Year : 2022 | Volume
: 14 | Issue : 1 | Page : 66--70
Role of stem cells in periodontology: A review
Shruti Singh, Deepa Dhruvakumar
Department of Periodontology, Teerthanker Mahaveer Dental College and Research Centre, Teerthanker Mahaveer University, Moradabad, Uttar Pradesh, India
Professor and Head, Department of Periodontology, Teerthanker Mahaveer Dental College and Research Centre, Teerthanker Mahaveer University, Moradabad - 244 001, Uttar Pradesh
Periodontal regeneration is thought theoretically possible but clinically unpredictable. In periodontitis, inflammation clinically manifests as the deterioration of periodontal tissue support, and the regeneration of weakened tissue is the primary objective of therapy. For years, periodontists have attempted to remedy the damage through a combination of surgical techniques, the use of growth factors with grafting materials, and barrier membranes. Reports also appeared indicating the populations of adult stem cells (SCs) exist in periodontal ligaments of humans as well as animals. This paves the wave in modern cell treatment for periodontal regeneration. This review offers a description of adult human SCs and their potential for periodontal regeneration.
|How to cite this article:|
Singh S, Dhruvakumar D. Role of stem cells in periodontology: A review.J Oral Res Rev 2022;14:66-70
|How to cite this URL:|
Singh S, Dhruvakumar D. Role of stem cells in periodontology: A review. J Oral Res Rev [serial online] 2022 [cited 2022 May 25 ];14:66-70
Available from: https://www.jorr.org/text.asp?2022/14/1/66/334821
Periodontitis is an inflammation in periodontium exemplified by destruction of connective tissue attachment and alveolar bone. As diseases progress, esthetics and dentition are compromised. For many years, periodontists have been concerned about tissue regeneration in periodontitis patient. Periodontal regeneration refers to the reconstitution of the lost or injured periodontium to their novel structure and serves by reiterating wound healing properties coupled with its growth. Various methods, including growth factor administration, bone graft, root biomodifications, guided tissue regeneration, host modulation, and combination of the above modalities, have been tried to achieve periodontal regeneration. Although there is some documentation that manifests by applying these procedures, periodontal regeneration can be achieved; all regenerative treatment techniques have shown limited potential toward periodontal regeneration. Thus, elective treatment techniques to attain expected regeneration in periodontium are yet advantageous.
Latest efforts to cure periodontal disease have been related to cell-based regenerative therapies utilizing stem cells (SCs). SCs seem to have an excellent therapeutic potential for regenerative medicine because of their plasticity and their ability to distinguish themselves into different cell lineages consequently provides a cellular source for periodontal regeneration. The aim of this review is to explore the overview of therapeutic approaches in SC-based periodontal regeneration and challenges for further studies.
Definition and types of stem cells
A “SC” refers to a clonogenic, undifferentiated cell capable of self-renewal and differentiation.
SC has two major properties:
Self-renewal potential to give rise to new SCsThe potential to divide into variety of advanced daughter cells to bear particular functions.
A pluripotent SC can distinguish between all types of cells in the body, while a multipotent SC can divide over many lineages into several distinct cell types.
The two main categories of SCs based on the ability of differentiation and origin includes embryonic SCs and adult SCs.
Embryonic stem cells
These are pluripotent cells originating from the blastocyst's inner cell structure (Thomson et al., 1998). They have the ability to form variants of their three germ layers and are able of evolving more than 200 cell forms. Human endothelial SCs (ESCs) are yet to be examined in vivo for their aptness to function in embryonic growth. Accordingly, embryonic SCs have substantial opportunities for regenerative cell therapy. The therapeutic potential of embryonic SCs, however, has posed serious ethical questions and other safety problems such as the immunogenicity and tumorigenicity.
Adult stem cells
Adult SCs are somatic and undifferentiated cells which rejuvenate by its own and divided into specific cell types of tissues and organ. These are multipotent and commonly referred to as tissue sources, for example, mesenchymal SCs (MSCs), ESCs, dental pulp SCs (DPSCs), adipose-derived SCs, and periodontal ligament SCs (PDLSCs).
