Lesion stage-dependent causes for impaired remyelination in MS

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

doi:10.1007/s00401-020-02189-9

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.

Highlights

Multiple sclerosis (MS) is the most frequent inflammatory and demyelinating disease of the CNS; it affects approximately 2.3 million people worldwide [15]
Our findings indicate that in active/demyelinating lesions, impaired myelin sheath formation despite the presence of mature oligodendrocytes contributes to remyelination failure, whereas in mixed lesions, loss of oligodendrocytes and a hostile tissue environment prevent successful remyelination
MS lesions display a relative preservation of oligodendrocyte precursor cells (OPC), but lack mature oligodendrocytes suggesting that a differentiation block contributes to remyelination failure in MS

Summary

Introduction

Multiple sclerosis (MS) is the most frequent inflammatory and demyelinating disease of the CNS; it affects approximately 2.3 million people worldwide [15]. 50% of the patients require a walking aid after 10–15 years of disease duration. The socioeconomic costs are significant; in 2013, the annual costs for MS in the US have been estimated to be approximately 10 billion $ per year [1]. MS is characterized by multifocal demyelinating lesions, inflammatory infiltrates (macrophages, T cells, and B cells), damaged and reduced numbers of axons, and loss of oligodendrocytes [45]. Based on density and distribution of blood-derived monocytes and CNS-resident microglia (subsequently summarized as myeloid cells) active, mixed active/inactive and inactive lesions can be distinguished as described in an updated histological classification of MS [38].

Methods

Results

Conclusion