Biomedical Engineering Reference
In-Depth Information
Injury
http://dx.doi.org/10.5772/58906
generates anti-inflammatory conditions and promotes functional recovery (Yamagata et al.,
2013). Thus, tooth-derived stem cells have strong immunoregulatory properties that promote
tissue regeneration in the injured CNS.
4.2. Regeneration of the injured axon
Both axonal regeneration and the re-formation of appropriate neuronal connections are
required for functional recovery from SCI. However, multiple AGIs block the inherent
regenerative capacities of injured axons (Silver and Miller, 2004, Schwab et al., 2006, Yiu and
He, 2006, Rowland et al., 2008). It is well known that AGIs constitute an intricate molecular
network in the extracellular space of the injured CNS, where they activate a common intra‐
cellular signaling mediator, Rho GTPase, and its effector, Rho-associated kinase (ROCK)
(Maekawa et al., 1999, Winton et al., 2002, Dubreuil et al., 2003, Monnier et al., 2003, Yamashita
and Tohyama, 2003). Activation of the Rho-ROCK cascade induces growth-cone collapse and
axonal repulsion (Hall, 1998). In contrast, inactivation of either Rho by C3 transferase, or ROCK
by the kinase inhibitor Y-27632 down-regulates AGI signaling and promotes functional
recovery after SCI (Lehmann et al., 1999, Dergham et al., 2002, Fournier et al., 2003). Thus, Rho-
ROCK signaling is an important target for SCI treatments; however, few studies have inves‐
tigated the effect of stem-cell transplantation on regulating AGI/Rho-ROCK signaling
cascades.
Importantly, engrafted SHEDs were recently shown to promote the regeneration of two major
types of descending axons (CST and 5-HT) beyond the lesion epicenter, and to concomitantly
inhibit SCI-induced Rho activation. Furthermore, both SHED-CM and DPSC-CM (but not
BMSC-CM) promote neurite extension by primary cerebral granular neurons (CGNs) cultured
on two different AGIs (CSPG and MAG) (Sakai et al., 2012). Thus, tooth-derived stem cells
promote the regeneration of transected axons through the direct inhibition of multiple AGI
signals by paracrine mechanisms.
In addition, the engraftment of DPSCs into avian embryos results in the chemoattraction of
trigeminal ganglion axons via the chemokine CXCL12 and its receptor, CXCR4 (Arthur et al.,
2009). DPSCs and SHEDs express several neurotropic factors that promote neurite extension
(de Almeida et al., 2011, Sakai et al., 2012). Our preliminary analysis showed that these trophic
factors, when applied individually, failed to promote the neurite extension of CGNs cultured
on CSPG-coated dishes; however it is possible that they may promote axonal regeneration in
a synergistic manner.
4.3. Anti-apoptotic activity
Pharmacological blockade of neuron and/or oligodendrocyte apoptosis by a number of agents
promotes functional recovery after SCI. These agents include the following: erythropoietin
(Celik et al., 2002, Gorio et al., 2002), inhibitors of purine receptor P2X7 (OxATP and PPADS)
(Wang et al., 2004), a neutralizing antibody against CD95 (FAS) antigen (Demjen et al., 2004),
and minocycline (Stirling et al., 2004, Teng et al., 2004). Engrafted SHEDs suppress the
apoptosis of neurons and oligodendrocytes, resulting in the remarkable preservation of
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