Single-cell RNA sequencing of neural stem cells derived from human trisomic iPSCs reveals the abnormalities during neural differentiation of Down syndrome
Open accessAbstract
Introduction: Down syndrome (DS) is the most common genetic condition that causes intellectual disability in humans. The molecular mechanisms behind the DS phenotype remain unclear. Therefore, in this study, we present new findings on its molecular mechanisms through single-cell RNA sequencing. Methods: Induced pluripotent stem cells (iPSCs) from the patients with DS and the normal control (NC) patients were differentiated into iPSCs-derived neural stem cells (NSCs). Single-cell RNA sequencing was performed to achieve a comprehensive single-cell level differentiation roadmap for DS-iPSCs. Biological experiments were also performed to validate the findings. Results and Discussion: The results demonstrated that iPSCs can differentiate into NSCs in both DS and NC samples. Furthermore, 19,422 cells were obtained from iPSC samples (8,500 cells for DS and 10,922 cells for the NC) and 16,506 cells from NSC samples (7,182 cells for DS and 9,324 cells for the NC), which had differentiated from the iPSCs. A cluster of DS-iPSCs, named DS-iPSCs-not differentiated (DSi-PSCs-ND), which had abnormal expression patterns compared with NC-iPSCs, were demonstrated to be unable to differentiate into DS-NSCs. Further analysis of the differentially expressed genes revealed that inhibitor of differentiation family (ID family) members, which exhibited abnormal expression patterns throughout the differentiation process from DS-iPSCs to DS-NSCs, may potentially have contributed to the neural differentiation of DS-iPSCs. Moreover, abnormal differentiation fate was observed in DS-NSCs, which resulted in the increased differentiation of glial cells, such as astrocytes, but decreased differentiation into neuronal cells. Furthermore, functional analysis demonstrated that DS-NSCs and DS-NPCs had disorders in axon and visual system development. The present study provided a new insight into the pathogenesis of DS.
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When cultured long enough to enable the generation of astrocytes, trisomy 21 induced pluripotent stem cells generate more astrocytes than control induced pluripotent stem cells, concomitant with a reduction in the generation of neurons.
“Similarly, when cultured for long enough to enable the generation of astrocytes, T21 iPSCs generate more of this cell type than control iPSCs, concomitant with a reduction in the generation of neurons79,82,96,103.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [103]
The Results section (‘DS-NSCs have an abnormal differentiation fate compared with NC-NSCs’; page unavailable) reports more glial progenitors and fewer neuronal progenitors in Down syndrome iPSC-derived neural stem cells than in controls. It interprets this as a shift toward glial cells, such as astrocytes, and away from neuronal cells. The study does not show that prolonged culture generated more mature astrocytes and fewer neurons. (LLM, conf=0.88)
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- Authors
- Qiu, J.-J., Liu, Y.-N., Wei, H., Zeng, F., & Yan, J.-B.
- Affiliations
- Shanghai Jiao Tong University (CN)
- Corresponding author
- Zeng, Fanyi
- ORCID
- Venue
- Frontiers in Molecular Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2023-06-15
- Volume
- 16
- Pages
- 1137123-1137123
- ISSN
- 1662-5099 (ISSN-L)
- PMC
- PMC10311021
- OpenAlex
- W4380680711
- Cited by
- 12
- References
- 38
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 6
- FWCI
- 3.07
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Molecular Neuroscience (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (81971421, 81471485)
- National Key Research and Development Program of China (2019YFA0801402)
- 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, neural stem cells, induced pluripotent stem cells, neuronal differentiation, single-cell transcriptomics, glial differentiation, astrocytes, axon development, visual system development, intellectual disability
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