The GPR17 agonist galinex restores oligodendrocyte maturation under inflammatory conditions

Transcriptomics analysis revealed that CTK (Cytokines) induced coordinated transcriptional remodelling involving protein synthesis/proteostasis, mitochondrial metabolism, and lipid-related pathways, together with a shift towards an immunogenic-like, senescence/DNA-damage–associated phenotype. Cross-comparison with publicly available transcriptomic signatures of neuroinflammatory patterns from both mouse models and Alzheimer’s and multiple sclerosis human brains, revealed significant overlap with disease-associated modules, supporting the relevance of the inflammatory pathways engaged in our model.

We then showed that treatment of OLs with GAL restored cells’ terminal maturation and morphological features. Moreover, in a synthetic nanofiber myelination assay, GAL significantly increased the length of myelinated segments compared to CTK-treated cells, suggesting an improvement of OL myelinating capacity after inflammatory damage. Together, this study establishes a controlled in vitro model linking alteration of disease-relevant transcriptional pathways to impaired OL differentiation and highlights GPR17 pharmacological modulation as a feasible strategy to promote OL maturation under non permissive inflammatory contexts.