The potential therapy with dental tissue-derived mesenchymal stem cells in Parkinson’s disease
Stem Cell Research & Therapy volume 12, Article number: 5 (2021)
Parkinson’s disease (PD), the second most common neurodegenerative disease worldwide, is caused by the loss of dopaminergic (DAergic) neurons in the substantia nigra resulting in a series of motor or non-motor disorders. Current treatment methods are unable to stop the progression of PD and may bring certain side effects. Cell replacement therapy has brought new hope for the treatment of PD. Recently, human dental tissue-derived mesenchymal stem cells have received extensive attention. Currently, dental pulp stem cells (DPSCs) and stem cells from human exfoliated deciduous teeth (SHED) are considered to have strong potential for the treatment of these neurodegenerative diseases. These cells are considered to be ideal cell sources for the treatment of PD on account of their unique characteristics, such as neural crest origin, immune rejection, and lack of ethical issues. In this review, we briefly describe the research investigating cell therapy for PD and discuss the application and progress of DPSCs and SHED in the treatment of PD. This review offers significant and comprehensive guidance for further clinical research on PD.
Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world after Alzheimer’s disease with incidences of 1% and 5% for populations aged over 65 and 80, respectively . One of the main pathological features of PD is that the loss of DAergic neurons in the substantia nigra pars compacta (SNpc) leads to a significant decrease in the content of dopamine (DA) in the striatum, and there are Lewy bodies with α-synuclein as the main component in the surviving neurons [2, 3]. The loss of these neurons will lead to some clinical symptoms related to the disease, such as static tremor, bradykinesia, rigidity, and postural gait disorders, along with other non-motor symptoms . Although the exact pathogenesis of PD is still uncertain, it has been reported that mitochondrial dysfunction, oxidative stress, neuroinflammation, and environmental toxins are important factors for the death of DAergic neurons [5, 6].
At present, drug therapy is the most effective and widely used treatment for PD patients, including administration of levodopa, DA agonists, amantadine, monoamine oxidase B (MAO-B) inhibitors , catechol-O-methyltransferase (COMT) inhibitors , and some anticholinergic drugs. As physiotherapy, nucleus destruction and deep brain stimulation (DBS)  are new and effective methods, which have great potential for popularization and application. In addition, some adjuvant therapies also are effective for remission and partial treatment of patients with PD. Although these treatments have improved certain symptoms of the disease to some extent, they have not prevented the progression of PD and also cause some side effects. In recent years, cell transplantation has been considered to be a new option for the treatment of neurodegenerative diseases [10, 11]. Stem cells are widely used in PD to counteract the harmful effects of DAergic neuron loss, because of their high proliferative capacity and multi-lineage differentiation potential.
Of all available stem cell sources, human dental tissue-derived mesenchymal stem cells (such as DPSCs and SHED) not only feature the universal characteristics of stem cells but have also attracted increasing attention from PD researchers for their neural crest origin, immunomodulatory activity, and non-tumorigenic properties  and for avoidance of ethical problems caused by transplantation [12, 13]. Owing to the neurocrest origin of DPSCs and SHED, they achieve previously unimagined capability for treating central nervous system diseases and peripheral nerve injuries such as caries and alveolar bone atrophy [14, 15]. DPSCs and SHED can play a powerful role in the treatment of PD. They can be differentiated into DAergic neuron-like cells and secrete neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) [16,17,18]. DPSCs and SHED have high proliferation ability, immunomodulatory characteristics, neurodifferentiation ability, and non-ethical and material advantages, which make them potential clinical therapeutic materials for PD. These cells are gradually becoming the priority of researchers in the cell therapy of PD. In recent years, DPSCs and SHED have been applied to the preclinical study of PD (Table 1). So far, there is no comprehensive overview of the application of DPSCs and SHED in the treatment of PD. Therefore, this review briefly describes the research course of cell therapy for PD and reports the application and research progress of DPSCs and SHED in the treatment of PD.
Cell therapy for PD
PD research has always pioneered cell transplantation therapy because of the unique pathological characteristics—loss of DAergic neurons. Since the 1980s, researchers have been trying to save the lost DAergic neurons by cell transplantation . Initially, a variety of catecholaminergic cells were selected , but the most successful method was to use tissue dissected from the developing foetal midbrain. However, although this method has proved successful in experiments, the clinical effect is not satisfactory. This is mainly due to the following reasons: (1) ethical problems are inherent in the use of human foetal tissue, (2) there are practical problems caused by the need for sufficient foetal tissue for each patient, and (3) inconsistent results and side effects of dyskinesia were obtained in the “TRANSEURO” study [9, 27, 28]. Therefore, in order to find more easily available sources of substantia nigra DA cells for transplantation, researchers have studied dopaminergic neurons in different species and have begun to explore different types of stem cells. At present, this field has been developed to produce a large number of substantia nigra DA cells safely and effectively from different types of stem cells. Compared with foetal tissue cell transplantation, stem cells play an irreplaceable role for the following reasons: (1) better availability , (2) standardized production , (3) controllable cell characteristics before transplantation (unfavourable consequences can be avoided [31, 32]), (4) good preservation conditions , and (5) precise preoperative control , including of dose, concentration, and volume. Therefore, these properties further promote the favourable prospect for stem cell transplantation in PD and inspire researchers to begin to treat the disease through cellular reprogramming.
With the development of stem cell therapy, many types of cells have been used for derivation and differentiation of DAergic neurons, drug screening, and cell therapy for PD . At present, embryonic stem cells (ESCs), neural stem cells (NSCs), induced pluripotent stem cells (iPSCs), and mesenchymal stem cells (MSCs) are considered to be reliable cell sources for PD therapy [28, 34, 35]. To better understand the efficacy and safety of cell replacement therapy, a variety of experimental models of PD have been established. Toxicity-inducing drugs include 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA), and rotenone. These drugs act on cells or animal models to simulate the pathological characteristics of PD. Next, transfer of differentiated or undifferentiated ESCs, NSCs, iPSCs, and other types of stem cells into an animal model can restore a number of lost neurons or improve the behaviour of the animal model to varying degrees.