Among adult SCs, hematopoietic and bone marrow SCs are two main type cells that have been efficiently used for many years to manage various diseases and disorders related to bone and blood including leukemia and tumors through marrow transplantation. Adult SCs are not as problematic in research and treatment as the use of ESC since no embryo is destructed in the development of adult SCs.
Aging of stem cell
After 120 days, MSCs tend to lose their proliferative capacity in vitro. Several modifications take place in the SCs through culturing which implies:
Proliferation index decrease steadilyLessening of telomereFunctional deteriorationTypical Hayflick phenomenon of cellular aging.
The human cell go through division by several times till the cell division stops is called Hayflick phenomenon. Forty years ago, Leonard Hayflick found that cultured normal human cells had a restricted ability to differentiate and become senescent after that, a fact today known as the Hayflick limit.
Stem cells in healthy and systemic conditions
SCs play a vital role in homeostasis regeneration, repair of injured tissues, and wound healing. MSCs are multipotent, likely have major therapeutic uses and can give rise to osteoblasts, myoblasts, chondrocytes, adipocytes, and endothelial cell progenitors. MSCs drift to damaged tissue and produce stromal cells but do not tend to have normal homeostasis of tissue. SC-based procedures for the treatment of various conditions consisting of neurogenic disorder, namely, Parkinson's disease, multiple sclerosis and hepatic disorder, autoimmune diseases, cardiovascular disease, musculoskeletal disorders, diabetes, and brain or spinal cord injury are also being investigated.
SCs participate in the production of multicellular species and the development of tumors. Cancer SCs emerge from progenitor cells mutation and differentiated to form primary tumors. The origin of malignant cells in primary tumors may be cancer SCs as they may form the minute drug-resistant cell reservoir responsible for a recurrence after remission induced by chemotherapy. In many solid tumors, such as tumors of brain, pancreas, colon, breast, prostate, ovary, melanomas, and cancer, SCs were recently detected.
Stem cells in dentistry
SC biology offers novel alternatives for heavily weakened or missing tooth including individual structures. Adult dental ectomesenchymal SC treatment looks exciting for potential therapy because it differentiates into dentin, cementum, periodontal ligaments (PDLs), dental pulp, and even whole tooth someday. Unpredictable time eruption of tooth, color, and anatomy of tooth produced and the still unlikely restoration of human enamel are currently preventing clinical application.
Dental SCs may attained from PDLs such as apical region of growing teeth, dental pulp, and more dental structures.
Oral cavities are a good source for obtaining SCs in children. Ideal replacements for deciduous teeth are canines and incisors with the presence of good pulp that starts to shed. Additional sources in children are supranumerary teeth, preventive reduction of primary molars with orthodontic signs, and retained primary teeth related with missing permanent teeth congenitally. Adolescents provide two enormous prospects for the upturn of SCs from removed teeth: after premolar extraction for orthodontic care and after third molar extraction. At the ages of 12 and 14 years, premolars are not fully developed. The unerupted tooth follicular sac may also be a beneficial source of SCs.
A new approachable method of extracting viable SCs is pulpectomy on a vital pulp. Further SC sources available in oral cavity during surgical treatment are buccal mucosa, gingiva, alveolar bone, and periosteum.
An acceptable and easy alternative to removing SCs from other tissue requiring invasive surgical techniques is the banking of teeth and SCs extracted from teeth. Cryopreservation is a method where cells, as well as entire tissues, are preserved by cooling to the low subzero temperature at −196°C (liquid nitrogen boiling point). Every biological process, especially biochemical reactions, is essentially stopped at such low temperatures which would contribute to cell death.
Tissue introduced by Langer and Vacanti, “an interdisciplinary area that extends the concepts of engineering and life sciences to the creation of biological replacements that repair, sustain, or enhance tissue function.”
Tissue engineering triad
Bioengineered scaffolds: The basic function of scaffolds is to serve as cell carriers, to preserve space, and to establish an area, in which cells can proliferate and produce a tissue matrix. Scaffolds may be Natural scaffolds, Mineral scaffolds, or Synthetic scaffolds.
