title: 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.
authors.affiliation: University of Miami School of Medicine, Miami Project to Cure Paralysis, Department of Neurological Surgery, Miami, FL 33136, United States.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: University of Miami School of Medicine, Miami Project to Cure Paralysis, Department of Neurological Surgery, Miami, FL 33136, United States.
authors.forename: C
authors.initials: C
authors.lastname: Soderblom
authors.affiliation: University of Miami School of Medicine, Miami Project to Cure Paralysis, Department of Neurological Surgery, Miami, FL 33136, United States.
authors.forename: V
authors.initials: V
authors.lastname: Krishnan
authors.affiliation: University of Miami School of Medicine, Miami Project to Cure Paralysis, Department of Neurological Surgery, Miami, FL 33136, United States.
authors.forename: J
authors.initials: J
authors.lastname: Ashbaugh
authors.affiliation: University of Miami School of Medicine, Miami Project to Cure Paralysis, Department of Neurological Surgery, Miami, FL 33136, United States.
authors.forename: J R
authors.initials: JR
authors.lastname: Bethea
authors.affiliation: University of Miami School of Medicine, Miami Project to Cure Paralysis, Department of Neurological Surgery, Miami, FL 33136, United States. Electronic address: JLee22@med.miami.edu.
authors.forename: J K
authors.initials: JK
authors.lastname: Lee
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology / Q000502:physiology*; D001485:Basement Membrane / Q000473:pathology / Q000503:physiopathology; D016026:Bone Marrow Transplantation / Q000379:methods; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D053285:CD30 Ligand / Q000378:metabolism; D002921:Cicatrix / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000473:pathology / Q000502:physiology; D008264:Macrophages / Q000473:pathology / Q000502:physiology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009416:Nerve Regeneration / Q000502:physiology*; D013119:Spinal Cord Injuries / Q000473:pathology / Q000503:physiopathology*; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D053285:CD30 Ligand; C491959:Tnfsf13 protein, mouse; C505775:Tnfsf8 protein, mouse; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13
keywords: Axonal growth; Bone morphogenetic protein; Fibroblasts; Fibrotic scar; Hematogenous macrophages; Spinal cord injury; Tumor necrosis factor