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to spinal cord injury and it has been repeated [ 87 ]. Nestin is a protein expressed by
stem cells: presence of it indicates neural stem cells are much more active then
previously believed. Our brain naturally increases the production of stem cells to
aid an injured CNS. If the brain responds in this way, why does not the spinal cord
repair itself? In 1999, Johansson and Momma observed that the only active progenitor
cells were differentiating into astrocytes [ 88 ]. They labeled ependymal cells with a
Dil injection so migration could be followed. After making lesions in the spinal cord
they waited 4 weeks and then observed the progress of the ependymal cells. They
tested the cells found in the scar tissue around the site of injury and found that all
DIL marked cells were astrocytes. This indicates that the progeny from ependymal
cells had only differentiated to astrocytes. Stem cells do respond to spinal cord
injury, just not for the purpose of reestablishing connection between neurons.
This realization sparked scientist's interest in understanding what triggers these
progenitor cells to proliferate. The active progenitor cells may be ineffective in
maintaining a functional CNS after injury, but if scientists could learn what signals
triggered differentiation, perhaps they could induce differentiation of neurons and
oligodendrocytes. Scientists began to focus on neurotrophic factors that triggered
this differentiation, specifically the presence of brain-derived neurotrophic factors
(BDNF) and neurotrophin 3 and 4 (NT-3 and NT-4). In the early 1990s these trophic
factors were targeted as what triggered axon growth during early development.
NT-3 also is expressed in greater amounts in response to spinal cord injury. In 1994
Schwab reported dramatic increase in function, and regrowth of a partially severed
cord of rats after treatment with NT-3 [ 89 ]. In 1997 Grill, Gage, and colleagues
published a paper examining the effects of transplanted NT-3 on motor skills and
morphology after induced spinal injury in mice [ 90 ]. They focused on the corticospinal
tract, the pathway in charge of making voluntary movements. NT-3 has been previously
observed to promote regrowth of corticospinal axons and preserves degenerating
motor neurons.
Grill and colleagues induced lesions in the dorsal hemisection of adult rat's spi-
nal cord, resulting in severely limited motor ability. Next grafts of syngenic
fibroblasts, genetically altered to produce NT-3, were transplanted into the lesion
cavity of the experimental group. These rats were kept alive for 3 months and put
though a series of tests to monitor motor improvement. These tests examined coor-
dination, ability to walk on inclined surfaces and precision of foot placement. After
3 months these rats were killed for the purpose of a quantitative cell count.
Recipients of the NT-3 secreting grafts showed significant improvement in motor
skills over the control group, although they did not recover to the full ability they
had before injury. After 3 months recipients of the NT-3 grafts demonstrated growth
of corticospinal axons up to 8 mm from where the transplant had taken place. Only
the injured axons at the lesion site showed any sign of regrowth [ 90 ] . Uninjured
axons showed no effort to reestablish connections across the site of injury [ 90 ] . This
suggests that NT-3 only responds when corticospinal axons are injured. If scientists
could pinpoint signals triggering this response, there is potential to manipulate the
process in a manner causing neural cells to differentiate.
Triggering neurotrophic factors in hopes of inducing progenitors to proliferate is
one of the two major areas of study in spinal cord regeneration. Scientists also can
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