Stem cell-based biological tooth repair and regeneration
2010; Elsevier BV; Volume: 20; Issue: 12 Linguagem: Inglês
10.1016/j.tcb.2010.09.012
ISSN1879-3088
AutoresAna Angelova Volponi, Yvonne Pang, Paul T. Sharpe,
Tópico(s)Mesenchymal stem cell research
ResumoTeeth exhibit limited repair in response to damage, and dental pulp stem cells probably provide a source of cells to replace those damaged and to facilitate repair. Stem cells in other parts of the tooth, such as the periodontal ligament and growing roots, play more dynamic roles in tooth function and development. Dental stem cells can be obtained with ease, making them an attractive source of autologous stem cells for use in restoring vital pulp tissue removed because of infection, in regeneration of periodontal ligament lost in periodontal disease, and for generation of complete or partial tooth structures to form biological implants. As dental stem cells share properties with mesenchymal stem cells, there is also considerable interest in their wider potential to treat disorders involving mesenchymal (or indeed non-mesenchymal) cell derivatives, such as in Parkinson's disease. Teeth exhibit limited repair in response to damage, and dental pulp stem cells probably provide a source of cells to replace those damaged and to facilitate repair. Stem cells in other parts of the tooth, such as the periodontal ligament and growing roots, play more dynamic roles in tooth function and development. Dental stem cells can be obtained with ease, making them an attractive source of autologous stem cells for use in restoring vital pulp tissue removed because of infection, in regeneration of periodontal ligament lost in periodontal disease, and for generation of complete or partial tooth structures to form biological implants. As dental stem cells share properties with mesenchymal stem cells, there is also considerable interest in their wider potential to treat disorders involving mesenchymal (or indeed non-mesenchymal) cell derivatives, such as in Parkinson's disease. Teeth are complex organs containing two separate specialized hard tissues, dentine and enamel, which form an integrated attachment complex with bone via a specialized (periodontal) ligament. Embryologically, teeth are ectodermal organs that form from sequential reciprocal interactions between oral epithelial cells (ectoderm) and cranial neural crest derived mesenchymal cells. The epithelial cells give rise to enamel forming ameloblasts, and the mesenchymal cells form all other differentiated cells (e.g., dentine forming odontoblasts, pulp, periodontal ligament) (Box 1). Teeth continue developing postnatally; the outer covering of enamel gradually becomes harder, and root formation, which is essential for tooth function, only starts to occur as part of tooth eruption in children.Box 1Tooth developmentTooth development is traditionally considered a series of stages that reflect key processes (Figure I). The first step is induction, in which signals from the epithelium to the mesenchyme initiate the developmental process. As localized proliferation of the dental epithelial cells takes place, the cells form a bud around which the mesenchymal cells condense. Differentiation and localized proliferation of the epithelial cells in the bud leads to the cap stage. It is at this stage that crown morphogenesis is initiated by the epithelial signalling centre, an enamel knot regulating the folding of the epithelium. By the bell stage, the precursors of the specialized tooth cells, ameloblasts, coordinate enamel deposition, and odontoblasts, which produce dentine, are formed. Tooth eruption involves the coordination of bone resorption and root development, and occurs postnatally.Throughout tooth development, signals are exchanged between epithelial and mesenchymal cells to coordinate each process. The key initial signals occur at induction (epithelium) and bud formation (mesenchyme). Once the mesenchymal cells receive signals from the epithelium, the mesenchyme sends reciprocal signals back to the epithelium. Strategies for biological replacement teeth aim to utilize these first signal exchanges by identifying either epithelial cells that can induce a naive mesenchyme or mesenchymal cells that can induce a naive epithelium to stimulate tooth development. Tooth development is traditionally considered a series of stages that reflect key processes (Figure I). The first step is induction, in which signals from the epithelium to the mesenchyme initiate the developmental process. As localized proliferation of the dental epithelial cells takes place, the cells form a bud around which the mesenchymal cells condense. Differentiation and localized proliferation of the epithelial cells in the bud leads to the cap stage. It is at this stage that crown morphogenesis is initiated by the epithelial signalling centre, an enamel knot regulating the folding of the epithelium. By the bell stage, the precursors of the specialized tooth cells, ameloblasts, coordinate enamel deposition, and odontoblasts, which produce dentine, are formed. Tooth eruption