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Fracaro et al. Neuroimmunol Neuroinflammation 2020;7:1-12 I http://dx.doi.org/10.20517/2347-8659.2019.009 Page 5

Electroacupuncture/electrostimulation is another treatment that has long been used in spinal cord injury
therapy and has been shown to inhibit inflammation, promote the secretion of neurotrophic factors, and
[31]
reduce secondary injuries [29,30] . Chen et al. performed electroacupuncture on rats with spinal cord injury
and found that this treatment is effective to prevent oligodendrocyte apoptosis and to improve functional
[32]
recovery after spinal cord injury. Krueger et al. performed the association of electrostimulation with
mesenchymal stromal cells derived from adipose tissue in dogs with SCI and observed improvement, but
without statistical difference between the associated treatments (electrostimulation and MSCs) and isolated.

There are many studies developing different techniques to assist the recovery of spinal cord injury patients.
These studies aim to combat the primary or secondary events of the injury, aiming at patient improvement,
but without regenerating the nervous tissue. Cell-based therapy is the only promising treatment aimed at
regeneration. Many cell types from different sources and infusion pathways have been studied or are being
evaluated in ongoing studies.

STROMAL CELLS THERAPY
Cell therapy brought the promise of regenerating tissue after SCI, although the mechanism by which
this type of cell therapy achieves neurological recovery have not yet been fully explained. Adult stem
cells, such as MSCs, are stromal cells with potential self-renovation, multiple lineage differentiation, and
immunomodulatory potential . MSCs are major candidates for tissue regeneration due to release of
[33]
[34]
bioactive factors, as well as anti-apoptotic, scar inhibitor, and angiogenic effects . These cells also have the
potential for differentiation into various adult cell types, including neurons [35,36] . The main source of MSCs
is bone marrow, but other sources such as adipose tissue and umbilical cord, which are easily collected
tissues, are also being used in preclinical and clinical studies. Following MSC transplantation, several repair
processes occur, including: (1) the release of neurotrophic factors that may prevent nerve degeneration
and apoptosis, as well as support neurogenesis, axonal growth, remyelination, and cellular metabolism; (2)
reduction of neuroinflammation because MSCs can secrete a variety of soluble molecules, such as anti-
inflammatory cytokines; (3) induction of angiogenesis, an important process by which new vasculature
sprouts from pre-existing blood vessels; and (4) activation of endogenous spinal cord mechanisms capable
of restoring some previously lost neurological functions [37-39] [Figure 3].

Although the precise mechanism by which MSCs transplantation promotes functional recovery after SCI is
still unclear, it is widely accepted that most benefits of MSCs transplanted rely on the secretion of different
[40]
factors and biomolecules . MSCs release cytokines that may be neuroprotective and neuroregenerative.
Some cytokines, e.g., neurotrophic factor, monocyte chemoattractant protein-1, and granulocyte-
macrophage colony stimulating factor, play a role in neuroprotection; induce monocyte recruitment during
inflammation, enhancing myelin debris clearance in central nervous system injuries; and inhibit apoptosis
[41]
of neuronal cells and gliosis after SCI . Other neurotrophic factors expressed by bone marrow derived
mesenchymal stromal cell (BM-MSC) such as brain derived neurotrophic factor, glial-derived neurotrophic
factor, and nerve growth factor can assist nervous tissue neuroregeneration including the formation of new
synapses and myelination and promote axonal regeneration and functional recovery after SCI [42,43] .

MSCs also reduce inflammation, which is a secondary event after trauma. These cells change the
inflammatory profile to the anti-inflammatory one, which could have a beneficial effect on functional
[42]
recovery after SCI . Transplantation of MSCs also reduces the expression of glial scar marker (GFAP), a
[42]
characteristic compatible with a resolutive inflammatory reaction , and increases the expression of Treg-
[44]
gene .
Among the molecules secreted by MSCs, pro-angiogenic factors such as vascular endothelial growth factor
(VEGF) are essential for repair of damaged tissue. VEGF/PDGF (platelet-derived growth factor) stimulated