ESCs were once thought to constitute the best source of cells such as substantia nigra DAergic neurons . It has been known for a long time that undifferentiated ESCs can be smoothly transplanted into the striatum of a rodent and have the ability to differentiate into DAergic neurons, which slows progression of behavioural abnormality in PD rat models [37, 38]. It is a good choice to induce more DAergic neurons in vitro, so the percentage of DAergic neurons can be greatly increased by inhibiting certain molecular pathways [39, 40] and/or using developmental factors related to DA formation, such as Sonic hedgehog, fibroblast growth factor 8, and brain-derived neurotrophic factor. These derived neurons can also be transplanted to experimental animal models and achieve unexpected benefits. However, the same outstanding problem as with iPSCs is that the tumorigenicity after transplantation cannot effectively be solved. In addition, ESC transplantation also involves certain ethical issues. There are more-or-less unsolved problems regarding the safety and effectiveness of other stem cell transplantation approaches which are not discussed in detail in this review. It is worth noting that a breakthrough clinical trial was launched in Japan in 2018 to transplant allogeneic human iPSC-derived dopaminergic neuronal precursors into the striatum of patients with PD [9, 41]. Further clinical trials of cell transplantation in the treatment of PD are expected to begin soon.
Mesenchymal stem cells (MSCs) are a type of adult stem cells isolated from a variety of tissues . MSCs have the potential for multi-directional differentiation, such as with osteogenesis, adipogenesis, and neuroblast formation, and have a unique function of secreting cytokines, which has been used in a number of clinical trials. At present, eight unique MSCs  have been isolated from different dental tissues and used in the treatment of various diseases. DPSCs and SHED have proved to be promising potential options for the treatment of PD by multiple modes of action (Fig. 1). Next, we will discuss the current application and progress of DPSCs and SHED in the treatment of PD.
Dental pulp stem cells therapy for PD
Characteristics of DPSCs
DPSCs were first discovered by Gronthos and colleagues through the study of dental pulp cells in 2000 . DPSCs share similar characteristics with bone marrow mesenchymal stem cells (BMSCs), such as the morphology of fibroblasts and the ability to form colonies in vitro. They can express many surface markers such as CD73, CD90, and CD105 but do not express surface markers such as CD14, CD34, and CD 45 [44,45,46]. However, compared with BMSCs, DPSCs exhibit a higher proliferation rate, more exuberant colony and colonies formation ability, and stronger mineralization potential [44, 47, 48]. In addition, DPSCs can also express the ESCs markers OCT4, SOX2, and MYC, which are not common in MSCs . Similarly, in addition to odontogenic potential, DPSCs also have potential for multi-lineage differentiation. In vitro, DPSCs can be differentiated into various types of cells, such as adipocytes, hepatocytes, osteoblasts, and neuronal cells under suitable conditions. Additionally, there is sufficient evidence to show their immunomodulatory properties and the capacity of ectopic formation in vivo .
DPSCs are stem cells derived from ectoderm, which originate from migrated neural crest cells and exhibit strong plasticity. They can express markers of nerve lineage [50, 51], such as low-affinity nerve growth factor receptor p75, intermediate filament nestin, and glial fibrillary acidic protein (GFAP), and more mature markers of nerve lineage such as β-III tubulin and nuclear antigen, which also reflects their origin and high heterogeneity [52, 53]. Of course, a large number of studies have shown that it can differentiate into DAergic neuron-like cells [10, 16, 54, 55]. In addition, DPSCs can also produce and secrete neurotrophic factors, induce axon guidance, and differentiate into functionally active neurons, which also illustrates great potential for cell transplantation therapy for PD.
Preclinical application of DPSCs in Parkinson’s disease
The neural differentiation of DPSCs has been studied in vitro. According to the cell morphology and the expression of early neuronal markers, it has been suggested that these cells can differentiate into neurons [46, 52, 54, 56, 57]. In vivo studies have further shown that DPSCs can survive and express neuronal markers after transplantation into the brain . This potential for spontaneous differentiation of DPSCs also convincingly proves its role in treatment by nerve regeneration. With cell therapy for PD, from the initial transplantation of foetal midbrain tissue to the study of animal models and clinical trials with PD patients, research has provided us with proof-of-concept evidence that transplantation of DAergic neuroblasts into the striatum can effectively relieve the symptoms of PD. We mentioned above that DPSCs can differentiate into dopaminergic neuron-like cells and secrete neurotrophic factors (Fig. 1). For example, Claudia  studied the neuroprotective effect of DPSCs using DPSCs and a midbrain cell indirect co-culture system and proved for the first time the protective effect of DPSCs on dopaminergic neurons in PD models induced by MPP+ or rotenone. It is speculated that their neuroprotective effects may be caused by soluble factors released by DPSCs, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Therefore, in PD cell therapy, the differentiation of stem cells into DAergic neurons is not the only purpose, but the ability to produce and secrete neuroprotective factors may be more important . These secreted neuroprotective factors may bind to specific receptors and trigger the activation of certain signalling pathways that coordinate cell function.
Transplanting DPSCs directly into the brain of an animal model of PD does not seem to be a very effective treatment. At present, a nerve-inducing mixture of various chemicals and cytokines is widely used to cause DPSCs to progress towards the fate of neurogenesis in vitro (Fig. 1). The neuronal differentiation of DPSCs basically consists of two steps: the addition of medium for epigenetic reprogramming and neural induction and subsequent neuronal maturation. One study differentiated DPSCs into DAergic neuron-like cells after five stages . After the formation of neurospheres in the second stage, they were cultured in N-2 medium containing a mixture of nerve inducers including fibroblast growth factor (FGF), FGF-8b, sonic hedgehog-N, and ascorbic acid, and the differentiation rate of DAergic neuron-like cells was 14.49% (refers to the ratio of tyrosine hydroxylase positive cells). This method not only has a low differentiation rate but is also time-consuming. Some reports have shown that DPSCs can differentiate into functional DAergic neurons [59,60,61]. However, other researchers have found that they may only differentiate into premature DAergic neurons rather than functional and mature DAergic neurons . These contradictory findings led a team recently to study the differentiation into dopaminergic neurons of DPSCs under different chemical and photobiological regulation conditions . Their results showed that photobiological regulation can increase the expression of dopaminergic neuron protective protein mRNAs in DPSCs under certain conditions. However, DPSC-induced DAergic neurons have the characteristics of immature neurons and are prone to death. The reason for the analysis may be that there is no cell niche including other cell types and extracellular matrix structure in vitro. For now, the research on the treatment of PD by inducing DPSCs to differentiate into DAergic neurons still needs improvement.
