Introduction: The 20th Anniversary of Dental Stem Cells

GUEST EDITOR

Rungnapa Yang Warotayanont, DDS, PhD, received her dental degree from Chulalongkorn University in Bangkok and completed her doctoral degree at the Herman Ostrow School of Dentistry of USC with a focus on craniofacial molecular biology. Her interest in stem cell research began at USC, and she has worked with Dr. Songtao Shi, the pediatric dentist scientist who discovered dental pulp stem cells. Her research was in enamel matrix protein as well as the characterization of dental pulp stem cells. Dr. Yang continued her specialty training in pediatric dentistry at the University of California, San Francisco, and continued her research focusing on the clinical translation aspect of dental stem cells. Dr. Yang is a board-certified pediatric dentist and practices in Mountain View, Calif. Conflict of Interest Disclosure: None reported.

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Since the outbreak of COVID-19, our dental offices have focused on new office safety protocols, having all personal protective equipment ready, installing new air purifier systems and buying extraoral high-velocity suction, while checking on availability of the vaccination and getting vaccinated. As scientists and clinicians work toward finding the effective treatment and cure for COVID-19, little did we, the dentists, know that the cells isolated from extracted teeth in our dental offices could be one of the most powerful therapeutic approaches to treat COVID-19 patients. [1]

Stem cells were discovered in tooth tissue over two decades ago. Dental pulp stem cells (DPSCs) were the first dental stem cells identified in human permanent teeth and primary teeth. [2] These cells are characterized as stem cells because they possess the ability to self-renew and to differentiate into cells of various lineages. Stem cells from orofacial tissue have subsequently been identified in many other sites such as the periodontal ligament, gingival tissue, apical papilla and alveolar tissue. We can even find stem cells in an exfoliated deciduous tooth. [3]

Stem cells isolated from the oral cavity are derived from the cranial neural crest. These stem cells share many characteristics with mesenchymal stem cells (MSCs) isolated from other parts of the body, such as bone marrow and adipose tissue. Of particular interest, DPSCs have been extensively studied and characterized due to their advantages over other MSCs in many aspects. DPSCs are easily accessible in extracted teeth, have favorable regenerative property, possess unique angioneurogenic potential, have high proliferative ability and are anti-inflammatory.

For medical applications, DPSCs are a prime candidate for cell-based therapy of many cardiovascular conditions including stroke, myocardial infarction and spinal cord injury. [4] More recently, DPSCs have emerged as a potential treatment option for COVID-19. In recent clinical trials, the cells were injected intravenously in COVID-19 patients and showed promising outcomes, as they were shown to deregulate cytokine and promote regeneration of damaged lung tissue. [1,5]

There are increasing numbers of clinical trials for evaluation of the therapeutic property of various stem cells for dentofacial restoration. Human deciduous pulp stem cells implanted into necrotic pulp showed continued root development and pulp regeneration with formation of blood and nerve tissue compared to traditional apexification treatment. [6] Small blood stem cells as well as human adipose tissuederived MSCs were used to accelerate osteointegration in implant patients. [7,8]

As there are various categories of stem cells combining with a variety of clinical medical and dental applications, for this issue of the Journal, we invited practicing clinicians and scientists to give us a comprehensive review on their perspective of stem cells related to their scope of practice. The article from Dr. Phimon Atsawasuwan at the University of Illinois Chicago highlights the potential use of stem cells in orthodontics. The combination of stem cells and bone grafting was shown to increase biocompatibility for treatment of craniofacial anomalies. Stem cells injected into the rapid maxillary expansion site contributed to increased osteoclastic activity and accelerated rapid maxillary expansion. Transplantation of stem cells was shown to promote growth of the periodontal ligament after surgery.

The article prepared by Dr. Chi T. Viet and colleagues at Loma Linda University provides a comprehensive review of the potential use of stem cell therapy to enhance oral and maxillofacial reconstruction. Research and strategies to enhance bone regeneration around implant tissue, a comparison of the autologous graft versus the stem cell-engineered graft, the regeneration of nerve tissue, the importance of vascular supply in the grafted tissue and the limitation of stem cell therapy in oral maxillofacial constructions are among the topics discussed.

