A single cell multi-omics map of cell type specific mechanistic drivers of multiple sclerosis lesions

Abstract Despite major progress in understanding the mechanisms in progressive multiple sclerosis (PMS), the underlying drivers of compartmentalized and sustained inflammation have not been resolved. To gain insights into the interplay between inter- and intra-cellular mechanisms and deconvolute the complex niche of lesion evolution, we have integrated single cell chromatin accessibility and transcriptome data for different white matter (WM) lesions from patients with PMS combined with spatial transcriptomics of chronic active lesion border. The PMS-specific oligodendrocyte genetic program was governed by the KLF/SP gene family involved in myelination and stress-induced iron uptake. The transferrin gene (TF) and its receptor LRP2 were highly expressed across all lesion types in oligodendrocytes suggesting autocrine communication of iron uptake and were co-localized at the outer border of the chronic active lesion. The genomic accessibility of the structural protein (VIM) and the cystine/glutamate antiporter (SLC7A11) was significantly reduced, and the genes were downregulated in oligodendrocytes. We identified oligodendrocytes expressing the osteopontin gene and complement at the outer edge of the chronic active lesion. We describe a metabolic astrocyte phenotype at the lesion border and an astrocytic-neuronal axis through FGF signaling (FGFR3-FGF13) inside the chronic active lesion. We also identified two distinct B cell co-expression networks with different location and gene expression preferring different lesion types. With single cell multi-omics, we were able to get a snapshot of specific cell types with distinctive molecular signatures and pathways, including their interactions and locations contributing to lesion fate.