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Cited by 56Genetics and Neurodevelopmental DisordersPluripotent Stem Cells ResearchNeuroscience and Neuropharmacology Research

Novel fragile X syndrome 2D and 3D brain models based on human isogenic FMRP-KO iPSCs.

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Brighi, Carlo, Salaris, Federico, Soloperto, Alessandro, Cordella, Federica, Ghirga, Silvia, de Turris, Valeria, Rosito, Maria, Porceddu, Pier Francesca +4 more·2021·Cell Death & Disease
DOI 10.1038/s41419-021-03776-8PMC PMC8124071

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Abstract

Fragile X syndrome (FXS) is a neurodevelopmental disorder, characterized by intellectual disability and sensory deficits, caused by epigenetic silencing of the FMR1 gene and subsequent loss of its protein product, fragile X mental retardation protein (FMRP). Delays in synaptic and neuronal development in the cortex have been reported in FXS mouse models; however, the main goal of translating lab research into pharmacological treatments in clinical trials has been so far largely unsuccessful, leaving FXS a still incurable disease. Here, we generated 2D and 3D in vitro human FXS model systems based on isogenic FMR1 knock-out mutant and wild-type human induced pluripotent stem cell (hiPSC) lines. Phenotypical and functional characterization of cortical neurons derived from FMRP-deficient hiPSCs display altered gene expression and impaired differentiation when compared with the healthy counterpart. FXS cortical cultures show an increased number of GFAP positive cells, likely astrocytes, increased spontaneous network activity, and depolarizing GABAergic transmission. Cortical brain organoid models show an increased number of glial cells, and bigger organoid size. Our findings demonstrate that FMRP is required to correctly support neuronal and glial cell proliferation, and to set the correct excitation/inhibition ratio in human brain development.

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  • In a human FMR1 KO iPSC cortical model, KO NPCs produced larger organoids and displayed increased GFAP expression compared with isogenic controls.

    “In a separate human FMR1 KO iPSC cortical model, KO NPCs produced larger organoids and displayed increased glial fibrillary acidic protein (GFAP) expression when compared with isogenic controls (Brighi et al., 2021).”

    From Astrocytes in fragile X syndrome (2024) · cites this paper as Brighi et al., 2021

    The Results section, ‘Development of a brain organoid-based FXS 3D disease model,’ reports that FMRP-KO organoids were larger and had increased GFAP staining compared with isogenic FMRP-WT organoids. However, the Methods section, ‘Generation of self-assembled brain organoids,’ says the organoids were generated from dissociated hiPSCs, not from KO neural progenitor cells (NPCs); the GFAP finding is reported for organoids, not specifically for NPCs. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Increased GFAP expression is found in a human FMR1 KO iPSC cortical organoid model.

    “Increased GFAP expression is also found in a human FMR1 KO iPSC cortical organoid model (Brighi et al., 2021).”

    From Astrocytes in fragile X syndrome (2024) · cites this paper as Brighi et al., 2021

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Cited by

Sorted by citations

Authors
Brighi, C., Salaris, F., Soloperto, A., Cordella, F., Ghirga, S., de Turris, V., Rosito, M., Porceddu, P. F., D’Antoni, C., Reggiani, A., Rosa, A., & Di Angelantonio, S.
Affiliations
Italian Institute of Technology (IT)
Corresponding author
Rosa, Alessandro
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2021-05-15
Volume
12
Issue
5
Pages
498-498
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/s41419-021-03776-8
PMC
PMC8124071
OpenAlex
W3160678528
Cited by
56
References
9
Citations by year
2026: 7 · 2025: 7 · 2024: 13 · 2023: 11 · 2022: 11 · 2021: 6 · 2020: 1
FWCI
5.80
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Istituto Italiano di Tecnologia
  • Regione Lazio
Topics
  • 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
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
fragile X syndrome, FMRP, induced pluripotent stem cells, cortical neurons, astrocytes, GABAergic neurotransmission, excitation-inhibition balance, neuronal differentiation, glial cell proliferation, brain development, isogenic cell lines
MeSH terms
Brain, Cell Differentiation, Fragile X Syndrome, Humans, Fragile X Messenger Ribonucleoprotein 1, Fragile X Mental Retardation Protein, Induced Pluripotent Stem Cells

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