Natural scaffolds: The examples for natural scaffolds are. These scaffolds were used in many craniofacial and dental applications and do not have the desired structural rigidity for load-bearing applications. Examples are collagen, chitosan, chitin, and hyaluronic acidMineral scaffolds: These scaffolds are brittle and susceptible to collapse, consisting of calcium phosphates in the form of hydroxyapatite or tricalcium phosphateSynthetic scaffolds: The most commonly used materials are polymers of polyglycolic acid, polylactic acid, and polydioxanone.
These are molecules that relay signals between cells and serve as growth stimulants/inhibitors, as well as differentiation modulators. These involve growth factors, differentiation factors, bone morphogenetic proteins (BMPs), and stimulating factors.
Stem cells in periodontology
Periodontium is an extremely challenging tissue containing soft and hard connective tissues. The diverse sequence of periodontal regeneration-related activities entails the recruitment to the site of progenitor cells, which can then divide into fibroblasts, cementoblasts, and osteoblasts.
Till date, repair of weakened and injured periodontium has depended over the use of structural components that are much less reparative. In recent years, biological methods focused on the tissue engineering concepts which arose as possible substitutes to traditional procedures. These procedures involve gene therapy, SC treatment, and administration of scaffolds.
The distribution of ex vivo extended progenitor cell populations or the recruitment of progenitor cells competent to proliferate into appropriate tissues is among the essential criteria of the tissue engineering strategy.
According to the definition, SCs satisfy these criteria and the current discovery of PDL marks an important step in advance toward periodontal regeneration. Efforts have been made in tissue engineering field to explore MSCs, for instance, SCs from human exfoliated deciduous teeth, dental follicle SCs, DPSCs, PDLSCs, SCs from apical part of the papilla, and bone marrow-derived MSCs.
Periodontal ligament stem cells
Various studies have indicated that PDL comprises cell communities that may differentiate into osteoblasts and cementoblasts. The multiple cell types present in PDL advocates the presence of progenitors that helps to sustain the tissue equilibrium and aids in the regeneration of periodontium.
Periodontal ligament stem cells in vitro characterization-multilineage differentiation potential
PDLSCs manifest MSCs-related markers CDs, STRO-1, and scleraxis, a tendon-specific signaling pathway, which is presented at elevated amount in PDLSCs than in BMMSCs and DPSCs. Western blot analysis and immunohistochemical stain revealed a variety of cementoblastic and osteoblastic markers that have been cultured in PDLSCs. Under specified culture conditions, PDLSCs possess osteogenic, adipogenic, and chondrogenic properties that are unique with various other dental SCs described above.
Periodontal ligament stem cells in vivo characterization – Formation of cementum- and periodontal ligament-like tissue
After implantation of ex vivo extended PDLSCs, PDL-like tissue may be revitalized in an immunosuppressed mouse. With scanty cells resembling the PDL structures, a thin layer of cementum along with dense collagen fibers are developed. Typical dentin/pulp-like structures produced by DPSCs and bone marrow structures induced by BMMSCs entirely differ from these cementum/PDL-like structures.
A PDL-like tissue with collagen inside the recipient is developed by transplanted PDLSCs. More specifically, the collagen fibers produced in vivo were able to bind to freshly formed cementum structures such as structures that imitate the biological attachment of the sharpey fibers responsible for cementum/PDL structures functionally attached.
It can be concluded from such outcomes that PDLSCs can comprise a cell population generally divided in vivo into cementum and collagen forming cells. PDL-like tissue has regenerated into periodontal defects in immunecompromised mice, after hPDLSC transplantation, which has also been identified to be closely aligned with the trabecular bone next to the PDL regeneration, implying its role in bone regeneration.
Stem cell and periodontal regeneration
Periodontal regeneration is being characterized as the thorough reconstruction of injury site into the existing structural features by the reiteration of critical healing events coupled with its growth. Such mechanisms reinforce the idea that certain mesenchymal cells persist in the PDL are essential for tissue equilibrium, acting only as a source of newly formed progenitors during adulthood. Since tissue seeding appears to be a success to facilitate tissue regeneration, a periodontal tissue attachment would be achieved through a tissue engineering procedure, combined with growth and differentiation factors in autologous blood clotting that have been developed inside an acceptable delivery scaffold.
