One-step Reprogramming of Human Fibroblasts into Oligodendrocyte-like Cells by SOX10, OLIG2, and NKX6.2

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Chanoumidou, Konstantina | Hernández-Rodríguez, Benjamín | Windener, Farina | Thomas, Christian | Stehling, Martin | Mozafari, Sabah | Albrecht, Stefanie | Ottoboni, Linda | Antel, Jack | Kim, Kee-Pyo | Velychko, Sergiy | Cui, Qiao, Ling | Xu, Yu, Kang T | Martino, Gianvito | Winkler, Jürgen | Schöler, Hans, R | Baron-van Evercooren, Anne | Boespflug-Tanguy, Odile | Vaquerizas, Juan, M | Ehrlich, Marc | Kuhlmann, Tanja

Edité par CCSD ; Elsevier -

International audience. 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.

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