Mapping the cellular heterogeneity of multiple sclerosis lesions
Mapping the cellular heterogeneity of multiple sclerosis lesions
Multiple sclerosis (MS) is a progressive disease of the central nervous system (CNS) characterised by demyelination and inflammation. Affected areas – termed lesions – are differentiated in lesion types based on inflammatory activity, degree of demyelination, and anatomical location. The prevalence of certain lesion types and a larger overall lesion load correlate with disease progression. The cellular and molecular processes behind the formation, progression and potential resolution of MS lesions are not completely understood. Affected and involved cells derive both from the CNS and the immune system, and their relative contributions differ between lesion types. This thesis of Mirjam Koster aimed to address this cellular heterogeneity to better understand lesions and thereby MS progression.
To address the aim, we compared the gene activity profiles of lesions at the cellular and spatial level. We detected a novel rim around active lesions, which was predicted to precede the lesion core during the progression of lesions. These rims were characterised by the presence of ‘responsive’ microglia, a microglial state involved with phagocytosis and lipid metabolism, which we propose takes part in lesion expansion. Moreover, astrocytes in white matter lesions adopted gene activity profiles typically detected in grey matter astrocytes. We also studied interactions between microglia and the immune cells in the leptomeninges – a CNS barrier which tends to become inflamed during MS – and found perturbed cellular communications. Overall, the findings presented in this thesis highlight cellular, molecular and spatial processes in MS lesions and might pave the way towards new strategies for interfering in MS.