Directional guidance to orient Schwann cell alignment in nerve regeneration requires Plexin-B1

Directional cues are essential for orienting cells during tissue morphogenesis and repair. In peripheral nerve regeneration, Schwann cells (SCs) align longitudinally in the nerve bridge to guide axonal pathfinding, but the mechanisms are not fully understood. We show here that after nerve injury, activated SCs up-regulate the guidance receptor Plexin-B1, enabling membrane plasticity required for SC polarization and longitudinal alignment along the axons. Aligned axon-SC provides positional cues to orient macrophages and extracellular matrix. Loss of Plexin-B1 disrupts SC morphological transformation, contact inhibition of locomotion between SCs, and axon-SC alignment, leading to SC misorientation, excessive inflammation, and delayed axon regeneration and functional recovery. These findings identify Plexin-B1 as a key orchestrator to orient SCs by regulating both SC-SC and axon-SC interactions during nerve repair. Elucidating the mechanisms of spatial guidance in nerve repair after injury has potential implications for therapeutic strategies to enhance neural regeneration.