TGF-β-induced fibrotic scar formation limits recovery of spinal cord injury.

Abstract

Spinal cord injury (SCI) often causes long-term disability. But effective means to promote proper regeneration after SCI has so far failed to reach the clinic. Here, we report that fibrotic scar formation at injury sites prevents recovery after SCI and that the inhibition of fibrotic scar formation significantly improved SCI recovery in adult mice. We found that after SCI there is an elevation of macrophages, which are a primary source of activated transforming growth factor-β 1 (TGF-β1) that in turn recruits mesenchymal stromal/stem cells (MSCs) to induce their fibroblast differentiation, thus promoting scar formation. We also found that activated TGF-β1 acts on resident pericytes in the endothelial niche of the blood-spinal cord barrier to promote their differentiation into fibroblasts, which also contributes to scarring. Interrupting these pathways by selective genetic KOs or treatment with a TGF-β-neutralizing antibody inhibited scar formation and improved SCI functional recovery. Notably, we found that neonatal mice recover scarlessly after SCI and with no active TGF-β at the injury site. Together, these findings suggest that fibrotic scarring occurs due to elevated activation of TGF-β, and preventing such activation or neutralizing active TGF-β may be an approach to improve outcome after SCI.