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Page 6 Fracaro et al. Neuroimmunol Neuroinflammation 2020;7:1-12 I http://dx.doi.org/10.20517/2347-8659.2019.009

Figure 3. A: following injury, trauma and ruptured blood vessels result in ischemia, anoxia, and inflammation. This environment leads
to neuronal death and degeneration; B: the infusion of MSCs can be done in different locations. There is still disagreement regarding
the number of cells and infusions, but MSCs from different sources can be used for treatment (umbilical cord, adipose tissue, and bone
marrow); C: after infusion, MSCs change the injured environment by releasing anti-inflammatory (TNF-β1, IL-13, IL-18, CNTF, NT-3, and
IL-10), neuroprotective (BDNF, GDNF, NGF, NT-1, NT-3, CNTF, and bFGF), and angiogenic cytokines (TIMP-1, VEGF, HGF, PDGF, IL-6, and
IL-8). Cell survival, remyelination, and vascular repair can also be observed. MSCs: mesenchymal stromal cells; TNF-β1: transforming
growth factor β1; IL-13: interleukin 13; IL-18: interleukin 18; CNTF: ciliary neurotrophic factor; IL-10: interleukin 10; BDNF: brain-derived
neurotrophic factor; GDNF: glial cell-derived neurotrophic factor; NGF: nerve growth factor; NT-1: neurotrophin 1; NT-3: neurotrophin
3; bFGF: basic fibroblast growth factor; TIMP-1: tissue inhibitor of metalloproteinase-1; VEGF: vascular endothelial growth factor; HGF:
hepatocyte growth factor; PDGF: platelet-derived growth factor; IL-6: interleukin 6; IL-8: interleukin 8

angiogenesis results in a higher blood vessel density at the injured site, lesion size reduction, and white
[45]
matter sparing with functional outcome after SCI .
Although most studies showed evidence that MSCs most likely act through their secretions (paracrine
effect) [46-48] and not via their own integration/differentiation within the host tissue, some authors have
reported the potential for MSCs transdifferentiation in cells of the nervous system and have shown that,
after infusion into the spinal cord, these cells possibly promote regeneration of neurons because they
have neuronal markers [49-52] . In vitro studies have shown that BM-MSC possess an intrinsic capacity to
differentiate into neural-like and glial-like cells and express nestin, βIII-tubulin, neurofilaments, neuron-
specific enolase, and glial fibrillary acidic protein (GFAP) [53-55] .

A better understanding of the mechanisms underlying the regenerative effects of stromal/progenitor cells
in the nervous system is essential for development of future cell-based therapies to treat SCI in humans.

Despite a lot of effort in recent years to develop new therapies using stromal cells to treat central nervous
system trauma, there is no consensus on the cell type, source, number of cells, infusion pathways, and
[56]
number of infusions suitable for achieving this goal .
Adult stromal cells have been used in preclinical research and clinical studies. These studies demonstrate
how research uses different strategies for treating spinal cord injury using different sources of MSCs,
multiple cell infusion pathways, and various models of SCI. Various types of SCI can be treated with
cell therapy using MSCs, including even in patients with complete SCI [57-59] . MSCs can be transplanted
intrathecally, intramedullary, intravenously, or intraarterially with different MSC sources (bone marrow,
[5]
adipose tissue, umbilical cord blood, skin, and dental tissues) [Tables 1 and 2].