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Stem Cells International
Volume 2018, Article ID 1731289, 15 pages
https://doi.org/10.1155/2018/1731289
Review Article

Potential Roles of Dental Pulp Stem Cells in Neural Regeneration and Repair

1WMU-UQ Group for Regenerative Medicine, Institute of Stem Cells and Tissue Engineering, School of Stomatology, Wenzhou Medical University, Wenzhou 325035, China
2School of Dentistry, The University of Queensland, Herston, QLD 4006, Australia
3School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
4School of Biomedical Engineering, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou 325035, China
5Wenzhou Institute of Biomaterials and Engineering, CAS, Wenzhou 325011, China
6Engineering Research Center of Clinical Functional Materials and Diagnosis & Treatment Devices of Zhejiang Province, Wenzhou Institute of Biomaterials and Engineering, CAS, Wenzhou 325011, China

Correspondence should be addressed to Huaqiong Li; nc.ca.ebiw@qhil and Qingsong Ye; moc.liamtoh@eygnosgniq

Received 7 November 2017; Accepted 22 March 2018; Published 7 May 2018

Academic Editor: Tao-Sheng Li

Copyright © 2018 Lihua Luo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

This review summarizes current advances in dental pulp stem cells (DPSCs) and their potential applications in the nervous diseases. Injured adult mammalian nervous system has a limited regenerative capacity due to an insufficient pool of precursor cells in both central and peripheral nervous systems. Nerve growth is also constrained by inhibitory factors (associated with central myelin) and barrier tissues (glial scarring). Stem cells, possessing the capacity of self-renewal and multicellular differentiation, promise new therapeutic strategies for overcoming these impediments to neural regeneration. Dental pulp stem cells (DPSCs) derive from a cranial neural crest lineage, retain a remarkable potential for neuronal differentiation, and additionally express multiple factors that are suitable for neuronal and axonal regeneration. DPSCs can also express immunomodulatory factors that stimulate formation of blood vessels and enhance regeneration and repair of injured nerve. These unique properties together with their ready accessibility make DPSCs an attractive cell source for tissue engineering in injured and diseased nervous systems. In this review, we interrogate the neuronal differentiation potential as well as the neuroprotective, neurotrophic, angiogenic, and immunomodulatory properties of DPSCs and its application in the injured nervous system. Taken together, DPSCs are an ideal stem cell resource for therapeutic approaches to neural repair and regeneration in nerve diseases.

1. Introduction

Traumatic events, iatrogenic injuries, and neurodegenerative diseases can lead to axonal degeneration, inflammation, neuron death, and cytoarchitectural malformation in both the peripheral nervous system (PNS) and central nervous system (CNS) [16]. Conventional medical therapies have limited efficacy in supporting functional recovery from nervous damage since the mature nervous system lacks the necessary precursor cells to generate new neurons and glial cells [7]. Recently, stem cell-based strategies in combination with novel technologies (e.g., precisely controlled hydrogels) have heralded potential new therapeutic approaches for addressing nerve regeneration and repair [811].

Mesenchymal stem cells (MSCs) harvested from adult tissues are potentially an important therapeutic cell source for treatment of CNS and PNS perturbations since they possess the capacity for both neuronal and glial differentiation. MSCs also express numerous anti-inflammatory and neurotrophic factors supporting nerve repair [814]. These multipotent stem cells are present in bone marrow [15, 16], adipose tissue [17, 18], umbilical cord [19, 20], and dental tissue [2125]. Dental pulp stem cells (DPSCs) can readily be obtained from the third molars, usually discarded as medical waste. DPSCs have MSC-like characteristics such as the ability for self-renewal and multilineage differentiation. These dental pulp-derived MSCs avoid ethical concerns when sourced from other tissue, and they can be obtained without unnecessary invasive procedures, for example, MSCs collected from bone marrow or adipose tissue [9, 2628]. DPSCs can differentiate into neuron-like cells and secrete neurotrophic factors such as neurotrophin (NT) [29, 30]. In addition, DPSCs express neuron-related markers even before being induced to neuronal differentiation [29, 31, 32]. Taken together, these unique properties make DPSCs an excellent candidate for stem cell-related therapies in nerve diseases.

2. Dental Pulp Stem Cells (DPSCs)

2.1. The Characteristics of DPSCs

The basic tooth structure consists of an outer enamel layer, a middle dentin layer, and an inner dental pulp layer. It develops from both cranial neural crest-derived mesenchymal stem cells (MSCs) and oral-derived epithelial stem cells in the early stages of embryogenesis [3335]. Dental pulp, a soft connective tissue containing blood vessels, nerves, and mesenchymal tissue, has a central role in primary and secondary tooth development and ongoing maintenance for instance in reaction to caries [36, 37]. Stem cells can be isolated from the dental pulp tissue and possess MSC-like characteristics including self-renewal and multipotency [21, 3840]. The first dental pulp-related stem cells were isolated from the third molar dental pulp by Gronthos et al. in 2000 [21]. Subsequently, it was reported that DPSCs could also be isolated from other dental pulps including human exfoliated deciduous teeth [22], human permanent and primary teeth [41], and supernumerary teeth [42]. Meanwhile, they are featured by high-proliferative capacity [4347]. Most importantly, compared with collection procedures of other tissue-derived stem cells, the collection of DPSCs involves none harm to the donor or invasive surgical procedures [27, 40].

There are currently no specific biomarkers that uniquely define DPSCs. They express MSC-like phenotypic markers such as CD27, CD29, CD44, CD73, CD90, CD105, CD146, CD166, CD271, and STRO-1. Yet they do not express CD34, CD45, CD14, or CD19 and HLA-DR surface molecules [38, 39, 48]. Similar to embryonic stem cells, DPSCs express stemness-related markers such as Oct-4, Nanog, and Sox-2, as well as the cytoskeleton-related markers (Nestin and Vimentin) [29, 49, 50]. In addition, DPSCs express other cranial neural crest cell-related neural markers such as glial fibrillary acidic protein (GFAP), β-III tubulin, and microtubule-associated protein-2 (MAP-2) [29, 50, 51].

DPSCs are multipotent and can be induced to differentiate into cells for osteogenesis [52], chondrogenesis [53], adipogenesis [53], neurogenesis [54], dentinogenesis [53], odontogenesis [55], and myogenic lineages [56] (Figure 1). Using classic reprogramming factors (e.g., Oct3/4, Sox2, Klf4, and c-MYC), human DPSCs can be converted into induced pluripotent stem cells (iPSCs) [57, 58]. iPSCs exhibit the characteristics of embryonic stem cells and can differentiate into all three germ layers [59, 60]. Human DPSCs have a higher reprogramming efficiency than human dermal fibroblasts because they have a rapid proliferation rate and endogenously express high levels of the reprogramming factors c-MYC and Klf4 [57]. Therefore, DPSCs are potentially an important patient-specific cell source of iPSCs for clinical applications, regenerative medicine, and tissue engineering.

Figure 1: Multidifferentiation potential of DPSCs. DPSCs possess MSC-like properties and are multipotent. NCAM: neural cell adhesion molecule; MAP2: microtubule-associated protein 2; NeuN: neuron-specific nuclear protein; Fit-I: VEGF receptor 1; KDR: VEGF receptor 2; CD34: cluster of differentiation 34; ICAM-I: intercellular cell adhesion molecule-1; vWF: von Willebrand factor, DSP: dentin sialoprotein, DMP1: dentin matrix acidic phosphoprotein 1, BSP: bone sialoprotein, OCN: osteocalcin, MyoD1: myoblast determination protein 1; MHC: major histocompatibility complex; PCR: polymerase chain reaction; FC: flow cytometry; ICC: immunocytochemical.
2.2. Neuronal Differentiation of DPSCs

DPSCs arise from the cranial neural crest and possess neuron-like characteristics that facilitate their in vitro induction into functional neurons. Numerous protocols have been developed to differentiate DPSCs into neurons. Typically, such methods rely on growth factors and various small molecules including basic fibroblast growth factor (bFGF) [61, 62], epidermal growth factor (EGF) [63], nerve growth factor (NGF) [62, 64], brain-derived neurotrophic factor (BDNF) [65], glial cell line-derived neurotrophic factor (GDNF) [66], sonic hedgehog [66], neurotrophin 3 (NT-3) [61], retinoic acid (RA) [63], forskolin [50, 67], and heparin [66] as well as culture supplements such as B27 [61], insulin-transferrin-sodium selenite (ITS) [54], nonessential amino acids [66], and N2 [61, 66]. Under controlled in vitro conditions (e.g., spheroid suspension culture in serum-free media), it is possible to differentiate DPSCs into neural lineages that expressed numerous neural markers [61, 63, 64, 68]. Chun et al. have demonstrated that DPSCs could be differentiated into dopaminergic neural cells by the formation of neurosphere [69]. However, huge variations exist in the neural differentiation of DPSCs due to alterations made to the culture of neurosphere, which indicates a delicate regulatory approach is necessary to achieve target differentiation. It is controversial on the timing of neurosphere formation. The study of Gervois et al. showed that it formed in the initial phase during a neural induction [61], whereas studies of Karbanova et al. observed that the neurosphere formed in a rather late phase during the differentiation [70].

Nevertheless, it is possible to bypass neurosphere formation by using endogenous environmental cues and directly differentiate DPSCs into motor and dopaminergic neuronal sublineages [65, 71]. Studies of Chang et al. reported that DPSCs could be directly differentiated into motor neurons by growth factors and small molecules, for example, BDNF and all-trans retinoic acid [71]. Gnanasegaran et al. demonstrated that DPSCs could be induced to differentiate into dopaminergic-like cells by multistage inductive protocols [72]. The study of Singh et al. showed that DPSCs are induced by a two-step method to generate functional dopaminergic neurons: FGF2 first with an addition of BDNF on 9th day. Furthermore, when induced, DPSCs showed much more distinct neuronal characteristics comparing to the other tissue-derived MSCs, for example, bone marrow and adipose tissue [73]. In addition, DPSCs could be differentiated into spiral ganglion neuron-like cells by treating with BDNF, NT-3, and GDNF [74].

Typically, a successful neuronal differentiation of DPSCs is confirmed by the increased expression of neuronal markers such as NeuN [61], neurofilament-200 [54], MAP-2 [61, 75], synaptophysin [61], and neural cell adhesion molecules [76]. Few studies have used ultrastructural and/or electrophysiological analyses to confirm the state of differentiation [61]. Previous studies focus on differentiation directions: DPSCs could be differentiated into either neuronal precursor cells (rather than mature neurons capable of generating action potentials) or immature Schwann cells and oligodendrocytes that can support nerve regeneration [7780] (Figure 2). Recently, research has evolved into in-depth studies on functional and mechanism of DPSC-differentiated neurons. A series of studies have explored the functional activities of DPSC-differentiated neurons in voltage-gated sodium and potassium channels as well the neuronal marker expressions, indicating a successful differentiation is active and functional new neurons have emerged [50, 54, 67]. Further, these predifferentiated DPSCs have been traced and proved well integrated into the central nervous tissue when transplanted in animal models [54, 67]. In summary, versatile differentiations of DPSCs depend on inductive protocols. They can be differentiated into neurons, dopaminergic-like cells, Schwann cells, and oligodendrocytes. Thus, DPSCs are an attractive cell source for stem cell therapy to treat the nervous diseases.

