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Alternatively, SCs can be isolated from white adipose tissue neuronal activity, promoting nerve regeneration. [63,64] In
using liposuction to avoid invasive procedures. [46,47] Like addition, their expression is strictly dependent on time
MSC, adipose‑derived SCs (ASCs) are able to differentiate after axotomy, which biases the regenerative capacity of
into a SC phenotype, and their characteristic elongated axons, as well as the supporting activity of SCs. [3]
spindle‑shaped morphology has been confirmed Neurotrophins constitute one of the most important
through microscopy. [47‑49] Their ability to express specific family of factors, including NGF, BDNF, NT‑3, and
glial‑markers, that is, S‑100, p75 and glial fibrillary acidic NT‑4/5. After release, a density gradient of factors is
[65]
protein, [50,51] as well as the protein P0 responsible for formed around regenerating axons. NGF is the one of
[62]
the myelin formation, has also been demonstrated. the most important NTs involved in nerve regeneration
[51]
Finally, differentiated ASC (dASC) are able to express the and is up‑regulated rapidly in the distal stump after
neuronal‑associated protein nestin, [48,50,51] as well as the injury. It is able to promote the survival and outgrowth
[66]
neuron‑specific enolase and the neuron‑specific protein. [48]
of sensory neurons, although NGFs are not involved in
When undifferentiated ASC were preloaded in the motor neuron response. BDNF is up‑regulated in
[65]
polycaprolactone conduits to investigate their effect denervated SCs in order to allow myelination and nerve
on axonal outgrowth, it was observed that they were regeneration. It is involved in the outgrowth of both
[66]
able to prevent neuron apoptosis by up‑regulating the sensory and motor neurons. [62,65] Finally, NT‑3 and NT‑4/5
expression of anti‑apoptotic BCL‑2 and down‑regulating promote survival of both motor and sensory neurons.
the expression of caspase and BAX. These results
[52]
were comparable to N‑acetylcysteine treatments, which Besides NTs, other neurotrophic factors are involved in
guarantee the preservation of cell signaling and survival the regenerative process of nerves. CNTF is a neurokine
[65]
as previously demonstrated. [53‑55] Both ASC and dASC protein down‑regulated after injury, implicated in motor
[65]
[63]
have been frequently used for transplantation in NGC neuron survival, outgrowth and sprouting. Moreover,
to repair injury gaps, although different and sometimes glial cell line‑derived neurotrophic factor (GDNF), [64,66]
conflicting results have been observed due to the FGF, [62,65] neuregulin‑1, [64,66] and leukemia inhibitory
various experimental conditions. [56‑59] Signs of in vivo factor [63,64] also play an important role in peripheral
transdifferentiation of undifferentiated SCs into an SC‑like nerve regeneration. Finally, TGF‑β is necessary for the
phenotype have been also observed, further stimulating nonmyelinating status of SCs during the proliferation
[64]
interest in using ASC for peripheral nerve repair. process. Nevertheless, all neurotrophic factors described
[59]
However, depending on the scaffold used, the viability of above co‑operate in order to enable neuron survival and
the preloaded cells can be strongly affected, reducing the axonal outgrowth. [63]
initial beneficial effect of the cell therapy. All of these Following injury, axotomy conditions and chronic
[56]
results suggest the potential use of ASC (or dASC) in denervation cause a reduced availability of neurotrophic
peripheral nerve repair, substituting SC. factors and their supplement at the injury site is needed
The ultimate strategy in cell therapy is the formation of to stimulate and support regeneration. [3,67] As reviewed
[68]
tissue engineered nerve grafts with the application of a by Pfister et al., growth factors can be released
intraluminal “cellular coating” composed of co‑cultured into the lumen through different mechanisms of drug
SC and dorsal root ganglia, which are able to release and delivery from an empty conduit (i.e. dissolution in a
up‑regulate the production of neurotrophic factors in the solution, encapsulation in the conduit wall, diffusion
lumen over time. Long‑term results of up to 12 weeks through microspheres) or by use of an intraluminal filler
have shown a significant ability to regenerate the nerve (i.e. microfiber impregnation, binding and release in
[60]
comparable to nerve grafts. An even more advanced a matrix). However, results reported in the literature
development would be the fabrication of scaffoldless are sometimes contradictory, and optimization of their
neural conduits providing a confined environment without concentration and the release mechanism is, therefore,
[61]
using polymeric structures, as proposed by Adams et al., necessary. In addition, due to their low stability in
In their study, their group attempted to construct a solution, growth factors need to be protected when
nerve guide using a monolayer of ASC differentiated into encapsulated or bond to a substrate in order to prevent
fibroblasts co‑cultured with neurospheres. This system their degradation and prolong their activity in situ. In fact,
supported the in vivo expression of growth factors, some ECM molecules can form specific bonds with growth
such as FGF, ascorbic acid, epidermal growth factor, and factors, preserving their functionality. For example, it
transforming growth factor (TGF)‑β1, which induced the was found that binding to heparin or heparin sulfate can
transdifferentiation of the SCs into SC‑like cells. [61] specifically stabilize FGF, GDNF, and NGF, which are then
[68]
gradually released in the delivery system. Furthermore,
GROWTH FACTORS AND THEIR RELEASE polymer coatings of the surface of the loaded biomaterial
[12,69‑71]
IN NERVE GUIDANCE CONDUIT or microsphere with polylactide‑co‑glycolide can
protect and gradually control the neurotrophic factor
delivery over time.
Neurotrophic factors belong to the family of growth
factors, and they are produced by SCs during Wallerian Gordon’s group has extensively investigated the role of
degeneration after injury. Acting through their neurotrophic factors in nerve regeneration, particularly
[62]
receptors, neurotrophic factors are involved in the focusing on the effect of BDNF and GDNF in the system.
216 Plast Aesthet Res || Vol 2 || Issue 4 || Jul 15, 2015