One-step Reprogramming of Human Fibroblasts into Oligodendrocyte-like Cells by SOX10, OLIG2, and NKX6.2
In: Stem Cell Reports, Jg. 16 (2021-04-01), S. 771-783
Online
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Zugriff:
Summary Limited access to human oligodendrocytes impairs better understanding of oligodendrocyte pathology in myelin diseases. Here, we describe a method to robustly convert human fibroblasts directly into oligodendrocyte-like cells (dc-hiOLs), which allows evaluation of remyelination-promoting compounds and disease modeling. Ectopic expression of SOX10, OLIG2, and NKX6.2 in human fibroblasts results in rapid generation of O4+ cells, which further differentiate into MBP+ mature oligodendrocyte-like cells within 16 days. dc-hiOLs undergo chromatin remodeling to express oligodendrocyte markers, ensheath axons, and nanofibers in vitro, respond to promyelination compound treatment, and recapitulate in vitro oligodendroglial pathologies associated with Pelizaeus-Merzbacher leukodystrophy related to PLP1 mutations. Furthermore, DNA methylome analysis provides evidence that the CpG methylation pattern significantly differs between dc-hiOLs derived from fibroblasts of young and old donors, indicating the maintenance of the source cells’ “age.” In summary, dc-hiOLs represent a reproducible technology that could contribute to personalized medicine in the field of myelin diseases.
Graphical abstract
Highlights • SOX10, OLIG2, and NKX6.2 directly convert human fibroblasts into dc-hiOLs in 16 days • dc-hiOLs express key oligodendrocyte markers • dc-hiOLs preserve the epigenetic age of donor cells • dc-hiOLs from PMD patients show maturation deficit and vulnerability to cell death
In this article, Kuhlmann and colleagues show that human fibroblasts can be directly converted into oligodendrocyte-like cells (dc-hiOLs) upon overexpression of SOX10, OLIG2, and NKX6.2. dc-hiOLs undergo chromatin remodeling to activate oligodendrocyte-related genes, perform ensheathment in vitro, and maintain the epigenetic age of donor cells. The applicability of dc-hiOLs in promyelination compound screening and disease-modeling studies is demonstrated.
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One-step Reprogramming of Human Fibroblasts into Oligodendrocyte-like Cells by SOX10, OLIG2, and NKX6.2
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| Autor/in / Beteiligte Person: | Windener, Farina ; Boespflug-Tanguy, Odile ; Qiao Ling Cui ; Mozafari, Sabah ; Hernández-Rodríguez, Benjamín ; Anne Baron-Van Evercooren ; Thomas, Christian ; Kuhlmann, Tanja ; Schöler, Hans R. ; Winkler, Jürgen ; Yu Kang T. Xu ; Stehling, Martin ; Ottoboni, Linda ; Martino, Gianvito ; Ehrlich, Marc ; Albrecht, Stefanie ; Chanoumidou, Konstantina ; Velychko, Sergiy ; Vaquerizas, Juan M. ; Antel, Jack P. ; Kim, Kee-Pyo ; University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM) ; Max Planck Institute for Molecular Biomedicine ; Max-Planck-Gesellschaft ; Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP] ; Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS) ; IRCCS Ospedale San Raffaele [Milan, Italy] ; Montreal Neurological Institute and Hospital ; McGill University = Université McGill [Montréal, Canada] ; Johns Hopkins University (JHU) ; Friedrich-Alexander Universität Erlangen-Nürnberg (FAU) ; Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP) ; Institut du Cerveau = Paris Brain Institute (ICM) ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP] ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité) ; HAL-SU, Gestionnaire |
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| Zeitschrift: | Stem Cell Reports, Jg. 16 (2021-04-01), S. 771-783 |
| Veröffentlichung: | Elsevier BV, 2021 |
| Medientyp: | unknown |
| ISSN: | 2213-6711 (print) |
| DOI: | 10.1016/j.stemcr.2021.03.001 |
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