|Year : 2021 | Volume
| Issue : 4 | Page : 457-463
Clinical applications of dental stem cells in modern regenerative medicine: A systematic review with updates
TY Alhazzazi, FT Alghamdi
King Abdulaziz University, Faculty of Dentistry, Department of Oral Biology, Jeddah, Saudi Arabia
|Date of Submission||10-Aug-2020|
|Date of Acceptance||03-Oct-2020|
|Date of Web Publication||13-Apr-2021|
Dr. T Y Alhazzazi
Department of Oral Biology, King Abdulaziz University, Faculty of Dentistry, Jeddah
Source of Support: None, Conflict of Interest: None
| Abstract|| |
The use of dental stem cells (DSCs) has emerged as a promising new approach for therapeutic purposes to treat dental and non-dental diseases. Thus, the aim of this systematic review was to compile all current information on the role and clinical applications of DSCs in modern regenerative medical therapy. PubMed and Google Scholar electronic databases were used to search the literature for relevant studies after applying specific inclusion and exclusion criteria. The search included articles that were published from 2009 to 2019. Several keywords were combined for the search: (1) “Clinical applications”, (2) “Dental Stem Cell”, and (3) “Medicine”. Only the 17 studies that fulfilled both the inclusion and exclusion criteria were included in this systematic review. These studies investigated different aspects of DSCs, including cell types, clinical applications, and updates of their use in regenerative medicine. All 17 studies favored the use of different DSCS in regenerative medicine to treat diseases, such as bone defects, neural and skin injuries, Parkinson's disease, ischemia, and others. None of the studies were conducted on humans. This systematic review demonstrated the growing body of evidence supporting the role of DSCs in the field of modern generative medicine. The noninvasive methods of isolating these cells compared to those for isolating non-DSCs make them promising potential sources for the treatment of chronic and devastating diseases. However, more studies are needed to develop the proper guidelines for cases in which DSCs could be considered an accurate and reliable tool for modern regenerative medicine in clinical trials.
Keywords: Clinical application, dental stem cells, DSCs, regenerative medicine, regenerative therapies, systematic review
|How to cite this article:|
Alhazzazi T Y, Alghamdi F T. Clinical applications of dental stem cells in modern regenerative medicine: A systematic review with updates. Niger J Clin Pract 2021;24:457-63
|How to cite this URL:|
Alhazzazi T Y, Alghamdi F T. Clinical applications of dental stem cells in modern regenerative medicine: A systematic review with updates. Niger J Clin Pract [serial online] 2021 [cited 2023 Feb 2];24:457-63. Available from: https://www.njcponline.com/text.asp?2021/24/4/457/313603
| Introduction|| |
Tissue engineering and regenerative medicine (TERM) is an evolving field that utilize all three aspects of stem cells, scaffolds, and growth factors to achieve and restore normal biological characteristics and functions.,, Stem cells are non-specialized cells possessing the unique characteristics of self-renewal and differentiation in response to a suitable stimulus. Stem cells can be divided into two main groups: (1) embryonic (ESCs) and (2) adult. Although the use of ESCs in modern regenerative therapy is still controversial, adult stem cells still hold the potential to be a useful, convenient, and effective source for regenerative therapy without any ethical concerns. While ESCs are pluripotent, adult stem cells are multipotent. This difference gives ESCs the advantage of differentiating to mostly all cell types and lineages under the appreciated signals and conditions.
Adult stem cells can be isolated from several adult tissues, such as umbilical cord, bone marrow, adipose tissue, skin, and dental tissue., The non-invasive methods of extracting dental stem cells (DSCs) from both permanent and deciduous teeth compared to other cell types have made them interesting and viable sources of stem cells for regenerative therapy., The mouth and sounding dental tissues are enriched with several stem cells types, including dental pulp stem cells (DPSCs),, periodontal ligament stem cells (PDLSCs), stem cells of apical papilla (SCAP), and dental follicle stem cells (DFSCs) of wisdom teeth,, salivary grand stem cells (SGSCs), gingival mesenchyme stem cells (GMSCs), and stem cells from human exfoliated deciduous dental pulp (SHED).