Any injury can cause inflammation. Neuroinflammation is one of the many pathogenic mechanisms that lead to the death of DAergic neurons in the substantia nigra of patients with PD. Autopsy studies have basically confirmed the existence of innate immunity and adaptive immunity in the injured brain regions of patients with PD . Activated microglia and T lymphocytes can be detected in the substantia nigra of patients, and increased expression of pro-inflammatory mediators can also be detected [64, 65]. Thus, a perfect cell transplantation programme should include suppressing inflammation in addition to maintaining the number of neurons, which DPSCs can do. In vitro, inflammation can be achieved by a variety of methods, including the use of MPTP or LPS for induction. Both toxins can inhibit the proliferation of DAergic neurons and enhance the expression of inflammatory mediators. At the same time, microglia clearly proliferate, which leads to the co-activation of TLR4 and IFN- γ receptors and initiates the mechanism of nerve cell death . A study was conducted to investigate the effects of DPSCs in an inflammatory microenvironment when neurons and microglia were exposed to the neurotoxin MPTP to observe the neuroimmunomodulatory properties of DPSCs in an in vitro PD model . The results showed that DPSCs could significantly inhibit the production of ROS and NO and regulate the levels of pro-inflammatory factors such as IL-1α, IL-1β, IFN-γ, and TNF-α. In addition, although DPSCs were exposed to environmental toxins, they were still able to express neuronal markers such as Nestin, Pax6, and Nurr1. At the same time, similar results were obtained in another in vivo experiment in which the behavioural defects of PD mice were reversed to some extent . In both studies, elevated levels of anti-inflammatory factors IL-13, IL-4, IL-10, and TNF-α were observed, which can neutralize the inflammatory process. Some researchers speculate that these factors can be secreted by neurons or microglia, and they may reduce inflammation by promoting the M2 microglia phenotype and causing death of the M1 microglia phenotype or by enhancing the effects of oxidative stress on neurons through the JAK/STAT pathway . We tend to hold that these secreted factors originate from the transplanted DPSCs. This paracrine process of producing and secreting various nutritional factors may be the main mechanism by which DPSCs play a role in the treatment of PD.
However, one of the challenges is to find a safe and effective method of cell delivery before DPSC transplantation is used in clinical applications. It has been reported that the survival rate of transplanted cells, the full enrichment of therapeutic cells in the brain, and success in avoiding the distribution of stem cells to peripheral organs are all affected by transplantation methods [28, 68]. Due to the existence of the blood-brain barrier (BBB), DPSC transplantation is also faced with the problem of invasiveness and invalidity. However, some studies have explored the nasal system as a new pathway for stem cell delivery, which can bypass the BBB and directly target brain therapy for PD [69, 70]. Therefore, a recent study showed that degenerated tyrosine hydroxylase (TH)-positive neurons, motor coordination, and olfactory function were significantly improved by intranasal administration of PKH26 pre-labelled DPSCs into MPTP-induced PD mice . In another study, intrathecal injection also significantly promoted the recovery of neurons and the improvement of behavioural function . Comparatively, the method of intrathecal injection may be cumbersome and difficult. Regardless of how the DPSCs are administered, the ability of DPSCs to differentiate into DAergic neurons in vivo or in vitro and its positive role in PD therapy have been convincingly confirmed.
Treatment of PD with stem cells from human exfoliated deciduous teeth
Characteristics of SHED
Stem cells from human exfoliated deciduous teeth (SHED) constitutes a unique population of pluripotent stem cells first isolated from the residual pulp of deciduous teeth by Miura et al. in 2003 . They also have the characteristics of MSCs, but compared with DPSCs and BMSCs, SHED exhibit a stronger proliferation rate, higher cell population doubling rate, and more vigorous ability to form spherical cell clusters. The surface labelling of SHED meets the minimum standard proposed by ISCT. They express CD13, CD29, CD44, CD56, CD73, CD90, CD105, CD146, and CD166 but not CD14, CD19, CD24, CD31, CD34, CD45, CD117, or CD133 [46, 71,72,73,74]. SHED are also derived from migrated neural crest cells. They can express the neural stem cell marker nestin, embryonic stem cell markers Oct4 and Nanog, and stage-specific embryonic antigens SSEA-3 and SSEA-4 . Additionally, SHED has higher levels of basic fibroblast growth factor (bFGF) and bone morphogenic protein 2 (BMP-2) gene expression than do BMSCs and DPSCs . In addition, the favourable immunomodulatory properties of SHED have been fully proven in the research of related diseases .
SHED has highly potential for multi-directional differentiation. In addition to odontogenic potential, they can differentiate into osteogenic, adipogenic, hepatogenic, and neurogenic lineage cells under suitable conditions in vitro. Under the condition of neural induction culture, SHED has been found to express the early neural marker nestin, the late neural marker neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), and 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNP) . It has been reported that transplantation of undifferentiated or nerve-induced SHED into a rat spinal cord injury (SCI) model can promote functional recovery . This indicates the potential of implanted SHED or its derivatives in the treatment of SCI in rodents and other neurodegenerative diseases. In addition, a large number of studies on the culture of SHED-derived neurospheres and the induction of dopaminergic neurons as well as the treatment of PD rat models have shown that they constitute a very suitable cell source for cell therapy in PD [22,23,24].
Preclinical application of SHED in Parkinson’s disease
Previous studies on the neural potential of DPSCs and SHED without neural induction have shown that these cells can express nestin, a neural progenitor cell marker, and GFAP, a glial cell marker, at the mRNA and protein levels [45, 46]. In vitro differentiation studies have also shown that they can differentiate into nerve cells and can survive and express neuronal markers when SHED is transplanted into the brain of adult rodents. In addition, they are neural crest-derived cells and are easy to obtain, which further indicates their potential application value for the treatment of PD.
A recent study explored the efficiency of SHED for differentiation into DAergic neuron-like cells and the ability of DAergic neuron-like cells to secrete dopamine and evaluated the therapeutic effect when SHED were transplanted into a 6-OHDA-induced (nigrostriatal damage mainly caused by oxidative stress) PD rat model . The team used a hypoxia-induced differentiation scheme to effectively differentiate SHED into DAergic neuron-like cells. After undifferentiated and differentiated SHED were transplanted into the PD rat model, behavioural disorder and the number of TH-positive cells were significantly improved, and the protective effect on endogenous DAergic neurons was also observed. This subject also demonstrates that the paracrine mechanism during this differentiation helps to combat 6-OHDA-induced neurodegeneration and repair nigrostriatal damage, confirming the conclusions of previous studies showing that these dental pulp-derived stem cells promote the functional recovery of various acute and chronic central nervous system injuries through cell replacement and paracrine mechanisms [79, 80]. In another study, transplantation after induced differentiation in vitro also significantly restored the dyskinesia of a 6-OHDA-treated PD mouse model . To understand the mechanism of treatment, this study also determined that SHED secreted a large number of cytokines such as IL-6, GDNF, BDNF, and VEGF, which proved its immunomodulatory effect from the side. It is worth noting that the researchers added to the medium at the middle stage of neural induction the small molecule CHIR99021, which can inhibit the Wnt signal pathway of cells activated by GSK3β, thus increasing the production of DAergic neuron progenitor cells [81, 82]. Considering the survival rate of transplanted cells, a study used SHED-derived spheres instead of induced DAergic neurons for transplantation into a 6-OHDA-treated PD rat model . Although it improved the dyskinesia of rats, the results were not very satisfactory. It may have been due to immune rejection, inflammatory response, correct integration of transplanted cells with the host brain, or for other reasons, which still needs to be further studied.
