Abstract
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 first 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 fibronectin 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 findings elucidate the mechanism by which SC invade and contribute to spinal cord repair.
Highlights
Myelination, the evolutionary characteristic acquired by vertebrates to allow rapid and saltatory nerve conduction, is supported by two different glial cell types, oligodendrocytes in the central nervous system (CNS), and SchwannElectronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.1 3 Vol.:(0123456789)Acta Neuropathologica (2019) 138:457–476CNS white matter [9, 17, 32] inhibits Schwann cells (SC) migration
LPC injections were performed in the dorsal funiculus of adult mice (2–3 months old), and mice were killed at 3 days post-injection. YFP+SC were detected only in the spinal cord cross sections of demyelinated mice
As our in vivo study indicated that the grafted SC were embedded in perivascular extracellular matrix (ECM), we studied the effect of EphrinB3 on SC–ECM binding, in particular FN, that favors SC migration [11]
Summary
EphrinB3 acts as a repellent molecule in the guidance of axon tracts in the spinal cord during development [49]. These receptors could mediate similar SC repulsion by myelin-associated EphrinB3. EphrinB ligands control cell migration through positive adhesion to substrates such as collagen and fibronectin (FN) [54, 60], main components of perivascular extracellular matrix (ECM). These cues could influence the capacity of SC to migrate within the CNS and/or interact with CNS myelin
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