome
Fernández‐Blanco, Á., González-Arias, C., Sierra, C., Zamora‐Moratalla, A., Perea, G., & Dierssen, M. (2025) · Cells · doi:10.3390/cells14171332 · Cited by 2 · see citing works
Astroglial Activation Is Exacerbated in a Down Syndrome Mouse Model
Zhou, Z., Bi, Y., Zhi, C., Chen, S., Chen, D., Wei, Z. C., & Jiang, X. (2024) · Neuroscience · doi:10.1016/j.neuroscience.2024.04.003 · Cited by 2 · see citing works
The restoration of REST inhibits reactivity of Down syndrome iPSC-derived astrocytes
Huang, T., Fakurazi, S., Cheah, P.-S., & Ling, K. (2025) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2025.1552819 · Cited by 2 · see citing works
REST deficiency and neurogenic-to-gliogenic shift in down syndrome human cerebral organoids
Huang, T., Lim, C.-T., Li, W., Fakurazi, S., Mason, J. O., Cheah, P.-S., Li, Y., & Ling, K. (2026) · Molecular Brain · doi:10.1186/s13041-026-01313-2 · Cited by 1 · see citing works
Organoids: the third dimension of human brain development and disease
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Analysis of Clonal Composition in Human iPSC and ESC and Derived 2D and 3D Differentiated Cultures
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Human induced pluripotent stem cell modeling of neurofibromatosis type 1
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Realizing the potential of exploiting human IPSCs and their derivatives in research of Down syndrome
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Trisomy 21 Drives ADARB1 Overexpression and Premature RNA Recoding in the Developing Fetal Brain
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GPCR-mediated regulation of glial TNF productionPreprint
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GPCR-mediated regulation of glial TNF productionPreprint
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- Authors
- Ponroy Bally, B., Farmer, W. T., Jones, E. V., Jessa, S., Kacerovsky, J. B., Mayran, A., Peng, H., Lefebvre, J. L., Drouin, J., Hayer, A., Ernst, C., & Murai, K. K.
- Affiliations
- Department of Neurology & Neurosurgery, Brain Repair and Integrative Neuroscience Program, Centre for Research in Neuroscience, Research Institute of the McGill University Health Centre, Montreal, QC H3G 1A4, Canada
- McGill University Health Centre (CA)
- Montreal Clinical Research Institute (CA)
- Douglas Mental Health University Institute (CA)
- University of Toronto (CA)
- McGill University (CA)
- Corresponding author
- Murai, Keith K
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2020-01-15
- Volume
- 29
- Issue
- 5
- Pages
- 785-802
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC7104679
- OpenAlex
- W2999698688
- Cited by
- 49
- References
- 112
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 8 · 2023: 6 · 2022: 6 · 2021: 12 · 2020: 6
- FWCI
- 5.62
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (OGB 111152, PJT148569, 156247)
- Natural Sciences and Engineering Research Council of Canada (408044-2011, 69404, 05831-2018)
- Canada Research Chairs
- Brain Canada
- Weston Foundation
- Sandra and Alain Bouchard Intellectual Disability Research Program
- McGill Faculty of Medicine
- Canada First Research Excellence Fund
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- Down syndrome, astrocytes, induced pluripotent stem cells, gene expression dysregulation, chromatin accessibility, cell adhesion, extracellular matrix, cell motility, intellectual disability, brain development
- MeSH terms
- Astrocytes, Cell Adhesion, Cell Differentiation, Cell Movement, Down Syndrome, Gene Expression Regulation, Humans, Genome, Human, Induced Pluripotent Stem Cells, Neural Stem Cells, Transcriptome
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