Based on the above studies, there may be three main mechanisms of SHED in the treatment of PD (Fig. 1). First, DAergic neurons or other neurons differentiated by SHED in vivo form a functional connection with the host neuron. Transplanted DAergic neuron-like cells can secrete DA to restore the functional activity of neurons. Second, the transplanted SHED can secrete cell growth factors, such as VEGF, BDNF, and GDNF. Some studies have reported that undifferentiated MSCs can secrete neurotrophic factors such as BDNF, GDNF, NGF, HGF, and VEGF to play a neuroprotective role [12, 83]. Third, through the immune regulation by cytokines such as IL-6 and TNF-α, these factors may combine with VEGF, BDNF, and GDNF to enhance immune regulation and reverse the damage to host neurons .
Like other approaches to stem cell transplantation, non-invasive cell therapy remains to be explored. Recently, some studies have suggested that the exosome of SHED may offer a new strategy for the treatment of PD. All cultured cell types can secrete exosomes, which carry a variety of proteins, RNA, lipids, and various metabolites [85, 86]. From the point of view of the treatment of PD, the transfer of exosomes has several advantages. First, they can cross the BBB to reach the brain without complicated neurosurgery . Second, this technique is safer because it avoids the risks of cell transplantation, such as low survival rate, immune rejection, and malignant transformation. Finally, it is a relatively simple, stable, and controllable system which is suitable for large-scale clinical production . So, this technique may have equal or even superior potential to treat PD as the use of SHED. A study demonstrated the neuroprotective effects of SHED-derived exosomes in vitro through ReNcell VM human neural stem cell lines, inhibiting about 80% of 6-OHDA-induced apoptosis . In another study, the SHED exosomes were delivered into a 6-OHDA-treated PD rat model by intranasal administration, and it was found that the rat recovered from dyskinesia, and expression of TH in substantia nigra and striatum was normalized . However, it has not been proven that exosomes increase the expression of TH in substantia nigra and striatum by directly affecting dopaminergic neurons or indirectly increase the expression of TH by regulating the response of astrocytes and microglia. It is also possible that both mechanisms operate at the same time. Taken together, these findings suggest that the use of exosomes in early preclinical studies may be a promising method for the treatment of PD.
In contrast to a large amount of evidence reported in basic studies, there is no clinical application of DPSCs or SHED in the clinical treatment of PD.
Many regenerative medicine studies have shown that DPSCs and SHED can provide a good therapeutic effect for a variety of diseases, including various central nervous system diseases such as spinal cord injury, stroke, retinal injury, Alzheimer’s disease, and peripheral nerve injury . In addition, clinical studies on related diseases are also under way. Some research groups use autologous DPSCs to transplant into patients with dental pulp injury to promote pulp formation. Long-term follow-up monitoring shows that they can safely and effectively promote pulp regeneration, and no adverse reactions are observed [90,91,92]. In addition, a number of clinical trials have been carried out on bone regeneration, stroke, and diabetes [93, 94]. All in all, DPSCs and SHED are expected to become clinical-grade cells that can be widely used in the treatment of various diseases in the future.
The first clinical trial of cell transplantation for PD began more than 30 years ago, using DAergic neuronal precursor cells derived from human foetal midbrain tissue, which are still being used in ongoing TRANSEURO studies . According to the investigation and statistics, the clinical projects involving stem cell therapy for PD under research in the world include work with MSCs (NCT03550183, NCT03684122), NSCs (NCT03309514, NCT02452723), ESCs (NCT03119636), and iPSCs . In these studies, cells are delivered to patients by intravenous or intracerebral injection, and the transplanted cells play a neuroprotective role through neuronal differentiation or anti-inflammatory activity. The subjects have been followed up at different times to evaluate the safety and effectiveness of the treatment through various rating scales so as to provide a basis for further clinical research.
For DPSCs and SHED, first, they have the characteristics common to other stem cells. Second, these cells have unique advantages. (1) They have strong potential for neural differentiation because of the origin of their neural crest. (2) The ethical problems caused by transplantation can be avoided. (3) More importantly, these cells do not express costimulatory molecules, such as MHC-II, CD40, CD80, or CD86; therefore, they not only do not activate the immune system but also regulate immune rejection [95, 96]. Therefore, these cells are a good potential material among all the stem cell sources that can be used to treat PD.
Many studies demonstrated that just MSCs alone are not effective enough for neurodegenerative diseases and neurotrophin engineered MSCs are more effective [97, 98]. The engineering of dental stem cells aims to enhance specific functions to achieve stable therapeutic effects, including proliferation and neurogenic differentiation. In general, there are three common embellishments: (1) Differentiation in vitro. It is common to add neurotrophins such as EGF, bFGF, and BDNF to the differentiation medium in vitro to promote their maturation into DAergic neuron-like cells [99, 100]. Compared with undifferentiated cell transplantation, it can increase the level of DA and the secretion of neurotrophic factors more effectively and promote the recovery of neurological impairment . (2) Genetic engineering. It is well known that DPSCs and SHED can secrete a variety of cytokines and nerve growth factors, such as BDNF and GDNF. Studies have shown that BDNF and GDNF have significant repair and protection effects on neurodegenerative diseases, including promoting axonal regeneration and reducing apoptosis [101, 102]. Therefore, some new treatments emerge as the times require, including the overexpression of BDNF and GDNF and the use of genetically engineered MSCs as a carrier to directly transfer cytokines to the microenvironment . A team has tested the safety and efficacy of genetically engineered human MSCs in transgenic Huntington’s disease (HD) mouse models and published the results of new drug licensing . Their results show that human genetically engineered MSCs can significantly reduce striatal atrophy in HD mice by about 50% compared with non-transgenic mice. In addition, it has been confirmed that MSCs transfected with GDNF can protect the nigrostriatal pathway from inflammatory Parkinson’s syndrome . (3) Modification of chemical materials. The use of MSC-based nanostructured and microstructural materials for neurotrophic delivery is an effective way to improve the characteristics and therapeutic efficacy of stem cells, such as hydrogels and graphene [104,105,106]. These results suggest that it may be a promising direction to consider the engineering treatment of these cells in the future research on the treatment of PD with DPSCs and SHED.
