Abstract
Developing successful therapies for spinal cord injury (SCI) is a formidable medical challenge in part because of the axonal growth-inhibitory environment that develops following injury characterized by a glial and fibrotic scar [3]. Whereas the glial scar has been an important research focus for many years, less attention has been given to the fibrotic scar. Recent work from our lab has demonstrated that hematogenous macrophages are important for the formation of the fibrotic scar [4]. Depletion of hematogenous macrophages following SCI resulted in reduced fibrotic scar formation and increased growth of axons into the lesion site. In order to identify the signaling pathways responsible for these changes a qPCR array was used to look at the expression of 84 different cytokines and chemokines in macrophage depleted tissue compared to PBS controls. Surprisingly, of the 29 differentially regulated genes identified, the vast majority (26) were upregulated. Many of the upregulated genes were anti-fibrotic and pro-growth factors like VEGF and BMPs. On the other hand, only three genes were downregulated one of them being tumor necrosis factor superfamily member 13 (tnfsf13). Tnfsf13, also known as A Proliferation Inducing Factor (April), has been previously associated with fibrosis thus we tested its role in fibrotic scar formation following SCI using April knockout mice. We identified that April and one of its receptors, Bcma, were significantly upregulated following SCI. Additionally, similar to the macrophage depletion effect, April KO mice had a smaller fibrotic scar and increased axons in the injury site. In addition, April KO mice also had reduced macrophage infiltration and reduced early proinflammatory cytokine expression, suggesting that April indirectly influences the fibrotic scar size via modulation of the inflammatory response. As an alternate strategy towards application of the macrophage depletion effect, we tested the combination of macrophage depletion and Schwann cell transplantation hypothesizing that the macrophage-depleted environment would promote axon growth through the transplant. Macrophage depletion reduced cyst size in Schwann cell transplanted rats; however, axon regeneration through the graft was unaffected and combination of macrophage depletion and Schwann cell transplantation did not improve functional recovery as compared to Schwann cell transplantation alone. Overall, my findings identified a novel mediator of early pro-inflammatory changes following spinal cord injury, April, but disproved the idea that macrophages are a limitation to axon growth through the Schwann cell transplant.