Figure 2: Neural differentiation potential of DPSCs. DPSCs can be induced to differentiate into neural cell lineages including Schwann cells, astrocytes, and dopaminergic neurons.
2.3. Neuroprotective and Neurotrophic Properties of DPSCs

The efficacy of stem cell therapies in nervous diseases is strongly influenced by trophic factors, for example, BDNF, GDNF, NGF, NT-3, vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) [29, 30]. The expression of these trophic factors by DPSCs is remarkably higher than those of MSCs derived from bone marrow (BMSCs) and adipose tissue [9, 30]. Further in vivo study also demonstrates a more efficient secretion of BDNF and GDNF than BMSCs [81]. These findings confirm that in comparison to other MSCs, DPSCs exhibit superior neuroprotective and neural supportive properties in response to injuries and pathologies of the nervous system. DPSCs have the ability to reduce neurodegeneration in the early stages of neuronal apoptosis and promote motor and sensory neuron survival in spinal cord injury (SCI) by the secretion of BDNF and NGF [82, 83]. Furthermore, trophic factors secreted by DPSCs promoted axon regeneration despite the presence of axon growth inhibitors in the completely transected spinal cord model of SCI [84, 85]. DPSCs also provided both direct and indirect protections against cell death by secreting cytoprotective factors in an ischemic astrocyte model of injury [86, 87]. Compared with other stem cells (DFSCs, SCAP, and BMSCs), DPSCs have shown a higher cytokine expression facilitating neuronal differentiations [88].

2.4. Angiogenic Properties of DPSCs

In general, the human body needs abundant nutrition and blood supply in order to maintain its tissues and organs in a healthy condition. The sprouting of new capillaries from existing blood vessels during inflammation and hypoxic conditions depends on the expression and secretion of specific angiogenic trophic factors [89, 90]. Some MSCs are able to promote therapeutic angiogenesis by the secretion of angiogenic growth factors and by differentiating into endothelial cells [9193]. In particular, DPSCs have been found to secrete and produce abundant angiogenic factors, for example, colony-stimulating factor, interleukin-8, angiogenin, endothelin-1, angiopoietin-1, and insulin-like growth factor binding protein-3 [9496]. DPSCs also secrete and express other stimulatory growth factors such as VEGF, PDGF, bFGF, and NGF [19, 30, 97]. Synergistically, these factors can promote proliferation and survival of vascular endothelial cells [98, 99] as well as endothelial tubulogenesis [100]. Both the formation and function of new blood vessels are improved by either injection of DPSCs into neuronal disease models or transplantation of DPSCs into ischemia and myocardial infarction animal models [101, 102]. Moreover, Nam et al. observed that by coinjection of DPSCs and HUVECs into immunodeficient mice, microvessel-like structures would be formed, which illustrated that DPSCs could perform as perivascular cells for in vivo angiogenesis [103]. DPSCs also have the ability to differentiate into endothelial-like cells. When incubated with VEGF, the expression of VEGFR1, VEGFR2, von Willebrand factor, and CD54 is increased [104, 105]. These VEGF-induced DPSCs exhibited endothelial features and formed capillary-like structures when cultured on a fibrin clot [105]. More recently, a structured dentin-/pulp-like tissue with vasculatures has been created using DPSCs via 3D print technique, suggesting a new direction for customized application for individual design of defect repair [106].

2.5. Immunomodulatory Properties of DPSCs

MSCs exhibit some immunomodulatory and anti-inflammatory factors, for example, interleukin-10 (IL-10) [107], hepatocyte growth factor (HGF), [108], transforming growth factor-β (TGF-β) [109], and prostaglandin E2 [110]. MSCs can act as an immunosuppressive agent by modulating the immune response in inflammatory or autoimmune diseases [111, 112]. DPSCs also have immunomodulatory properties associated with expression of soluble factors that inhibit T cell function. For instance, it has been reported that DPSCs express interleukin-8 (IL-8), interleukin-6 (IL-6), and TGF-β via Toll-like receptor (TLR) 4 during neuroinflammation in neurodegenerative diseases [8, 113]. An upregulated expression of TLR4 appeared to increase the expression of IL-8 in DPSCs [114], particularly in SCI crush injury where IL-8 preserves axon integrity and decreases cavitation [115, 116]. DPSCs also express TGF-β, HGF, and indoleamine 2,3-dioxygenase (IDO) without prior activation [117, 118] and suppress the proliferation of peripheral blood mononuclear cells and the activation of T cells [119, 120]. Coculture of DPSCs and T cells promoted T cell secretion of human leukocyte antigen-G, vascular adhesion molecule-1, intracellular adhesion molecule-1, IL-6, TGF-β, HGF, and IL-10, while it downregulated proinflammatory cytokines such as IL-2, IL-6 receptor, IL-12, IL-17A, and tumor necrosis factor-α (TNF-α) [121]. It was reported that the proliferation of T cells was inhibited by over 90% when cocultured with DPSCs in vitro [8, 122]. In addition, recent studies demonstrated that human and rat DPSCs were able to induce FasL-mediated apoptosis of IL-17 T-helper cells, and rat DPSCs exhibited a very strong ameliorating effect on DSS-induced colitis in mice [123, 124]. The study of Hong et al. reported that DPSCs could modulate immune tolerance by increasing CD4+CD25+FoxP3+ regulatory T cells. The results of the intraperitoneal injection of DPSCs into Balb/c(H-2d) mice demonstrated that DPSCs had a meaningful effect on mixed lymphocyte reaction [125]. Studies of Kwack et al. demonstrated that DPSCs could inhibit acute allogeneic immune responses by the release of TGF-β as a result of allogeneic stimulation of T lymphocytes and provide a novel insight for the allogeneic transplantation of DPSCs in future clinical use [120]. Recent animal studies conclude that DPSCs could modulate immune tolerance and influence apoptosis via T cells and lymphocytes.

3. Dental Pulp Stem Cells (DPSCs) and Central Nervous System Diseases

Traumatic damage to the brain and spinal cord leading to a CNS dysfunction, stroke, Parkinson’s disease, Alzheimer’s disease, and retinal injury is a common central nervous system disease. The CNS typically has a poor ability to repair and regenerate new neurons because of its limited pool of precursor cells [126, 127], expression of myelin-associated growth inhibitory factors [128], and the inherent propensity of resident glial cells to form scar tissue [129]. At present, it is very difficult to treat CNS diseases with conventional clinical therapies. Some studies have suggested that stem cell treatment may offer a novel therapeutic strategy for CNS disease [127, 130]. The hope is that the application of exogenous stem cells (particularly DPSCs) will lead to both regeneration of new neural precursor cells and their enhanced neuronal and glial differentiation as well as to survival and maintenance of existing neural cells through secretion of trophic factors [29, 30, 40].

3.1. DPSCs and SCI

SCI in humans can cause partial or complete loss of motor and sensory function that reduces the quality of an individual’s life and leads to an economic burden on society [124, 131]. SCI involves an initial primary tissue disruption (e.g., mechanical damage to nerve cells and blood vessels) and then a secondary injury caused by neuroinflammatory responses (e.g., excitotoxicity, blood-brain barrier disruption, oxidative stress, and apoptosis) [132, 133]. Because of their neural crest lineage, DPSCs have championed as preferred stem cells for SCI therapies supported by growing evidence of DPSCs differentiating into neuron-like and oligodendrocyte-like cells that may promote axonal regeneration and tissue repair after SCI [28, 127, 134, 135]. DPSCs also reduce secondary inflammatory injury, which facilitates axonal regeneration and reduces progressive hemorrhagic necrosis associated with interleukin-1β (IL-1β), ras homolog gene family member A (RhoA), and sulfonylurea receptor1 (SUR1) expression [136]. When transplanted together with artificial scaffolds such as chitosan, DPSCs promoted motor functional recovery and inhibited cell apoptosis after SCI by secreting BDNF, GDNF, and NT-3 and reducing the expression of active-caspase 3 [8, 137].

3.2. DPSCs and Stroke

Stroke is an ischemic cerebrovascular condition that leads to brain damage, long-term disability, and even death [138]. Due to prolonged period of insufficient blood supply and poor oxygen perfusion, damages on affected brain are irreversible. There are unfortunately few effective strategies that can reverse the damage effect on the brain or restore one’s function to prestrike level [139]. Recent studies indicate that stem cell therapy may present a novel strategy for stroke treatment due to the multipotency, immunomodulatory, and neuroprotective and angiogenic properties of these cells [140, 141]. Some in vivo studies have shown that transplantation of DPSCs into the ischemic areas of middle cerebral artery occlusion (MCAO) in Sprague-Dawley (SD) rats promoted locomotor functional recovery and decreased infarct areas by their differentiation into dopaminergic neurons and secretion of neurotrophic factors [102, 142]. DPSC transplantation into ischemic areas of focal cerebral ischemia in rats led to expression of proangiogenic factors that supported dense capillary formation and renormalization of blood flow [143]. Intracerebral transplantation of DPSCs into regions of focal cerebral ischemia in rodent models promoted forelimb sensory and motor functional recovery at 4 weeks posttreatment [140]. DPSCs also provided cytoprotection for astrocytes by reducing reactive gliosis and preventing free radical and IL-1β secretion within in vitro ischemic models [86]. Thus, DPSCs may play an immunomodulatory role to promote functional recovery after ischemic stroke.

3.3. DPSCs and Parkinson’s Disease

Parkinson’s disease (PD) is a progressive neurodegenerative condition associated with loss of nigrostriatal dopaminergic (DA) neurons that leads to muscle rigidity, bradykinesia, resting tremor, and postural instability [144]. Stem cell-based therapies hold some promise as a novel strategy for PD treatment [145]. DPSCs can be induced to differentiate into dopamine expressing DA neuron-like cells in vitro by using experimental cell induction media [65]. Intrathecal transplantation of DPSCs into the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- (MPTP-) induced old-aged mouse model of PD promoted recovery of behavioral deficits, restored DA functions, and attenuated MPTP-induced damage by reducing the secretion of proinflammatory factors such as IL-1α, IL-1β, IL6, IL8, and TNF-α and by upregulating the expression levels of anti-inflammatory factors such as IL2, IL4, and TNF-β [146]. DPSCs also showed neuroimmunomodulatory activity in an in vitro model of PD by reducing MPTP-induced deficits associated with reactive oxygen species, DNA damage, and nitric oxide release [146, 147]. DPSCs also promoted survival of DA neurons and enhanced nigrostriatal tract functional recovery in a 6-hydroxydopamine- (6-OHDA-) induced PD rat model by 6 weeks posttransplantation [148]. Some studies have also shown that DPSCs reduced 6-OHDA-induced damage in the in vitro model of PD [69, 145]. The clinical use of DPSCs may be a promising approach for treating PD in the future.