The response of stem cells to the modified zirconia surface of dental implants was assessed in the original research by Dr. Weerachai Singhatanadgit and colleagues at the Thammasat University in Thailand. The group studied approaches to modify the surface of a dental implant to optimize clinical outcome. Modification of a fully sintered zirconia dental implant surface can be problematic due to its high strength and bio-inert surface. The study demonstrated that well-optimized pre-sintering airborne-particle abrasion of a zirconia dental implant can render a highly roughened and hydrophilic surface of the fully sintered zirconia. The resulting zirconia showed an increased fibronectinto-albumin adsorption ratio and mesenchymal stem cell adhesion, therefore increasing a favorable clinical outcome. This technique may be suitable for modifying a zirconia surface to facilitate osseointegration of zirconiabased dental implants.

The way we practice dentistry remains largely the same compared to many years, decades, if not a century ago. The treatment options offered to our patients remain focused on the use of synthetic materials to restore form and function of the lost craniofacial structures. Practical clinical application of the use of stem cells still faces many challenges. The major obstacles will be the cost of cell retrieval, expansion and maintenance. Given that our teeth do not regenerate as enamel-forming cells, the ameloblasts, undergo apoptosis at the completion of enamel formation, the concept of whole tooth tissue regeneration remains challenging. The questions that remain unanswered are the number of required stem cells, the length required for tooth development after stem cell implantation, how to achieve the correct size and shape of the tooth and how to prevent teratogenic formation, which is one of the major downsides of the use of stem cells.

The tremendous advancement in stem cell research gives us hope that stem cell-based therapy will become a viable treatment option and provide promising benefits compared to traditional dentistry.

REFERENCES

1. Zayed M, Iohara K. Immunomodulation and regeneration properties of dental pulp stem cells: A potential therapy to treat coronavirus disease 2019. Cell Transplant 2020 Jan–Dec;29:963689720952089. doi: 10.1177/0963689720952089. PMID: 32830527; PMCID: PMCPMC7443577.

2. 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 Dec 5;97(25):13625– 30. doi: 10.1073/pnas.240309797. PMID: 11087820; PMCID: PMCPMC17626.

3. 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 May 13;100(10):5807–12. doi: 10.1073/pnas.0937635100. Epub 2003 Apr 25. PMID: 12716973; PMCID: PMCPMC156282.

4. 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 Mar 6;20(5). doi: 10.3390/ijms20051132. PMID: 30845639; PMCID: PMCPMC6429131.

5. Ye Q, Wang H, Xia X, Zhou C, Liu Z, Xia ZE, et al. Safety and efficacy assessment of allogeneic human dental pulp stem cells to treat patients with severe COVID-19: Structured summary of a study protocol for a randomized controlled trial (Phase I/II). Trials 2020 Jun;21(1):520. doi: 10.1186/ s13063-020-04380-5. PMID: 32532356; PMCID: PMCPMC7290137.

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 Aug 22;10(455)eaaf3227. doi: 10.1126/scitranslmed.aaf3227. PMID: 30135248.

7. Feng SW, Su YH, Lin YK, Wu YC, Huang YH, Yang FH, et al. Small blood stem cells for enhancing early osseointegration formation on dental implants: A human phase I safety study. Stem Cell Res Ther 2021 Jul 2;12(1):380. doi: 10.1186/ s13287-021-02461-z. PMID: 34215319; PMCID: PMCPMC8254299.

8. Tzur E, Ben-David D, Gur Barzilai M, Rozen N, Meretzki S. Safety and efficacy results of BonoFill first-in-human, phase I/IIa clinical trial for the maxillofacial indication of sinus augmentation and mandibular bone void filling. J Oral Maxillofac Surg 2021 Apr;79(4):787–98 e2. doi: 10.1016/j. joms.2020.12.010. Epub 202 Dec 17. PMID: 33434518.