Macrophage-Induced Blood Vessels Guide Schwann Cell-Mediated Regeneration of Peripheral Nerves

TLDR

The peripheral nervous system can fully repair a cut nerve by requiring Schwann cells to migrate collectively and guide regrowing axons across a new tissue bridge. This study investigates how coordinated interactions among multiple cell types are essential for adult peripheral nerve regeneration. Hypoxia in the bridge is sensed by macrophages, which secrete VEGF‑A to polarize blood vessels that then serve as tracks for Schwann cells to transport axons across the bridge. Blood vessels direct Schwann cell migration, and disrupting vessel organization impairs Schwann cell directionality and results in defective nerve repair.

Abstract

The peripheral nervous system has remarkable regenerative capacities in that it can repair a fully cut nerve. This requires Schwann cells to migrate collectively to guide regrowing axons across a ‘bridge’ of new tissue, which forms to reconnect a severed nerve. Here we show that blood vessels direct the migrating cords of Schwann cells. This multicellular process is initiated by hypoxia, selectively sensed by macrophages within the bridge, which via VEGF-A secretion induce a polarized vasculature that relieves the hypoxia. Schwann cells then use the blood vessels as “tracks” to cross the bridge taking regrowing axons with them. Importantly, disrupting the organization of the newly formed blood vessels in vivo, either by inhibiting the angiogenic signal or by re-orienting them, compromises Schwann cell directionality resulting in defective nerve repair. This study provides important insights into how the choreography of multiple cell-types is required for the regeneration of an adult tissue.