Macrophage-Induced Blood Vessels Guide Schwann Cell-Mediated Regeneration of Peripheral Nerves.
Bottom Line: Here we show that blood vessels direct the migrating cords of Schwann cells.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.
Affiliation: MRC Laboratory for Molecular Cell Biology, UCL, Gower Street, London WC1E 6BT, UK.Show MeSH
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Mentions: In order to determine the mechanism by which SC cords are directed across the bridge, we first determined the cell composition of the bridge, prior to SC migration. In the vast majority of rats (>95%), a bridge between the distal and proximal nerve stumps was formed 2 days following transection (day 2). In agreement with previous observations (Avellino et al., 1995; Jurecka et al., 1975), we found that the bridge was mostly composed of macrophages (50%) and neutrophils (24%) with fibroblasts (13%) and endothelial cells (ECs) (5%) as minor components (Figures 1A and S1A). At day 3, however, we noted a significant increase in the number of ECs indicating that the bridge may have become vascularized (Figure 1A). Consistent with this, vascularization could be observed macroscopically (Figure S1B) and confocal analysis of the entire bridge region confirmed this to be the case; at day 2, the bridge contained very few blood vessels whereas by day 3, there was a dramatic influx of blood vessels, which permeated the entire bridge (Figure 1B, quantified in Figures 1C and 1D). Analysis of nerves in which the vascularization was at a slightly earlier stage showed that the blood vessels appeared to emanate from both proximal and distal stumps (Figure S1C) but importantly, the nerve was fully vascularized by the time the SC cords entered into the bridge from either stump (Figures 1B and S1D). In mice, the regeneration process is similar but takes place more slowly, but as observed in rats, we found that the bridge was fully vascularized prior to SC migration into the bridge (Figures 1E and S1D). Thus in both rats and mice, ECs cross the bridge prior to the migration of the SC cords.
Affiliation: MRC Laboratory for Molecular Cell Biology, UCL, Gower Street, London WC1E 6BT, UK.