3.4. DPSCs and Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive neurodegenerative condition caused by the loss of neurons, intracellular neurofibrillary tangles, and deposition of insoluble β-amyloid peptides in the brain [149, 150]. Clinical symptoms of AD include memory loss, cognitive deficits, and linguistic disorders [150]. Recently, several studies reported that stem cell-based therapies in both in vitro and in vivo models of AD improved AD-induced pathologies and behavioral deficits [151153]. DPSCs promoted neuronal repair and regeneration by restoring cytoskeletal structure, protecting microtubule stability, and reducing tau phosphorylation in the okadaic acid- (OA-) induced cellular model of AD [154]. DPSCs can also reduce amyloid beta (Aβ) peptide-induced cytotoxicity and apoptosis in the AD cellular model by secreting higher levels of VEGF, fractalkine, RANTES, fms-related tyrosine kinase 3, and monocyte chemotactic protein 1 [155, 156]. These results suggest that DPSCs are a promising cell source for secretome-based treatment of AD.

3.5. DPSCs and Retinal Injury

The retina is a part of the CNS and is composed of photoreceptors, bipolar cells, and retinal ganglion cells (RGCs) [43, 157]. Head injuries can cause traumatic optic neuropathy (TON) while ocular chronic degenerative diseases such as glaucoma lead to the slow loss of RGCs [158]. Retinal and optic nerve injuries have a limited capacity to repair and regenerate because of axon growth inhibitory molecules and reduced production of neurotrophic growth factors [7, 159]. One study reported that DPSC transplantation into the vitreous of optic nerve injury rat model could promote axonal regeneration and RGC survival by a neurotrophin-mediated mechanism [83]. This same study revealed that DPSCs were more beneficial for axonal regeneration than BMSCs because of their higher secretion of neurotrophin factors. A subsequent report showed that intravitreal transplantation of DPSCs in an animal model of glaucoma maintained visual function up to 35 days after treatment by preventing RGC death [160]. Although not assessed in vivo, some in vitro studies have reported that DPSCs can be induced to differentiate into both RGC-like and photoreceptor cells [161, 162]. Taken together, these results suggest that DPSCs may become an important cell source for stem cell-based therapies in ocular diseases.

4. DPSCs and Peripheral Nerve Injury

Peripheral nerve injury caused by traumatic accidents and iatrogenic damage often accompanies physical disability and neuropathic pain. There are many current clinical treatments including direct end-to-end nerve suturing, nerve grafts, and nerve conduits containing growth-stimulatory biomaterials to repair and regenerate injured peripheral nerves [163165]. Among them, autologous nerve grafting is the gold standard therapy for the long gap of peripheral nerve deficits [166, 167]. However, there are some disadvantages which restrict the clinical use of autografting, such as donor nerve availability and morphometric mismatching [168171]. With the development of nerve tissue engineering and stem cell-related therapy, various novel nerve conduits in combination with stem cells are providing alternate strategies and approaches for the treatment of peripheral nerve injury [165, 172]. Some studies suggest that DPSC-embedded biomaterial nerve conduits such as polylactic glycolic acid tubes have the ability to promote regeneration of injured facial nerve and to improve functional recovery comparable to that of autografts [173]. Collagen conduits loaded with Schwann-like cells induced from DPSCs in vitro have facilitated repair and regeneration of 15 mm sciatic nerve defects [174]. In another report, differentiated DPSCs combined with collagen scaffolds exhibited Schwann cell-related properties and promoted axonal outgrowth and myelination in 2D or 3D culture conditions of an in vitro model [78]. Moreover, DPSCs transfected with oligodendrocyte lineage transcription factor 2 differentiated into functional oligodendrocytes in vitro and promoted injured peripheral nerve repair and regeneration in a mouse model [175]. DPSCs transplanted into diabetic rats secreted various cytokines that modulated the proportions of M1/M2 macrophages and provided beneficial anti-inflammatory effects in diabetic polyneuropathy [176].

In summary, DPSCs have the capacity to differentiate into Schwann-like and oligodendrocyte-like cells and they secrete neurotrophic factors that provide neuroprotection and modulate the immune response. These cells are poised to become a promising cell source for peripheral nerve injury treatment in the future.

5. Conclusions and Future Insights

This review summarizes the neuronal differentiation potential, neuroprotective features, and neurotrophic, angiogenic, and immunomodulatory properties of DPSCs in the pathological and injured nervous system. DPSCs have the biological properties of MSCs and possess a considerable capacity to differentiate into neuron-like cells and secrete neuron-related trophic factors due to their cranial neural crest origin. DPSCs are able to express neuronal markers without preinduced differentiation. Thus, both nondifferentiated and differentiated DPSCs are emerging as new cell sources for the treatment of nervous system deficits associated with SCI, stroke, AD, PD, and long gaps of peripheral nerve injury. DPSCs have several advantages over other exogenous stem cells for nervous system therapies because they are easily harvested without highly invasive surgery, have low immunogenicity, and arise from a neural crest origin that facilitates their neural differentiation. Moreover, after lentiviral transfection with Lin28, Nanog, Oct4, and Sox2 or retroviral transfection with Oct3/4, Sox2, and Klf4, DPSCs can be reprogrammed to generate an embryoid body of iPSCs. The DPSC-derived iPSCs have ability to differentiate into β-III tubulin neuron-like cells and tyrosine hydroxylase-positive dopaminergic neuron-like cells and may become another DPSC-related cell sources for the treatment of nervous system diseases in the future.

Because of the vascularization and immunomodulatory properties of DPSCs, these cells can both directly and indirectly stimulate formation of new blood vessels and enhance blood flow to injury sites. In addition to their roles in regeneration and repair of injured neural tissue (Table 1), therapies using DPSCs are emerging as a promising novel strategy for treating other brain conditions and syndromes such as traumatic brain injury, multiple sclerosis, and autism spectrum disorders.

Table 1: Examples for the beneficial of DPSCs on the central nervous system (CNS) diseases and the peripheral nervous system (PNS) diseases.

However, despite the functional advantages of using DPSCs for the treatment of nervous system injuries and diseases, there remain significant roadblocks with respect to overcoming the nervous system’s seemingly inherent and immutable resistance to regeneration and repair. Nerve tissue engineering approaches are now beginning to adopt combinatorial strategies that involve simultaneous manipulations to cells, growth factors, and scaffolds in order to circumvent the recalcitrant nature of the nervous system (Figure 3). In particular, novel scaffolds such as hydrogels have a 3D porous structure and good cytocompatibility that can be used to provide an in vivo-like microenvironment and structural support for cell adhesion, proliferation, and growth. Scaffolds can be designed to embed biological important macromolecules such as bFGF and NGF and to precisely tune their diffusion rate and enzymatic degradation. Seed cells such as DPSCs have beneficial effects on neural regeneration and repair associated with their neural differentiation potential and their neurotrophic, angiogenic, and immunomodulatory properties. Therefore, the spatiotemporal combination of DPSCs, scaffolds, and growth factors provides a promising strategy for treating nervous system-related diseases and injuries in future clinical approaches.

Figure 3: Tissue-engineered constructs of DPSCs, scaffolds, and growth factors and their applications in nervous system diseases. In the constructs, scaffolds can provide biomimetic environments and structural support for cell survival and proliferation. Growth factors can promote neuronal cell proliferation and survival in vivo and in vitro. DPSCs can enhance neuronal regeneration and repair due to their neuronal differentiation potential and their neurotrophic, neuroprotective, angiogenic, and immunomodulatory properties.

Conflicts of Interest

The authors declare that they have no competing interests regarding the publication of this paper.

Authors’ Contributions

Lihua Luo and Yan He contributed equally to this work.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (81601626 to Huaqiong Li), the UQDVCR (610709 to Qingsong Ye), the Wenzhou Medical University (QTJ16026 to Lihua Luo), and Research and Development Program Project of Xiangyang (20270268020 to Lihua Luo).

