Sex Specific Differences in Oligodendrocytes and Oligodendrocyte Progenitor Cells in Progressive MS

Multiple sclerosis is a neurological autoimmune disease with sex-imbalanced incidence; in the USA, the disease is more likely to effect females at a ratio of 3:1. In addition, males are more likely to have a more severe disease course at time of diagnosis. Questions about both causes and downstream effects of this disparity remain. We aim to investigate gene expression differences at a cellular level while considering sex to discover fine-scale sex disparities. These investigations could provide new avenues for treatment targeting, or treatment planning based on sex. Public single-nuclei RNA-sequencing data from progressive MS and control brains was analyzed in a sex-specific manner using the Seurat R package. Differential gene and pathway expression was looked at both within a specific data set which has sub-lesion level sample dissection, and across other studies with a broader lens. Our analysis showed expression changes in the female MS oligodendrocytes and OPCs compared to healthy controls, which were not observed in the corresponding male affected cells. Differentially up-regulated genes in females include HLA-A and clusterin (CLU), as well as several mitochondrial genes and oxidative phosphorylation pathways. These results point to altered states in OPCs and OLs that in combination with known physiological dissimilarities between sexes initiate different programming in males and females in response to the presence of brain lesions. The potential for increased debris clearance mediated by CLU and availability of OPCs in females may explain, in part, the disparity in incidence of relapsing and progressive forms, and longer time to progression, seen in females versus males.