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Despite revealed that DPSCs releases angiogenic factors

Despite of the fact that CNS has a
limited capacity to repair (Nakagomi et al., 2011), some degree of possibility
of spontaneous recovery remains there. One promising field of
investigation is focused upon triggering and stimulating the self-repair system
to regenerate new neurons (Marlier et al., 2015) or to establish an effective
vascular network (Xu et al., 2011). Vasculogenesis is a complex
process involving various growth factors, chemokines, and mural cells (the
cells which are involved in the formation of normal vasculature), all of
which play different roles in promoting and refining this process (Shen et al.,
2015). 

Dental pulp tissue is a
highly innervated and vascularized tissue which contains blood vessels and
neuron precursor cells thus can differentiate into vascular and neuronal cells
(Marchionni et al., 2009 and Pierdomenico et al., 2005). DSCs are considered to
establish therapeutic angiogenesis either by differentiation into
vascular cells e.g. endothelial cells or by paracrine secretion of angiogenic
growth factors. Identification of factors responsible for
angiogenesis revealed that DPSCs releases angiogenic factors and
cytokines such as VEGF, monocyte chemotactic protein 1 (MCP1; chemokine
C-C motif ligand 2), and stromal cell-derived factor 1 (SDF1) and Platelet-derived
growth factor BB (PDGF-BB) (Shen et al., 2015). The finding also showed
that DPSC conditioned media can induce the migration and tube formation in
vascular smooth muscle cells (VSMCs) and human umbilical venous endothelial
cells (HUVECs), suggesting the ability of DPSCs to give rise to vessel like
structures. 

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Importantly, the trophical factors
such as VEGF, Chemokine (C-C motif) ligand 5 (CCL5), SDF-1 and MCP-1
expressed by the DSCs are critical for vascular network remodeling. VEGF has
been suggested to play an important role in DSCs mediated vascular repair
(Inoue et al., 2013; Sugiyama et al., 2011; Marchionni et al., 2009), as they
can bypass the blood brain barrier (BBB) (Yang et al., 2009). DPSC has been
found to mediate localized discontinuities in BBB through up-regulating
VEGF-alpha, allowing passage into the brain parenchyma (Winderlich et al.,
2016). Similarly, the transplantation of side population of DSCs increased the blood
flow in infracted brain, through enhanced expression of VEGF (Iohara
et al., 2008). 

The
trophic factors released by DSCs may affect synaptogenesis. When quantitative
analysis of tooth pulp afferent terminals in the rat brain stem
was done, distinct roles of trigeminal sensory nuclei in processing of pulpal
information were indicated, as the results suggest that pulpal afferent
information is regulated in a unique manner in the each trigeminal sensory
nucleus. In an avian embryonic model system, implanted DPSC secreted
factors, which coordinated axon guidance within a receptive host nervous
system. This was the first direct evidence of transplanted DPSC induce
neuroplastic changes (Arthur et al., 2009). human DPSC when grafted in a stroke
rodent model,  promoted neuroplasticity through
the bidirectional cross-talk between IGF1R/IGF1 and CXCR4/SDF-1? signaling
pathways, as revealed by interaction of the two receptors and synergistic
activation of both signaling pathways leading to improvement in neurological
function  (Lee, et al., 2016). The IGF1
receptor (IGF1R) expressed in human DSCs has also promoted neuroplasticity, as When
IGF1R+ hDSCs were transplanted in neonatal hypoxia
ischemia rats it enhanced neuroplasticity as evident by neurite regeneration, and
increased neurogenesis and angiogenesis both (Chiu et al., 2017). In a recent
comparative between human DPSC and SHED for their differentiation-potential towards
dopaminergic neuron, DPSC possess superior neuronal plasticity toward
dopaminergic-neurons (Majumdar et al., 2016). Further, the GO analysis of
representative common protein spots among PDLSC and DPSC and BMSC strongly
suggests a high plasticity, proliferative ability and differentiation potency
of these stem cells (Eleuterio et al., 2013). Thus it is reasonable to say that
DSCs may induce functional recovery via modulating the synaptogenetic
mechanism.