Recently, stem cell transplantation has attracted increasing attention as a treatment for neurodegenerative diseases. Many results have been achieved in the use of DPSCs and SHED in various in vitro and in vivo models of PD. This review summarizes their current research progress in the treatment of PD in some detail. Whether from the perspective of basic research or in clinical application, they have more advantages than do other stem cells and are a great choice for PD treatment. This insight has a profound enlightening effect for the further clinical research on PD. However, further research is warranted to study the mechanisms, immune rejection, survival rate, and delivery mode associated with this treatment.
Availability of data and materials
Brain-derived neurotrophic factor
Basic fibroblast growth factor
Bone morphogenic protein 2
Bone marrow mesenchymal stem cells
2′, 3′-Cyclic nucleotide 3′-phosphodiesterase
Deep brain stimulation
Dental pulp stem cells
Embryonic stem cells
Fibroblast growth factor
Glial cell line-derived neurotrophic factor
Glial fibrillary acidic protein
Induced pluripotent stem cells
Monoamine oxidase B
Mesenchymal stem cells
Nerve growth factor
Neural stem cells
Spinal cord injury
Stem cells from human exfoliated deciduous teeth
Substantia nigra pars compacta
Shulman JM, De Jager PL, Feany MB. Parkinson’s disease: genetics and pathogenesis. Annu Rev Pathol. 2011;6:193–222.
Xiong N, Long X, Xiong J, Jia M, Chen C, Huang J, et al. Mitochondrial complex I inhibitor rotenone-induced toxicity and its potential mechanisms in Parkinson’s disease models. Crit Rev Toxicol. 2012;42(7):613–32.
Tamura T, Yoshida M, Hashizume Y, Sobue G. Lewy body-related α-synucleinopathy in the spinal cord of cases with incidental Lewy body disease. Neuropathol. 2012;32(1):13–22.
Schapira AHV, Chaudhuri KR, Jenner P. Non-motor features of Parkinson disease. Nat Rev Neurosci. 2017;18(7):435–50.
Ryan BJ, Hoek S, Fon EA, Wade-Martins R. Mitochondrial dysfunction and mitophagy in Parkinson’s: from familial to sporadic disease. Trends Biochem Sci. 2015;40(4):200–10.
Gibson GE, Huang HM. Mitochondrial enzymes and endoplasmic reticulum calcium stores as targets of oxidative stress in neurodegenerative diseases. J Bioenerg Biomembr. 2004;36(4):335–40.
Alborghetti M, Nicoletti F. Different generations of type-B monoamine oxidase inhibitors in Parkinson’s disease: from bench to bedside. Curr Neuropharmacol. 2019;17(9):861–73.
Müller T. Catechol-O-methyltransferase inhibitors in Parkinson’s disease. Drugs. 2015;75(2):157–74.
Parmar M, Grealish S, Henchcliffe C. The future of stem cell therapies for Parkinson disease. Nat Rev Neurosci. 2020;21(2):103–15.
Gnanasegaran N, Govindasamy V, Simon C, Gan QF, Vincent-Chong VK, Mani V, et al. Effect of dental pulp stem cells in MPTP-induced old-aged mice model. Eur J Clin Investig. 2017;47(6):403–14.
Martens W, Bronckaers A, Politis C, Jacobs R, Lambrichts I. Dental stem cells and their promising role in neural regeneration: an update. Clin Oral Investig. 2013;17(9):1969–83.
Apel C, Forlenza OV, de Paula VJ, Talib LL, Denecke B, Eduardo CP, et al. The neuroprotective effect of dental pulp cells in models of Alzheimer’s and Parkinson's disease. J Neural Transm. 2009;116(1):71–8.
Ledesma-Martínez E, Mendoza-Núñez VM, Santiago-Osorio E. Mesenchymal stem cells derived from dental pulp: a review. Stem Cells Int. 2016;2016:4709572.
Rosa V, Zhang Z, Grande RH, Nör JE. Dental pulp tissue engineering in full-length human root canals. J Dent Res. 2013;92(11):970–5.
Yamada Y, Nakamura S, Ito K, Sugito T, Yoshimi R, Nagasaka T, et al. A feasibility of useful cell-based therapy by bone regeneration with deciduous tooth stem cells, dental pulp stem cells, or bone-marrow-derived mesenchymal stem cells for clinical study using tissue engineering technology. Tissue Eng A. 2010;16(6):1891–900.
Nesti C, Pardini C, Barachini S, D'Alessandro D, Siciliano G, Murri L, et al. Human dental pulp stem cells protect mouse dopaminergic neurons against MPP+ or rotenone. Brain Res. 2011;1367:94–102.
Jarmalavičiūtė A, Tunaitis V, Pivoraitė U, Venalis A, Pivoriūnas A. Exosomes from dental pulp stem cells rescue human dopaminergic neurons from 6-hydroxy-dopamine-induced apoptosis. Cytotherapy. 2015;17(7):932–9.
Nosrat IV, Smith CA, Mullally P, Olson L, Nosrat CA. Dental pulp cells provide neurotrophic support for dopaminergic neurons and differentiate into neurons in vitro; implications for tissue engineering and repair in the nervous system. Eur J Neurosci. 2004;19(9):2388–98.
Simon C, Gan QF, Kathivaloo P, Mohamad NA, Dhamodharan J, Krishnan A, et al. Deciduous DPSCs ameliorate MPTP-mediated neurotoxicity, sensorimotor coordination and olfactory function in Parkinsonian mice. Int J Mol Sci. 2019;20(3):568.
Gnanasegaran N, Govindasamy V, Mani V, Abu Kasim NH. Neuroimmunomodulatory properties of DPSCs in an in vitro model of Parkinson’s disease. IUBMB Life. 2017;69(9):689–99.
Narbute K, Piļipenko V, Pupure J, Dzirkale Z, Jonavičė U, Tunaitis V, et al. Intranasal administration of extracellular vesicles derived from human teeth stem cells improves motor symptoms and normalizes tyrosine hydroxylase expression in the substantia nigra and striatum of the 6-hydroxydopamine-treated rats. Stem Cells Transl Med. 2019;8(5):490–9.
