Stem cells--a window to regenerative dentistry.
Studies to understand the concept of regeneration and repair of a living organism have explored the new era of stem cells in the last decade. Stem cells have the remarkable potential to develop into many different cell types in the body during early life and growth. These pluripotent stem cell populations persist in multiple organs and when stimulated they proliferate and differentiate in response to local cues provided by the organs they are recruited to. Stem cells are distinguished from other cell types by two important characteristics. First, they are unspecialized cells capable of renewing themselves through cell division, sometimes after long periods of inactivity. Second, under certain physiologic or experimental conditions, they can be induced to become tissue- or organ-specific cells with special functions.
Scientists discovered ways to derive embryonic stem cells from early mouse embryos nearly 30 years ago, in 1981. The detailed study of the biology of mouse stem cells led to the discovery, in 1998, of a method to derive stem cells from human embryos and grow the cells in the laboratory. Research on adult stem cells has led scientists to its various applications in treatment of diseases and disorders which were once thought untreatable.
Given their unique regenerative abilities, stem cells offer new potentials for treating diseases such as diabetes, and heart disease. Scientists are already using stem cells in the laboratory to screen new drugs and to develop model systems to study normal growth and identify the causes of birth defects.
Types of stem cells: fig 1
Based on their origin, stem cells are categorized either as embryonic stem cells (ESCs) or as postnatal stem cells/ somatic stem cells/ adult stem cells.
Embryonic stem cells are best derived from embryos of 2-11 days old called blastocyst. ESCs are considered as immortal as they can be propagated and maintained in an undifferentiated state indefinitely. The therapeutic benefit of these totipotent cells is heralded by the moral and ethical concerns as extracting stem cells from embryo destroys the embryo itself. (2) Because of these shortfalls, ESCs remained only as platform for research.
Adult stem cells are multipotent, 'capable of differentiating in to more than one cell type but not all cell types' and have plasticity that is 'its ability to expand beyond its potential irrespective of the parent cell from which it is derived'. Adult stem cells can be hemopoetic stem cells (HSCs) or mesenchymal stem cells (MSCs).
[FIGURE 1 OMITTED]
Sources of stem cells from orofacial origin:
Stem cells have also been isolated from orofacial tissues that include adult tooth pulp tissue, deciduous tooth pulp tissue, periodontal ligament, apical papilla (SCAPs), dental follicle precursor cells (DFPCs) and buccal mucosa. (3) Stem cells from human exfoliated deciduous teeth (SHED) are multipotent and are very immature in the cell hierarchy than the adult pulp stem cells. Recently mesenchymal stem cells from apical papilla of incompletely developed teeth have been isolated.
Stem cell applications
With continued research, stem cells have opened a new era of cell based therapy in medicine and also used in genomic studies to understand human embryonic gene expression, to study biological processes and as an alternative to animal toxicology thereby hastening the drug to the market. Pilot studies have already shown the potential of stem cells in cell based therapy. The property of stem cells to reach the site of injury or disease (homing) makes them suitable in cell based therapy. The two common methods of cell delivery are intravenous injection and cell encapsulation systems. (4)
In the field of dentistry, stem cell research is directed towards achieving the following;
* Regeneration of damaged coronal dentine and pulp
* Regeneration of resorbed root, cervical or apical dentin and perforations
* Periodontal regeneration
* Craniofacial defects
* Whole tooth regeneration
Regeneration of damaged coronal dentine and pulp: fig 2
Pulp tissue regeneration involves either delivery of autologous/Allogenic stem cells in to the root canals or implantation of the pulp that is grown in the laboratory using stem cells. (5)
[FIGURE 2 OMITTED]
Granthos et al demonstrated both in vitro and in vivo in animals that dental pulp stem cells (DPSCs) were capable of forming ectopic dentin and associated pulp tissue (6). But these techniques need further studies to evaluate their efficacy with clinical trials. Batouli et al used an in vivo stem cell transplantation system to investigate differential regulation mechanisms of bone marrow stromal stem cells and DPSCs. DPSCs were found to be able to generate a reparative dentine like tissue on the surface of human dentin in vivo. This study provided direct evidence to suggest that osteogenesis and dentinogenesis mediated by BMSCs and DPSCs, respectively, may be regulated by distinct mechanisms, leading to the different organization of the mineralized and nonmineralized tissues. (7)
Periodontal regeneration: fig 3
Periodontal regeneration has always remained a challenge as it consists of hard and soft tissues. It is evident, that the ligament complex contains stem cells that can commit to a number of pathways (bone, cementum and ligament). Moreover, the cells respond to inductive factors that include members of the TGF- super-family such as BMP-2, BMP-12, BMP7, TGF-a, PDGF and b-FGF.
[FIGURE 3 OMITTED]
In an exciting recent study, Kawaguchi et al (2004) used autologous bone marrow MSC in combination with allocollagen to regenerate periodontal ligament in an experimental grade III defects in dogs. One month after implantation, there was regeneration of cementum, periodontal ligament, and alveolar bone. This study provided firm evidence that MSC embedded in the appropriate environmental niche, can be used to regenerate a tissue as complex as the periodontium. (8) Hasegawa et al demonstrated that autologous periodontal ligament cells cultured in vitro were successfully re implanted in to periodontal defects in order to promote periodontal regeneration in dogs and a subsequent study confirmed this evidence in humans. (9)
Craniofacial defects: fig 4
At present craniofacial bone grafting procedure rely on autologous bone grafting, devitalized allogenic bone grafting and natural/synthetic osteo conductive biomaterials. Stem cell transplantation procedures have been studied to overcome the complications associated with these procedures.
