Lesion stage-dependent causes for impaired remyelination in MS

作者：Katharina Heß, Laura Starost, Nicholas W. Kieran, Christian Thomas, Maria C. J. Vincenten, Jack P. Antel, Gianvito Martino, Inge Huitinga, Luke M. Healy, Tanja Kuhlmann · 发表于：Acta Neuropathologica · 年份：2020 · DOI：10.1007/s00401-020-02189-9 · 被引用次数：142 · 研究领域：Neurogenesis and neuroplasticity mechanisms、Neuroinflammation and Neurodegeneration Mechanisms、Multiple Sclerosis Research Studies

Multiple sclerosis (MS) is the most frequent demyelinating disease and a leading cause for disability in young adults. Despite significant advances in immunotherapies in recent years, disease progression still cannot be prevented. Remyelination, meaning the formation of new myelin sheaths after a demyelinating event, can fail in MS lesions. Impaired differentiation of progenitor cells into myelinating oligodendrocytes may contribute to remyelination failure and, therefore, the development of pharmacological approaches which promote oligodendroglial differentiation and by that remyelination, represents a promising new treatment approach. However, this generally accepted concept has been challenged recently. To further understand mechanisms contributing to remyelination failure in MS, we combined detailed histological analyses assessing oligodendroglial cell numbers, presence of remyelination as well as the inflammatory environment in different MS lesion types in white matter with in vitro experiments using induced-pluripotent stem cell (iPSC)-derived oligodendrocytes (hiOL) and supernatants from polarized human microglia. Our findings suggest that there are multiple reasons for remyelination failure in MS which are dependent on lesion stage. These include lack of myelin sheath formation despite the presence of mature oligodendrocytes in a subset of active lesions as well as oligodendroglial loss and a hostile tissue environment in mixed active/inactive lesions. Therefore, we c...