Zhang N, Lu X, Wu S, Li X, Duan J, Chen C, et al. Intrastriatal transplantation of stem cells from human exfoliated deciduous teeth reduces motor defects in Parkinsonian rats. Cytotherapy. 2018;20(5):670–86.
Fujii H, Matsubara K, Sakai K, Ito M, Ohno K, Ueda M, et al. Dopaminergic differentiation of stem cells from human deciduous teeth and their therapeutic benefits for Parkinsonian rats. Brain Res. 2015;1613:59–72.
Wang J, Wang X, Sun Z, Wang X, Yang H, Shi S, et al. Stem cells from human-exfoliated deciduous teeth can differentiate into dopaminergic neuron-like cells. Stem Cells Dev. 2010;19(9):1375–83.
Ali F, Stott SR, Barker RA. Stem cells and the treatment of Parkinson’s disease. Exp Neurol. 2014;260:3–11.
Barker RA, Dunnett SB. Functional integration of neural grafts in Parkinson’s disease. Nat Neurosci. 1999;2(12):1047–8.
Barker RA. Designing stem-cell-based dopamine cell replacement trials for Parkinson’s disease. Nat Med. 2019;25(7):1045–53.
Allan LE, Petit GH, Brundin P. Cell transplantation in Parkinson’s disease: problems and perspectives. Curr Opin Neurol. 2010;23(4):426–32.
Lindvall O, Björklund A. Cell therapy in Parkinson’s disease. NeuroRx. 2004;1(4):382–93.
Nolbrant S, Heuer A, Parmar M, Kirkeby A. Generation of high-purity human ventral midbrain dopaminergic progenitors for in vitro maturation and intracerebral transplantation. Nat Protoc. 2017;12(9):1962–79.
Doi D, Samata B, Katsukawa M, Kikuchi T, Morizane A, Ono Y, et al. Isolation of human induced pluripotent stem cell-derived dopaminergic progenitors by cell sorting for successful transplantation. Stem Cell Rep. 2014;2(3):337–50.
Lehnen D, Barral S, Cardoso T, Grealish S, Heuer A, Smiyakin A, et al. IAP-based cell sorting results in homogeneous transplantable dopaminergic precursor cells derived from human pluripotent stem cells. Stem Cell Rep. 2017;9(4):1207–20.
Bagheri-Mohammadi S, Karimian M, Alani B, Verdi J, Tehrani RM, Noureddini M. Stem cell-based therapy for Parkinson’s disease with a focus on human endometrium-derived mesenchymal stem cells. J Cell Physiol. 2019;234(2):1326–35.
Duke CM, Taylor HS. Stem cells and the reproductive system: historical perspective and future directions. Maturitas. 2013;76(3):284–9.
Kirkeby A, Grealish S, Wolf DA, Nelander J, Wood J, Lundblad M, et al. Generation of regionally specified neural progenitors and functional neurons from human embryonic stem cells under defined conditions. Cell Rep. 2012;1(6):703–14.
Kriks S, Shim JW, Piao J, Ganat YM, Wakeman DR, Xie Z, et al. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease. Nature. 2011;480(7378):547–51.
Deacon T, Dinsmore J, Costantini LC, Ratliff J, Isacson O. Blastula-stage stem cells can differentiate into dopaminergic and serotonergic neurons after transplantation. Exp Neurol. 1998;149(1):28–41.
Bjorklund LM, Sánchez-Pernaute R, Chung S, Andersson T, Chen IY, McNaught KS, et al. Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc Natl Acad Sci U S A. 2002;99(4):2344–9.
Lee SH, Lumelsky N, Studer L, Auerbach JM, McKay RD. Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells. Nat Biotechnol. 2000;18(6):675–9.
Jaeger I, Arber C, Risner-Janiczek JR, Kuechler J, Pritzsche D, Chen IC, et al. Temporally controlled modulation of FGF/ERK signaling directs midbrain dopaminergic neural progenitor fate in mouse and human pluripotent stem cells. Development. 2011;138(20):4363–74.
Takahashi J. Strategies for bringing stem cell-derived dopamine neurons to the clinic: the Kyoto trial. Prog Brain Res. 2017;230:213–26.
Caplan AI. Mesenchymal stem cells. J Orthop Res. 1991;9(5):641–50.
Liu J, Yu F, Sun Y, Jiang B, Zhang W, Yang J, et al. Concise reviews: Characteristics and potential applications of human dental tissue-derived mesenchymal stem cells. Stem Cells. 2015;33(3):627–38.
Gronthos S, Mankani M, Brahim J, Robey PG, Shi S. Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci U S A. 2000;97(25):13625–30.
Gronthos S, Brahim J, Li W, Fisher LW, Cherman N, Boyde A, et al. Stem cell properties of human dental pulp stem cells. J Dent Res. 2002;81(8):531–5.
Miura M, Gronthos S, Zhao M, Lu B, Fisher LW, Robey PG, et al. SHED: stem cells from human exfoliated deciduous teeth. Proc Natl Acad Sci U S A. 2003;100(10):5807–12.
Shi S, Robey PG, Gronthos S. Comparison of human dental pulp and bone marrow stromal stem cells by cDNA microarray analysis. Bone. 2001;29(6):532–9.
Alge DL, Zhou D, Adams LL, Wyss BK, Shadday MD, Woods EJ, et al. Donor-matched comparison of dental pulp stem cells and bone marrow-derived mesenchymal stem cells in a rat model. J Tissue Eng Regen Med. 2010;4(1):73–81.
Liu L, Wei X, Ling J, Wu L, Xiao Y. Expression pattern of Oct-4, Sox2, and c-Myc in the primary culture of human dental pulp derived cells. J Endod. 2011;37(4):466–72.
Chai Y, Jiang X, Ito Y, Bringas P, Han J, Rowitch DH, et al. Fate of the mammalian cranial neural crest during tooth and mandibular morphogenesis. Development. 2000;127(8):1671–9.
Graham A, Begbie J, McGonnell I. Significance of the cranial neural crest. Dev Dynamics. 2004;229(1):5–13.
Govindasamy V, Abdullah AN, Ronald VS, Musa S, Ab Aziz ZA, Zain RB, et al. Inherent differential propensity of dental pulp stem cells derived from human deciduous and permanent teeth. J Endod. 2010;36(9):1504–15.
Gancheva MR, Kremer KL, Gronthos S, Koblar SA. Using dental pulp stem cells for stroke therapy. Front Neurol. 2019;10:422.
Chun SY, Soker S, Jang YJ, Kwon TG, Yoo ES. Differentiation of human dental pulp stem cells into dopaminergic neuron-like cells in vitro. J Korean Med Sci. 2016;31(2):171–7.