To date, research has demonstrated that SCs inside the periodontal ligament can be separated and characterized. Efficient production of cementoblast progenitors was accomplished in 2005 by Saito et al. On hydroxyapatite tricalcium phosphate scaffold, PDLSCs were grafted into the mice. Histopathological evaluation revealed bone-like tissue produced by cementum type cell in mineralized plexus. It is interesting to note that PDLSCs can serve mostly as cell source of cementum development.
Orciani et al. confirmed the angiogenic ability of PDLSCs and observed that an increase in the productivity of Ca2+ and nitric oxides were also characterized by differentiating cells. The authors showed that a promising approach for the treatment of periodontal defects could be the local relocation of enlarged cells in combination with a donor of N2O.
A fascinating research by Yamada et al. reveals the use of tissue engineering concepts in modern methods for periodontal regeneration of tissue with platelet-rich plasma (PRP) and MSCs. Patients of iliac crest marrow aspirates are derived from MSCs, and PRP has been taken from blood. The MSC-PRP gel has been formulated and applied to neighboring defective areas. One year later, it was found that the application of MSC-PRP at vertical defect sites led to a reduction by 4 mm in pocket depth, increase in clinical attachment level, while no bleeding and mobility were observed. Radiographic evaluation indicated depth reduction in bone defects. Tissue engineering principles have regenerated interdental papillas. Thus, MSC-PRP shown promising results in tissue regeneration, esthetics, also decreased patient morbidity.
Recently, Li et al. associates in 2020 compared PDLSCs isolated from young and adult individuals and demonstrated that with aging, the proliferation, and osteogenic/adipogenic/chondrogenic differentiation potential of PDLSCs was decreased, whereas apoptosis of PDLSCs was increased. Moreover, the immunosuppressive ability of PDLSCs decreased with aging. Thus, according to their study, it is more appropriate to utilize PDLSCs from young individuals for tissue regeneration, postaging treatment, and allotransplantation.
Current Challenges In Stem Cell-Based Periodontal Regeneration
Given the limitations and shortcomings in the awareness and usage of periodontal growth in periodontal therapy, such impediments need to be dealt with before SC therapy becomes a practicePeriodontal regeneration is not possible due to insufficient knowledge of the specific cell types, inductive factors, and cell processes involved in periodontal development due to the reproduction of significant cellular events linked to concurrent periodontal developmentFurther refining is also needed for the process of proliferation and integration of these cells into a carrier scaffoldThe arrangement of therapeutic type SC lineages using an animal-free media to avoid cross-contamination in humans also raises challengesA number of therapeutic challenges are identified and overcome in the clinical MSC therapy including immune resistance, development of tumors, and effectiveness of cell transplantationIt is unknown if human SC derivatives may be incorporated within recipient tissue to perform the basic roles of wounded tissue.
SCs have many functions to play within medicine and dentistry. The full restoration of the biochemical, structural, and mechanical integrity of native tissue system is an interesting reality and a way to meet human paws. Advances in adult SC biology have given the biomedical world a great deal of motivation to transform these discoveries into clinical practice. In consideration of the fact that the researchers have in-hand populations of SC that regenerate bone, cementum, and dentin and may be even PDLs, it is able to achieve a complete regeneration of tissue structure using the patient's own cells, thus preventing histocompatibility problems. In addition, advancements in strategies to genetically alter the gene function of the SCs during their ex vivo expansion give a rare ability to make the patient's own SCs much healthier.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
|1||Pihlstrom BL, Michalowicz BS, Johnson NW. Periodontal diseases. Lancet 2005;366:1809-20.|
