16, 17 Using a mouse model of contusive SCI, we demonstrated that perivascular fibroblasts detach from blood vessels and form a compact fibrotic scar at the injury site. 15 However, the most prevalent type of SCI in human patients is contusion, in which the dura remains largely intact and the lesion core often develops fluid-filled cavities. This is similar to penetrating SCI in mice, as we described previously. Penetrating SCI in humans that disrupts dura mater often leads to invasion of meningeal fibroblasts and deposition of a fibrous connective tissue in the lesion core. 11 However, whether or how this fibronectin matrix assembly occurs after SCI is not known. Upon binding to fibronectin, integrin receptors cluster and bring adjacent fibronectin fibrils close together, thereby promoting their association and formation into a matrix. To be a functional matrix, fibronectin needs to polymerize into a fibrillar network, which is initiated by binding to cellular integrin receptors. During this process, the provisional clot, along with plasma fibronectin, is degraded by infiltrating cells expressing many different isoforms of cellular fibronectin that is assembled into a more stable matrix. Plasma fibronectin is produced by liver hepatocytes and released into the blood where it functions in forming a provisional blood clot that allows cells to migrate into the injury site and perform tissue remodeling for wound repair. 12–14 Fibronectin is expressed by a single gene with multiple isoforms generated by alternative splicing-the two major types being plasma and cellular fibronectin. 9–11 In addition to serving as a scaffold to which many other extracellular matrix molecules can bind, fibronectin is known to be involved in many cellular functions, including migration, proliferation, and differentiation. 7, 8 While fibronectin is not expressed at high levels in the normal adult spinal cord, previous studies suggest that its excess deposition after SCI could come from multiple sources, such as reactive astrocytes, macrophages, and fibroblasts. The fibrotic scar has traditionally been described as areas with high fibronectin immunoreactivity. 6 Thus, understanding how the fibrotic scar is formed may provide novel insights into SCI pathology. 3–5 In vivo ablation of fibroblasts after SCI lead to compromised tissue integrity and cavitation at injury site.
In vitro models of the scar tissue using co-culture of astrocytes and meningeal fibroblasts show that the fibrotic scar is inhibitory for axon growth. 1, 2 Recent studies of the scar tissue have been mostly focused on the glial scar while the fibrotic component has received less attention. The scar tissue not only plays a protective role by limiting spreading of inflammation and secondary damage to nearby intact tissue, but it also serves as an inhibitory barrier for axon regeneration. The fibrotic scar occupies the injury core and is made up of fibroblasts and a dense extracellular matrix (ECM). The glial scar is characterized by extensive astrogliosis surrounding the central core region of the injury site. Taken together, our study provides insight into the mechanism of fibrotic scar formation after spinal cord injury.Ī fter spinal cord injury (SCI), a scar tissue forms at the injury site that comprises glial and fibrotic components. Despite the pronounced cavitation after rat SCI, fibrotic scar also is observed in a rat SCI model, which is considered to be more similar to human pathology. Assembly of the fibronectin matrix may be mediated by the canonical fibronectin receptor, integrin α5β1, which is primarily expressed by activated macrophages/microglia in the fibrotic scar. In addition, we demonstrate that fibronectin is initially present in a soluble form and is assembled into a matrix at 7 d post-SCI. By deleting fibronectin in myeloid cells, we demonstrate that fibroblasts are most likely the major source of fibronectin in the fibrotic scar. The mechanism behind how fibronectin contributes to the inhibitory environment and how the fibronectin matrix is assembled in the fibrotic scar is unknown. While fibronectin is a growth-permissive substrate for axons, the fibrotic scar is inhibitory to axon regeneration. After spinal cord injury (SCI), a fibrotic scar forms at the injury site that is best characterized by the accumulation of perivascular fibroblasts and deposition of the extracellular matrix protein fibronectin.