Faster nerve regeneration after sciatic nerve injury in mice over‐expressing basic fibroblast growth factor

Abstract

Basic fibroblast growth factor (FGF-2) is expressed in the peripheral nervous system and is up-regulated after nerve lesion. It has been demonstrated that administration of FGF-2 protects neurons from injury-induced cell death and promotes axonal regrowth. Using transgenic mice over-expressing FGF-2 (TgFGF-2), we addressed the importance of endogenously generated FGF-2 on sensory neuron loss and sciatic nerve regeneration. After sciatic nerve transection, wild-type and transgenic mice showed the same degree of cell death in L5 spinal ganglia. Also, the number of chromatolytic, eccentric, and pyknotic sensory neurons was not changed under elevated levels of FGF-2. Morphometric evaluation of intact nerves from TgFGF-2 mice revealed no difference in number and size of myelinated fibers compared to wild-type mice. One week after crush injury, the number of regenerated axons was doubled and the myelin thickness was significantly smaller in transgenic mice. After 2 and 4 weeks, morphometric analysis and functional tests revealed no differences in recovery of sensory and motor nerve fibers. To study the role of FGF-2 over-expression on Schwann cell proliferation during the early regeneration process, we used BrdU-labeling to mark dividing cells. In transgenic mice, the number of proliferating cells was significantly increased distal to the crush site compared to wild-types. We propose that endogenously synthesized FGF-2 influences early peripheral nerve regeneration by regulating Schwann cell proliferation, axonal regrowth, and remyelination.

c-Jun Gene-Modified Schwann Cells: Upregulating Multiple Neurotrophic Factors and Promoting Neurite Outgrowth

“…10,11 Schwann cells (SCs), which play a pivotal role during nerve regeneration in vivo, are an attractive type of transplant cell with potentiated functionality due to the expression of multiple neurotrophic factors (NFs), the organization of Büngner bands, and the ability to form myelin. [12][13][14] Recent studies have revealed that delivery of SCs to NCs is advantageous for nerve repair, particularly when using SCs that overexpress an NF, such as basic fibroblast growth factor (FGF-2), 15,16 glial cell line-derived neurotrophic factor (GDNF), 17,18 nerve growth factor (NGF), 19 brainderived neurotrophic factor (BDNF), 20 or neurotrophin-3 (NT-3). 21 However, an increasing number of studies have indicated that the application of multiple NFs, rather than a single type, holds greater therapeutic promise.…”

Long-Term Efficacy and Safety Outcomes of Transplantation of Induced Pluripotent Stem Cell-Derived Neurospheres with Bioabsorbable Nerve Conduits for Peripheral Nerve Regeneration in Mice

“…The print length factor (PLF) for each mouse was determined as the mean of four values calculated from the experimental print length (EPL) of the limb with the conduit and the normal print length (NPL) of the normal limb as follows: PLF = (EPL − NPL)/NPL. The recovery of sensory function was assessed by the hot water behavior test as described previously [Derby et al, 1993;Jungnickel et al, 2006]. Mice were immobilized and then the hind limbs of the experimental and normal side were submerged into a 50 ° C water bath.…”

Future Perspectives in Nerve Repair and Regeneration

“…The overexpression of FGF-2 showed no difference in number and size of myelinated fibers compared to wild-type mice in intact nerves. On the other hand, 1 week after crush injury, the number of regenerated axons was doubled and the myelin thickness was significantly smaller in transgenic mice, but after 2 and 4 weeks, there were no differences in the recovery of sensory and motor nerve fibers, showing that FGF-2 influences early peripheral nerve regeneration by regulating Schwanncell proliferation, axonal regrowth, and remyelination (Jungnickel, Haase, Konitzer, Timmer, & Grothe, 2006). Transgenic mice expressing Nogo-C in peripheral Schwann cells regenerate axons less rapidly than do wild-type mice after mid-thigh sciatic nerve crush (Kim, Bonilla, Qiu, & Strittmatter, 2003).…”