Interestingly, these cells have the potential to not only regenerate to cells of dental origin., but also to regenerate to other cell types, such as cardiac cells, neural cells, muscles cells, hepatocytes cells, pancreatic cells, bone cells, and others,, under the proper signaling and environmental conditions.
Although numerous experimental studies and reviews have focused on the use of non-DSCs in regenerative medicine and even evaluated their efficacy in clinical trials,,, few available systematic reviews have been conducted on the role and potential use of DSCs in modern regenerative medicine. Therefore, the aim of this systematic review was to compile all current information on the role and clinical applications of DSCs in modern regenerative medical therapy.
| Materials and Methods|| |
This systematic review was conducted by two independent reviewers following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.
Can DSCs be used as a promising future approach in the field of regenerative medicine with the aim of treating chronic and devastating diseases?
The research was performed using two electronic databases: (1) Public Medline [PubMed] and (2) Google Scholar. The search was conducted by two independent reviewers. A combination of several keywords were used for the search: (1) “Clinical applications”, (2) “Dental Stem Cell”, and (3) “Medicine”. For inclusion of papers, several criteria were assumed: (1) Scientific papers published between 2009 and 2019, (2) Scientific papers that was published in the English language, and (3) Studies performed in vitro, in vivo, or with human subjects. As exclusion criteria, several different types of papers were omitted: (1) Review articles, (2) Editorial or personal opinion articles, (3) Papers that illustrated clinical relevance about DSC or non-DSCs in dentistry regeneration and (4) Articles that studied non-DCSs in regenerative medicine. After performing the database searches using the selected keywords, papers were selected on the basis of the title and abstract to focus on the samples. Duplicate papers from the two databases were eliminated. Afterwards, each paper was selected for its own research study after applying the inclusion and exclusion criteria. Independent research investigators also studied the selected articles' references to appraise the search.
Data extraction and presentation
A total of 15,885 articles were initially retrieved using the database with the selected keywords. Of those, 14,975 were deleted after reading the title and abstract because they displayed either duplicity or an unrelated topic. After the application of the inclusion and exclusion criteria, 63 articles remained. Of these, 17 papers were selected to be included in this review. A summary of the search flow chart for this systematic review is shown in [Figure 1].
|Figure 1: Flow chart of the search strategy used in this systematic review|
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| Results|| |
The search resulted in 17 studies that fulfilled both the inclusion and exclusion criteria and were conducted within the last 10 years [Figure 1]. These studies investigated different aspects of DSCs, including cell types, clinical applications, and updated studies of their use in the field of regenerative medicine. Study types included in this systematic review were four in-vitro studies,,, and a combination of in-vivo and in-vitro studies in 13 studies.,,,,,,,,,,,, In regards to the types of stem cells used, seven studies were performed using DPSCs only,,,,,,, one study was performed using DBSCs, and another study was performed using apical SCAP cells. GMSCs and PDLSCs were investigated together by Moshaverinia and colleagues. SHED and DPSCs were investigated in three studies.,, SHED cells were investigated alone in three studies.,, In addition, Yan et al. also explored the role of DPSCs, SHED, and SCAP cells in their study. In regards to clinical applications of DPSCs, several studies have shown a positive neo-bone formation by the DPSCs in cranial bone defects and bone regeneration, a finding that suggests their potential impact in the developing field of regenerative medicine including bone diseases.,,,,,, Moreover, other studies have investigated the role of DSCs in differentiating into nerve tissues and pancreatic cells and their effectiveness as a source for producing incurable pluripotent stem cells (iPS). In addition, several studies discuss the role of DSCs in different tissue regeneration processes: (1) four studies investigated the use of different DSCs in neuronal regeneration,,,,,, (2) two in skin regeneration,, and (3) one study in lupus erythematosus. An informative description of all included studies and their main conclusions are summarized in [Table 1]. A summary of all DSCs included in this systematic review and their clinical application in modern regenerative medicine is illustrated in [Figure 2].
