Initial phases of multiple sclerosis (MS) are characterized by recurrent focal inflammation within the central nervous system associated with demyelination and variable subsequent remyelination, indicating that both injury and repair are ongoing within the same microenvironment. An array of pro-inflammatory molecules including tumor necrosis factor α (TNF) and interferon γ (IFNG) are implicated as contributing to oligodendrocyte (OL) lineage cell injury in MS and its models. Using OL lineage cells derived from human surgical samples, we observed that TNF and IFNG in combination enhanced ensheathment of synthetic nanofibers by mature OLs compared to those observed under control conditions or in the presence of individual cytokines, reaching levels comparable to those of A2B5+ late-stage progenitor cells. The combination reversed the individual cytokine mediated inhibition of A2B5+ cell ensheathment. Molecular analysis of the mature OL population identified increased expression of myelination relevant genes in the cytokine combination treated cells, of STAT and IRF transcription factors (TFs) that regulate many of these genes, and of mature OL structural genes (MOBP and CNP). TNF and IFNG combination also reduced expression of OPC signature genes in the mature OLs compared to IFNG alone. The combination effect on ensheathment was reversed using a JAK/STAT pathway inhibitor. The combination of TNF and IFNG induced a stronger immune signature in mature OLs compared to individual cytokines. These results emphasize the complex positive and negative interplay of inflammatory responses in the CNS and the potential for therapeutic modulation.
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