Human iPSC-based models highlight defective glial and neuronal differentiation from neural progenitor cells in metachromatic leukodystrophy
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Le résumé fourni par la source
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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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Human iPSC-based models highlight defective glial and neuronal differentiation from neural progenitor cells in metachromatic leukodystrophy
- Date Crossref
- 13/06/2018
- Éditeur
- Springer Science and Business Media LLC
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
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The San Raffaele Telethon Institute for Gene Therapy pays non établi dans la noticeStructure de recherche
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Istituti di Ricovero e Cura a Carattere Scientifico pays non établi dans la noticeÉtablissement de santé
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Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele pays non établi dans la noticeÉtablissement de santé
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Institut des Maladies Génétiques Imagine pays non établi dans la noticeStructure de recherche
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German Center for Neurodegenerative Diseases pays non établi dans la noticeStructure de recherche
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Sahlgrenska University Hospital Department of Molecular and Clinical Medicine pays non établi dans la noticeÉtablissement de santé
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University of Gothenburg Department of Clinical Chemistry and Transfusion Medicine pays non établi dans la noticeUniversité ou école supérieure
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Istituto Giannina Gaslini pays non établi dans la noticeÉtablissement de santé
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University of Perugia Department of Chemistry pays non établi dans la noticeUniversité ou école supérieure
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Vita-Salute San Raffaele University pays non établi dans la noticeUniversité ou école supérieure
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San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) pays non établi dans la noticeStructure de recherche
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Institute Imagine pays non établi dans la noticeStructure de recherche
The San Raffaele Telethon Institute for Gene Therapy, Istituti di Ricovero e Cura a Carattere Scientifico et Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.