|2||Polimeni G, Xiropaidis AV, Wikesjö UM. Biology and principles of periodontal wound healing/regeneration. Periodontol 2000 2006;41:30-47.|
|3||Wang HL, Greenwell H, Fiorellini J, Giannobile W, Offenbacher S, Salkin L, et al. Periodontal regeneration (American Academy of Periodontology Position Paper). J Periodontol 2005;76:1601-22.|
|4||Caton J, Nyman S, Zander H. Histometric evaluation of periodontal surgery. II. Connective tissue attachment levels after four regenerative procedures. J Clin Periodontol 1980;7:224-31.|
|5||Amos TA, Gordon MY. Sources of human hematopoietic stem cells for transplantation – A review. Cell Transplant 1995;4:547-69.|
|6||Fortier LA. Stem cells: Classifications, controversies, and clinical applications. Vet Surg 2005;34:415-23.|
|7||Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, et al. Embryonic stem cell lines derived from human blastocysts. Science 1998;282:1145-7.|
|8||Chen SC, Marino V, Gronthos S, Bartold PM. Location of putative stem cells in human periodontal ligament. J Periodontal Res 2006;41:547-53.|
|9||Crain BJ, Tran SD, Mezey E. Transplanted human bone marrow cells generate new brain cells. J Neurol Sci 2005;233:121-3.|
|10||Ahmed AS, Sheng MH, Wasnik S, Baylink DJ, Lau KW. Effect of aging on stem cells. World J Exp Med 2017;7:1-10.|
|11||Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143-7.|
|12||Burns JS, Abdallah BM, Guldberg P, Rygaard J, Schrøder HD, Kassem M. Tumorigenic heterogeneity in cancer stem cells evolved from long-term cultures of telomerase-immortalized human mesenchymal stem cells. Cancer Res 2005;65:3126-35.|
|13||Hakki SS, Kayis SA, Hakki EE, Bozkurt SB, Duruksu G, Unal ZS, et al. Comparison of mesenchymal stem cells isolated from pulp and periodontal ligament. J Periodontol 2015;86:283-91.|
|14||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.|
|15||Seo BM, Miura M, Sonoyama W, Coppe C, Stanyon R, Shi S. Recovery of stem cells from cryopreserved periodontal ligament. J Dent Res 2005;84:907-12.|
|16||Laxman VK, Desai RG. Tooth for a tooth: Tissue engineering made easy at dental chairside. J Indian Soc Periodontol 2017;21:169-71.|
|17||Langer R, Vacanti JP. Tissue engineering. Science 1993;260:920-6.|
|18||Griffith LG, Naughton G. Tissue engineering – current challenges and expanding opportunities. Science 2002;295:1009-14.|
|19||Coura GS, Garcez RC, de Aguiar CB, Alvarez-Silva M, Magini RS, Trentin AG. Human periodontal ligament: A niche of neural crest stem cells. J Periodontal Res 2008;43:531-6.|
|20||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.|
|21||Nagatomo K, Komaki M, Sekiya I, Sakaguchi Y, Noguchi K, Oda S, et al. Stem cell properties of human periodontal ligament cells. J Periodontal Res 2006;41:303-10.|
|22||Park JC, Kim JM, Jung IH, Kim JC, Choi SH, Cho KS, et al. Isolation and characterization of human periodontal ligament (PDL) stem cells (PDLSCs) from the inflamed PDL tissue: In vitro and in vivo evaluations. J Clin Periodontol 2011;38:721-31.|
|23||Cho MI, Matsuda N, Lin WL, Moshier A, Ramakrishnan PR. In vitro formation of mineralized nodules by periodontal ligament cells from the rat. Calcif Tissue Int 1992;50:459-67.|
|24||Kawaguchi H, Hirachi A, Hasegawa N, Iwata T, Hamaguchi H, Shiba H, et al. Enhancement of periodontal tissue regeneration by transplantation of bone marrow mesenchymal stem cells. J Periodontol 2004;75:1281-7.|
|25||Saito M, Handa K, Kiyono T, Hattori S, Yokoi T, Tsubakimoto T, et al. Immortalization of cementoblast progenitor cells with Bmi-1 and TERT. J Bone Miner Res 2005;20:50-7.|
|26||Orciani M, Trubiani O, Vignini A, Mattioli-Belmonte M, Di Primio R, Salvolini E. Nitric oxide production during the osteogenic differentiation of human periodontal ligament mesenchymal stem cells. Acta Histochem 2009;111:15-24.|
|27||Yamada Y, Okabe K, Ito K, Kohgo T, Yoshimi R, Ueda M, et al. Autogenous injectable bone for regeneration with mesenchymal stem cells and platelet-rich plasma: Tissue engineered bone regeneration. Tissue Eng 2004;10:955-64.|
|28||Li X, Zhang B, Wang H, Zhao X, Zhang Z, Ding G, et al. The effect of aging on the biological and immunological characteristics of periodontal ligament stem cells. Stem Cell Res Ther 2020;11:326.|