PT  - JOURNAL ARTICLE
AU  - Sabah Mozafari
AU  - Laura Starost
AU  - Blandine Manot-Saillet
AU  - Beatriz Garcia-Diaz
AU  - Yu Kang T. Xu
AU  - Delphine Roussel
AU  - Marion J. F. Levy
AU  - Linda Ottoboni
AU  - Kee-Pyo Kim
AU  - Hans R. Schöler
AU  - Timothy E. Kennedy
AU  - Jack P. Antel
AU  - Gianvito Martino
AU  - Maria Cecilia Angulo
AU  - Tanja Kuhlmann
AU  - Anne Baron-Van Evercooren
TI  - Multiple sclerosis iPSC-derived oligodendroglia conserve their intrinsic properties to functionally interact with axons and glia in vivo
AID  - 10.1101/2020.05.05.078642
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.05.05.078642
4099  - http://biorxiv.org/content/early/2020/05/06/2020.05.05.078642.short
4100  - http://biorxiv.org/content/early/2020/05/06/2020.05.05.078642.full
AB  - The remyelination failure in multiple sclerosis (MS) is associated with a migration/differentiation block of oligodendroglia. The reason for this block is highly debated. It could result from disease-related extrinsic regulators of the oligodendroglial biology or reflect MS oligodendrocyte intrinsic properties. To avoid confounding immune-mediated extrinsic effect, we used an immune-deficient, dysmyelinating mouse model, to compare side-by-side induced pluripotent stem-cell-derived O4+ oligodendroglia from MS and healthy donors following their engraftment in the developing CNS. We show that the MS-progeny survives, proliferates and differentiates into oligodendrocytes to the same extent as controls. Quantitative multi-parametric imaging indicates that MS and control oligodendrocytes generate equal amounts of myelin, with bona-fide nodes of Ranvier and promote equal restoration of their host slow conduction. Moreover, the MS-derived progeny expressed oligodendrocyte- and astrocyte-specific connexins and established functional connections with donor and host glial cells. Thus, MS pluripotent stem cell-derived progeny fully integrates into functional axo-glial and glial-glial components, reinforcing the view that the MS oligodendrocyte differentiation block is not due to intrinsic oligodendroglial deficits. These biological findings as well as the fully integrated human-murine chimeric model should facilitate the development of pharmacological or cell-based therapies to promote CNS remyelination.One Sentence Summary Multiple Sclerosis oligodendroglia, regardless of major immune manipulators, are intrinsically capable of myelination and making functional axo-glia and glia-glia connections after engraftment in the murine CNS, reinforcing the view that the MS oligodendrocyte differentiation block is not due to major intrinsic oligodendroglial deficits but most likely to environmental conditions.Competing Interest StatementT.K. has a pending patent application for the generation of human oligodendrocytes.