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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 9  |  Issue : 4  |  Page : 305-310

Contemporary research in the field of dental pulp stem cells – A critical review


1 Department of Oral and Dental Sciences, JIS University; Department of Pedodontics and Preventive Dentistry, Dr. R. Ahmed Dental College and Hospital, Kolkata, West Bengal, India
2 Centre for Healthcare Science and Technology, Indian Institute of Engineering Science and Technology, Howrah, West Bengal, India
3 Department of Pedodontics and Preventive Dentistry, Gurunanak Institute of Dental Science and Research, Kolkata, West Bengal, India
4 Department of Oral and Dental Sciences, JIS University, Kolkata, West Bengal, India

Date of Submission27-Jan-2020
Date of Decision11-Jun-2020
Date of Acceptance05-Aug-2020
Date of Web Publication15-Oct-2020

Correspondence Address:
Dr. Monalisa Das
No. 2 Durganagar, Sripally, Chakdaha, Nadia, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijhas.IJHAS_10_20

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  Abstract 


Stem cell research is one of the most promising and fascinating field in regenerative medicine and dentistry. The use of embryonic stem cells is restricted due to the very many ethical issues while the dental pulp stem cell research is relatively free from such embargoes. Recently published research articles relating to dental pulp stem cells are voluminous but are very diversifying in nature. The observations of these researchers require critical analysis and evaluation in a focused way as is presented in this review article.

Keywords: Regeneration, stem cells, tissue


How to cite this article:
Das M, Barui A, Kundu GK, Paul RR. Contemporary research in the field of dental pulp stem cells – A critical review. Int J Health Allied Sci 2020;9:305-10

How to cite this URL:
Das M, Barui A, Kundu GK, Paul RR. Contemporary research in the field of dental pulp stem cells – A critical review. Int J Health Allied Sci [serial online] 2020 [cited 2020 Dec 3];9:305-10. Available from: https://www.ijhas.in/text.asp?2020/9/4/305/298106




  Introduction Top


We are in the era where new fields are emerging every day, opening new concepts and ways. Interestingly, regenerative field is one of those new areas which hold promise to revolutionize the treatment modalities in medicine and dentistry. The interest in stem cells and regeneration is now dominating our time. Working on human embryonic stem cells seemed attractive but still controversial due to the legal and ethical limitations.[1] Perhaps, these restrictions are the motivation for dental regenerative approaches.

Dental pulp stem cells (DPSCs) are multipotent adult stem cells. They can differentiate into pulp mesenchymal cells as well as other cell lineages with enormous future prospects for the treatment of degenerative diseases.[2] The extensive proliferation and differentiation capabilities make these cells an important source for stem cell-based research and therapy. Recent advances indicate the possibility of whole tooth bioengineering in the near future with a drastic change in routine dentistry. Observations from different studies demonstrated promising results, but more research is needed to further validate these findings. This article will review publications to understand the basic knowledge, current research, and future prospects of DPSCs.


  Materials and Methods Top


Data base

The method employed to search articles was mostly Internet based. A PubMed and Google search using the following search terms, i.e., “stem cells,”“dental pulp stem cells,”“regeneration,”and “regenerative dentistry,”was done. A hand-search of books and papers was performed. The reference section of the selected papers was also searched in order to identify additional articles. The search was limited to papers written in English and published between March 2000 and June 2020 in order to avoid unduly lengthening of the article. One hundred and twenty-nine papers were identified as relevant based on their titles. Finally, 57 papers selected as informative on the basis of their abstracts and text.


  Basic Characteristics of Dental Pulp Stem Cells Top


DPSCs are highly proliferative adult stem cells with multipotent character. These cells exhibit the ability to differentiate into odontoblasts, osteoblasts, chondrocytes, neurocytes, melanocytes, myocytes, cardiomyocytes, hepatocyte-like cells, and corneal epithelial cells in vitro. Dental pulp and other mesenchymal tissues are derived from the neural crest during embryonic development. Thus, DPSCs express other neural crest cell-related markers such as glial fibrillary acidic protein, microtubule-associated protein-2, and β-III tubulin.[3],[4] Morikawa et al., 2016, suggested that DPSCs maintain a homeostasis by acting as a reservoir for dental pulp fibroblasts. It can regenerate new odontoblasts on the basis of the requirement of reparative dentin production.[5] Gronthos et al., 2000, isolated the first dental pulp-related stem cells from the third molar dental pulp.[6] Later, it was reported that DPSCs could also be isolated from human permanent, primary, and supernumerary teeth.

