Abstract
ObjectivesA major impediment for recovery after mammalian spinal cord injury (SCI) is the glial scar formed by proliferating reactive astrocytes. Finding factors that may reduce glial scarring, increase neuronal survival, and promote neurite outgrowth are of major importance for improving the outcome after SCI. Exogenous fibroblast growth factor (Fgf) has been shown to decrease injury volume and improve functional outcome; however, the mechanisms by which this is mediated are still largely unknown.MethodsIn this study, Fgf2 was administered for 2 weeks in mice subcutaneously, starting 30 min after spinal cord hemisection.ResultsFgf2 treatment decreased the expression of TNF-a at the lesion site, decreased monocyte/macrophage infiltration, and decreased gliosis. Fgf2 induced astrocytes to adopt a polarized morphology and increased expression of radial markers such as Pax6 and nestin. In addition, the levels of chondroitin sulfate proteoglycans (CSPGs), expressed by glia, were markedly decreased. Furthermore, Fgf2 treatment promotes the formation of parallel glial processes, “bridges,” at the lesion site that enable regenerating axons through the injury site. Additionally, Fgf2 treatment increased Sox2-expressing cells in the gray matter and neurogenesis around and at the lesion site. Importantly, these effects were correlated with enhanced functional recovery of the left paretic hind limb.ConclusionsThus, early pharmacological intervention with Fgf2 following SCI is neuroprotective and creates a proregenerative environment by the modulation of the glia response.
Highlights
In mammals, a major barrier for axonal regeneration after spinal cord injury (SCI) is the formation of the glial scar at the lesion
We recently demonstrated that fibroblast growth factor (Fgf) signaling plays a crucial role in glial cell differentiation and morphogenesis that is required for regeneration after SCI in zebrafish (Goldshmit et al 2012)
In order to examine whether subcutaneous Fgf2 injections can activate Fgf signaling within the spinal cord, mRNA levels of the Fgf downstream target gene Spry4, which we have previously shown to be expressed in a mouse spinal cord (Goldshmit et al 2012), were quantified using quantitative polymerase chain reaction (qPCR), 2 days after SCI
Summary
A major barrier for axonal regeneration after spinal cord injury (SCI) is the formation of the glial scar at the lesion. The glial scar is composed of astrocytes, which are triggered in response to extrinsic signals to activate and proliferate to generate a dense network of hypertrophic stellate cells that form an impenetrable barrier to the regrowth of damaged axons. One therapeutic strategy could be to improve the environmental conditions at the lesion site post-SCI to better support neuronal survival and axonal regrowth. Brain and Behavior published by Wiley Periodicals, Inc. Brain and Behavior published by Wiley Periodicals, Inc
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