|Figure 2: Sources of dental stem cells (DSCs) in the oral cavity and surrounding structures. Numbers represent the present study shown in [Table 1]. Salivary gland stem cells (SGSCs), which were not discussed in this review. Dental follicle stem cells of wisdom teeth (DFSCs), dental bud stem cells (DBSCs), stem cells of apical papilla (SCAPs), periodontal ligament stem cells (PDLSCs), stem cells from human exfoliated deciduous dental pulp (SHED), dental pulp stem cells (DPSCs), gingival mesenchyme stem cells (GMSCs)|
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| Discussion|| |
This systematic review was conducted to summarize and appraise all appreciated studies published within the last 10 years that fulfilled the inclusion and exclusion criteria. Thus, the aim of this current systematic review was to compile all current information on the role and clinical applications of dental stem cells in modern regenerative medical therapy.
We only found two old systematic reviews that focused on dental stem cells with respect to their role and clinical application in regenerative medicine [Table 2]., Daltoé FP et al. concluded in their systematic review that most of the retrieved studies regarding SHED and DPSCs suggest their effectiveness in bone tissue repair and regeneration in clinical application; however, fewer studies were found to support the role of those cells in other functional repair in non-dental tissues such as muscles, neurons, cartilages, blood vessels, or others., In contrast, de Souza et al. suggested that human immature dental pulp stem cells (hIDPSCs) have a promising role for treating systemic diseases, such as lupus erythematosus and Parkinson's disease, as shown in animal models. These findings clearly show the discrepancies in the conclusions among the previously published systematic reviewers although their studies were published within a similar period of time [Table 2]. These discrepancies may result mainly from the differences in the applied inclusion and exclusion criteria in addition to the authors' opinions. However, in agreement with the previously published systematic reviews, we could not find any studies to support the use of DSCs in regenerative modern medicine in humans. In addition, those two articles covered the period between 2000 and 2012 [Table 2]. Thus, our systematic review covered all eligible articles published within the last decade [Table 1].
|Table 2: Summary of all previous systematic reviews in the scope of our study|
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In our updated systematic review, all 17 studies favored the use of different DSCs in regenerative medicine [Table 1] and [Figure 2]. In addition to the defined role of different types of DSCs in bone regeneration, they seem to have great promise due to their invasive isolation compared to non-DSCs for treat systemic diseases such as Lupus erythematosus and Parkinson's as well as patients with corneal defects and spinal cord and skin injuries [Table 1] and [Figure 2]. However, since all of these studies were carried out on animal models, more research is needed to strengthen the evidence of these studies before proceeding to clinical trials. Interestingly, SHED, DPSCs, and SCAP cells have all been shown to be excellent potential sources to produce iPS cells. This would give those multipotent stem cells a biological behavior to differentiate into more cell lineages similar to those of the PESCs. In addition, others have investigated the role of DSC-derived secretome/conditioned medium in regenerative medicine. Hence, the paracrine secretion of the secretome, that is, the bioactive growth factors released by the cell from DSCs, seem to mediate a unique cell-free repair phenomena that has a promising future in regenerative medicine without the use of the actual cell themselves in treating systemic conditions, such as diabetes mellitus, cardiovascular and neurogenic diseases, skin injuries, and others.,
Studies included in this review used various techniques in extracting, isolating, culturing, and characterizing DSCs. Interestingly, none of them reported adverse or negative effects related to clinical DSC applications. The recognition of the diverse DSC sources could bring a new era to the field of modern regenerative medicine as the mouth is enriched with different stem cells types, and their isolation may be easier due to increased visibility rather than isolating other types from different origins. Hence, the simple approach of minimum intervention required to retrieve these cells offers a definite benefit and avoids the possibility of refusal by recipients. Recent advances in isolation methods and knowledge of DSCs have opened the doors for scientific research to regrow lost dental and non-dental structures.,,, Thus, the emerging popularity of using DSCs is mainly due to the extension of dental applications over other fields of medicine. Current studies continue to unlock new potential of DSCs to differentiate other cell types and may hopefully offer a promising future for better quality treatment to overcome the shortcomings of currently available treatments for devastating known diseases, such as diabetes mellitus, Parkinson's and Alzheimer's diseases, myocardial infection, and others.