Interestingly, human DPSCs can be converted into induced pluripotent stem cells (iPSCs) using classic reprogramming factors.[7] Different transcription factors (Oct4, So × 2, Klf4, and Myc) can be used to reprogram adult human cells to generate embryonic stem-like cells or iPSCs. Park et al., 2008, first described the method of human iPSC generation. Human DPSCs have a higher reprogramming efficiency than human dermal fibroblasts. Hence, DPSCs are potentially an important patient-specific cell source of iPSCs for regenerative medicine and tissue engineering.[8],[9],[10] iPSCs exhibit pluripotency, i.e., the characteristics of embryonic stem cells, and can differentiate into all three germ layers. Application of these cells can be a wise approach in regenerative therapies without issues related to immune compatibility. However, a significant risk of tumorigenesis and cell transformation poses this approach to controversy [Figure 1].
Figure 1: Induced pluripotent nature of dental pulp stem cells

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Dental pulp stem cells and bone marrow-derived mesenchymal stem cells

DPSCs and bone marrow-derived mesenchymal stem cells (BMMSCs) have a number of similarities. Both cells show a fibroblast-like phenotype in culture and stain positively for mesenchymal cell markers. BMMSCs and DPSCs have clonogenic and multidifferentiation potentials and can differentiate into osteogenic, adipogenic, and chondrogenic lineages (Gronthos et al., 2000).[6] Mesenchymal stem cells may have two different origins called pericytic and nonpericytic. Feng et al., 2011, explained that tissues harboring higher vascularity may provide more stem cells with a “pericytic”origin to the repair process. According to Alge et al., 2010, donor-matching experiments have demonstrated that DPSCs contain a bigger population of stem/progenitor cells and have higher population doubling times than BMMSCs.[11] DPSCs also had significantly higher alkaline phosphatase activity than BMMSC following osteogenic differentiation. This indicates the possibility of using DPSC to regenerate mineralized tissue. Subcloned DPSCs were shown to retain their ability to proliferate, whereas BMMSC did not. As such, researchers have strongly suggested that DPSCs populations may possess enhanced features allowing them to be better candidates than BMMSCs for tissue engineering applications (Huang et al., 2009).[12]

Role of Dental pulp stem cells in regeneration and repair

Commonly, MSCs are involved in growth, wound healing, and cell replacement in physiological and pathological conditions. These cells have been shown to be effective in regenerating periodontal tissue, diabetic critical limb ischemic tissue, bone damage caused by osteonecrosis, and skin lesions caused by burns.[13],[14] These cells also can regenerate the liver, neuronal and skeletal muscle tissues, and blood vessels.[15],[16],[17],[18] DPSCs have a major role in tooth tissue engineering along with the capability of repairing extraoral tissues like musculoskeletal system because of their close similarities with BMMSCs.[19],[20]

Regeneration of dentin–pulp complex

In an animal study, Rutherford and Gu, 2000, used bone morphogenetic protein (BMP-7) in inflamed ferret pulp to determine its dentinogenicity. The data revealed that a single application of up to 50 μg/tooth of exogenous recombinant BMP-7 was insufficient to induce reparative dentinogenesis in ferret teeth with reversible pulpitis. Later, he proposed gene therapy with BMPs to overcome the limitations observed with the use of recombinant protein. He tested bothin vivo and ex vivo gene transfer strategies for tissue regeneration in an adult ferret model of vital pulp therapy.[21],[22] Anin vitro study suggested that long-term calcium hydroxide therapy for apexification may leave the thin walls even more prone to fracture. Therefore, an alternative approach would be preferable to develop and validate biologically based endodontic procedures designed to restore a functional pulp–dentin complex.[23] According to Shi and Gronthos, 2003, the odontoblastoid cells displayed phenotypes consistent with a perivascular niche.[24] Huang et al., 2006, conducted anin vitro study to characterize human adult dental pulp cells and observed cell differentiation potential grown on dentin. They concluded that isolated human pulp stem cells may differentiate into odontoblasts on dentin in vitro.[25] Apart from the traditional treatment for pulpally exposed young permanent teeth with calcium hydroxide, mineral trioxide aggregate, which produces artificial apical barrier, can be used. Both the treatment modalities decrease the fracture resistance of the teeth and diminish the chance of tissue regeneration from the periapical region. Recently, some researchers have claimed that if odontoblasts are stimulated to form excessive peritubular dentin by the application of an appropriate biologic signaling molecule to the floor of cavity preparations, and then, the tubules of the remaining dentin could be occluded. Such dentin is impermeable and protects the pulp from the inward diffusion of noxious substances that might leak around restorations. These are examples of how molecular biology may be used in future restorative dentistry.[26] Nakashim and Iohora, 2011, evaluated the whole pulp regeneration by autologous pulp stem/progenitor cells with stromal cell-derived factor-1 (SDF-1) into the root canals of mature teeth with complete apical closure after pulpectomy in dogs. They achieved pulp regeneration by cell therapy, harnessing pulp stem/progenitor cells with high angiogenic/neurogenic potential with SDF-1 in endodontic treatment.[27] About, 2011, for the first time highlighted the pivotal role of pulp-supportive cells in dentin regeneration.[28] He clearly showed that these cells are not in the pulp to fill a space but to play a major role in producing the activation of signals of pulp progenitor cells. They also play a major role in neoangiogenesis, which is a prerequisite for progenitor cell migration.

