Oligodendroglial precursors orchestrate immune cellular network instigating multiple sclerosis

The immunomodulatory cellular network that triggers early inflammation and demyelination, the key steps in multiple sclerosis (MS) pathogenesis remains poorly characterized. Here, we demonstrate that overactivation of the Wnt pathway promotes pathological transformation of oligodendrocyte precursor cells (OPCs) to replicate pathological OPCs in human MS. In mouse experimental autoimmune encephalomyelitis (EAE), pathological OPCs attract CD4+ T-helper 1 (Th1) cells into the spinal cord and the brain through CC-chemokine ligand 4 (CCL4). Th1 cells cooperate with OPCs inducing subpopulation of cytotoxic macrophages that execute early demyelination. Simultaneously, Th1 cells and cytotoxic macrophages upregulate Wnt signaling and CCL4 expression in OPCs, thus exerting positive feedback onto the OPC-immune cascade and establishing a vicious cycle propagating EAE pathogenesis. Breaking this cascade by targeting CCL4 reduces immune cell infiltration, alleviates demyelination, and attenuates EAE severity. Our findings demonstrate a closely coordinated network of OPCs and immune cells therefore providing an alternative insight into MS pathophysiology To investigate the transcriptomic change in APC knockout oligodendrocyte precursor cells (OPCs) compared to the wild type, OPCs were isolated from Olig2-Cre:Apc-fl/fl mice and their Apc-fl/fl littermate (as wild type control) by immunopanning, cultured with PDGFAA-supplemented media for 3 days, and collected for RNA sequencing. To investigate the transcriptomic signature of infiltrated cytotoxic macrophage and Th1 in the EAE model, EAE model was established in the Pdgfra-CreER:Apc-fl/fl mice; on day 18 post induction, the spinal cords of the mice were collected, digested, and the resulting single cell suspension was subjected to FACS; the CD11b+Gr-1+NK1.1+ cytotoxic macrophages and the CD4+ Th1 cells were isolated by FACS, and subjected to RNA-sequencing ================================================ On April 28, 2025 the raw files for samples GSM7823493,GSM7823495-GSM7823498 were replaced. Raw data are not available for sample GSM7823494