involves the coordination of bone resorption and root development, and occurs postnatally. Throughout tooth development, signals are exchanged between epithelial and mesenchymal cells to coordinate each process. The key initial signals occur at induction (epithelium) and bud formation (mesenchyme). Once the mesenchymal cells receive signals from the epithelium, the mesenchyme sends reciprocal signals back to the epithelium. Strategies for biological replacement teeth aim to utilize these first signal exchanges by identifying either epithelial cells that can induce a naive mesenchyme or mesenchymal cells that can induce a naive epithelium to stimulate tooth development. Repair, restoration and replacement of teeth is unique among clinical treatments because of the huge numbers of patients involved. Paradoxically, although teeth are nonessential for life and thus not considered a major target for regenerative medicine research, in comparison with neural or cardiac diseases, for example, this very fact makes teeth ideal for testing new cell-based treatments. Because the patients are not usually ill, if anything goes wrong it is far less life threatening, and the accessibility of teeth means that treatment does not require major surgery. Added to this is the existence of highly proliferative stem cell populations in teeth, which can be easily obtained from naturally lost or surgically removed teeth. These stem cells can be used for tooth repair, restoration and regeneration and, significantly, non-dental uses, such as developing stem cell-based therapies for major life-threatening diseases. An important but often overlooked advantage of teeth as a source of stem cells is that postnatal root formation (a rich source of dental stem cells) is a developmental process, and thus cells involved in root formation are more embryonic-like than other sources of dental stem cells. The humble tooth clearly has a very important role to play in future developments in regenerative medicine. In this review, we outline the important biological properties of dental stem cells and illustrate examples of research showing the rapid progress being made in using these cells for tooth repair. We also highlight the major obstacles that need to be overcome before any form of usable, cell-based tooth replacement becomes available to practising dentists. Several populations of cells with stem cell properties have been isolated from different parts of the tooth. These include cells from the pulp of both exfoliated (children's) and adult teeth, from the periodontal ligament that links the tooth root with the bone, from the tips of developing roots and from the tissue (dental follicle) that surrounds the unerupted tooth. All these cells probably share a common lineage of being derived from neural crest cells and all have generic mesenchymal stem cell-like properties, including expression of marker genes and differentiation into mesenchymal cell lineages (osteoblasts, chondrocytes and adipocytes) in vitro and, to some extent, in vivo. The different cell populations do, however, differ in certain aspects of their growth rate in culture, marker gene expression and cell differentiation, although the extent to which these differences can be attributed to tissue of origin, function or culture conditions remains unclear. The possibility that tooth pulp might contain mesenchymal stem cells was first suggested by the observation that severe tooth damage that penetrates both enamel and dentine and into the pulp stimulates a limited natural repair process, by which new odontoblasts are formed, which produce new dentine to repair the lesion [1Smith A.J. et al.Reactionary dentinogenesis.Int. J. Dev. Biol. 1995; 39: 273-280PubMed Google Scholar, 2Smith A.J. Lesot H. Induction and regulation of crown dentinogenesis: embryonic events as a template for dental tissue repair?.Crit. Rev. Oral Biol. Med. 2001; 12: 425-437Crossref PubMed Scopus (201) Google Scholar]. Putative stem cells from the tooth pulp and several other dental tissues have now been identified (Box 2) [3Gronthos S. et al.Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo.Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 13625-13630Crossref PubMed Scopus (3288) Google Scholar, 4Gronthos S. et al.Stem cell properties of human dental pulp stem cells.J. Dent. Res. 2002; 81: 531-535Crossref PubMed Scopus (1500) Google Scholar, 5Jo Y.Y. et al.Isolation and characterization of postnatal stem cells from human dental tissues.Tissue Eng. 2007; 13: 767-773Crossref PubMed Scopus (278) Google Scholar, 6Huang G.T. et al.Mesenchymal stem cells derived from dental tissues vs. those from other sources: their biology and role in regenerative medicine.J. Dent. Res. 2009; 88: 792-806Crossref PubMed Scopus (1251) Google Scholar, 7Balic A. et al.Characterization of stem and progenitor cells in the dental pulp of erupted and unerupted murine molars.Bone. 2010; 46: 1639-1651Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 8Waddington R.J. et al.Isolation of distinct progenitor stem cell populations from dental pulp.Cells Tissues Organs. 