References

  1. K. Kahveci, M. Dincer, C. Doger, and A. K. Yarici, “Traumatic brain injury and palliative care: a retrospective analysis of 49 patients receiving palliative care during 2013–2016 in Turkey,” Neural Regeneration Research, vol. 12, no. 1, pp. 77–83, 2017. View at Publisher · View at Google Scholar · View at Scopus
  2. P. Ciaramitaro, M. Mondelli, F. Logullo et al., “Traumatic peripheral nerve injuries: epidemiological findings, neuropathic pain and quality of life in 158 patients,” Journal of the Peripheral Nervous System, vol. 15, no. 2, pp. 120–127, 2010. View at Publisher · View at Google Scholar · View at Scopus
  3. Y. Esquenazi, S. H. Park, D. G. Kline, and D. H. Kim, “Surgical management and outcome of iatrogenic radial nerve injection injuries,” Clinical Neurology and Neurosurgery, vol. 142, pp. 98–103, 2016. View at Publisher · View at Google Scholar · View at Scopus
  4. J. Baumard, M. Lesourd, C. Remigereau et al., “Tool use in neurodegenerative diseases: planning or technical reasoning?” Journal of Neuropsychology, 2017. View at Publisher · View at Google Scholar · View at Scopus
  5. A. Rolfe and D. Sun, “Stem cell therapy in brain trauma: implications for repair and regeneration of injured brain in experimental TBI models,” in Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects, F. H. Kobeissy, Ed., pp. 587–596, CRC Press/Taylor & Francis, Boca Raton, FL, USA, 2015. View at Google Scholar
  6. H. Hong, B. S. Kim, and H. I. Im, “Pathophysiological role of neuroinflammation in neurodegenerative diseases and psychiatric disorders,” International Neurourology Journal, vol. 20, Supplement 1, pp. S2–S7, 2016. View at Publisher · View at Google Scholar · View at Scopus
  7. M. Berry, Z. Ahmed, B. Lorber, M. Douglas, and A. Logan, “Regeneration of axons in the visual system,” Restorative Neurology and Neuroscience, vol. 26, no. 2-3, pp. 147–174, 2008. View at Google Scholar
  8. J. Bianco, P. De Berdt, R. Deumens, and A. des Rieux, “Taking a bite out of spinal cord injury: do dental stem cells have the teeth for it?” Cellular and Molecular Life Sciences, vol. 73, no. 7, pp. 1413–1437, 2016. View at Publisher · View at Google Scholar · View at Scopus
  9. A. R. Caseiro, T. Pereira, G. Ivanova, A. L. Luís, and A. C. Maurício, “Neuromuscular regeneration: perspective on the application of mesenchymal stem cells and their secretion products,” Stem Cells International, vol. 2016, Article ID 9756973, 16 pages, 2016. View at Publisher · View at Google Scholar · View at Scopus
  10. B. Mead, M. Berry, A. Logan, R. A. H. Scott, W. Leadbeater, and B. A. Scheven, “Stem cell treatment of degenerative eye disease,” Stem Cell Research, vol. 14, no. 3, pp. 243–257, 2015. View at Publisher · View at Google Scholar · View at Scopus
  11. H. Ghasemi Hamidabadi, Z. Rezvani, M. Nazm Bojnordi et al., “Chitosan-intercalated montmorillonite/poly(vinyl alcohol) nanofibers as a platform to guide neuronlike differentiation of human dental pulp stem cells,” ACS Applied Materials & Interfaces, vol. 9, no. 13, pp. 11392–11404, 2017. View at Publisher · View at Google Scholar · View at Scopus
  12. L. Ferroni, C. Gardin, I. Tocco et al., “Potential for neural differentiation of mesenchymal stem cells,” Advances in Biochemical Engineering/Biotechnology, vol. 129, pp. 89–115, 2012. View at Publisher · View at Google Scholar · View at Scopus
  13. V. Neirinckx, C. Coste, B. Rogister, and S. Wislet-Gendebien, “Concise review: adult mesenchymal stem cells, adult neural crest stem cells, and therapy of neurological pathologies: a state of play,” Stem Cells Translational Medicine, vol. 2, no. 4, pp. 284–296, 2013. View at Publisher · View at Google Scholar · View at Scopus
  14. F. G. Teixeira, M. M. Carvalho, N. Sousa, and A. J. Salgado, “Mesenchymal stem cells secretome: a new paradigm for central nervous system regeneration?” Cellular and Molecular Life Sciences, vol. 70, no. 20, pp. 3871–3882, 2013. View at Publisher · View at Google Scholar · View at Scopus
  15. B. M. Abdallah and M. Kassem, “Human mesenchymal stem cells: from basic biology to clinical applications,” Gene Therapy, vol. 15, no. 2, pp. 109–116, 2008. View at Publisher · View at Google Scholar · View at Scopus
  16. M. Ohishi and E. Schipani, “Bone marrow mesenchymal stem cells,” Journal of Cellular Biochemistry, vol. 109, no. 2, pp. 277–282, 2010. View at Publisher · View at Google Scholar · View at Scopus
  17. H. Jin, Y. Bae, M. Kim et al., “Comparative analysis of human mesenchymal stem cells from bone marrow, adipose tissue, and umbilical cord blood as sources of cell therapy,” International Journal of Molecular Sciences, vol. 14, no. 9, pp. 17986–18001, 2013. View at Publisher · View at Google Scholar · View at Scopus
  18. M. H. Lim, W. K. Ong, and S. Sugii, “The current landscape of adipose-derived stem cells in clinical applications,” Expert Reviews in Molecular Medicine, vol. 16, article e8, 2014. View at Publisher · View at Google Scholar · View at Scopus
  19. J. Ribeiro, A. Gartner, T. Pereira et al., “Chapter four - perspectives of employing mesenchymal stem cells from the Wharton’s jelly of the umbilical cord for peripheral nerve repair,” International Review of Neurobiology, vol. 108, pp. 79–120, 2013. View at Publisher · View at Google Scholar · View at Scopus
  20. S. Frausin, S. Viventi, L. Verga Falzacappa et al., “Wharton’s jelly derived mesenchymal stromal cells: biological properties, induction of neuronal phenotype and current applications in neurodegeneration research,” Acta Histochemica, vol. 117, no. 4-5, pp. 329–338, 2015. View at Publisher · View at Google Scholar · View at Scopus
  21. S. Gronthos, M. Mankani, J. Brahim, P. G. Robey, and S. Shi, “Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 25, pp. 13625–13630, 2000. View at Publisher · View at Google Scholar · View at Scopus
  22. M. Miura, S. Gronthos, M. Zhao et al., “SHED: stem cells from human exfoliated deciduous teeth,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 10, pp. 5807–5812, 2003. View at Publisher · View at Google Scholar · View at Scopus
  23. W. Sonoyama, Y. Liu, T. Yamaza et al., “Characterization of the apical papilla and its residing stem cells from human immature permanent teeth: a pilot study,” Journal of Endodontics, vol. 34, no. 2, pp. 166–171, 2008. View at Publisher · View at Google Scholar · View at Scopus
  24. B. M. Seo, M. Miura, S. Gronthos et al., “Investigation of multipotent postnatal stem cells from human periodontal ligament,” The Lancet, vol. 364, no. 9429, pp. 149–155, 2004. View at Publisher · View at Google Scholar · View at Scopus
  25. C. Morsczeck, W. Gotz, J. Schierholz et al., “Isolation of precursor cells (PCs) from human dental follicle of wisdom teeth,” Matrix Biology, vol. 24, no. 2, pp. 155–165, 2005. View at Publisher · View at Google Scholar · View at Scopus
  26. P. Y. Collart-Dutilleul, F. Chaubron, J. De Vos, and F. J. Cuisinier, “Allogenic banking of dental pulp stem cells for innovative therapeutics,” World Journal of Stem Cells, vol. 7, no. 7, pp. 1010–1021, 2015. View at Google Scholar
  27. Y. W. Geng, Z. Zhang, M. Y. Liu, and W. P. Hu, “Differentiation of human dental pulp stem cells into neuronal by resveratrol,” Cell Biology Interenational, vol. 41, no. 12, pp. 1391–1398, 2017. View at Publisher · View at Google Scholar · View at Scopus
  28. L. Hidalgo San Jose, P. Stephens, B. Song, and D. Barrow, “Microfluidic encapsulation supports stem cell viability, proliferation, and neuronal differentiation,” Tissue Engineering Part C: Methods, vol. 24, no. 3, pp. 158–170, 2018. View at Publisher · View at Google Scholar
  29. K. Sakai, A. Yamamoto, K. Matsubara et al., “Human dental pulp-derived stem cells promote locomotor recovery after complete transection of the rat spinal cord by multiple neuro-regenerative mechanisms,” The Journal of Clinical Investigation, vol. 122, no. 1, pp. 80–90, 2012. View at Publisher · View at Google Scholar · View at Scopus
  30. B. Mead, A. Logan, M. Berry, W. Leadbeater, and B. A. Scheven, “Paracrine-mediated neuroprotection and neuritogenesis of axotomised retinal ganglion cells by human dental pulp stem cells: comparison with human bone marrow and adipose-derived mesenchymal stem cells,” PLoS One, vol. 9, no. 10, article e109305, 2014. View at Publisher · View at Google Scholar · View at Scopus
  31. D. Foudah, M. Monfrini, E. Donzelli et al., “Expression of neural markers by undifferentiated mesenchymal-like stem cells from different sources,” Journal of Immunology Research, vol. 2014, Article ID 987678, 16 pages, 2014. View at Publisher · View at Google Scholar · View at Scopus
  32. I. Ullah, J. M. Park, Y. H. Kang et al., “Transplantation of human dental pulp-derived stem cells or differentiated neuronal cells from human dental pulp-derived stem cells identically enhances regeneration of the injured peripheral nerve,” Stem Cells and Development, vol. 26, no. 17, pp. 1247–1257, 2017. View at Publisher · View at Google Scholar · View at Scopus
  33. Y. Chai, X. Jiang, Y. Ito et al., “Fate of the mammalian cranial neural crest during tooth and mandibular morphogenesis,” Development, vol. 127, no. 8, pp. 1671–1679, 2000. View at Google Scholar
  34. S. Shi and S. Gronthos, “Perivascular niche of postnatal mesenchymal stem cells in human bone marrow and dental pulp,” Journal of Bone and Mineral Research, vol. 18, no. 4, pp. 696–704, 2003. View at Publisher · View at Google Scholar · View at Scopus
  35. E. Karaoz, P. C. Demircan, O. Saglam, A. Aksoy, F. Kaymaz, and G. Duruksu, “Human dental pulp stem cells demonstrate better neural and epithelial stem cell properties than bone marrow-derived mesenchymal stem cells,” Histochemistry and Cell Biology, vol. 136, no. 4, pp. 455–473, 2011. View at Publisher · View at Google Scholar · View at Scopus