Study strengths and limitations
Our study summarized and appraised all peer-reviewed studies published within the last 10 years that fulfilled both our exclusion and inclusion criteria. To our knowledge, our study is the only in-depth systematic review that covered the topic of using DSCs in regenerative medicine. The systematic review conducted by de Souza et al. (2013), and Daltoe et al. (2014) as shown in [Table 2] covered the period between 2001 and 2011 and 2000 and 2012, respectively. In addition, we used Public Medline (PubMed) and Google Scholar as search engines. One advantage of using Google Scholar is to prevent missing any relevant research published in journals that are still not cited in PubMed. On the other hand, due to heterogeneity of the final selected article with respect to the use of varied techniques in isolating, extracting, and characterizing DSCs, we were restricted to performing a systematic review without meta-analysis. In addition, although studies conducted in human subjects were part of the inclusion criteria, unfortunately, up to date, we could not find a single study that used DSCs in regenerative medicine. Areas of regenerative medicine using DSCs that have not been explored are now clear and should be tested to better understand these areas of strength and limitations before going to future clinical trials. These areas may include liver regeneration, ischemia and congenital heart diseases in addition to other untested autoimmune diseases.
| Conclusion|| |
This systematic review demonstrated the growing body of evidence supporting the role of DSCs in the field of modern generative medicine. The noninvasive methods of isolating these cells compared to non-dental stem cells make them promising potential sources for the treatment of chronic and devastating diseases. However, more studies are needed to develop the proper guidelines as to cases in which DSCs can be considered an accurate and reliable tool for modern regenerative medicine in clinical trials.
This project was supported by the Deanship of Scientific Research (DSR) King Abdulaziz University, Jeddah, Saudi Arabia, under grant no. 255/165/1433. The authors also thank Dr. Dania Bogari for her help in reviewing the manuscript.
Financial support and sponsorship
This project was funded by deanship of Scientific Research (DSR) at King Abdulaziz University, Jeddah, Saudi Arabia, under grant no. G-255/165/1433. The authors, therefore, acknowledge with thanks DSR for their technical and financial support.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Amrollahi P, Shah B, Seifi A, Tayebi L. Recent advancements in regenerative dentistry: A review. Mater Sci Eng C Mater Biol Appl 2016;69:1383-90.
Nakashima M, Akamine A. The application of tissue engineering to regeneration of pulp and dentin in endodontics. J Endod 2005;31:711-8.
Murray PE, Garcia-Godoy F, Hargreaves KM. Regenerative endodontics: A review of current status and a call for action. J Endod 2007;33:377-90.
Windley W 3rd
, Teixeira F, Levin L, Sigurdsson A, Trope M. Disinfection of immature teeth with a triple antibiotic paste. J Endod 2005;31:439-43.
Ohazama A, Modino SA, Miletich I, Sharpe PT. Stem-cell-based tissue engineering of murine teeth. J Dent Res 2004;83:518-22.
Daley GQ. Stem cells and the evolving notion of cellular identity. Philos Trans R Soc Lond B Biol Sci 2015;370:20140376.
Yan M, Sun M, Zhou Y, Wang W, He Z, Tang D, et al
. Conversion of human umbilical cord mesenchymal stem cells in Wharton's jelly to dopamine neurons mediated by the Lmx1a and neurturin in vitro: Potential therapeutic application for Parkinson's disease in a rhesus monkey model. PLoS One 2013;8:e64000.
Ding L, Morrison SJ. Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches. Nature 2013;495:231-5.