2009; 189: 268-274Crossref PubMed Scopus (125) Google Scholar].Box 2Human third molar as a source of dental stem cellsHuman third molars ('wisdom teeth') start their development postnatally, during childhood (ages of 5–6 years) and begin their calcification process from the age of 7–10 years. By the age of 18–25 years, the roots of the third molars have completed their development. These teeth are most commonly extracted and discarded in the dental clinic, but because they are still undergoing root development, they provide an excellent source of dental stem cells including DPSC, PDL cells and SCAP cells (Figure II). Human third molars ('wisdom teeth') start their development postnatally, during childhood (ages of 5–6 years) and begin their calcification process from the age of 7–10 years. By the age of 18–25 years, the roots of the third molars have completed their development. These teeth are most commonly extracted and discarded in the dental clinic, but because they are still undergoing root development, they provide an excellent source of dental stem cells including DPSC, PDL cells and SCAP cells (Figure II). The first stem cells isolated from adult human dental pulp were termed dental pulp stem cells (DPSCs) [3Gronthos S. et al.Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo.Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 13625-13630Crossref PubMed Scopus (3288) Google Scholar]. They were isolated from permanent third molars, and exhibited high proliferation and high frequency of colony formation that produced sporadic, but densely calcified nodules. Additionally, in vivo transplantation into immunocompromised mice demonstrated the ability of DPSCs to generate functional dental tissue in the form of dentine/pulp-like complexes [4Gronthos S. et al.Stem cell properties of human dental pulp stem cells.J. Dent. Res. 2002; 81: 531-535Crossref PubMed Scopus (1500) Google Scholar]. Further characterization revealed that DPSCs were also capable of differentiating into other mesenchymal cell derivatives in vitro such as odontoblasts, adipoctyes, chondrocytes and osteoblasts [9Koyama N. et al.Evaluation of pluripotency in human dental pulp cells.J. Oral Maxillofac. Surg. 2009; 67: 501-506Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar, 10Yu J. et al.Differentiation potential of STRO-1+ dental pulp stem cells changes during cell passaging.BMC Cell Biol. 2010; 8: 32Crossref Scopus (139) Google Scholar, 11d'Aquino R. et al.Human postnatal dental pulp cells co-differentiate into osteoblasts and endotheliocytes: a pivotal synergy leading to adult bone tissue formation.Cell Death Differ. 2007; 14: 1162-1171Crossref PubMed Scopus (387) Google Scholar, 12Graziano A. et al.Dental pulp stem cells: a promising tool for bone regeneration.Stem Cell Rev. 2008; 4: 21-26Crossref PubMed Scopus (254) Google Scholar]. DPSCs differentiate into functionally active neurons, and implanted DPSCs induce endogenous axon guidance, suggesting their potential as cellular therapy for neuronal disorders [13Arthur A. et al.Adult human dental pulp stem cells differentiate toward functionally active neurons under appropriate environmental cues.Stem Cells. 2008; 26: 1787-1795Crossref PubMed Scopus (456) Google Scholar, 14Arthur A. et al.Implanted adult human dental pulp stem cells induce endogenous axon guidance.Stem Cells. 2009; S27: 2229-2237Crossref Scopus (116) Google Scholar, 15Yalvac M.E. et al.Potential role of dental stem cells in the cellular therapy of cerebral ischemia.Curr. Pharm. Des. 2009; 15: 3908-3916Crossref PubMed Scopus (43) Google Scholar]. Stem cells isolated from the pulp of human exfoliated deciduous (children's milk) teeth (SHED) have the capacity to induce bone formation, generate dentine and differentiate into other non-dental mesenchymal cell derivatives in vitro[16Miura M. et al.SHED: stem cells from human exfoliated deciduous teeth.Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 5807-5812Crossref PubMed Scopus (2038) Google Scholar, 17Shi S. et al.The efficacy of mesenchymal stem cells to regenerate and repair dental structures.Orthod. Craniofac. Res. 2005; 8: 191-199Crossref PubMed Scopus (381) Google Scholar, 18Sakai V.T. et al.SHED differentiate into functional odontoblasts and endothelium.J. Dent. Res. 2010; 89: 791-796Crossref PubMed Scopus (301) Google Scholar, 19Cordeiro M.M. et al.Dental pulp tissue engineering with stem cells from exfoliated deciduous teeth.J. Endod. 2008; 34: 962-969Abstract Full Text Full Text PDF PubMed Scopus (467) Google Scholar, 20Wang J. et al.Stem cells from human exfoliated deciduous teeth can differentiate into dopaminergic neuron-like cells.Stem Cells Dev. 2010; 19: 1375-1383Crossref PubMed Scopus (163) Google Scholar]. In contrast to DPSCs, SHED exhibit higher proliferation rates [21Nakamura S. et al.Stem cell proliferation pathways comparison between human exfoliated deciduous teeth and dental pulp stem cells by gene expression profile from promising dental pulp.J. Endod. 