Periodontal tissue regeneration

Periodontitis is manifested by progressive destruction of the supporting structures of teeth. The complete restoration of all components of the periodontal ligament, including periodontal and gingival connective tissue, cementum, and alveolar bone, is a challenge in clinical practice.[29],[30] The repair of the periodontium involves healing of wounds, even without completely restoring the original architecture or tissue function. However, in regeneration, lost or damaged part is reproduced in such a way that the original functionality is completely restored. The present protocols using autologous bone grafts, allografts, or alloplastic materials also have limitations because they generally result in tissue repair but not in true regeneration.[31] Other procedures such as the addition of growth factors and anti-inflammatory molecules yielded positive results by inducting periodontal regeneration. The average half-life of these factors is short, which limits their use in regenerative therapy.[32],[33],[34] Fundamental studies have shown that DPSCs, isolated from human third molars can be differentiated into cementoblast-like cells, adipocytes, and collagen forming cells with the ability to generate material similar to periodontal tissue in immunodeficient mice and rats. Animal studies have shown that it is possible to form complex structures such as pulp–dentin, root cementum, and periodontal ligament by transplanting DPSCs. Stem cells from human exfoliated deciduous teeth (SHED) are also able to stimulate bone formation, which indicates the possibility that they could be used to induce bone in the craniofacial region.[35] Although experimental animal data showed clear evidence of the potential of DPSCs to induce dental tissue formation, clinical trials are crucial for establishment of this information.

Neuronal regeneration

DPSCs arise from the neural crest and possess neuron-like characteristics that facilitate theirin vitro induction into functional neurons. A recent study showed evidence that adult dental follicle cells have the ability to differentiate into neurons, osteoblasts, adipocytes, and other cytotypes.[20] An animal study revealed that cells derived from dental tissue have the capability to give rise to cells of the nervous system. This explains that DPSCs have regenerative potential in the damaged central nervous system to replace lost neurons through differentiation.[36],[37] Chun et al. have demonstrated that DPSCs could be differentiated into dopaminergic neural cells by the formation of neurosphere. A study showed that neurosphere is formed in the initial phase during neural induction, whereas another study observed that it is formed in a rather late phase during the differentiation.[38] In an animal study, it has shown that grafting dental pulp into hemisected spinal cords increased the number of surviving motor neurons suggestive of neuron regeneration.[39]

Vascularization and angiogenesis

The human body needs abundant nutrition and blood supply in order to maintain its vitality. Neovascularization depends on the expression and secretion of few specific angiogenic trophic factors.[40] Some MSCs are able to promote therapeutic angiogenesis by the secretion of angiogenic growth factors and by differentiating into endothelial cells.[41] DPSCs have been found to produce and secrete abundant angiogenic factors such as colony-stimulating factor, interleukin-8 (IL-8), angiogenin, endothelin-1, angiopoietin-1, and insulin-like growth factor binding protein-3. They also secrete and express other stimulatory growth factors such as vascular endothelial growth factor, platelet-derived growth factor, basic fibroblast growth factor, and nerve growth factor (NGF). [15,16] Interestingly, these cells have the ability to differentiate into endothelial-like cells and capable of forming capillary-like structures when cultured on a fibrin clot. More recently, a structured dentin-/pulp-like tissue with vasculatures has been created using DPSCs through a three-dimensional print technique, suggesting a new direction for customized application in repair of defects.[31],[42]


  Immunomodulation Capability of Dental Pulp Stem Cells Top


MSCs exhibit some immunomodulatory and anti-inflammatory behavior with expression of factors such as IL-10, hepatocyte growth factor (HGF), transforming growth factor-β (TGF-β), and prostaglandin E2. DPSCs have immunomodulatory properties associated with expression of soluble factors that inhibit T-cell functions. They also express IL-8, IL-6, and TGF-β through toll-like receptor 4 during neuroinflammation associated with neurodegenerative diseases.[43] Hong et al. reported that DPSCs can modulate immune tolerance by increasing CD4+, CD25+, FoxP3+ regulatory T-cells. Recent animal studies conclude that DPSCs can modulate immune tolerance and influence apoptosis through T-cells and lymphocytes.[44]


