Spatial cell type mapping of multiple sclerosis lesions

Multiple sclerosis (MS) is a prototypic chronic-inflammatory disease of the central nervous system. After initial lesion formation during active demyelination, inflammation is gradually compartmentalized and restricted to specific tissue areas such as the lesion rim in chronic-active lesions. However, the cell type-specific and spatially restricted drivers of chronic tissue damage and lesion expansion are not well understood. Here, we investigated the properties of subcortical white matter lesions by creating a cell type-specific spatial map of gene expression across various inflammatory lesion stages in MS. An integrated analysis of single-nucleus and spatial transcriptomics data enabled us to uncover patterns of glial, immune and stromal cell subtype diversity, as well as to identify cell-cell communication and signaling signatures across lesion and non-lesion tissue areas in MS. Our results provide insights into the conversion of the tissue microenvironment from a ‘homeostatic’ to a pathogenic or ‘dysfunctional’ state underlying lesion progression in MS. We expect that this study will help identify spatially resolved cell type-specific biomarkers and therapeutic targets for future interventional trials in MS. ### Competing Interest Statement J.S.R. reports funding from GSK and Sanofi and fees from Travere Therapeutics and Astex Pharmaceuticals. P.E. has received travel expenses from Bayer Health Care and is a member of the Editorial Board of the Journal of Neuroimaging. D.S. reports funding from GSK. L.S. reports research support and consultancy fees from Novartis, Roche, Bristol-Myers Squibb and Merck and filed a patent for the detection of antibodies against KIR4.1 in a subpopulation of patients with multiple sclerosis (WO2015166057A1).