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Cited by 78Pluripotent Stem Cells ResearchDown syndrome and intellectual disability researchAlzheimer's disease research and treatments

Brief Report: Isogenic Induced Pluripotent Stem Cell Lines From an Adult With Mosaic Down Syndrome Model Accelerated Neuronal Ageing and Neurodegeneration

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Murray, Aoife, Letourneau, Audrey, Canzonetta, Claudia, Stathaki, Elisavet, Gimelli, Stefania, Sloan-Bena, Frederique, Abrehart, Robert, Goh, Pollyanna +14 more·2015·Stem Cells
DOI 10.1002/stem.1968PMC PMC4737213
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Abstract

Trisomy 21 (T21), Down Syndrome (DS) is the most common genetic cause of dementia and intellectual disability. Modeling DS is beginning to yield pharmaceutical therapeutic interventions for amelioration of intellectual disability, which are currently being tested in clinical trials. DS is also a unique genetic system for investigation of pathological and protective mechanisms for accelerated ageing, neurodegeneration, dementia, cancer, and other important common diseases. New drugs could be identified and disease mechanisms better understood by establishment of well-controlled cell model systems. We have developed a first nonintegration-reprogrammed isogenic human induced pluripotent stem cell (iPSC) model of DS by reprogramming the skin fibroblasts from an adult individual with constitutional mosaicism for DS and separately cloning multiple isogenic T21 and euploid (D21) iPSC lines. Our model shows a very low number of reprogramming rearrangements as assessed by a high-resolution whole genome CGH-array hybridization, and it reproduces several cellular pathologies seen in primary human DS cells, as assessed by automated high-content microscopic analysis. Early differentiation shows an imbalance of the lineage-specific stem/progenitor cell compartments: T21 causes slower proliferation of neural and faster expansion of hematopoietic lineage. T21 iPSC-derived neurons show increased production of amyloid peptide-containing material, a decrease in mitochondrial membrane potential, and an increased number and abnormal appearance of mitochondria. Finally, T21-derived neurons show significantly higher number of DNA double-strand breaks than isogenic D21 controls. Our fully isogenic system therefore opens possibilities for modeling mechanisms of developmental, accelerated ageing, and neurodegenerative pathologies caused by T21. Stem Cells 2015;33:2077–2084 Video Highlight: https://youtu.be/MoMwXg2azGo

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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 [75]

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  • 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 [75]

    The Results report no increase in the proportion of nonviable T21 neural progenitor cells, supporting the cited paper's placement among studies finding no increase in cell death. The passage does not report a direct measure of apoptosis, so it does not fully establish the more specific claim of no effect on apoptosis. (LLM, conf=0.82)

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  • Two studies found no changes in differentiation of excitatory cortical neurons from trisomic iPSCs.

    “Two studies using isogenic pairs of iPSCs did not identify any changes in differentiation of excitatory cortical neurons (Weick et al., 2013; Murray et al., 2015).”

    From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Murray et al., 2015

    In the Results (page unavailable), Murray et al. report that both isogenic trisomic and disomic iPSCs produced neurons, and that the cortical-neuron protocol yielded predominantly neuronal cells. But their statement that cortical-layer subpopulations did not differ refers to an earlier study; they say they cannot fully rule out cell-type differences in their own cultures. Thus their findings support comparable neuronal differentiation in part, not an unqualified finding of no changes in excitatory cortical-neuron differentiation. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Trisomic iPSC-derived NPCs show a proliferation deficit compared to controls.

    “In two different isogenic pairs, the trisomic NPCs showed a proliferation deficit compared to their control (Hibaoui et al., 2014; Murray et al., 2015).”

    From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Murray et al., 2015

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References 33 · Cited by 78

Research works printed but not linked: 28

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Authors
Murray, A., Letourneau, A., Canzonetta, C., Stathaki, E., Gimelli, S., Sloan-Bena, F., Abrehart, R., Goh, P., Lim, S., Baldo, C., Dagna-Bricarelli, F., Hannan, S., Mortensen, M., Ballard, D., Syndercombe Court, D., Fusaki, N., Hasegawa, M., Smart, T. G., Bishop, C., Antonarakis, S. E., Groet, J., & Nizetic, D.
Affiliations
  • Blizard Institute (GB)
  • University of Geneva (CH)
  • University Hospital of Geneva (CH)
  • Service of Genetic Medicine, University Geneva Hospitals, Geneva, Switzerland
  • Nanyang Technological University (SG)
  • Ente Ospedaliero Ospedali Galliera (IT)
  • Liguria Department of Genetics, Genoa, Italy
  • University College London (GB)
  • King's College London (GB)
  • Department of Forensic and Analytical Science King's College, London, United Kingdom
  • Japan Science and Technology Agency (JP)
  • ID Pharma (Japan) (JP)
  • Queen Mary University of London (GB)
  • The Blizard Institute Barts and The London School of Medicine, London, United Kingdom
Corresponding author
Groet, Jürgen
ORCID
Venue
Stem Cells
Publisher
Oxford University Press (OUP)
Published
2015-05-21
Volume
33
Issue
6
Pages
2077-2084
ISSN
  • 1066-5099 (ISSN-L)
  • 1549-4918
DOI
10.1002/stem.1968
PMC
PMC4737213
OpenAlex
W1608695637
Cited by
78
References
33
Citations by year
2026: 7 · 2025: 11 · 2024: 6 · 2023: 6 · 2022: 11 · 2021: 4 · 2020: 6 · 2019: 5 · 2018: 7 · 2017: 4 · 2016: 5 · 2015: 6
FWCI
3.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Stem Cells (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Portal (King's College London) (publishedVersion, other-oa)
  • Archive ouverte UNIGE (University of Geneva) (publishedVersion)
  • DR-NTU (Nanyang Technological University) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Queen Mary Research Online (Queen Mary University of London) (submittedVersion, cc-by)
  • Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
Funders
Wellcome Trust (098330/Z/12/Z)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
Down syndrome, induced pluripotent stem cells, isogenic cell models, constitutional mosaicism, iPSC-derived neurons, accelerated aging, neurodegeneration, amyloid fibril formation, mitochondrial dysfunction, DNA double-strand breaks, intellectual disability, dementia
MeSH terms
Aging, Animals, Cell Differentiation, Cells, Cultured, Down Syndrome, Fibroblasts, Humans, Mitochondria, Neurons, Induced Pluripotent Stem Cells

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