Schwann cells (SC) enter the central nervous system (CNS) in pathophysiological conditions. However, how SC invade
the CNS to remyelinate central axons remains undetermined. We studied SC migratory behavior ex vivo and in vivo after
exogenous transplantation in the demyelinated spinal cord. The data highlight for the frst time that SC migrate preferentially
along blood vessels in perivascular extracellular matrix (ECM), avoiding CNS myelin. We demonstrate in vitro and in vivo
that this migration route occurs by virtue of a dual mode of action of Eph/ephrin signaling. Indeed, EphrinB3, enriched in
myelin, interacts with SC Eph receptors, to drive SC away from CNS myelin, and triggers their preferential adhesion to ECM
components, such as fbronectin via integrinβ1 interactions. This complex interplay enhances SC migration along the blood
vessel network and together with lesion-induced vascular remodeling facilitates their timely invasion of the lesion site. These
novel fndings elucidate the mechanism by which SC invade and contribute to spinal cord repair.