Yurtsever MÇ, Kiremitci A, Gümüşderelioğlu M. Dopaminergic induction of human dental pulp stem cells by photobiomodulation: comparison of 660nm laser light and polychromatic light in the nir. J Photochemistry Photobiol B Biol. 2020;204:111742.
Janebodin K, Horst OV, Ieronimakis N, Balasundaram G, Reesukumal K, Pratumvinit B, et al. Isolation and characterization of neural crest-derived stem cells from dental pulp of neonatal mice. PLoS One. 2011;6(11):e27526.
Victor AK, Reiter LT. Dental pulp stem cells for the study of neurogenetic disorders. Hum Mol Genet. 2017;26:R166–71.
de Almeida FM, Marques SA, Ramalho Bdos S, Rodrigues RF, Cadilhe DV, Furtado D, et al. Human dental pulp cells: a new source of cell therapy in a mouse model of compressive spinal cord injury. J Neurotrauma. 2011;28(9):1939–49.
Kanafi M, Majumdar D, Bhonde R, Gupta P, Datta I. Midbrain cues dictate differentiation of human dental pulp stem cells towards functional dopaminergic neurons. J Cell Physiol. 2014;229(10):1369–77.
Majumdar D, Kanafi M, Bhonde R, Gupta P, Datta I. Differential neuronal plasticity of dental pulp stem cells from exfoliated deciduous and permanent teeth towards dopaminergic neurons. J Cell Physiol. 2016;231(9):2048–63.
Bueno C, Ramirez C, Rodríguez-Lozano FJ, Tabarés-Seisdedos R, Rodenas M, Moraleda JM, et al. Human adult periodontal ligament-derived cells integrate and differentiate after implantation into the adult mammalian brain. Cell Transplant. 2013;22(11):2017–28.
Aanismaa R, Hautala J, Vuorinen A, Miettinen S, Narkilahti S. Human dental pulp stem cells differentiate into neural precursors but not into mature functional neurons. Stem Cell Discov. 2012;2(3):85–91.
Aron Badin R, Vadori M, Vanhove B, Nerriere-Daguin V, Naveilhan P, Neveu I, et al. Cell therapy for Parkinson’s disease: a translational approach to assess the role of local and systemic immunosuppression. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2016;16(7):2016–29.
Macchi B, Di Paola R, Marino-Merlo F, Felice MR, Cuzzocrea S, Mastino A. Inflammatory and cell death pathways in brain and peripheral blood in Parkinson's disease. CNS & Neurol Disord Drug Targets. 2015;14(3):313–24.
Walker DG, Lue LF, Serrano G, Adler CH, Caviness JN, Sue LI, et al. Altered expression patterns of inflammation-associated and trophic molecules in substantia nigra and striatum brain samples from Parkinson’s disease, Incidental Lewy Body Disease and Normal Control Cases. Front Neurosci. 2015;9:507.
Russo MV, McGavern DB. Immune surveillance of the CNS following infection and injury. Trends Immunol. 2015;36(10):637–50.
Mori S, Maher P, Conti B. Neuroimmunology of the interleukins 13 and 4. Brain Sci. 2016;6(2):18.
Piccini P, Pavese N, Hagell P, Reimer J, Björklund A, Oertel WH, et al. Factors affecting the clinical outcome after neural transplantation in Parkinson's disease. Brain. 2005;128:2977–86.
Danielyan L, Schäfer R, von Ameln-Mayerhofer A, Bernhard F, Verleysdonk S, Buadze M, et al. Therapeutic efficacy of intranasally delivered mesenchymal stem cells in a rat model of Parkinson disease. Rejuvenation Res. 2011;14(1):3–16.
Reitz M, Demestre M, Sedlacik J, Meissner H, Fiehler J, Kim SU, et al. Intranasal delivery of neural stem/progenitor cells: a noninvasive passage to target intracerebral glioma. Stem Cells Transl Med. 2012;1(12):866–73.
Huang GT, Gronthos S, Shi S. Mesenchymal stem cells derived from dental tissues vs. those from other sources: their biology and role in regenerative medicine. J Dent Res. 2009;88(9):792–806.
Pivoriuūnas A, Surovas A, Borutinskaite V, Matuzeviccius D, Treigyte G, Savickiene J, et al. Proteomic analysis of stromal cells derived from the dental pulp of human exfoliated deciduous teeth. Stem Cells Dev. 2010;19(7):1081–93.
Suchánek J, Visek B, Soukup T, El-Din Mohamed SK, Ivancaková R, Mokrỳ J, et al. Stem cells from human exfoliated deciduous teeth--isolation, long term cultivation and phenotypical analysis. Acta Med (Hradec Kralove). 2010;53(2):93–9.
Zhang N, Chen B, Wang W, Chen C, Kang J, Deng SQ, et al. Isolation, characterization and multi-lineage differentiation of stem cells from human exfoliated deciduous teeth. Mol Med Rep. 2016;14(1):95–102.
Kunimatsu R, Nakajima K, Awada T, Tsuka Y, Abe T, Ando K, et al. Comparative characterization of stem cells from human exfoliated deciduous teeth, dental pulp, and bone marrow-derived mesenchymal stem cells. Biochem Biophys Res Commun. 2018;501(1):193–8.
Yamaza T, Kentaro A, Chen C, Liu Y, Shi Y, Gronthos S, et al. Immunomodulatory properties of stem cells from human exfoliated deciduous teeth. Stem Cell Res Ther. 2010;1(1):5.
Su WT, Shih YA, Ko CS. Effect of chitosan conduit under a dynamic culture on the proliferation and neural differentiation of human exfoliated deciduous teeth stem cells. J Tissue Eng Regen Med. 2016;10(6):507–17.
Sakai K, Yamamoto A, Matsubara K, Nakamura S, Naruse M, Yamagata M, et al. Human dental pulp-derived stem cells promote locomotor recovery after complete transection of the rat spinal cord by multiple neuro-regenerative mechanisms. J Clin Invest. 2012;122(1):80–90.
Yamamoto A, Sakai K, Matsubara K, Kano F, Ueda M. Multifaceted neuro-regenerative activities of human dental pulp stem cells for functional recovery after spinal cord injury. Neurosci Res. 2014;78:16–20.
Young F, Sloan A, Song B. Dental pulp stem cells and their potential roles in central nervous system regeneration and repair. J Neurosci Res. 2013;91(11):1383–93.
Ying QL, Wray J, Nichols J, Batlle-Morera L, Doble B, Woodgett J, et al. The ground state of embryonic stem cell self-renewal. Nature. 2008;453(7194):519–23.
