FGF-2-Responsive and Spinal Cord-Resident Cells Improve Locomotor Function after Spinal Cord Injury

Abstract

The adult central nervous system has only a limited capacity for axonal regeneration. In this study, fibroblast growth factor-2 (FGF-2) was injected once into the spinal cord tissue around the injury site immediately after complete spinal cord transection in rats. This treatment markedly improved the locomotor function of the animals. Histological analysis demonstrated that tissue composed of FGF-2-induced fibronectin-positive cells (FIFs) had infiltrated the injury site and filled large cystic cavities, into which numerous axons with growth-associated protein-43 immunoreactivity penetrated. The FIFs could also be cultured from the intact spinal cord tissue, demonstrating that they were resident in the noninjured spinal cord. They had a spindle-shaped morphology and enhanced expression of mRNAs of N-cadherin and neurotrophic factors, suggesting the beneficial properties of the FIFs for axonal regeneration. Thus, these results argue for the continual use of autologous transplantation as a novel and promising cell therapy for the treatment of spinal cord injury.

JNK/ERK/FAK Mediate Promigratory Actions of Basic Fibroblast Growth Factor in Astrocytes via CCL2 and COX2

“…Recent evidence indeed challenges the prevailing view that astrocyte scars impair tissue repair by hindering axon growth. Firstly, scars are dynamic, highly regulative proteoglycan networks the composition of which can, by controlling the activity of signaling molecules like FGF2, render the microenvironment conducive for axon regeneration [77] . Secondly, astrocyte scars lead to the compaction of microglia and macrophages within necrotic areas thereby preventing inflammation-derived secondary damage [78] .…”

Neurotrophic Factors Used to Treat Spinal Cord Injury

“…Tissue sparing has been improved in most contusion studies with FGF2 infusions (Grulova et al, 2015;Kasai et al, 2014;Kim et al, 2006;Lee et al, 1999;Rabchevsky et al, 1999), one study reporting significant reduction if treated with FGF2 within 1 h post-SCI but not if treatment was delayed for 3 h (Lee et al, 1999). Some studies report βIII-tubulin, MAP2, Gap-43, or 5HT-positive axons within the lesion site of FGF1-or FGF2-treated animals.…”

“…After more severe or complete transection injuries, FGFs are usually administered in association with fibrin bridges and either Schwann cell or PN grafts, or with hydrogels (Chen et al, 2015). Increased axonal growth has been reported in some of these studies (Chen et al, 2015;Guzen et al, 2012;Kasai et al, 2014;Lee et al, 2008Lee et al, , 2010Tsai et al, 2006) but not in others (Meijs et al, 2004).…”

“…Behaviorally, there have been mixed results, with locomotor improvement reported in several studies after contusion injuries (Grulova et al, 2015;Hwang et al, 2011;Kim et al, 2006;Meng et al, 2008;Rabchevsky et al, 1999;Shin et al, 2014;Tsai et al, 2008), and with some (Chen et al, 2015;Goldshmit et al, 2014;Guzen et al, 2012;Kasai et al, 2014;Lee et al, 2008;Tsai et al, 2006) or no (Meijs et al, 2004) functional improvement after complete transection. A human trial using FGF1 and fibrin glue in nine patients with cervical SCI reported improvement in ASIA grade for some patients, as well as some improvement in bowel/ bladder function and reduced neuropathic pain for one patient .…”

Decreased anti-regenerative effects after spinal cord injury in spry4−/− mice

“…In addition, Fgf2 treatment promoted neuronal survival, which improved functional recovery (Goldshmit et al, 2014). Other studies, using brain and spinal cord injury models and exogenous Fgf administration, have also shown therapeutic promise, reporting better functional recovery, decreased inflammation and decreased injury volume (Kasai et al, 2014;Rabchevsky et al, 1999;Rabchevsky et al, 2000;Rottlaender et al, 2011;Ruffini et al, 2001).…”