Distinct transcriptional changes distinguish efficient and poor remyelination in multiple sclerosis

Multiple sclerosis (MS) is a highly heterogeneous disease with varying remyelination potential across individuals and between lesions. However, the molecular mechanisms underlying the potential to remyelinate remain poorly understood. In this study, we aimed to take advantage of the intrinsic heterogeneity in remyelinating capacity between MS donors and lesions to uncover known and novel pro-remyelinating molecules for MS therapies. To elucidate distinct molecular signatures underlying the potential to remyelinate, we stratified MS donors from the Netherlands Brain Bank cohort (n=239) based on proportions of remyelinated lesions (RLs) into efficiently remyelinating donors (ERDs; n=21) and poorly remyelinating donors (PRDs; n=19). We performed bulk RNA sequencing of RLs, active lesions with ramified and amoeboid microglia/macrophage morphology (ALs non-foamy), active lesions with foamy microglia/macrophage morphology (ALs foamy), and normal-appearing white matter (NAWM) from ERDs and PRDs. We found that ALs non-foamy were positively correlated with remyelination, whereas ALs foamy were not, indicating a role for microglia/macrophage state in influencing remyelination potential. Bioinformatics analyses were performed to identify key pathways and molecules implicated in the remyelination process. We found distinct differences between the donors with differing remyelination potential in comparable MS lesion types. RLs and ALs non-foamy of ERDs versus PRDs showed upregulation of epithelial-mesenchymal transition pathway, while in ALs foamy of PRDs, inflammation and damage-associated pathways (i.e. MTORC1 signaling, TNF signaling and oxidative phosphorylation) were upregulated compared to ALs foamy of ERDs, suggesting that these latter pathways may counteract remyelination. We found genes significantly upregulated in RLs and/or ALs non-foamy of ERDs that have previously been associated with remyelination, including CXCL12, EGF, HGF, IGF2, IL10, PDGFB, PPARG, and TREM2, illustrating the strength of our donor and lesion stratification. TGFB1, TGFB2, EGF, and IGF1 were determined as key upstream regulators of genes upregulated in RLs and ALs non-foamy of ERDs. We further identified potential novel pro-remyelinating molecules, such as BTC, GDF10, GDF15, CCN1, CCN4, FGF5, FGF10, and INHBB. Our study identified both known and novel genes associated with efficient remyelination that may facilitate the development of therapeutic strategies to promote tissue repair and c