Chen L, Song J, Cui J, Hou J, Zheng X, Li C, et al
. microRNAs regulate adipocyte differentiation. Cell Biol Int 2013;37:533-46.
Blanpain C, Fuchs E. Epidermal homeostasis: A balancing act of stem cells in the skin. Nat Rev Mol Cell Biol 2009;10:207-17.
Morsczeck C, Schmalz G, Reichert TE, Vollner F, Galler K, Driemel O. Somatic stem cells for regenerative dentistry. Clin Oral Investig 2008;12:113-8.
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;97:13625-30.
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;81:531-5.
Seo BM, Miura M, Gronthos S, Bartold PM, Batouli S, Brahim J, et al
. Investigation of multipotent postnatal stem cells from human periodontal ligament. Lancet 2004;364:149-55.
Sonoyama W, Liu Y, Fang D, Yamaza T, Seo BM, Zhang C, et al
. Mesenchymal stem cell-mediated functional tooth regeneration in swine. PLoS One 2006;1:e79.
Morsczeck C, Gotz W, Schierholz J, Zeilhofer F, Kuhn U, Mohl C, et al
. Isolation of precursor cells (PCs) from human dental follicle of wisdom teeth. Matrix Biol 2005;24:155-65.
Mitroulia A, Gavriiloglou M, Athanasiadou P, Bakopoulou A, Poulopoulos A, Panta P, et al
. Salivary gland stem cells and tissue regeneration: An update on possible therapeutic application. J Contemp Dent Pract 2019;20:978-86.
Fawzy El-Sayed KM, Dorfer CE. Gingival mesenchymal stem/progenitor cells: A unique tissue engineering gem. Stem Cells Int 2016;2016:7154327.
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;100:5807-12.
Yadav P, Tahir M, Yadav H, Sureka R, Garg A. Test tube tooth: The next big thing. J Clin Diagn Res 2016;10:ZE01-3.
Kabir R, Gupta M, Aggarwal A, Sharma D, Sarin A, Kola MZ. Imperative role of dental pulp stem cells in regenerative therapies: A systematic review. Niger J Surg 2014;20:1-8.
] [Full text]
Xin LZ, Govindasamy V, Musa S, Abu Kasim NH. Dental stem cells as an alternative source for cardiac regeneration. Med Hypotheses 2013;81:704-6.
Shammaa R, El-Kadiry AE, Abusarah J, Rafei M. Mesenchymal stem cells beyond regenerative medicine. Front Cell Dev Biol 2020;8:72.
Yin L, Liu X, Shi Y, Ocansey DKW, Hu Y, Li X, et al
. Therapeutic advances of stem cell-derived extracellular vesicles in regenerative medicine. Cells 2020;9:707.
Barakat AH, Elwell VA, Lam KS. Stem cell therapy in discogenic back pain. J Spine Surg 2019;5:561-83.
Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med 2009;6:e1000097.
Ballini A, Di Benedetto A, De Vito D, Scarano A, Scacco S, Perillo L, et al
. Stemness genes expression in naïve vs. osteodifferentiated human dental-derived stem cells. Eur Rev Med Pharmacol Sci 2019;23:2916-23.
Kim BC, Jun SM, Kim SY, Kwon YD, Choe SC, Kim EC, et al
. Engineering three dimensional micro nerve tissue using postnatal stem cells from human dental apical papilla. Biotechnol Bioeng 2017;114:903-14.
Ishkitiev N, Yaegaki K, Kozhuharova A, Tanaka T, Okada M, Mitev V, et al
. Pancreatic differentiation of human dental pulp CD117(+) stem cells. Regen Med 2013;8:597-612.
Alleman M, Low E, Truong K, Huang E, Hill C, Chen T, et al
. Dental pulp-derived stem cells (DPSC) differentiation in vitro
into odontoblast and neuronal progenitors during cell passaging is associated with alterations in cell survival and viability. Int J Med Biomed Res 2013;2:133-41.
