Adult NG2+ Cells Are Permissive to Neurite Outgrowth and Stabilize Sensory Axons during Macrophage-Induced Axonal Dieback after Spinal Cord Injury

Abstract

We previously demonstrated that activated ED1ϩ macrophages induce extensive axonal dieback of dystrophic sensory axons in vivo and in vitro. Interestingly, after spinal cord injury, the regenerating front of axons is typically found in areas rich in ED1ϩ cells, but devoid of reactive astrocyte processes. These observations suggested that another cell type must be present in these areas to counteract deleterious effects of macrophages. Cells expressing the purportedly inhibitory chondroitin sulfate proteoglycan NG2 proliferate in the lesion and intermingle with macrophages, but their influence on regeneration is highly controversial. Our in vivo analysis of dorsal column crush lesions confirms the close association between NG2ϩ cells and injured axons. We hypothesized that NG2ϩ cells were growth promoting and thereby served to increase axonal stability following spinal cord injury. We observed that the interactions between dystrophic adult sensory neurons and primary NG2ϩ cells derived from the adult spinal cord can indeed stabilize the dystrophic growth cone during macrophage attack. NG2ϩ cells expressed high levels of laminin and fibronectin, which promote neurite outgrowth on the surface of these cells. Our data also demonstrate that NG2ϩ cells, but not astrocytes, use matrix metalloproteases to extend across a region of inhibitory proteoglycan, and provide a permissive bridge for adult sensory axons. These data support the hypothesis that NG2ϩ cells are not inhibitory to regenerating sensory axons and, in fact, they may provide a favorable substrate that can stabilize the regenerating front of dystrophic axons in the inhibitory environment of the glial scar.

Astrocytic and Vascular Remodeling in the Injured Adult Rat Spinal Cord after Chondroitinase ABC Treatment

“…Further, this interpretation is corroborated by data demonstrating that during the first days post-injury NG2-positive, metalloprotease (MMP)-secreting cells, rather than astrocytes, invade the lesion site, where they provide a stabilizing substrate for injured axons, thus protecting them against macrophage-mediated die-back. 71 ChABC treatment modifies revascularization and blood vessel basement membrane morphology…”

Cell biology of spinal cord injury and repair

“…After CNS injury, NG2-OPCs are present in two compartments, scar borders and spared reactive neural tissue ( Figure 1A and Figure 3A). In scar borders, NG2-OPCs are hypertrophied and are reported to restrict axon dieback and axon regrowth (68)(69)(70). Other reports show that robust axon growth can…”

Taxol Facilitates Axon Regeneration in the Mature CNS

“…Given that the inactivation of inhibitory CSPGs by chondroitinase ABC improves axon regeneration in the CNS, in particular when combined with an enhancement of the intrinsic growth capacity of neurons (Moon et al, 2001;Bradbury et al, 2002;Steinmetz et al, 2005), it is possible that the reduction in CSPG expression may have also contributed to the improved regeneration seen after Taxol treatment. Next to reactive astrocytes, macrophages at the injury site of the CNS act as a significant barrier for initial regeneration (Busch and Silver, 2007;Horn et al, 2008;Busch et al, 2009Busch et al, , 2010. Depletion of macrophages reportedly prevents axonal retraction after spinal cord injury Figure 9.…”