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of FGF-2 [ 179 ]. These VEGF-mediated molecular and cellular changes have been
observed by some to correlate with improvements in motor function after various
murine SCI models. Liu et al. found that induction of VEGF with an engineered
transcription factor after clip compression SCI promoted revascularization,
decreased apoptosis, and was associated with greater functional outcomes for ani-
mals expressing VEGF compared to wild type animals [ 180 ]. Similarly, Nori et al.
observed enhanced motor recovery when NPSCs were implanted after murine con-
tusion SCI models, and these results were directly linked to presence of VEGF in
treated animals as compared to saline injected controls [ 181 ]. In general, VEGF
appears to promote neuroregeneration in the CNS: supporting the regeneration of
brain and spinal cord microvasculature, axonal growth in the spinal cord, and direct
neurotrophic effects in both the brain and spinal cord.
7.5.2 Brain-Derived Neurotrophic Factor and Neurotrophin- 3
Other molecules found to be effective in preventing apoptosis are BDNF and neuro-
trophin- 3 (NT-3) [ 155 , 182 ]. Similar to BDNF, NT-3 is a neurotrophin in the nerve
growth factor (NGF) family that is diversely expressed in the CNS, with greater
expression in the spinal cord than the brain after injury. In fact, levels of NT-3
mRNA have been shown to decrease after hippocampal fl uid percussion injury
[ 178 , 183 ]. Nonetheless, experimental induction of NT-3 has been shown to stabi-
lize calcium concentrations and reduce apoptosis due to excitotoxic insults in the
brain [ 183 ]. In the spinal cord, NT- 3 is associated with promoting survival of endog-
enous neurons. For example, NT- 3 signifi cantly enhanced the survival of anterior
horn neurons in mouse compression SCI models and signifi cantly improved cell
survival and reduced cell atrophy in both in vitro and in vivo models of SCI [ 184 –
186 ]. Signifi cant data has also been collected associating NT-3 with increased plas-
ticity, axonal growth, and augmented myelination post-injury [ 187 – 192 ]. As such,
researchers have primarily investigated the pro-growth effects that NT-3 has on
axons in the regenerating spinal cord. Early studies suggested that acute, sustained
delivery of NT-3 promoted the growth of axons post-cortical lesion injury [ 187 ,
188 , 193 ]; however, this growth did not continue beyond the lesion site [ 187 ].
Taylor et al. found that this barrier can be overcome by creating an NT-3 gradient
that leads out of the lesion site [ 188 ], but growth for long distances was not attain-
able simply using a neurotrophic signal. A recent study performed by Hou et al.
corroborates the data found by Taylor et al., and further suggests that continuous
expression of NT-3 is essential for sustaining the viability and continued growth of
new axons post- spinal lesion [ 189 ]. Further, there is some evidence to suggest that
NT- 3 can promote re-myelination when expressed by transplanted NPSCs [ 194 ].
Similarly, multiple studies have shown that BDNF promotes sustained axonalgrowth and sprouting [ 195 – 198 ]. Blesch et al. found that transient BDNF deliv-
ery is suffi cient to sustain regenerated axons in spinal cord injury sites [ 196 ].
Sasaki et al. corroborated this fi nding in a rat model of SCI, where transplanting
A. Roussas et al.