  36. W. Martens, A. Bronckaers, C. Politis, R. Jacobs, and I. Lambrichts, “Dental stem cells and their promising role in neural regeneration: an update,” Clinical Oral Investigations, vol. 17, no. 9, pp. 1969–1983, 2013. View at Publisher · View at Google Scholar · View at Scopus
  37. R. Kuang, Z. Zhang, X. Jin et al., “Nanofibrous spongy microspheres for the delivery of hypoxia-primed human dental pulp stem cells to regenerate vascularized dental pulp,” Acta Biomaterialia, vol. 33, pp. 225–234, 2016. View at Publisher · View at Google Scholar · View at Scopus
  38. S. Gronthos, J. Brahim, W. Li et al., “Stem cell properties of human dental pulp stem cells,” Journal of Dental Research, vol. 81, no. 8, pp. 531–535, 2002. View at Publisher · View at Google Scholar · View at Scopus
  39. N. Kawashima, “Characterisation of dental pulp stem cells: a new horizon for tissue regeneration?” Archives of Oral Biology, vol. 57, no. 11, pp. 1439–1458, 2012. View at Publisher · View at Google Scholar · View at Scopus
  40. L. Xiao, R. Ide, C. Saiki, Y. Kumazawa, and H. Okamura, “Human dental pulp cells differentiate toward neuronal cells and promote neuroregeneration in adult organotypic hippocampal slices in vitro,” International Journal of Molecular Sciences, vol. 18, no. 8, p. 1745, 2017. View at Publisher · View at Google Scholar · View at Scopus
  41. E. Karaoz, B. N. Dogan, A. Aksoy et al., “Isolation and in vitro characterisation of dental pulp stem cells from natal teeth,” Histochemistry and Cell Biology, vol. 133, no. 1, pp. 95–112, 2010. View at Publisher · View at Google Scholar · View at Scopus
  42. A. H.-C. Huang, Y.-K. Chen, L.-M. Lin, T.-Y. Shieh, and A. W.-S. Chan, “Isolation and characterization of dental pulp stem cells from a supernumerary tooth,” Journal of Oral Pathology & Medicine, vol. 37, no. 9, pp. 571–574, 2008. View at Publisher · View at Google Scholar · View at Scopus
  43. S. Rai, S. Kaur, M. Kaur, and S. P. Arora, “Redefining the potential applications of dental stem cells: an asset for future,” Indian Journal of Human Genetics, vol. 18, no. 3, pp. 276–284, 2012. View at Publisher · View at Google Scholar · View at Scopus
  44. R. Kabir, M. Gupta, A. Aggarwal, D. Sharma, A. Sarin, and M. Z. Kola, “Imperative role of dental pulp stem cells in regenerative therapies: a systematic review,” Nigerian Journal of Surgery, vol. 20, no. 1, pp. 1–8, 2014. View at Publisher · View at Google Scholar
  45. P. Torkzaban, A. Saffarpour, M. Bidgoli, and S. Sohilifar, “In vitro evaluation of isolation possibility of stem cells from intra oral soft tissue and comparison of them with bone marrow stem cells,” Journal of Dentistry, vol. 9, no. 1, pp. 1–6, 2012. View at Google Scholar
  46. P. Stanko, K. Kaiserova, V. Altanerova, and C. Altaner, “Comparison of human mesenchymal stem cells derived from dental pulp, bone marrow, adipose tissue, and umbilical cord tissue by gene expression,” Biomedical Papers, vol. 158, no. 3, pp. 373–377, 2014. View at Publisher · View at Google Scholar · View at Scopus
  47. E. P. Chalisserry, S. Y. Nam, S. H. Park, and S. Anil, “Therapeutic potential of dental stem cells,” Journal of Tissue Engineering, vol. 8, 2017. View at Publisher · View at Google Scholar
  48. A. Palmieri, F. Pezzetti, A. Graziano et al., “Comparison between osteoblasts derived from human dental pulp stem cells and osteosarcoma cell lines,” Cell Biology International, vol. 32, no. 7, pp. 733–738, 2008. View at Publisher · View at Google Scholar · View at Scopus
  49. P.-H. Cheng, B. Snyder, D. Fillos, C. C. Ibegbu, A. Huang, and A. W. S. Chan, “Postnatal stem/progenitor cells derived from the dental pulp of adult chimpanzee,” BMC Cell Biology, vol. 9, no. 1, p. 20, 2008. View at Publisher · View at Google Scholar · View at Scopus
  50. M. Kiraly, B. Porcsalmy, A. Pataki et al., “Simultaneous PKC and cAMP activation induces differentiation of human dental pulp stem cells into functionally active neurons,” Neurochemistry International, vol. 55, no. 5, pp. 323–332, 2009. View at Publisher · View at Google Scholar · View at Scopus
  51. X. Feng, J. Xing, G. Feng et al., “Age-dependent impaired neurogenic differentiation capacity of dental stem cell is associated with Wnt/β-catenin signaling,” Cellular and Molecular Neurobiology, vol. 33, no. 8, pp. 1023–1031, 2013. View at Publisher · View at Google Scholar · View at Scopus
  52. L. Liu, J. Ling, X. Wei, L. Wu, and Y. Xiao, “Stem cell regulatory gene expression in human adult dental pulp and periodontal ligament cells undergoing odontogenic/osteogenic differentiation,” Journal of Endodontics, vol. 35, no. 10, pp. 1368–1376, 2009. View at Publisher · View at Google Scholar · View at Scopus
  53. K. Iohara, L. Zheng, M. Ito, A. Tomokiyo, K. Matsushita, and M. Nakashima, “Side population cells isolated from porcine dental pulp tissue with self-renewal and multipotency for dentinogenesis, chondrogenesis, adipogenesis, and neurogenesis,” Stem Cells, vol. 24, no. 11, pp. 2493–2503, 2006. View at Publisher · View at Google Scholar · View at Scopus
  54. A. Arthur, G. Rychkov, S. Shi, S. A. Koblar, and S. Gronthos, “Adult human dental pulp stem cells differentiate toward functionally active neurons under appropriate environmental cues,” Stem Cells, vol. 26, no. 7, pp. 1787–1795, 2008. View at Publisher · View at Google Scholar · View at Scopus
  55. Y. X. Wang, Z. F. Ma, N. Huo et al., “Porcine tooth germ cell conditioned medium can induce odontogenic differentiation of human dental pulp stem cells,” Journal of Tissue Engineering and Regenerative Medicine, vol. 5, no. 5, pp. 354–362, 2011. View at Publisher · View at Google Scholar · View at Scopus
  56. W. Zhang, X. F. Walboomers, S. Shi, M. Fan, and J. A. Jansen, “Multilineage differentiation potential of stem cells derived from human dental pulp after cryopreservation,” Tissue Engineering, vol. 12, no. 10, pp. 2813–2823, 2006. View at Publisher · View at Google Scholar · View at Scopus
  57. X. Yan, H. Qin, C. Qu, R. S. Tuan, S. Shi, and G. T. J. Huang, “iPS cells reprogrammed from human mesenchymal-like stem/progenitor cells of dental tissue origin,” Stem Cells and Development, vol. 19, no. 4, pp. 469–480, 2010. View at Publisher · View at Google Scholar · View at Scopus
  58. N. Tamaoki, K. Takahashi, T. Tanaka et al., “Dental pulp cells for induced pluripotent stem cell banking,” Journal of Dental Research, vol. 89, no. 8, pp. 773–778, 2010. View at Publisher · View at Google Scholar · View at Scopus
  59. N. Nordin, M. I. Lai, A. Veerakumarasivam et al., “Induced pluripotent stem cells: history, properties and potential applications,” The Medical Journal of Malaysia, vol. 66, no. 1, pp. 4–9, 2011. View at Google Scholar
  60. N. Malhotra, “Induced pluripotent stem (iPS) cells in dentistry: a review,” International Journal of Stem Cells, vol. 9, no. 2, pp. 176–185, 2016. View at Publisher · View at Google Scholar · View at Scopus
  61. P. Gervois, T. Struys, P. Hilkens et al., “Neurogenic maturation of human dental pulp stem cells following neurosphere generation induces morphological and electrophysiological characteristics of functional neurons,” Stem Cells and Development, vol. 24, no. 3, pp. 296–311, 2015. View at Publisher · View at Google Scholar · View at Scopus
  62. J. Zhang, M. Lian, P. Cao et al., “Effects of nerve growth factor and basic fibroblast growth factor promote human dental pulp stem cells to neural differentiation,” Neurochemical Research, vol. 42, no. 4, pp. 1015–1025, 2017. View at Publisher · View at Google Scholar · View at Scopus
  63. T. Osathanon, C. Sawangmake, N. Nowwarote, and P. Pavasant, “Neurogenic differentiation of human dental pulp stem cells using different induction protocols,” Oral Diseases, vol. 20, no. 4, pp. 352–358, 2014. View at Publisher · View at Google Scholar · View at Scopus
  64. L. Xiao and T. Tsutsui, “Characterization of human dental pulp cells-derived spheroids in serum-free medium: stem cells in the core,” Journal of Cellular Biochemistry, vol. 114, no. 11, pp. 2624–2636, 2013. View at Publisher · View at Google Scholar · View at Scopus
  65. M. Kanafi, D. Majumdar, R. Bhonde, P. Gupta, and I. Datta, “Midbrain cues dictate differentiation of human dental pulp stem cells towards functional dopaminergic neurons,” Journal of Cellular Physiology, vol. 229, no. 10, pp. 1369–1377, 2014. View at Publisher · View at Google Scholar · View at Scopus
  66. C. C. Chang, K. C. Chang, S. J. Tsai, H. H. Chang, and C. P. Lin, “Neurogenic differentiation of dental pulp stem cells to neuron-like cells in dopaminergic and motor neuronal inductive media,” Journal of the Formosan Medical Association, vol. 113, no. 12, pp. 956–965, 2014. View at Publisher · View at Google Scholar · View at Scopus
  67. M. Kiraly, K. Kadar, D. B. Horvathy et al., “Integration of neuronally predifferentiated human dental pulp stem cells into rat brain in vivo,” Neurochemistry International, vol. 59, no. 3, pp. 371–381, 2011. View at Publisher · View at Google Scholar · View at Scopus
  68. N. Fatima, A. A. Khan, and S. K. Vishwakarma, “Immunophenotypic and molecular analysis of human dental pulp stem cells potential for neurogenic differentiation,” Contemporary Clinical Dentistry, vol. 8, no. 1, pp. 81–89, 2017. View at Publisher · View at Google Scholar · View at Scopus
  69. S. Y. Chun, S. Soker, Y. J. Jang, T. G. Kwon, and E. S. Yoo, “Differentiation of human dental pulp stem cells into dopaminergic neuron-like cells in vitro,” Journal of Korean Medical Science, vol. 31, no. 2, pp. 171–177, 2016. View at Publisher · View at Google Scholar · View at Scopus
  70. J. Karbanova, T. Soukup, J. Suchanek, R. Pytlik, D. Corbeil, and J. Mokry, “Characterization of dental pulp stem cells from impacted third molars cultured in low serum-containing medium,” Cells, Tissues, Organs, vol. 193, no. 6, pp. 344–365, 2011. View at Publisher · View at Google Scholar · View at Scopus
