ArticleCell death & disease2018
Human iPSC-based models highlight defective glial and neuronal differentiation from neural progenitor cells in metachromatic leukodystrophy.
Article in Cell death & disease, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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36 citing papers in PubMed, 47 citations in OpenAlex.
- Review
- The long-acting anticoagulant rodenticide brodifacoum induces neuropathology in adult New Zealand White rabbits and is reduced by the bile sequestrant cholestyramine.Neurotoxicology · 2026Article
- Generation of Donor-Specific iPSC for Modelling Lysosomal Storage Disorders.Methods in molecular biology (Clifton, N.J.) · 2026Article
- A scoping review of stem cell models of leukodystrophies: advances in understanding pathophysiological mechanisms.NPJ genomic medicine · 2025Article
- Stem cell and gene therapies for leukodystrophies.Molecular therapy. Methods & clinical development · 2025Review
- AAV vectors trigger DNA damage response-dependent pro-inflammatory signalling in human iPSC-derived CNS models and mouse brain.Nature communications · 2025Article
- Glial interactions in the formation and plasticity of the corpus callosum.Frontiers in cellular neuroscience · 2025Review
- A novel iPSC model reveals selective vulnerability of neurons in multiple sulfatase deficiency.Molecular genetics and metabolism · 2024Article
- The use of induced pluripotent stem cells as a platform for the study of depression.Frontiers in psychiatry · 2024Review
- A novel CRISPR/Cas9-based iduronate-2-sulfatase (IDS) knockout human neuronal cell line reveals earliest pathological changes.Scientific reports · 2023Article
- Single Systemic Administration of a Gene Therapy Leading to Disease Treatment in Metachromatic LeukodystrophyThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2023Article
- rAAV2-Mediated Restoration of GALC in Neural Stem Cells from Krabbe Patient-Derived iPSCs.Pharmaceuticals (Basel, Switzerland) · 2023Article
- Utilizing hiPSC-derived oligodendrocytes to study myelin pathophysiology in neuropsychiatric and neurodegenerative disorders.Frontiers in cellular neuroscience · 2023Review
- Review
- A model of metformin mitochondrial metabolism in metachromatic leukodystrophy: first description of human Schwann cells transfected with CRISPR-Cas9.Open biology · 2022Article
- Generation and characterization of motor neuron progenitors and motor neurons using metachromatic leukodystrophy-induced pluripotent stem cells.Molecular genetics and metabolism reports · 2022Article
- Molecular Mechanisms in Lysosomal Storage Diseases: From Pathogenesis to Therapeutic Strategies.Biomedicines · 2022Article
- DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes.The Journal of experimental medicine · 2022Article
- Identification of neurodegeneration indicators and disease progression in metachromatic leukodystrophy using quantitative NMR-based urinary metabolomics.JIMD reports · 2022Article
- Human iPSC-based neurodevelopmental models of globoid cell leukodystrophy uncover patient- and cell type-specific disease phenotypes.Stem cell reports · 2021Article
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Authors and funding
12 authors at 6 institutions in 2 countries.
Funding
Abstract
The pathological cascade leading from primary storage to neural cell dysfunction and death in metachromatic leukodystrophy (MLD) has been poorly elucidated in human-derived neural cell systems. In the present study, we have modeled the progression of pathological events during the differentiation of patient-specific iPSCs to neuroepithelial progenitor cells (iPSC-NPCs) and mature neurons, astrocytes, and oligodendrocytes at the morphological, molecular, and biochemical level. We showed significant sulfatide accumulation and altered sulfatide composition during the differentiation of MLD iPSC-NPCs into neuronal and glial cells. Changes in sulfatide levels and composition were accompanied by the expansion of the lysosomal compartment, oxidative stress, and apoptosis. The neuronal and glial differentiation capacity of MLD iPSC-NPCs was significantly impaired. We showed delayed appearance and/or reduced levels of oligodendroglial and astroglial markers as well as reduced number of neurons and disorganized neuronal network. Restoration of a functional Arylsulfatase A (ARSA) enzyme in MLD cells using lentiviral-mediated gene transfer normalized sulfatide levels and composition, globally rescuing the pathological phenotype. Our study points to MLD iPSC-derived neural progeny as a useful in vitro model to assess the impact of ARSA deficiency along NPC differentiation into neurons and glial cells. In addition, iPSC-derived neural cultures allowed testing the impact of ARSA reconstitution/overexpression on disease correction and, importantly, on the biology and functional features of human NPCs, with important therapeutic implications.
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