Mozafari Sabah, Starost Laura, Manot-Saillet Blandine, Garcia-Diaz Beatriz, Xu Yu Kang T, Roussel Delphine, Levy Marion J F, Ottoboni Linda, Kim Kee-Pyo, Schöler Hans R, Kennedy Timothy E, Antel Jack P, Martino Gianvito, Angulo Maria Cecilia, Kuhlmann Tanja, Baron-Van Evercooren Anne
INSERM, U1127, F-75013 Paris, France.
CNRS, UMR 7225, F-75013 Paris, France.
Sci Adv. 2020 Dec 4;6(49). doi: 10.1126/sciadv.abc6983. Print 2020 Dec.
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 or intrinsic regulators in oligodendroglial biology. To avoid confounding immune-mediated extrinsic effect, we used an immune-deficient mouse model to compare induced pluripotent stem cell-derived oligodendroglia from MS and healthy donors following engraftment in the developing CNS. We show that the MS-progeny behaves and differentiates into oligodendrocytes to the same extent as controls. They generate equal amounts of myelin, with bona fide nodes of Ranvier, and promote equal restoration of their host slow conduction. MS-progeny expressed oligodendrocyte- and astrocyte-specific connexins and established functional connections with donor and host glia. Thus, MS oligodendroglia, regardless of major immune manipulators, are intrinsically capable of myelination and making functional axo-glia/glia-glia connections, reinforcing the view that the MS oligodendrocyte differentiation block is not from major intrinsic oligodendroglial deficits.
多发性硬化症（MS）中的髓鞘再生失败与少突胶质细胞的迁移/分化阻滞有关。这种阻滞的原因备受争议。它可能是由少突胶质细胞生物学中与疾病相关的外在或内在调节因子导致的。为了避免混淆免疫介导的外在效应，我们使用免疫缺陷小鼠模型，比较了在发育中的中枢神经系统中移植后，来自MS患者和健康供体的诱导多能干细胞衍生的少突胶质细胞。我们发现，MS后代的行为和分化为少突胶质细胞的程度与对照组相同。它们产生等量的髓磷脂，具有真正的郎飞结，并促进宿主慢传导的同等恢复。MS后代表达少突胶质细胞和星形胶质细胞特异性连接蛋白，并与供体和宿主神经胶质建立功能连接。因此，无论主要免疫操纵因素如何，MS少突胶质细胞在本质上都能够进行髓鞘形成并建立功能性轴突-神经胶质/神经胶质-神经胶质连接，这进一步支持了MS少突胶质细胞分化阻滞并非源于主要的内在少突胶质细胞缺陷这一观点。