Beyond
substitution of the lost neurons, immunomodulation could be a potential tool in
neurorestorative effort. The immune system plays a crucial role in the success
of cell replacement. Failure to consider the interactions between transplants
and the immune system can result in rejection of the implant and devastating
clinical consequences. Recent research into DSCs, a potent immunomodulator, indicates
that they may play a beneficial role modulating the immune system.  DSCs have been shown to modulate
immunological responses via T-cell suppression, better than bone marrow MSCs
(BMMSCs) (Sonoyama et al., 2007 and Krampera et al., 2003). Thus makes them an
appropriate cell type for allogenic bone marrow replacement therapy.
Transplantation SHED (Cristiano et al., 2017 and Sun et al., 2009) has shown
inhibition of the immune response by suppressing T cells, inducing regulatory T
cells. This immunomodulatory activity indicates that SHED could be suitable to
suppress T cell-mediated graft-versus-host reaction. SHED has been shown to
suppress Th17 function proposing that SHED could be valuable source to treat
systemic lupus erythematosus (Yamaza et al., 2010). Further, SHED can induce
immune regulator phenotype in monocyte-derived dendritic cells, and can convert
dendritic cells and macrophages into a regulatory phenotype (Cristiano et al.,
2017). Thus it is reasonable to suppose that these cells can be effectively
applied for the treatment of autoimmune diseases. Several reports indicate
that the immunomodulatory responses are due to the bystander mechanism (Ozdemir
et al., 2016 and, Martino and Pluchino, 2006). In the line of above notion, DPSCs
have shown to inhibit the proliferation of stimulated T cells (Bianco et al.,
2001 and Sonoyama et al., 2008). This response was through TGF- ? signaling (Wada
et al., 2004), at least in part. Similarly, DPSCs through the
increased expression of TGF- ? and IL-6 immunosuppressed the
Toll-like receptor, the receptors implicated in several neurological disorders
associated with neuroinflammation. In addition, DPSCs has been shown to trigger
T cell apoptosis in vitro and improve
inflammation dependent tissue injuries in
vivo (Zhao et al., 2012). The DPSCs induced immunoregulation is found to be
associated with the expression of Fas ligand (FasL), a trans-membrane protein
that plays an important role in inducing the Fas apoptotic pathway. Thus,
altogether, the immunosuppressive potential of these cells is clearly a distinctive
advantage for a clinical management of neurodegenerative diseases.

A
crucial intention of stem cell therapy is to prevent early secondary cell
death by suppressing apoptosis, a key secondary cell death mechanism.
Apoptosis accounts for approximately 90% of neuronal loss in CNS injury
models (Casella et al., 2006; Lou et al., 1998, thus an important avenue
for treatment. Both SHED (Nicola et al., 2017) and DPSC (Sakai et al.,
2012) can reduce cell loss though attenuation of apoptosis, thus contributing
to tissue and motor neuron preservation. The exosomes derived from SHED or the intracerebral
administration of SHED-conditioned medium can also improve the neurological
outcome through inhibition of apoptosis in an in vitro dopaminergic neuronal model (Jarmalaviciute et al., 2015) and
in an in vivo hypoxia ischemic (Yamagata
et al., 2013) model contributing to the neurorestoration process. Further, to
prevent programmed cell death, DSCs secrete proteins that are classic
inhibitors of apoptosis such as B-cell lymphoma 2 (Bcl-2) (Ahmed et al., 2016).
Interestingly, DPSC downreglated the level of apoptotic regulator (Bcl-2-associated
X protein) Bax. The Bcl-2/Bax ratio is critical for the cells to a pathological
stimulus (Oltvai et al., 1993). The high Bcl-2 expression prevents the release
of caspase inhibitors; thus, cells are less likely to respond to the apoptotic
signaling (Green et al., 1998). The ability to secrete cytokines such as VEGF,
MCP-1 etc. by DSCs also contributes in the restorative process, as these
cytokines are known to neutralize the effect of apoptosis (Ahmed et al., 2016).
VEGF was instrumental in preventing serum starvation-induced apoptosis by
upregulating Bcl-2 expression in vascular endothelial cells (Gerber et al.,
1998). Similarly, DPSCs secretome significantly decreased the cytotoxicity of
A? peptide by stimulating the endogenous survival factor Bcl-2 and decreasing
the apoptotic regulator Bax (Ahmed et al., 2016).

Taken together it can be suggested
that stem cells of dental origin have a therapeutic potential specifically as a
stimulator and modulator of the local repair response in the CNS.

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