Hematogenous macrophage depletion reduces the fibrotic scar and increases axonal growth after spinal cord injury

Abstract

Spinal cord injury (SCI) leads to formation of a fibrotic scar that is inhibitory to axon regeneration. Recent evidence indicates that the fibrotic scar is formed by perivascular fibroblasts, but the mechanism by which they are recruited to the injury site is unknown. Using bone marrow transplantation in mouse model of spinal cord injury, we show that fibroblasts in the fibrotic scar are associated with hematogenous macrophages rather than microglia, which are limited to the surrounding astroglial scar. Depletion of hematogenous macrophages results in reduced fibroblast density and basal lamina formation that is associated with increased axonal growth in the fibrotic scar. Cytokine gene expression analysis after macrophage depletion indicates that decreased Tnfsf8, Tnfsf13 (Tumor necrosis factor superfamily members) and increased BMP1-7 (Bone Morphogenetic Proteins) expression may serve as anti-fibrotic mechanisms. Our study demonstrates that hematogenous macrophages are necessary for fibrotic scar formation and macrophage depletion results in changes in multiple cytokines that make the injury site less fibrotic and more conducive to axonal growth.

Intravenous immune-modifying nanoparticles as a therapy for spinal cord injury in mice

“…The rapid influx of immune cells into an injured spinal cord contributes to a cascade of secondary injury processes that lead to further axonal damage, cell death, demyelination and fibrosis and reactive gliosis with scar formation (Popovich et al, 1999; Fleming et al, 2006; Donnelly and Popovich, 2008; Evans et al, 2014; Zhu et al, 2015a). Systemic depression of monocytes and/or macrophages through administration of liposome-encapsulated clodronate (Popovich et al, 1999; Zhu et al, 2015a), dehydroepiandrosterone (Fiore et al, 2004), minocycline (Stirling et al, 2004), FK506 (Lopez-Vales et al, 2005), or antibody to alphaD (Mabon et al, 2000) improves tissue repair and enhances functional recovery after SCI.…”

“…SCI leads to scarring at the lesion site that includes both fibrotic and gliotic responses (Goritz et al, 2011; Soderblom et al, 2013; Zhu et al, 2015a; Zhu et al, 2015b). The lesional scar inhibits axonal regeneration through a number of mechanisms including accumulation of molecules that are inhibitory to axonal outgrowth, such as chondroitin sulfate proteoglycans (CSPGs), and acting as a physical impediment to axon elongation.…”

“…Traditionally astrogliosis has been viewed as an impediment to axon outgrowth, but some evidence suggests that certain populations of astrocytes could enhance regeneration after SCI (Bush et al, 1999; Faulkner et al, 2004; Anderson et al, 2016). The fibrotic response appears to arise from perivascular fibroblasts, which secrete the majority of fibronectin in spinal lesions (Goritz et al, 2011; Soderblom et al, 2013; Zhu et al, 2015a; Zhu et al, 2015b). Secreted fibronectin dimers are then assembled into an insoluble fibronectin matrix via an integrin dependent mechanism.…”

Understanding the NG2 Glial Scar after Spinal Cord Injury

“…Myelin debris and CSPGs, both inhibitory to axon regeneration, accumulate in the lesion core and the glial scar. Hematogenous macrophages start to infiltrate the lesion (30, 31) and attract perivascular fibroblasts that separate from blood vessels and form the fibrotic scar (32, 33) peaking in density by 7 days after SCI. By 14 days after SCI, the scar has started to mature and form tight borders between the glial and fibrotic components of the scar (20, 21, 33) (Figure 1E).…”

Glial scar-modulation as therapeutic tool in spinal cord injury in animal models

“…By intrathecal bone marrow cells transplantation, Zhu et al 40 demonstrated that gliosos is more associated with macrophages than microglia in mice. Depletion of these macrophages resulted in a reduction of fibroblasts and the formation of basal lamina, leading to a scar less fibrotic and more conducive to axonal growth.…”