Kwon DY, Kwon JS, Park SH, Park JH, Jang SH, Yin XY, et al
. A computer-designed scaffold for bone regeneration within cranial defect using human dental pulp stem cells. Sci Rep 2015;5:12721.
Moshaverinia A, Chen C, Xu X, Akiyama K, Ansari S, Zadeh HH, et al
. Bone regeneration potential of stem cells derived from periodontal ligament or gingival tissue sources encapsulated in RGD-modified alginate scaffold. Tissue Eng Part A 2014;20:611-21.
Pisciotta A, Riccio M, Carnevale G, Beretti F, Gibellini L, Maraldi T, et al
. Human serum promotes osteogenic differentiation of human dental pulp stem cells in vitro
and in vivo. PLoS One 2012;7:e50542.
Yan X, Qin H, Qu C, Tuan RS, Shi S, Huang GT. iPS cells reprogrammed from human mesenchymal-like stem/progenitor cells of dental tissue origin. Stem Cells Dev 2010;19:469-80.
Park KR, Yun HM, Yeo IJ, Cho S, Hong JT, Jeong YS. Peroxiredoxin 6 inhibits osteogenic differentiation and bone formation through human dental pulp stem cells and induces delayed bone development. Antioxid Redox Signal 2019;30:1969-82.
Riccio M, Maraldi T, Pisciotta A, La Sala GB, Ferrari A, Bruzzesi G, et al
. Fibroin scaffold repairs critical-size bone defects in vivo
supported by human amniotic fluid and dental pulp stem cells. Tissue Eng Part A 2012;18:1006-13.
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;122:80-90.
Nishino Y, Ebisawa K, Yamada Y, Okabe K, Kamei Y, Ueda M. Human deciduous teeth dental pulp cells with basic fibroblast growth factor enhance wound healing of skin defect. J Craniofac Surg 2011;22:438-42.
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;19:1375-83.
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;1:5.
Ueda M, Nishino Y. Cell-based cytokine therapy for skin rejuvenation. J Craniofac Surg 2010;21:1861-6.
Arthur A, Shi S, Zannettino AC, Fujii N, Gronthos S, Koblar SA. Implanted adult human dental pulp stem cells induce endogenous axon guidance. Stem Cells 2009;27:2229-37.
Gomes JA, Geraldes Monteiro B, Melo GB, Smith RL, Cavenaghi Pereira da Silva M, Lizier NF, et al
. Corneal reconstruction with tissue-engineered cell sheets composed of human immature dental pulp stem cells. Invest Ophthalmol Vis Sci 2010;51:1408-14.
Daltoe FP, Mendonca PP, Mantesso A, Deboni MC. Can SHED or DPSCs be used to repair/regenerate non-dental tissues? A systematic review of in vivo
studies. Braz Oral Res 2014;28:S1806-83242014000100401.
de Souza PV, Alves FB, Costa Ayub CL, de Miranda Soares MA, Gomes JR. Human immature dental pulp stem cells (hIDPSCs), their application to cell therapy and bioengineering: An analysis by systematic revision of the last decade of literature. Anat Rec (Hoboken) 2013;296:1923-8.
El Moshy S, Radwan IA, Rady D, Abbass MMS, El-Rashidy AA, Sadek KM, et al
. Dental stem cell-derived secretome/conditioned medium: The future for regenerative therapeutic applications. Stem Cells Int 2020;2020:7593402.
Muhammad SA, Nordin N, Fakurazi S. Regenerative potential of secretome from dental stem cells: A systematic review of preclinical studies. Rev Neurosci 2018;29:321-32.
Suardita K. The potential application of stem cell in dentistry. Dent J 2006;39:177-80.
Paz AG, Maghaireh H, Mangano FG. Stem cells in dentistry: Types of intra- and extraoral tissue-derived stem cells and clinical applications. Stem Cells Int 2018;2018:4313610.
[Figure 1], [Figure 2]
[Table 1], [Table 2]