  71. Y. Lu, X. Yuan, Y. Ou et al., “Autophagy and apoptosis during adult adipose-derived stromal cells differentiation into neuron-like cells in vitro,” Neural Regeneration Research, vol. 7, no. 16, pp. 1205–1212, 2012. View at Publisher · View at Google Scholar
  72. N. Gnanasegaran, V. Govindasamy, P. Kathirvaloo, S. Musa, and N. H. Abu Kasim, “Effects of cell cycle phases on the induction of dental pulp stem cells toward dopaminergic-like cells,” Journal of Tissue Engineering and Regenerative Medicine, vol. 12, no. 2, pp. e881–e893, 2018. View at Publisher · View at Google Scholar · View at Scopus
  73. M. Singh, A. Kakkar, R. Sharma et al., “Synergistic effect of BDNF and FGF2 in efficient generation of functional dopaminergic neurons from human mesenchymal stem cells,” Scientific Reports, vol. 7, no. 1, article 10378, 2017. View at Publisher · View at Google Scholar · View at Scopus
  74. T. Gonmanee, C. Thonabulsombat, K. Vongsavan, and H. Sritanaudomchai, “Differentiation of stem cells from human deciduous and permanent teeth into spiral ganglion neuron-like cells,” Archives of Oral Biology, vol. 88, pp. 34–41, 2018. View at Publisher · View at Google Scholar
  75. X. Feng, X. Lu, D. Huang et al., “3D porous chitosan scaffolds suit survival and neural differentiation of dental pulp stem cells,” Cellular and Molecular Neurobiology, vol. 34, no. 6, pp. 859–870, 2014. View at Publisher · View at Google Scholar · View at Scopus
  76. M. Ustiashvili, D. Kordzaia, M. Mamaladze, M. Jangavadze, and L. Sanodze, “Investigation of functional activity human dental pulp stem cells at acute and chronic pulpitis,” Georgian Medical News, vol. 9, no. 234, pp. 19–24, 2014. View at Google Scholar
  77. B. C. Heng, L. W. Lim, W. Wu, and C. Zhang, “An overview of protocols for the neural induction of dental and oral stem cells in vitro,” Tissue Engineering Part B: Reviews, vol. 22, no. 3, pp. 220–250, 2016. View at Publisher · View at Google Scholar · View at Scopus
  78. W. Martens, K. Sanen, M. Georgiou et al., “Human dental pulp stem cells can differentiate into Schwann cells and promote and guide neurite outgrowth in an aligned tissue-engineered collagen construct in vitro,” The FASEB Journal, vol. 28, no. 4, pp. 1634–1643, 2014. View at Publisher · View at Google Scholar · View at Scopus
  79. N. Askari, M. M. Yaghoobi, M. Shamsara, and S. Esmaeili-Mahani, “Human dental pulp stem cells differentiate into oligodendrocyte progenitors using the expression of olig2 transcription factor,” Cells, Tissues, Organs, vol. 200, no. 2, pp. 93–103, 2014. View at Publisher · View at Google Scholar · View at Scopus
  80. S. Goorha and L. T. Reiter, “Culturing and neuronal differentiation of human dental pulp stem cells,” Current Protocols in Human Genetics, vol. 92, pp. 21.6.1–21.6.10, 2017. View at Publisher · View at Google Scholar · View at Scopus
  81. Y. H. Li, J. E. Li, and W. W. Liu, “Comparing the effect of neurotrophic factor induced MSCs (BMSC and DPSC) on the expression of myelin proteins Nogo-A and OMgp in a glaucoma rat model,” International Journal of Clinical and Experimental Medicine, vol. 10, no. 3, pp. 4705–4713, 2017. View at Google Scholar
  82. I. V. Nosrat, J. Widenfalk, L. Olson, and C. A. Nosrat, “Dental pulp cells produce neurotrophic factors, interact with trigeminal neurons in vitro, and rescue motoneurons after spinal cord injury,” Developmental Biology, vol. 238, no. 1, pp. 120–132, 2001. View at Publisher · View at Google Scholar · View at Scopus
  83. B. Mead, A. Logan, M. Berry, W. Leadbeater, and B. A. Scheven, “Intravitreally transplanted dental pulp stem cells promote neuroprotection and axon regeneration of retinal ganglion cells after optic nerve injury,” Investigative Ophthalmology & Visual Science, vol. 54, no. 12, pp. 7544–7556, 2013. View at Publisher · View at Google Scholar · View at Scopus
  84. A. Arthur, S. Shi, A. C. W. Zannettino, N. Fujii, S. Gronthos, and S. A. Koblar, “Implanted adult human dental pulp stem cells induce endogenous axon guidance,” Stem Cells, vol. 27, no. 9, pp. 2229–2237, 2009. View at Publisher · View at Google Scholar · View at Scopus
  85. M. K. Kolar, V. N. Itte, P. J. Kingham, L. N. Novikov, M. Wiberg, and P. Kelk, “The neurotrophic effects of different human dental mesenchymal stem cells,” Scientific Reports, vol. 7, no. 1, article 12605, 2017. View at Publisher · View at Google Scholar · View at Scopus
  86. M. Song, S. S. Jue, Y. A. Cho, and E. C. Kim, “Comparison of the effects of human dental pulp stem cells and human bone marrow-derived mesenchymal stem cells on ischemic human astrocytes in vitro,” Journal of Neuroscience Research, vol. 93, no. 6, pp. 973–983, 2015. View at Publisher · View at Google Scholar · View at Scopus
  87. M. Song, J. H. Lee, J. Bae, Y. Bu, and E. C. Kim, “Human dental pulp stem cells are more effective than human bone marrow-derived mesenchymal stem cells in cerebral ischemic injury,” Cell Transplantation, vol. 26, no. 6, pp. 1001–1016, 2017. View at Publisher · View at Google Scholar · View at Scopus
  88. A. Kumar, V. Kumar, V. Rattan, V. Jha, and S. Bhattacharyya, “Secretome cues modulate the neurogenic potential of bone marrow and dental stem cells,” Molecular Neurobiology, vol. 54, no. 6, pp. 4672–4682, 2017. View at Publisher · View at Google Scholar · View at Scopus
  89. P. Carmeliet, “Mechanisms of angiogenesis and arteriogenesis,” Nature Medicine, vol. 6, no. 4, pp. 389–395, 2000. View at Publisher · View at Google Scholar · View at Scopus
  90. J. Folkman, “Tumor angiogenesis: therapeutic implications,” The New England Journal of Medicine, vol. 285, no. 21, pp. 1182–1186, 1971. View at Publisher · View at Google Scholar · View at Scopus
  91. A. Giordano, U. Galderisi, and I. R. Marino, “From the laboratory bench to the patient’s bedside: an update on clinical trials with mesenchymal stem cells,” Journal of Cellular Physiology, vol. 211, no. 1, pp. 27–35, 2007. View at Publisher · View at Google Scholar · View at Scopus
  92. P. J. Psaltis, A. C. W. Zannettino, S. G. Worthley, and S. Gronthos, “Concise review: mesenchymal stromal cells: potential for cardiovascular repair,” Stem Cells, vol. 26, no. 9, pp. 2201–2210, 2008. View at Publisher · View at Google Scholar · View at Scopus
  93. D. P. Sieveking and M. K. Ng, “Cell therapies for therapeutic angiogenesis: back to the bench,” Vascular Medicine, vol. 14, no. 2, pp. 153–166, 2009. View at Publisher · View at Google Scholar · View at Scopus
  94. P. Hilkens, Y. Fanton, W. Martens et al., “Pro-angiogenic impact of dental stem cells in vitro and in vivo,” Stem Cell Research, vol. 12, no. 3, pp. 778–790, 2014. View at Publisher · View at Google Scholar · View at Scopus
  95. A. Bronckaers, P. Hilkens, Y. Fanton et al., “Angiogenic properties of human dental pulp stem cells,” PLoS One, vol. 8, no. 8, article e71104, 2013. View at Publisher · View at Google Scholar · View at Scopus
  96. J. Ratajczak, A. Bronckaers, Y. Dillen et al., “The neurovascular properties of dental stem cells and their importance in dental tissue engineering,” Stem Cells International, vol. 2016, Article ID 9762871, 17 pages, 2016. View at Publisher · View at Google Scholar · View at Scopus
  97. L. Tran-Hung, P. Laurent, J. Camps, and I. About, “Quantification of angiogenic growth factors released by human dental cells after injury,” Archives of Oral Biology, vol. 53, no. 1, pp. 9–13, 2008. View at Publisher · View at Google Scholar · View at Scopus
  98. A. M. F. Aranha, Z. Zhang, K. G. Neiva, C. A. S. Costa, J. Hebling, and J. E. Nör, “Hypoxia enhances the angiogenic potential of human dental pulp cells,” Journal of Endodontics, vol. 36, no. 10, pp. 1633–1637, 2010. View at Publisher · View at Google Scholar · View at Scopus
  99. K. Iohara, L. Zheng, H. Wake et al., “A novel stem cell source for vasculogenesis in ischemia: subfraction of side population cells from dental pulp,” Stem Cells, vol. 26, no. 9, pp. 2408–2418, 2008. View at Publisher · View at Google Scholar · View at Scopus
  100. L. Tran-Hung, S. Mathieu, and I. About, “Role of human pulp fibroblasts in angiogenesis,” Journal of Dental Research, vol. 85, no. 9, pp. 819–823, 2006. View at Publisher · View at Google Scholar · View at Scopus
  101. C. Gandia, A. Armiñan, J. M. García-Verdugo et al., “Human dental pulp stem cells improve left ventricular function, induce angiogenesis, and reduce infarct size in rats with acute myocardial infarction,” Stem Cells, vol. 26, no. 3, pp. 638–645, 2008. View at Publisher · View at Google Scholar · View at Scopus
  102. M. Sugiyama, K. Iohara, H. Wakita et al., “Dental pulp-derived CD31-/CD146- side population stem/progenitor cells enhance recovery of focal cerebral ischemia in rats,” Tissue Engineering Part A, vol. 17, no. 9-10, pp. 1303–1311, 2011. View at Publisher · View at Google Scholar · View at Scopus
  103. H. Nam, G. H. Kim, Y. K. Bae et al., “Angiogenic capacity of dental pulp stem cell regulated by SDF-1α-CXCR4 axis,” Stem Cells International, vol. 2017, Article ID 8085462, 10 pages, 2017. View at Publisher · View at Google Scholar · View at Scopus
  104. R. d'Aquino, A. Graziano, M. Sampaolesi et al., “Human postnatal dental pulp cells co-differentiate into osteoblasts and endotheliocytes: a pivotal synergy leading to adult bone tissue formation,” Cell Death and Differentiation, vol. 14, no. 6, pp. 1162–1171, 2007. View at Publisher · View at Google Scholar · View at Scopus
  105. C. Marchionni, L. Bonsi, F. Alviano et al., “Angiogenic potential of human dental pulp stromal (stem) cells,” International Journal of Immunopathology and Pharmacology, vol. 22, no. 3, pp. 699–706, 2009. View at Publisher · View at Google Scholar · View at Scopus
  106. P. Hilkens, A. Bronckaers, J. Ratajczak, P. Gervois, E. Wolfs, and I. Lambrichts, “The angiogenic potential of DPSCs and SCAPs in an in vivo model of dental pulp regeneration,” Stem Cells International, vol. 2017, Article ID 2582080, 14 pages, 2017. View at Publisher · View at Google Scholar · View at Scopus
