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Human oligodendrocyte progenitor cells mediate synapse elimination through TAM receptor activation

ABSTRACT: Recent work in animal models suggests that oligodendrocyte progenitor cells (OPCs) contribute to elimination of synapses in the developing brain. However, a mechanistic understanding of this process is still missing, and it remains uncertain whether human OPCs also display this feature. In this study, we develop a human multi-lineage forebrain organoid model in which OPCs, alongside microglia, exhibit close interactions with synapses and spontaneously internalize synaptic material. Unbiased cell-cell communication analysis based on single-nucleus transcriptomic profiling predicted GAS6-TAM receptor interaction as a major signaling pathway, with neurons and microglia expressing GAS6 ligand and certain OPCs expressing the TAM receptor AXL. Dose-dependent pharmacological inhibition of TAM receptors then demonstrated the importance of AXL receptor activation, and specific knockdown of AXL in OPCs resulted in impaired uptake of synaptic material. In summary, these data define a role of GAS6-AXL signaling in promoting OPC-mediated internalization of synaptic structures during early brain development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE242275 | GEO | 2025/10/20

REPOSITORIES: GEO

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Microglia use TAM receptors to detect and engulf amyloid beta plaques

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