  Role in Degenerative Dental Diseases Top


Iohara et al., 2011, examined total pulp regeneration using an adult canine model of pulpectomy. They transplanted pulp CD105 + stem cells into a root canal with stromal cell-derived factor-1 after pulpectomy. This study demonstrated that the root canal was successfully filled with regenerated pulp, including nerves and vasculature, followed by new dentin formation.[45] Xuan et al., 2018, performed a randomized, controlled clinical trial using human deciduous autologous pulp stem cells for dental pulp regeneration. Patients with pulp necrosis after traumatic dental injuries were enrolled in the clinical trial, and 26 patients after DPSC implantation and 10 patients after apexification treatment were included in the study. Twelve months after the treatment, regeneration of three-dimensional pulp tissue equipped with blood vessels and sensory nerves was observed in the DPSC implantation group.[46]


  Role in Degenerative Medical Diseases Top


Several researchers from the field of medicine explored the role of DPSCs in different degenerative medical diseases and observed promising findings. Nosrat et al., 2001, first reported the possibility of using the dental pulp to treat spinal cord injuries. They grafted dental pulp tissue into a hemisected spinal cord and showed an increase in the number of surviving motor neurons in rats. This observation indicates functional bioactivity of the dental pulp-derived neurotrophic factorsin vivo by rescuing motoneurons.[47] Apel et al., 2009, investigated the therapeutic possibility of uses of DPSCs inin vitro Alzheimer's disease models and observed reduction of the toxicity of neurons with increased neuronal viability. They also showed that human dental pulp cells express neuronal phenotype and produce neurotrophic factors such as the NGF, glial-cell derived neurotrophic factor, brain-derived neurotrophic factor, and BMP-2.[48] Application of DPSCs in Parkinson's disease was studied by Majumdar et al. in 2016. They observed dopaminergic differentiation of SHED in parkinsonian rats and recorded an improvement of their behavioral disorders.[49]

In 2016, Mead et al. delivered DPSCs into the vitreous of glaucomatous rodent eyes and noted significant protection from retinal ganglion cell (RGC) loss with preserved visual function. From this study, they suggested that DPSCs have the potential to differentiate into RGCs or RGC-like cells.[50]

Amazingly, application of DPSCs in cardiac diseases was explored by Yamaguchi et al. in 2015. They observed improvement of cardiac function with reduction of infarct size in rat models affected with myocardial infarction. This is probably because of their ability of DPSCs to secrete proangiogenic and antiapoptotic factors.[51]

In 2015, Yamaza et al. demonstrated that transplantation of SHED resulted in recovery of liver dysfunction of CCl4-treated mice. They opined that SHED can express human hepatocyte-specific genes and able to secrete human albumin, urea, and blood urea nitrogen in CCl4-injured liver tissues. This experiment suggested that SHED-derived hepatocytes might have a therapeutic effect on liver fibrosis.[52]

Cancer is a multifactorial disease in genes and is regulated by complex molecular events. The role of stem cells including DPSCs relating to cancer is not yet very clearly understood. Salehi et al., 2018, demonstrated that DPSCs can be beneficial as a supportive therapy to systemic cancer treatment. These cells can be utilized as efficient vehicles for uptake and migration of the most common anticancer drug, namely paclitaxel, without detectable apoptosis.[53] Conversely, Doǧan et al., 2017, reported that DPSCs can increase cell proliferation and metastasis in prostate cancer in vitro. However, extensive researches need to be conducted to understand the biological role of DPSCs in cancer.[54]


  Conclusion and Future Prospects Top


Various preclinical and clinical studies have indicated numerous applications of DPSCs in regenerative therapies. The clinical application of these cells is not limited in the head-and-neck pathologies only but has paved the path for uses toward translational regenerative medicine, especially neurological diseases, cardiac diseases, liver diseases, and ophthalmological disorders. Recent researches have revealed that DPSCs might be a promising novel cell source for treating brain conditions and syndromes such as traumatic brain injury, multiple sclerosis, and autism spectrum disorders due to their vascularization and immunomodulatory properties. Moreover, evaluation of the biological role of these cells in repair and regeneration of human organs is a very promising field of research.

Several limitations have been identified as the hindrance for applications of DPSCs. The major difficulty remains in isolation, characterization, and differentiation in laboratory. At present, the researches are mainly confined in preclinical models and extensive clinical trials are yet to be performed. However, to assess the risk and benefit, long-term in-depth studies are advocated to determine the immunogenic and oncogenic potential of these cells.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Introduction
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