Human oligodendrocyte progenitor cells mediate synapse elimination through TAM receptor activation
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. Overall design: Four forebrain organoids per subject (n=2 subjects) were pooled and dissociated to isolate nuclei. High qulaity nuclei were processed for single-nuclei RNA sequencing using 10X Genomics 3' Chromium platform (dual index). The barcoded library was sequenced on Illumina Novaseq. S1-100.