Microglia-Derived Extracellular Vesicles Enhance Oligodendrocyte Maturation by Transcriptionally Regulating Mitochondrial Molecular Pathways

Degeneration of myelinating oligodendrocytes and the resulting breakdown of the myelin sheath are key drivers of neurodegeneration and disability across numerous central nervous system pathologies. Thus, a compelling strategy to preserve neuronal function is to promote endogenous myelin repair by oligodendrocyte precursor cells (OPCs). Extracellular vesicles (EVs) secreted by pro-regenerative microglia have been shown to enhance OPC maturation and remyelination across different experimental models. Yet, the mechanisms by which microglia-derived EVs exert their beneficial effects on OPCs are not fully understood. In this study, we performed transcriptomic profiling of primary murine OPCs treated during differentiation with EVs obtained from donor microglia following stimulation with pro-inflammatory cytokines (i-EVs), interleukin-4 (IL4-EVs), or mesenchymal stem cells in the presence of the inflammatory cocktail (MSC-EVs; GEO accession number: GSE304130). Compared to controls, IL4-EVs and MSC-EVs induced robust changes in gene expression, whereas i-EVs elicited far fewer alterations. Using bioinformatic analyses, we identified the molecular pathways significantly modulated by microglial EVs, revealing a large overlap between IL4-EV and MSC-EV targets. Notably, many of these shared pathways centered on mitochondrial function and bioenergetic metabolism. Upstream regulatory network inference further pinpointed candidate transcription factors and kinases that may drive EV-induced transcriptional reprogramming in OPCs. Hence, our findings indicate that rewiring mitochondria-associated pathways is a core mechanism underlying the pro-differentiation effects of microglial EVs on OPCs. Elucidating these intracellular circuits will open new avenues for developing EV-based or mitochondria-targeted remyelinating therapies.