Dynamics of oligodendrocyte generation in multiple sclerosis

• Published in: Nature (London) Vol. 566; no. 7745; pp. 538 - 542
• Main Authors: Yeung, Maggie S. Y., Djelloul, Mehdi, Steiner, Embla, Bernard, Samuel, Salehpour, Mehran, Possnert, Göran, Brundin, Lou, Frisén, Jonas
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2019; Nature Publishing Group
• Subjects: 13/31; 13/51; 14/19; 14/63; 38/22; 631/378/1687; 631/378/2183/2581; 631/378/2596/1705; 631/378/2606/1666; 631/532/489; Adult; Age; Age of Onset; Aging - pathology; Aging - physiology; Animal diseases; Animal models; Atmosphere; Autoimmune diseases; Brain; Carbon 14; Case-Control Studies; Cell Differentiation; Cell membranes; Cell Proliferation; Cell Separation; Central nervous system; Demyelinating diseases; Demyelination; Deoxyribonucleic acid; Disease; DNA; Dynamics; Female; Fibers; Human health and pathology; Humanities and Social Sciences; Humans; Immune system; Lesions; Letter; Life Sciences; Male; multidisciplinary; Multiple sclerosis; Multiple Sclerosis - genetics; Multiple Sclerosis - pathology; Myelin; Myelin Sheath - metabolism; Myelin Sheath - pathology; Myelination; Nerve regeneration; Nervous system; Neurobiology; Neurological research; Neurons and Cognition; Nuclear accidents & safety; Nuclear testing; Oligodendrocytes; Oligodendroglia; Oligodendroglia - cytology; Oligodendroglia - metabolism; Oligodendroglia - pathology; Pathology; Patients; Plaques; Remyelination; Rodents; Science; Science (multidisciplinary); Shadows; Sheaths; Substantia alba; White Matter - cytology; White Matter - metabolism; White Matter - pathology
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-018-0842-3

Oligodendrocytes wrap nerve fibres in the central nervous system with layers of specialized cell membrane to form myelin sheaths 1 . Myelin is destroyed by the immune system in multiple sclerosis, but myelin is thought to regenerate and neurological function can be recovered. In animal models of demyelinating disease, myelin is regenerated by newly generated oligodendrocytes, and remaining mature oligodendrocytes do not seem to contribute to this process 2 – 4 . Given the major differences in the dynamics of oligodendrocyte generation and adaptive myelination between rodents and humans 5 – 9 , it is not clear how well experimental animal models reflect the situation in multiple sclerosis. Here, by measuring the integration of 14 C derived from nuclear testing in genomic DNA 10 , we assess the dynamics of oligodendrocyte generation in patients with multiple sclerosis. The generation of new oligodendrocytes was increased several-fold in normal-appearing white matter in a subset of individuals with very aggressive multiple sclerosis, but not in most subjects with the disease, demonstrating an inherent potential to substantially increase oligodendrocyte generation that fails in most patients. Oligodendrocytes in shadow plaques—thinly myelinated lesions that are thought to represent remyelinated areas—were old in patients with multiple sclerosis. The absence of new oligodendrocytes in shadow plaques suggests that remyelination of lesions occurs transiently or not at all, or that myelin is regenerated by pre-existing, and not new, oligodendrocytes in multiple sclerosis. We report unexpected oligodendrocyte generation dynamics in multiple sclerosis, and this should guide the use of current, and the development of new, therapies. There are no new oligodendrocytes in potentially remyelinated multiple sclerosis shadow plaques, although oligodendrocyte generation is increased in the normal appearing white matter of patients with aggressive disease, informing the development of new therapies.