Abstract Multiple sclerosis ( MS ) is a chronic demyelinating autoimmune disease that targets mature oligodendrocytes (MOLs ) and their myelin. MOLs are transcriptionally heterogeneous and can transition to immune-like states in the context of MS. However, the intricacies of their dynamics throughout disease progression remain poorly understood. Here, we employed simultaneous single-cell multiome ATAC and RNA sequencing targeting oligodendroglia ( OLGs ) from the experimental autoimmune encephalomyelitis ( EAE ) MS mouse model at different stages of the disease course. We found that the transition to immune OLG states appear already at the early stages of EAE and persist to the late stages of the disease. Interestingly, transcription factor activity suggested immunosuppression in MOLs at early stages of EAE and we also observed a transitory activation of a regenerative program in MOLs at this stage. Importantly, different MOLs exhibit a differential responsiveness to EAE, with MOL2 exhibiting a stronger transcriptional immune response than MOL5/6. Moreover, we observed divergent responses at the epigenetic level of MOL2 and MOL5/6 during disease evolution. Thus, our single-cell multiomic resource highlights dynamic and distinct responses of OLG subpopulations to the evolving environment in EAE, which might modulate their response to regenerative therapeutic interventions in MS.

Distinct transcriptomic and epigenomic responses of mature oligodendrocytes during disease progression in a mouse model of multiple sclerosis