Microglia-Derived Small Extracellular Vesicles Reduce Glioma Growth by Modifying Tumor Cell Metabolism and Enhancing Glutamate Clearance through miR-124

Brain homeostasis needs continuous exchange of intercellular information among neurons,glial cells, and immune cells, namely microglial cells. Extracellular vesicles (EVs) are active playersof this process. All the cells of the body, including the brain, release at least two subtypes of EVs, themedium/large EVs (m/lEVs) and small EVs (sEVs). sEVs released by microglia play an importantrole in brain patrolling in physio-pathological processes. One of the most common and malignantforms of brain cancer is glioblastoma. Altered intercellular communications constitute a base for theonset and the development of the disease. In this work, we used microglia-derived sEVs to assay theireffects in vitro on murine glioma cells and in vivo in a glioma model on C57BL6/N mice. Our findingsindicated that sEVs carry messages to cancer cells that modify glioma cell metabolism, reducinglactate, nitric oxide (NO), and glutamate (Glu) release. sEVs affect Glu homeostasis, increasing theexpression of Glu transporter Glt-1 on astrocytes. We demonstrated that these effects are mediated bymiR-124 contained in microglia-released sEVs. The in vivo benefit of microglia-derived sEVs resultsin a significantly reduced tumor mass and an increased survival of glioma-bearing mice, dependingon miR-124.