Glial cells in white and grey matter: relevance for multiple sclerosis?

Thecla Anne van Wageningen

    Research output: PhD ThesisPhD-Thesis - Research and graduation internal

    84 Downloads (Pure)

    Abstract

    Multiple sclerosis (MS) is a chronic neuroinflammatory disease of the central nervous system (CNS). The disease is pathologically characterized by loss of myelin around axons, infiltration of peripheral immune cells, degeneration of axons and activation of local glial cells. These sites of damage within the CNS are also referred to as a lesion. Lesions can arise in various brain areas and thus lead to a very heterogeneous clinical presentation of MS, such as sensory and motor symptoms, as well as cognitive and psychiatric dysfunction. Pathological post-mortem tissue of-patients with MS, shows that the loss of myelin in the white matter coincides with a profound and marked inflammatory response of local glial cells and infiltration of peripheral immune cells. These white matter lesions can be classified based on the degree of inflammation visible from active (very high inflammation) to chronically active or mixed active/inactive (less inflammation in the center of the lesion but marked inflammation at the rim of the lesion e.g. smouldering lesions) to inactive (little signs of inflammation but a strong astrocyte response causing scarring of the tissue). In contrast to white matter lesions, gray matter lesions are categorized based on the location of the lesion only and not their inflammatory status. Historically, gray matter lesions have been relatively understudied because, unlike white matter lesions, they are poorly, or not all visible on MRI images made in the clinic. However, recent research has shown that gray matter lesions are present early in the disease process and may be related to disease progression, especially in the progressive forms of MS. However, in post-mortem tissue, grey matter lesions often do not feature the overt inflammation observed in white matter lesions. Whereas there is increasing knowledge on grey matter and white matter specific pathological events, it is unclear which pathological events (other than the event of demyelination) are shared or which are divergent between the two areas. In addition, much is known about the role of glial cells in white matter lesions, but less is known about glial cells in grey matter lesions. In this thesis we have elaborated on early observations indicating that notwithstanding the presence of demyelination, white and grey matter lesions pathologically appear different. The role glial cells play in neuropathological processes, i.e. in MS, has led us to further characterize the signature of glial cells among others in white and grey matter lesions of MS patients with a focus on combining histopathological findings with molecular techniques such as RNA-sequencing and in vitro models of white and grey matter derived glial cells. The strength of the research presented in this thesis lies in the direct comparisons made between (demyelinated) white and grey matter, including glial cells from both areas, in every study. Taken together this thesis has exposed several important topics which need to be further elucidated to get a better understanding of glial function in both white and grey matter. Important topics discussed here include the interplay of environment and development in the formation of glial subtypes in white and grey matter, defining what are ‘homeostatic’ glial cell markers and more specific for MS pathology: better understanding of the glial response in the grey matter lesions particularly. Gaining more insight in these topics will not only aid in a better understanding of MS pathology, but likely also of the specific role of glial cells in non-diseased white and grey matter.
    Original languageEnglish
    QualificationDr.
    Awarding Institution
    • Vrije Universiteit Amsterdam
    Supervisors/Advisors
    • Geurts, Jeroen Johan Guillaume, Supervisor, External person
    • van Dam, Valerie Anne-Marie Madeleine, Co-supervisor, External person
    • Boddeke, Erik, Co-supervisor, External person
    Award date25 Feb 2022
    Place of Publications.l.
    Publisher
    Print ISBNs9789464580457
    Publication statusPublished - 25 Feb 2022

    Keywords

    • multiple sclerosis
    • glial cells
    • microglia
    • astrocytes
    • cortical lesions
    • white matter lesions
    • demyelination

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