Neural and oligodendrocyte precursor cells (NPCs and OPCs) in the subventricular zone (SVZ) of the brain contribute to oligodendrogenesis throughout life, in part due to direct regulation by chemokines. The role of the chemokine fractalkine is well established in microglia; however, the effect of fractalkine on SVZ precursor cells is unknown. We show that murine SVZ NPCs and OPCs express the fractalkine receptor (CX3CR1) and bind fractalkine. Exogenous fractalkine directly enhances OPC and oligodendrocyte genesis from SVZ NPCs in vitro. Infusion of fractalkine into the lateral ventricle of adult NPC lineage-tracing mice leads to increased newborn OPC and oligodendrocyte formation in vivo. We also show that OPCs secrete fractalkine and that inhibition of endogenous fractalkine signaling reduces oligodendrocyte formation in vitro. Finally, we show that fractalkine signaling regulates oligodendrogenesis in cerebellar slices ex vivo. In summary, we demonstrate a novel role for fractalkine signaling in regulating oligodendrocyte genesis from postnatal CNS precursor cells.

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Neural stem and precursor cells (NPCs) build and regenerate the central nervous system (CNS) by maintaining their pool (self-renewal) and differentiating into neurons, astrocytes, and oligodendrocytes (multipotency) throughout life. This has inspired research into pro-regenerative therapies that utilize transplantation of exogenous NPCs or recruitment of endogenous adult NPCs for CNS regeneration and repair. Recent advances in single-cell RNA sequencing and other “omics” have revealed that NPCs express not just traditional progenitor-related genes, but also genes involved in immune function. Here, we review how NPCs exert immunomodulatory function by regulating the biology of microglia, immune cells that are present in NPC niches and throughout the CNS. We discuss the role of transplanted and endogenous NPCs in regulating microglia fates, such as survival, proliferation, migration, phagocytosis and activation, in the developing, injured and degenerating CNS. We also provide a literature review on NPC-specific mediators that are responsible for modulating microglia biology. Our review highlights the immunomodulatory properties of NPCs and the significance of these findings in the context of designing pro-regenerative therapies for degenerating and diseased CNS.