Biomedical Engineering Reference
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tically accelerate the progressive neuronal deterioration following SCI. Therefore, therapeutic
strategies for functional recovery from SCI must exert multifaceted reparative effects targeting
a variety of pathogenic mechanisms (Schwab et al., 2006).
4. Multifaceted neuro-regenerative activities of pulp stem cells
4.1. Anti-inflammatory activity
Under various pathogenic conditions, macrophages differentiate into polarized pro-inflam‐
matory (M1) or anti-inflammatory (M2) states, and direct either detrimental or beneficial
effects on tissue healing (Gordon, 2003, Mosser and Edwards, 2008). In the acute phase of SCI,
the majority of accumulating microglia/macrophages are of the M1 type, and few M2 macro‐
phages are seen throughout this period (Kigerl et al., 2009, David and Kroner, 2011). The
activated M1 macrophages secrete high levels of pro-inflammatory cytokines and neurotoxic
factors, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, glutamate, and
reactive oxygen species (Hausmann, 2003, Donnelly and Popovich, 2008). These neurotoxic
factors accelerate glial scar formation (Popovich and Longbrake, 2008), and they induce
neuronal cell death (Takeuchi et al., 2006, Block et al., 2007) and the retraction of damaged
dystrophic axons (Horn et al., 2008, Busch et al., 2009). In contrast, M2 cells counteract the pro-
inflammatory M1 effects and promote tissue remodeling by secreting anti-inflammatory
cytokines (e.g. IL-10 and TGF-β), and scavenging cellular debris (Gordon, 2003, Mosser and
Edwards, 2008, David and Kroner, 2011). Thus, macrophage polarity has the potential to
determine the level of inflammation and the resultant prognosis following SCI.
Recent studies have demonstrated the induction of M2 macrophage polarization following
SCI, and some of the underlying mechanisms are beginning to be elucidated. CSPG, a major
component of the glial scar that is mainly known for its ability to inhibit axonal growth, has
recently been shown to promote M2 polarization of infiltrating blood-derived macrophages
(Rolls et al., 2008, Shechter et al., 2009, Shechter et al., 2011). In addition, recent reports have
shown that BMSC transplantation using SCI or brain ischemia models leads to M2 induction
(Ohtaki et al., 2008, Nakajima et al., 2012). BMSC-mediated M2 induction requires both the
pre-sensitization of BMSCs by pro-inflammatory factors, such as IFN-γ, TNF-α, and LPS, and
direct cell-to-cell contact (Nemeth et al., 2009, Singer and Caplan, 2011). Thus, CSPG together
with pro-inflammatory factors in the injured SC may be involved in the pre-sensitization of
engrafted BMSCs to activate their M2-inducing machinery.
As described in the previous section, SHEDs also exhibit strong immunosuppressive proper‐
ties that effectively ameliorate several autoimmune diseases, including SLE and colitis
(Yamaza et al., 2010, Ma et al., 2012, Zhao et al., 2012). Importantly, intravenously administered
SHEDs express Fas-Ligand, which induces T-cell apoptosis, thereby triggering immune
tolerance (Zhao et al., 2012). This elevates the ratio of regulatory T cells (Tregs) to pro-
inflammatory T cells, resulting in anti-inflammatory conditions (Yamaza et al., 2010). We also
found that, in the mouse hypoxic ischemia model, both intracerebral transplantation of SHEDs,
and administration of serum-free conditioned media (CM) derived from SHEDs (SHED-CM),
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