Decoding spatial gene activity changes in multiple sclerosis lesion progression

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterised by myelin loss and progressive neurodegeneration. To better understand MS lesion initiation and progression, we generated spatial gene activity maps of white (WM) and grey matter (GM) MS lesions. In different MS lesion types, we detected novel transcriptional domains, including an identifiable rim around active WM lesions. These active lesion rims were characterised by changes in astrocytic, oligodendrocytic, and microglial gene activity. Furthermore, we identified three novel WM lesion trajectories, predicting how normal appearing WM could progress into WM lesions, with lesion rims, active lesion cores, and mixed active/inactive lesion cores as potential outcomes. Our findings offer new insights into MS lesion progression, and the dynamic molecular and cellular processes that underlie MS. Overall design: Visium ST profiling was performed on snap-frozen samples containing 3 control grey matter samples (from 3 donors), 3 normal-appearing grey matter samples (from 3 donors), 5 subpial lesions (from 5 donors), 2 control white matter samples (from 2 donors), 3 normal-appearing white matter samples (from 3 donors), 4 active lesions (from 3 donors), 6 mixed active/inactive lesions (from 6 donors). GeoMx Digital Spatial Profiling was performed on FFPE samples containing 3 active lesions (from 2 donors) and 3 mixed active/inactive lesions (from 3 donors). GeoMx Digital Spatial Profiling was performed on FFPE samples containing active (n=3 lesions from 2 donors) and act/inact (n=3 lesions from 3 donors) lesions.