  107. T. Deuse, M. Stubbendorff, K. Tang-Quan et al., “Immunogenicity and immunomodulatory properties of umbilical cord lining mesenchymal stem cells,” Cell Transplantation, vol. 20, no. 5, pp. 655–667, 2011. View at Publisher · View at Google Scholar · View at Scopus
  108. J. W. Kang, H. C. Koo, S. Y. Hwang et al., “Immunomodulatory effects of human amniotic membrane-derived mesenchymal stem cells,” Journal of Veterinary Science, vol. 13, no. 1, pp. 23–31, 2012. View at Publisher · View at Google Scholar · View at Scopus
  109. P. Comite, L. Cobianchi, M. A. Avanzini et al., “Immunomodulatory properties of porcine, bone marrow-derived multipotent mesenchymal stromal cells and comparison with their human counterpart,” Cellular and Molecular Biology, vol. 57, Supplement, no. 2, 2011. View at Google Scholar
  110. E. Soleymaninejadian, K. Pramanik, and E. Samadian, “Immunomodulatory properties of mesenchymal stem cells: cytokines and factors,” American Journal of Reproductive Immunology, vol. 67, no. 1, pp. 1–8, 2012. View at Publisher · View at Google Scholar · View at Scopus
  111. A. Pourgholaminejad, N. Aghdami, H. Baharvand, and S. M. Moazzeni, “The effect of pro-inflammatory cytokines on immunophenotype, differentiation capacity and immunomodulatory functions of human mesenchymal stem cells,” Cytokine, vol. 85, pp. 51–60, 2016. View at Publisher · View at Google Scholar · View at Scopus
  112. M. P. De Miguel, S. Fuentes-Julián, A. Blázquez-Martínez et al., “Immunosuppressive properties of mesenchymal stem cells: advances and applications,” Current Molecular Medicine, vol. 12, no. 5, pp. 574–591, 2012. View at Publisher · View at Google Scholar
  113. I. R. Rajput, A. Hussain, Y. L. Li et al., “Saccharomyces boulardii and bacillus subtilis B10 modulate TLRs mediated signaling to induce immunity by chicken BMDCs,” Journal of Cellular Biochemistry, vol. 115, no. 1, pp. 189–198, 2014. View at Publisher · View at Google Scholar · View at Scopus
  114. W. He, T. Qu, Q. Yu et al., “LPS induces IL-8 expression through TLR4, MyD88, NF-kappaB and MAPK pathways in human dental pulp stem cells,” International Endodontic Journal, vol. 46, no. 2, pp. 128–136, 2013. View at Publisher · View at Google Scholar · View at Scopus
  115. A. Heiman, A. Pallottie, R. F. Heary, and S. Elkabes, “Toll-like receptors in central nervous system injury and disease: a focus on the spinal cord,” Brain, Behavior, and Immunity, vol. 42, pp. 232–245, 2014. View at Publisher · View at Google Scholar · View at Scopus
  116. L. Guth, Z. Zhang, N. A. DiProspero, K. Joubin, and M. T. Fitch, “Spinal cord injury in the rat: treatment with bacterial lipopolysaccharide and indomethacin enhances cellular repair and locomotor function,” Experimental Neurology, vol. 126, no. 1, pp. 76–87, 1994. View at Publisher · View at Google Scholar · View at Scopus
  117. S. Tomic, J. Djokic, S. Vasilijic et al., “Immunomodulatory properties of mesenchymal stem cells derived from dental pulp and dental follicle are susceptible to activation by toll-like receptor agonists,” Stem Cells and Development, vol. 20, no. 4, pp. 695–708, 2011. View at Publisher · View at Google Scholar · View at Scopus
  118. A. T. Ozdemir, R. B. Ozgul Ozdemir, C. Kirmaz et al., “The paracrine immunomodulatory interactions between the human dental pulp derived mesenchymal stem cells and CD4 T cell subsets,” Cellular Immunology, vol. 310, pp. 108–115, 2016. View at Publisher · View at Google Scholar · View at Scopus
  119. S. Sugita, H. Kamao, Y. Iwasaki et al., “Inhibition of T-cell activation by retinal pigment epithelial cells derived from induced pluripotent stem cells,” Investigative Ophthalmology & Visual Science, vol. 56, no. 2, pp. 1051–1062, 2015. View at Publisher · View at Google Scholar · View at Scopus
  120. K. H. Kwack, J. M. Lee, S. H. Park, and H. W. Lee, “Human dental pulp stem cells suppress alloantigen-induced immunity by stimulating T cells to release transforming growth factor beta,” Journal of Endodontics, vol. 43, no. 1, pp. 100–108, 2017. View at Publisher · View at Google Scholar · View at Scopus
  121. P. C. Demircan, A. E. Sariboyaci, Z. S. Unal, G. Gacar, C. Subasi, and E. Karaoz, “Immunoregulatory effects of human dental pulp-derived stem cells on T cells: comparison of transwell co-culture and mixed lymphocyte reaction systems,” Cytotherapy, vol. 13, no. 10, pp. 1205–1220, 2011. View at Publisher · View at Google Scholar · View at Scopus
  122. L. Pierdomenico, L. Bonsi, M. Calvitti et al., “Multipotent mesenchymal stem cells with immunosuppressive activity can be easily isolated from dental pulp,” Transplantation, vol. 80, no. 6, pp. 836–842, 2005. View at Publisher · View at Google Scholar · View at Scopus
  123. Y. Zhao, L. Wang, Y. Jin, and S. Shi, “Fas ligand regulates the immunomodulatory properties of dental pulp stem cells,” Journal of Dental Research, vol. 91, no. 10, pp. 948–954, 2012. View at Publisher · View at Google Scholar · View at Scopus
  124. A. Földes, K. Kádár, B. Kerémi et al., “Mesenchymal stem cells of dental origin-their potential for antiinflammatory and regenerative actions in brain and gut damage,” Current Neuropharmacology, vol. 14, no. 8, pp. 914–934, 2016. View at Publisher · View at Google Scholar · View at Scopus
  125. J. W. Hong, J. H. Lim, C. J. Chung et al., “Immune tolerance of human dental pulp-derived mesenchymal stem cells mediated by CD4+CD25+FoxP3+ regulatory T-Cells and induced by TGF-β1 and IL-10,” Yonsei Medical Journal, vol. 58, no. 5, pp. 1031–1039, 2017. View at Publisher · View at Google Scholar · View at Scopus
  126. B. Mead, A. Logan, M. Berry, W. Leadbeater, and B. A. Scheven, “Concise review: dental pulp stem cells: a novel cell therapy for retinal and central nervous system repair,” Stem Cells, vol. 35, no. 1, pp. 61–67, 2017. View at Publisher · View at Google Scholar · View at Scopus
  127. G. Varga and G. Gerber, “Mesenchymal stem cells of dental origin as promising tools for neuroregeneration,” Stem Cell Research & Therapy, vol. 5, no. 2, p. 61, 2014. View at Publisher · View at Google Scholar · View at Scopus
  128. M. E. Schwab, “Myelin-associated inhibitors of neurite growth and regeneration in the CNS,” Trends in Neurosciences, vol. 13, no. 11, pp. 452–456, 1990. View at Publisher · View at Google Scholar · View at Scopus
  129. C. C. Stichel and H. W. Muller, “The CNS lesion scar: new vistas on an old regeneration barrier,” Cell and Tissue Research, vol. 294, no. 1, pp. 1–9, 1998. View at Publisher · View at Google Scholar · View at Scopus
  130. P. Gervois, E. Wolfs, Y. Dillen et al., “Paracrine maturation and migration of SH-SY5Y cells by dental pulp stem cells,” Journal of Dental Research, vol. 96, no. 6, pp. 654–662, 2017. View at Publisher · View at Google Scholar · View at Scopus
  131. Z. Khazaeipour, A. Norouzi-Javidan, M. Kaveh, F. Khanzadeh Mehrabani, E. Kazazi, and S. H. Emami-Razavi, “Psychosocial outcomes following spinal cord injury in Iran,” The Journal of Spinal Cord Medicine, vol. 37, no. 3, pp. 338–345, 2014. View at Publisher · View at Google Scholar · View at Scopus
  132. H. Huang, H.-Q. Chen, J. Gul, and R.-H. Yul, “Comparative study of hyperbaric oxygen therapy and conventional drug treatment on spinal cord injury at different therapeutic windows,” Scientific Research and Essays, vol. 6, no. 5, pp. 1117–1122, 2011. View at Google Scholar
  133. Y. Jiang, F. L. Gong, G. B. Zhao, and J. Li, “Chrysin suppressed inflammatory responses and the inducible nitric oxide synthase pathway after spinal cord injury in rats,” International Journal of Molecular Sciences, vol. 15, no. 7, pp. 12270–12279, 2014. View at Publisher · View at Google Scholar · View at Scopus
  134. A. Yamamoto, K. Matsubara, F. Kano, and K. Sakai, “Analysis of the neuroregenerative activities of mesenchymal stem cells in functional recovery after rat spinal cord injury,” Methods in Molecular Biology, vol. 1213, pp. 321–328, 2014. View at Publisher · View at Google Scholar · View at Scopus
  135. A. Yamamoto, K. Sakai, K. Matsubara, F. Kano, and M. Ueda, “Multifaceted neuro-regenerative activities of human dental pulp stem cells for functional recovery after spinal cord injury,” Neuroscience Research, vol. 78, pp. 16–20, 2014. View at Publisher · View at Google Scholar · View at Scopus
  136. C. Yang, X. Li, L. Sun, W. Guo, and W. Tian, “Potential of human dental stem cells in repairing the complete transection of rat spinal cord,” Journal of Neural Engineering, vol. 14, no. 2, article 026005, 2017. View at Publisher · View at Google Scholar · View at Scopus
  137. J. Zhang, X. Lu, G. Feng et al., “Chitosan scaffolds induce human dental pulp stem cells to neural differentiation: potential roles for spinal cord injury therapy,” Cell and Tissue Research, vol. 366, no. 1, pp. 129–142, 2016. View at Publisher · View at Google Scholar · View at Scopus
  138. M. E. Sughrue, A. Mehra, E. S. Connolly Jr, and A. L. D’Ambrosio, “Anti-adhesion molecule strategies as potential neuroprotective agents in cerebral ischemia: a critical review of the literature,” Inflammation Research, vol. 53, no. 10, pp. 497–508, 2004. View at Publisher · View at Google Scholar · View at Scopus
  139. K. A. Hossmann, “Pathophysiology and therapy of experimental stroke,” Cellular and Molecular Neurobiology, vol. 26, no. 7-8, pp. 1055–1081, 2006. View at Publisher · View at Google Scholar · View at Scopus
  140. W. K. Leong, M. D. Lewis, and S. A. Koblar, “Concise review: preclinical studies on human cell-based therapy in rodent ischemic stroke models: where are we now after a decade?” Stem Cells, vol. 31, no. 6, pp. 1040–1043, 2013. View at Publisher · View at Google Scholar · View at Scopus
