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Cited by 24Down syndrome and intellectual disability researchPluripotent Stem Cells ResearchNeurogenesis and neuroplasticity mechanisms

Asynchronous excitatory neuron development in an isogenic cortical spheroid model of Down syndrome

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Li, Zhen, Klein, Jenny A., Rampam, Sanjeev, Kurzion, Ronni, Campbell, Natalie Baker, Patel, Yesha, Haydar, Tarik F., Zeldich, Ella·2022·Frontiers in Neuroscience
DOI 10.3389/fnins.2022.932384PMC PMC9504873

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Abstract

The intellectual disability (ID) in Down syndrome (DS) is thought to result from a variety of developmental deficits such as alterations in neural progenitor division, neurogenesis, gliogenesis, cortical architecture, and reduced cortical volume. However, the molecular processes underlying these neurodevelopmental changes are still elusive, preventing an understanding of the mechanistic basis of ID in DS. In this study, we used a pair of isogenic (trisomic and euploid) induced pluripotent stem cell (iPSC) lines to generate cortical spheroids (CS) that model the impact of trisomy 21 on brain development. Cortical spheroids contain neurons, astrocytes, and oligodendrocytes and they are widely used to approximate early neurodevelopment. Using single cell RNA sequencing (scRNA-seq), we uncovered cell type-specific transcriptomic changes in the trisomic CS. In particular, we found that excitatory neuron populations were most affected and that a specific population of cells with a transcriptomic profile resembling layer IV cortical neurons displayed the most profound divergence in developmental trajectory between trisomic and euploid genotypes. We also identified candidate genes potentially driving the developmental asynchrony between trisomic and euploid excitatory neurons. Direct comparison between the current isogenic CS scRNA-seq data and previously published datasets revealed several recurring differentially expressed genes between DS and control samples. Altogether, our study highlights the power and importance of cell type-specific analyses within a defined genetic background, coupled with broader examination of mixed samples, to comprehensively evaluate cellular phenotypes in the context of DS.

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  • Results from induced pluripotent stem cell studies of neurogenesis are discordant: the generation of neurons from induced pluripotent stem cells has been reported in some studies to be impaired and in others not to be impaired, which may be explained by technical differences in the cell lines and protocols used.

    “However, results from these studies are discordant: the generation of neurons from iPSCs has been reported in some studies to be impaired74,77–79 and in others not to be impaired75,80,81, which may be explained by technical differences in the cell lines and protocols used (see Box 1).”

    From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [74]

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Analyses of neural progenitor cells arising from trisomy 21 induced pluripotent stem cells have provided conflicting data, with some suggesting that apoptosis is increased and others seeing no effect.

    “Analyses of NPCs arising from T21 iPSCs have provided conflicting data, with some suggesting that apoptosis is increased74,79,95 and others seeing no effect75,77,81,96.”

    From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [74]

    The Results section, “Trisomic cortical spheroids display a reduced cortical volume” (page unavailable), reports increased apoptosis-marker staining in trisomic versus euploid spheroids at days 90 and 130, but no significant difference at day 30. The spheroids were derived from iPSCs and contained neural progenitors alongside other cell types; the apoptosis measurement was not specific to progenitor cells, so the NPC-specific wording is not fully supported. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Genome-wide dysregulation of gene expression in neurons likely leads to over-expression and/or under-expression of key genes that regulate synaptogenesis.

    “Genome-wide dysregulation of gene expression (Box 3) in neurons likely leads to over-expression and/or under-expression of key genes that regulate synaptogenesis, but specific candidates have yet to be identified74,77,81,143.”

    From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [74]

    The Results report up- and down-regulated genes in excitatory neurons, and the Discussion identifies BCL11B—a gene important for synapse formation—as less associated with trisomic ExN4 cells. This supports a possible link between neuronal gene dysregulation and synaptic development, but the paper does not establish that genome-wide dysregulation causes altered expression of synaptogenesis-regulating genes. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • T21 impacts gene expression across the genome.

    “However, unbiased analyses using omics technology have recently revealed that T21 impacts gene expression across the genome39,74,143,156–159.”

    From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [74]

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Authors
Li, Z., Klein, J. A., Rampam, S., Kurzion, R., Campbell, N. B., Patel, Y., Haydar, T. F., & Zeldich, E.
Affiliations
  • Children's National (US)
  • Boston University (US)
Corresponding author
  • Haydar, Tarik F.
  • Zeldich, Ella
ORCID
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2022-09-07
Volume
16
Pages
932384-932384
ISSN
1662-453X (ISSN-L)
DOI
10.3389/fnins.2022.932384
PMC
PMC9504873
OpenAlex
W4294935527
Cited by
24
References
128
Citations by year
2026: 7 · 2025: 9 · 2024: 3 · 2023: 3 · 2022: 2
FWCI
3.75
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Neuroscience (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • School of Medicine, Boston University
  • Children’s Hospital of Wisconsin Research Institute
  • Children's National Hospital
  • National Institutes of Health (1r21ns125469-01a1)
  • Intellectual and Developmental Disabilities Research Center (P50HD105328)
  • Center for Neuroscience Research
  • National Institute on Aging (R01AG078460)
  • National Institute of Neurological Disorders and Stroke (R01NS105138, R21 NS125469, R21-HD098542)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD105328)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
Down syndrome, intellectual disability, excitatory neurons, isogenic iPSC lines, brain development, cell type-specific transcriptomics, asynchronous development, differentially expressed genes, single-cell RNA sequencing

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