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Open Access 01-09-2020 | Multiple Sclerosis | Original Paper

Lesion stage-dependent causes for impaired remyelination in MS

Authors: Katharina Heß, Laura Starost, Nicholas W. Kieran, Christian Thomas, Maria C. J. Vincenten, Jack Antel, Gianvito Martino, Inge Huitinga, Luke Healy, Tanja Kuhlmann

Published in: Acta Neuropathologica | Issue 3/2020

Abstract

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 conclude that better in vivo and in vitro models which mimic the pathological hallmarks of the different MS lesion types are required for the successful development of remyelination promoting drugs.

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Title: Lesion stage-dependent causes for impaired remyelination in MS
Authors: Katharina Heß
Laura Starost
Nicholas W. Kieran
Christian Thomas
Maria C. J. Vincenten
Jack Antel
Gianvito Martino
Inge Huitinga
Luke Healy
Tanja Kuhlmann
Publication date: 01-09-2020
Publisher: Springer Berlin Heidelberg
Keyword: Multiple Sclerosis
Published in: Acta Neuropathologica / Issue 3/2020
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-020-02189-9

At a glance: The STEP trials

Springer Medicine

Lesion stage-dependent causes for impaired remyelination in MS

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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