[FIGURE 4 OMITTED]
Abukawa et al used a novel scaffold design with a new fabrication protocol to generate an autologous tissue engineered construct which was used to repair a segmental mandibular defect (10). The technique promoted osteogenesis enhanced penetration of bone with blood vessels thereby accelerating tissue regeneration. The development of new scaffold fabrication technologies has facilitated a successful repair of three dimensionally complex cranial defects. (11) To further enhance the regenerative potential of MSCs, genetic engineering technologies have been utilized to extend the life of stem cells and to enhance osteogenesis.
Whole tooth regeneration:
Replacing a missing tooth has become a challenge in the field of dentistry. Although implants have solved the problem to an extent but they rely on direct integration of bone on tooth surface which is indeed an unnatural relationship as compared to natural tooth. Murine stem cells when transferred in to renal capsules resulted in development of tooth structure and associated bone (12). Also teeth are engineered ectopically and transplanted in to the jaw with some success. Recently some researchers have developed a bioroot in to which post and crown is placed. This developed a natural relationship with bone. (12)
Scaffold: fig 5
Regeneration of any tissue requires a physical support to the cells. These scaffolds should be biodegradable and rate of degradation should coincide with the rate of tissue formation. They should be porous and allow appropriate differentiation of cells without affecting their progeny. In the root canal system it is preferable to have a scaffold that promotes vascularization of the implanted cells as pulp has blood supply only from apical end. This is achieved by impregnating the scaffolds with growth factors that promote angiogenesis. (13)
Challenges in stem cell research:
Stem cells obtained from any source are less in number. (14) Isolation, culture and storage are technique sensitive. Their immunomodulatory characteristics are still questionable. As of now autologous stem cells have no risk of immune rejection, least expensive and no ethical concerns but is time consuming procedure. Using allogenic stem cells saves considerable time but the risk of immune rejection and pathogen transmission limits their use. However there are many in vivo studies which support that they are immunologically safe. (15)
Stem cell therapies have virtually unlimited applications. All the challenges must be overcome before this novel therapy can be translated from labs to clinics. Collaboration between basic scientists and clinicians is required to achieve this goal. Recent advancements in scaffold designing, better understanding of growth factor biology and interactions between allogenic stem cells and immune system result in new discipline in dentistry, 'regenerative dentistry'.
(1) Ruth K, Lana R.S. Stem cells: Scientific Progress and Future Research Directions. Report prepared by the National Institute of Health.
(2) Evans MJ, Kaufman MH. Estableshment in culture of pluripotent cells from mouse embryos. Nature 1981;292:154-156.
(3) Gronthos S, Mankani M, Brahim J, Gehron Robey PG, Shi S. Postnatal human dental pulp stem cells. 2000.
(4) Fuchs JR, Hannouche D, Terada S, Vacanti JP, Fauza DO. Cartilage engineering from ovine umbilical cord blood mesenchymal progenitor cells. Stem cells 2005;23:958-964.
(5) Granthos S, Brahim J, Fischer W, Cherman N, Boyde A, DenBesten P, et al. Stem cell properties of human dental pulp stem cells. J Dent RES 2002;81:533.
(6) Murray PE, Garcia-Gadoy F, Hargreaves KM. Regenerative endodontics: A Review of current status and a call for action. J Endod 2007;33:377-390.
(7) Batouli S, Miura M, Brahim J, Tsutsui TW, Fisher LW, Gronthos S, et al. Comparison of stem cell mediated osteogenesis and dentinogenesis. J Dent Res 2003;82:976-981.
(8) Abukawa H et al. Reconstruction of mandibular defects with autologous tissue engineered bone. J Oral Maxillofac Surg.2004;62:601-606.
(9) Hasegawa M, Yamato M, Kikuchi A, Okano T, Ishikawa I. Human periodontal ligament stem cell sheets can regenerate periodontal ligament tissue in athymical rat model. Tissue Eng. 2005;11:469-477.
(10) Abukawa H, Shin M, Williams WB, Vacanti JP, Kaban LB, Troulis MJ. Reconstruction of mandibular autologous tissue-engineered bone. J Oral Maxillofac Surg 2004;62:601-606.
(11) Hutmacher DW, Sittinger M, Risbud MV. Scaffold based tissue engineering: Rationale for compute solid free form fabrication systems. Trends Biotechnol 2004;22:354-362.
(12) Ohazama A, Miletech MS, Sharpe PT. Stem cell tissue engineering of Murine teeth. J Dent Res 2004;83:518-552.
(13) Kanamatsu A, Yamamato S, Ozeki M, Noguchi T, Kanatani I, Ogawa O, et al. Collagenous matrices as RELEASE CARRIERS OF EXOGENOUS GROWTH FACTORS. Biomaterials 2004;25:4513-520.
(14) Poulsom R, Alison MR, Forbes SJ, Wright NA. Adult stem cell plasticity. J Pathol 2002;197:441-456.
(15) Slifkin M, Doron S, Snydman DR. Viral prophylaxis in organ transplant patients. Drugs 2004;64:2763-2792.
Rajender Amireddy , Seetaram Kumar D , Surekha Murthi 
Dept of Periodontics, Institute of Dental education & Advance Studies, Gwalior, Madhyapradesh
Dept of Periodontics, SB Patil Dental College & Hospital, Bidar, Karnataka
Dept. of Oral Medicine & Radiology 
Received: April 10, 2010
Review Completed: May 15, 2010
Accepted: June 15, 2010
Available Online: July, 2010
Email for correspondence: email@example.com
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|Author:||Amireddy, Rajender; Seetaram, Kumar D.; Murthi, Surekha|
|Publication:||Indian Journal of Dental Advancements|
|Date:||Jul 1, 2010|
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