Distinct transcriptomic and epigenomic responses of mature oligodendrocytes during disease progression in a mouse model of multiple sclerosis [RNA-seq]
Multiple sclerosis (MS) is a chronic demyelinating autoimmune disease which 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 OLGs states occurs already at early stages of EAE and these persist at late stages of the disease. Interestingly, transcription factor activity suggested immunosuppression activity in MOLs at early stages of EAE and  we also observed a transitory activation of a regenerative programme in MOLs at this stage. Importantly, different MOLs present a differential responsiveness to EAE, with MOL2 exhibiting stronger transcriptional immune response than MOL5/6. Moreover, we observed divergence 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. Overall design: Mice brains from P3-6 pups were dissociated using the Neural Tissue Dissociation Kit (Miltenyi Biotec, 130-092-628) according to the manufacturer's protocol. OPCs were obtained with MACS with CD140a microbeads following the manufacturer's protocol (CD140a Microbead kit, Miltenyi Biotec, 130-101-547). Cells were seeded in Poly-L-lysine (Sigma, P4707)-coated dishes and grown on OPC proliferation media comprising DMEM/F-12/GlutaMAX (ThermoFisher, 10565018), N2 media (ThermoFisher, 17502048), penicillin–streptomycin (ThermoFisher, 15140122), NeuroBrew (Miltenyi, 130-097-263), bFGF 40 ng/ml (R&D, 233-FB) and PDGF-AA 20 ng/ml (Peprotech, 315-17).