Publication Date

2015-04-23

Availability

Open access

Embargo Period

2015-04-22

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Neuroscience (Medicine)

Date of Defense

2015-04-03

First Committee Member

Jae K. Lee

Second Committee Member

Coleen M. Atkins

Third Committee Member

Vance Lemmon

Fourth Committee Member

Marjana Tomic-Canic

Fifth Committee Member

Jeffery Alan Plunkett

Abstract

After spinal cord injury (SCI), a fibrotic scar forms at the injury site that is best characterized by accumulation of perivascular fibroblasts and microglia/macrohpages as well as deposition of extracellular matrix proteins such as fibronectin. While the fibronectin marix plays a critical role in non-central nervous system (CNS) organ wound healing, whether or how fibronectin forms a matrix after SCI is not known. The mechanism by which perivascular fibroblasts are recruited to the fibrotic scar after SCI is also not clear. Using mutant mice and bone marrow transplantation in a mouse model of contusive SCI, we demonstrate that the fibrotic scar is associated with hematogenous macrophages (hMΦ) rather than microglia, which are limited to the surrounding glial scar. We also demonstrate that fibronectin is initially present in a soluble form and is assembled into a matrix after SCI. Assembly of the fibronectin matrix may be mediated by the canonical fibronectin receptor, integrin α5β1, which is primarily expressed by hMΦ in the fibrotic scar. Depletion of hMΦ leads to a reduction in fibroblast density, basal lamina formation and ECM deposition that is associated with increased axonal growth in the fibrotic scar. Cytokine expression analysis suggests that these effects may be due to decreased tumor necrosis factor superfamily (Tnfsf) members and increased bone morphogenetic protein (BMP) expression. In conclusion, our study demonstrates that hMΦ 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.

Keywords

spinal cord injury; fibrotic scar; fibronectin; microglia; hematogenous macrophages

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