Xi J, Liu Y, Liu H, Chen H, Emborg ME, Zhang SC. Specification of midbrain dopamine neurons from primate pluripotent stem cells. Stem Cells. 2012;30(8):1655–63.
Zwart I, Hill AJ, Al-Allaf F, Shah M, Girdlestone J, Sanusi AB, et al. Umbilical cord blood mesenchymal stromal cells are neuroprotective and promote regeneration in a rat optic tract model. Exp Neurol. 2009;216(2):439–48.
Kemp K, Dey R, Cook A, Scolding N, Wilkins A. Mesenchymal stem cell-derived factors restore function to human frataxin-deficient cells. Cerebellum. 2017;16(4):840–51.
Kourembanas S. Exosomes: vehicles of intercellular signaling, biomarkers, and vectors of cell therapy. Annu Rev Physiol. 2015;77:13–27.
Maas SLN, Breakefield XO, Weaver AM. Extracellular vesicles: unique intercellular delivery vehicles. Trends Cell Biol. 2017;27(3):172–88.
Yang T, Martin P, Fogarty B, Brown A, Schurman K, Phipps R, et al. Exosome delivered anticancer drugs across the blood-brain barrier for brain cancer therapy in Danio rerio. Pharm Res. 2015;32(6):2003–14.
Gyorgy B, Hung ME, Breakefield XO, Leonard JN. Therapeutic applications of extracellular vesicles: clinical promise and open questions. Annu Rev Pharmacol Toxicol. 2015;55:439–64.
Yamada Y, Nakamura-Yamada S, Kusano K, Baba S. Clinical potential and current progress of dental pulp stem cells for various systemic diseases in regenerative medicine: a concise review. Int J Mol Sci. 2019;20(5):1132.
Nakashima M, Iohara K, Murakami M, Nakamura H, Sato Y, Ariji Y, et al. Pulp regeneration by transplantation of dental pulp stem cells in pulpitis: a pilot clinical study. Stem Cell Res Ther. 2017;8(1):61.
Nakashima M, Iohara K. Recent progress in translation from bench to a pilot clinical study on Total pulp regeneration. J Endod. 2017;43:S82–6.
Xuan K, Li B, Guo H, Sun W, Kou X, He X, et al. Deciduous autologous tooth stem cells regenerate dental pulp after implantation into injured teeth. Sci Transl Med. 2018;10(455):eaaf3227.
d'Aquino R, De Rosa A, Lanza V, Tirino V, Laino L, Graziano A, et al. Human mandible bone defect repair by the grafting of dental pulp stem/progenitor cells and collagen sponge biocomplexes. Eur Cells Mater. 2009;18:75–83.
Nagpal A, Kremer KL, Hamilton-Bruce MA, Kaidonis X, Milton AG, Levi C, et al. TOOTH (The Open study Of dental pulp stem cell Therapy in Humans): study protocol for evaluating safety and feasibility of autologous human adult dental pulp stem cell therapy in patients with chronic disability after stroke. Int J Stroke. 2016;11(5):575–85.
Wu Y, Cao Y, Li X, Xu L, Wang Z, Liu P, et al. Cotransplantation of haploidentical hematopoietic and umbilical cord mesenchymal stem cells for severe aplastic anemia: successful engraftment and mild GVHD. Stem Cell Res. 2014;12(1):132–8.
Wu Y, Wang Z, Cao Y, Xu L, Li X, Liu P, et al. Cotransplantation of haploidentical hematopoietic and umbilical cord mesenchymal stem cells with a myeloablative regimen for refractory/relapsed hematologic malignancy. Ann Hematol. 2013;92(12):1675–84.
Olson SD, Pollock K, Kambal A, Cary W, Mitchell GM, Tempkin J, et al. Genetically engineered mesenchymal stem cells as a proposed therapeutic for Huntington's disease. Mol Neurobiol. 2012;45(1):87–98.
Hoban DB, Howard L, Dowd E. GDNF-secreting mesenchymal stem cells provide localized neuroprotection in an inflammation-driven rat model of Parkinson’s disease. Neuroscience. 2015;303:402–11.
Luzuriaga J, Pastor-Alonso O, Encinas JM, Unda F, Ibarretxe G, Pineda JR. Human dental pulp stem cells grown in neurogenic media differentiate into endothelial cells and promote neovasculogenesis in the mouse brain. Front Physiol. 2019;10:347.
Kawase-Koga Y, Fujii Y, Yamakawa D, Sato M, Chikazu D. Identification of neurospheres generated from human dental pulp stem cells in xeno-/serum-free conditions. Regen Ther. 2020;14:128–35.
Cheng PL, Song AH, Wong YH, Wang S, Zhang X, Poo MM. Self-amplifying autocrine actions of BDNF in axon development. Proc Natl Acad Sci U S A. 2011;108(45):18430–5.
Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F. GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science. 1993;260(5111):1130–2.
Pollock K, Dahlenburg H, Nelson H, Fink KD, Cary W, Hendrix K, et al. Human mesenchymal stem cells genetically engineered to overexpress brain-derived neurotrophic factor improve outcomes in Huntington's disease mouse models. Mol Ther. 2016;24(5):965–77.
Chierchia A, Chirico N, Boeri L, Raimondi I, Riva GA, Raimondi MT, et al. Secretome released from hydrogel-embedded adipose mesenchymal stem cells protects against the Parkinson’s disease related toxin 6-hydroxydopamine. Eur J Pharm Biopharm. 2017;121:113–20.
Conese M, Cassano R, Gavini E, Trapani G, Rassu G, Sanna E, et al. Harnessing stem cells and neurotrophic factors with novel technologies in the treatment of Parkinson’s disease. Curr Stem Cell Res Ther. 2019;14(7):549–69.
Kim D, Yoo JM, Hwang H, Lee J, Lee SH, Yun SP, et al. Graphene quantum dots prevent α-synucleinopathy in Parkinson’s disease. Nat Nanotechnol. 2018;13(9):812–8.
This work was supported by Hebei Provincial Department of Science and Technology (No.19942410G).
Ethics approval and consent to participate
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Xiao, Z., Lei, T., Liu, Y. et al. The potential therapy with dental tissue-derived mesenchymal stem cells in Parkinson’s disease. Stem Cell Res Ther 12, 5 (2021). https://doi.org/10.1186/s13287-020-01957-4
- Cell therapy
- Dopaminergic neurons
- Dental pulp stem cells
- Parkinson’s disease
- Stem cells from human exfoliated deciduous teeth