  141. R. Lemmens and G. K. Steinberg, “Stem cell therapy for acute cerebral injury: what do we know and what will the future bring?” Current Opinion in Neurology, vol. 26, no. 6, pp. 617–625, 2013. View at Publisher · View at Google Scholar · View at Scopus
  142. K. L. Yang, M. F. Chen, C. H. Liao, C. Y. Pang, and P. Y. Lin, “A simple and efficient method for generating Nurr1-positive neuronal stem cells from human wisdom teeth (tNSC) and the potential of tNSC for stroke therapy,” Cytotherapy, vol. 11, no. 5, pp. 606–617, 2009. View at Publisher · View at Google Scholar · View at Scopus
  143. W. K. Leong, T. L. Henshall, A. Arthur et al., “Human adult dental pulp stem cells enhance poststroke functional recovery through non-neural replacement mechanisms,” Stem Cells Translational Medicine, vol. 1, no. 3, pp. 177–187, 2012. View at Publisher · View at Google Scholar · View at Scopus
  144. W. Dauer and S. Przedborski, “Parkinson’s disease: mechanisms and models,” Neuron, vol. 39, no. 6, pp. 889–909, 2003. View at Publisher · View at Google Scholar · View at Scopus
  145. Y. Wang, S. Chen, D. Yang, and W. D. Le, “Stem cell transplantation: a promising therapy for Parkinson’s disease,” Journal of Neuroimmune Pharmacology, vol. 2, no. 3, pp. 243–250, 2007. View at Publisher · View at Google Scholar · View at Scopus
  146. N. Gnanasegaran, V. Govindasamy, C. Simon et al., “Effect of dental pulp stem cells in MPTP-induced old-aged mice model,” European Journal of Clinical Investigation, vol. 47, no. 6, pp. 403–414, 2017. View at Publisher · View at Google Scholar · View at Scopus
  147. N. Gnanasegaran, V. Govindasamy, V. Mani, and N. H. Abu Kasim, “Neuroimmunomodulatory properties of DPSCs in an in vitro model of Parkinson’s disease,” IUBMB Life, vol. 69, no. 9, pp. 689–699, 2017. View at Publisher · View at Google Scholar · View at Scopus
  148. H. Fujii, K. Matsubara, K. Sakai et al., “Dopaminergic differentiation of stem cells from human deciduous teeth and their therapeutic benefits for Parkinsonian rats,” Brain Research, vol. 1613, pp. 59–72, 2015. View at Publisher · View at Google Scholar · View at Scopus
  149. M. Citron, “Alzheimer’s disease: strategies for disease modification,” Nature Reviews Drug Discovery, vol. 9, no. 5, pp. 387–398, 2010. View at Publisher · View at Google Scholar · View at Scopus
  150. Y. Huang and L. Mucke, “Alzheimer mechanisms and therapeutic strategies,” Cell, vol. 148, no. 6, pp. 1204–1222, 2012. View at Publisher · View at Google Scholar · View at Scopus
  151. M. Li, K. Guo, and S. Ikehara, “Stem cell treatment for Alzheimer’s disease,” International Journal of Molecular Sciences, vol. 15, no. 10, pp. 19226–19238, 2014. View at Publisher · View at Google Scholar · View at Scopus
  152. J. Y. Shin, H. J. Park, H. N. Kim et al., “Mesenchymal stem cells enhance autophagy and increase β-amyloid clearance in Alzheimer disease models,” Autophagy, vol. 10, no. 1, pp. 32–44, 2014. View at Publisher · View at Google Scholar · View at Scopus
  153. C. Apel, O. V. Forlenza, V. J. R. de Paula et al., “The neuroprotective effect of dental pulp cells in models of Alzheimer’s and Parkinson’s disease,” Journal of Neural Transmission, vol. 116, no. 1, pp. 71–78, 2009. View at Publisher · View at Google Scholar · View at Scopus
  154. F. Wang, Y. Jia, J. Liu et al., “Dental pulp stem cells promote regeneration of damaged neuron cells on the cellular model of Alzheimer’s disease,” Cell Biology International, vol. 41, no. 6, pp. 639–650, 2017. View at Publisher · View at Google Scholar · View at Scopus
  155. N. E.-M. B. Ahmed, M. Murakami, Y. Hirose, and M. Nakashima, “Therapeutic potential of dental pulp stem cell secretome for Alzheimer’s disease treatment: an in vitro study,” Stem Cells International, vol. 2016, Article ID 8102478, 11 pages, 2016. View at Publisher · View at Google Scholar · View at Scopus
  156. T. Mita, Y. Furukawa-Hibi, H. Takeuchi et al., “Conditioned medium from the stem cells of human dental pulp improves cognitive function in a mouse model of Alzheimer’s disease,” Behavioural Brain Research, vol. 293, pp. 189–197, 2015. View at Publisher · View at Google Scholar · View at Scopus
  157. T. A. Reh and A. J. Fischer, “Retinal stem cells,” Methods in Enzymology, vol. 419, pp. 52–73, 2006. View at Publisher · View at Google Scholar · View at Scopus
  158. Y. Munemasa and Y. Kitaoka, “Autophagy in axonal degeneration in glaucomatous optic neuropathy,” Progress in Retinal and Eye Research, vol. 47, pp. 1–18, 2015. View at Publisher · View at Google Scholar · View at Scopus
  159. P. M. Richardson, U. M. McGuinness, and A. J. Aguayo, “Axons from CNS neurones regenerate into PNS grafts,” Nature, vol. 284, no. 5753, pp. 264-265, 1980. View at Publisher · View at Google Scholar · View at Scopus
  160. B. Mead, L. J. Hill, R. J. Blanch et al., “Mesenchymal stromal cell–mediated neuroprotection and functional preservation of retinal ganglion cells in a rodent model of glaucoma,” Cytotherapy, vol. 18, no. 4, pp. 487–496, 2016. View at Publisher · View at Google Scholar · View at Scopus
  161. A. F. Bray, R. R. Cevallos, K. Gazarian, and M. Lamas, “Human dental pulp stem cells respond to cues from the rat retina and differentiate to express the retinal neuronal marker rhodopsin,” Neuroscience, vol. 280, pp. 142–155, 2014. View at Publisher · View at Google Scholar · View at Scopus
  162. R. Roozafzoon, A. Lashay, M. Vasei et al., “Dental pulp stem cells differentiation into retinal ganglion-like cells in a three dimensional network,” Biochemical and Biophysical Research Communications, vol. 457, no. 2, pp. 154–160, 2015. View at Publisher · View at Google Scholar · View at Scopus
  163. B. Battiston, S. Geuna, M. Ferrero, and P. Tos, “Nerve repair by means of tubulization: literature review and personal clinical experience comparing biological and synthetic conduits for sensory nerve repair,” Microsurgery, vol. 25, no. 4, pp. 258–267, 2005. View at Publisher · View at Google Scholar · View at Scopus
  164. T. Matsuyama, M. Mackay, and R. Midha, “Peripheral nerve repair and grafting techniques: a review,” Neurologia Medico-Chirurgica, vol. 40, no. 4, pp. 187–199, 2000. View at Publisher · View at Google Scholar
  165. B. J. Pfister, T. Gordon, J. R. Loverde, A. S. Kochar, S. E. Mackinnon, and D. K. Cullen, “Biomedical engineering strategies for peripheral nerve repair: surgical applications, state of the art, and future challenges,” Critical Reviews™ in Biomedical Engineering, vol. 39, no. 2, pp. 81–124, 2011. View at Publisher · View at Google Scholar · View at Scopus
  166. T. Tamaki, M. Hirata, N. Nakajima et al., “A long-gap peripheral nerve injury therapy using human skeletal muscle-derived stem cells (Sk-SCs): an achievement of significant morphological, numerical and functional recovery,” PLoS One, vol. 11, no. 11, article e0166639, 2016. View at Publisher · View at Google Scholar · View at Scopus
  167. V. Pertici, J. Laurin, F. Feron, T. Marqueste, and P. Decherchi, “Functional recovery after repair of peroneal nerve gap using different collagen conduits,” Acta Neurochirurgica, vol. 156, no. 5, pp. 1029–1040, 2014. View at Publisher · View at Google Scholar · View at Scopus
  168. S. K. Lee and S. W. Wolfe, “Peripheral nerve injury and repair,” The Journal of the American Academy of Orthopaedic Surgeons, vol. 8, no. 4, pp. 243–252, 2000. View at Publisher · View at Google Scholar · View at Scopus
  169. O. Alluin, C. Wittmann, T. Marqueste et al., “Functional recovery after peripheral nerve injury and implantation of a collagen guide,” Biomaterials, vol. 30, no. 3, pp. 363–373, 2009. View at Publisher · View at Google Scholar · View at Scopus
  170. L. G. Dai, G. S. Huang, and S. H. Hsu, “Sciatic nerve regeneration by cocultured Schwann cells and stem cells on microporous nerve conduits,” Cell Transplantation, vol. 22, no. 11, pp. 2029–2039, 2013. View at Publisher · View at Google Scholar · View at Scopus
  171. A. Faroni, S. A. Mobasseri, P. J. Kingham, and A. J. Reid, “Peripheral nerve regeneration: experimental strategies and future perspectives,” Advanced Drug Delivery Reviews, vol. 82-83, pp. 160–167, 2015. View at Publisher · View at Google Scholar · View at Scopus
  172. A. Gärtner, I. Amorim, A. Almeida et al., “Promoting nerve regeneration in a neurotmesis rat model using poly(DL-lactide-ɛ-caprolactone) membranes and mesenchymal stem cells from the Wharton’s jelly: in vitro and in vivo analysis,” BioMed Research International, vol. 2014, Article ID 302659, 17 pages, 2014. View at Publisher · View at Google Scholar · View at Scopus
  173. R. Sasaki, S. Aoki, M. Yamato et al., “PLGA artificial nerve conduits with dental pulp cells promote facial nerve regeneration,” Journal of Tissue Engineering and Regenerative Medicine, vol. 5, no. 10, pp. 823–830, 2011. View at Publisher · View at Google Scholar · View at Scopus
  174. K. Sanen, W. Martens, M. Georgiou, M. Ameloot, I. Lambrichts, and J. Phillips, “Engineered neural tissue with Schwann cell differentiated human dental pulp stem cells: potential for peripheral nerve repair?” Journal of Tissue Engineering and Regenerative Medicine, vol. 11, no. 12, pp. 3362–3372, 2017. View at Publisher · View at Google Scholar · View at Scopus
  175. N. Askari, M. M. Yaghoobi, M. Shamsara, and S. Esmaeili-Mahani, “Tetracycline-regulated expression of OLIG2 gene in human dental pulp stem cells lead to mouse sciatic nerve regeneration upon transplantation,” Neuroscience, vol. 305, pp. 197–208, 2015. View at Publisher · View at Google Scholar · View at Scopus
  176. M. Omi, M. Hata, N. Nakamura et al., “Transplantation of dental pulp stem cells suppressed inflammation in sciatic nerves by promoting macrophage polarization towards anti-inflammation phenotypes and ameliorated diabetic polyneuropathy,” Journal of Diabetes Investigation, vol. 7, no. 4, pp. 485–496, 2016. View at Publisher · View at Google Scholar · View at Scopus