2009; 35: 1536-1542Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar], increased population doublings, osteoinductive capacity in vivo and an ability to form sphere-like clusters [16Miura M. et al.SHED: stem cells from human exfoliated deciduous teeth.Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 5807-5812Crossref PubMed Scopus (2038) Google Scholar]. SHED seeded onto tooth slices/scaffolds and implanted subcutaneously into immunodeficient mice differentiated into functional odontoblasts capable of generating tubular dentine and angiogenic endothelial cells [18Sakai V.T. et al.SHED differentiate into functional odontoblasts and endothelium.J. Dent. Res. 2010; 89: 791-796Crossref PubMed Scopus (301) Google Scholar]. Studies using SHED as a tool in dental pulp tissue engineering in vivo, where pulp removed because of infection is replaced with stem cells, have revealed that the tissue formed has architecture and cellularity closely resembling that of dental pulp, a tissue important for tooth vitality [19Cordeiro M.M. et al.Dental pulp tissue engineering with stem cells from exfoliated deciduous teeth.J. Endod. 2008; 34: 962-969Abstract Full Text Full Text PDF PubMed Scopus (467) Google Scholar]. Another interesting clinical application has been suggested by investigations of the therapeutic efficacy of SHED in alleviating Parkinson's disease (PD) [20Wang J. et al.Stem cells from human exfoliated deciduous teeth can differentiate into dopaminergic neuron-like cells.Stem Cells Dev. 2010; 19: 1375-1383Crossref PubMed Scopus (163) Google Scholar]. Transplantation of SHED spheres into the striatum of parkinsonian rats partially improved the apomorphine evoked rotation of behavioural disorders. The results of this study indicate that SHED might be a useful source of postnatal stem cells for PD treatment. SHED are isolated from children's exfoliated teeth, however, so autologous stem cell therapy for a disease such as PD would require that these cells be stored from childhood. DPSCs, which are obtained from adult tooth pulp, might well have similar properties, however, and collection and expansion of these autologous cells would simply require removal of a tooth from the patient. SHED and other dental stem cells are derived from cranial neural crest ectomesenchyme, and so developmentally and functionally would appear identical, but studies have shown that they do differ and have different gene expression profiles. SHED have significantly higher proliferation rates compared with DPSC and bone marrow-derived mesenchymal stem cells [21Nakamura S. et al.Stem cell proliferation pathways comparison between human exfoliated deciduous teeth and dental pulp stem cells by gene expression profile from promising dental pulp.J. Endod. 2009; 35: 1536-1542Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar]. Comparison of the gene expression profiles showed 4386 genes that are differentially expressed between DPSC and SHED by two-fold or more. Higher expression in SHED was observed for genes that participate in pathways related to cell proliferation and extracellular matrix formation, including several growth factors such as fibroblast growth factor and transforming growth factor (TGF)-β [21Nakamura S. et al.Stem cell proliferation pathways comparison between human exfoliated deciduous teeth and dental pulp stem cells by gene expression profile from promising dental pulp.J. Endod. 2009; 35: 1536-1542Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar]. TGF-β in particular is important, because it is released after damage to dentine and might act to mobilize pulp stem cells to differentiate into odontoblasts [1Smith A.J. et al.Reactionary dentinogenesis.Int. J. Dev. Biol. 1995; 39: 273-280PubMed Google Scholar, 22Sloan A.J. et al.TGF-beta receptor expression in human odontoblasts and pulpal cells.Histochem. J. 1999; 31: 565-569Crossref PubMed Scopus (40) Google Scholar]. DPSC are highly proliferative and retain their stem cell characteristics after prolonged culture [23Govindasamy V. et al.Micromanipulation of culture niche permits long-term expansion of dental pulp stem cells-an economic and commercial angle.In Vitro Cell Dev. Biol. Anim. 2010; 46: 764-773Crossref PubMed Scopus (31) Google Scholar]. They could therefore be used as a generic allogeneic source of mesenchymal stem cells. Their use as autologous cells, however, is currently restricted to children who have not yet lost all their deciduous teeth. Commercial banking of these cells is thus becoming widespread to enable them to be used once the child becomes an adult. Limited studies have shown that frozen SHED cells do maintain their properties after cryopreservation for 2 years [24Papaccio G. et al.Long-term cryopreservation of dental pulp stem cells (SBP-DPSCs) and their differentiated osteoblasts: a cell source for tissue repair.J. Cell Physiol. 2006; 208: 319-325Crossref PubMed Scopus (190) Google Scholar], but one caveat is that the effects of long-term storage (10 years, plus) have not yet been assessed. Because children naturally lose 20 deciduous teeth, there are multiple opportunities to bank these cells, unlike cord blood, for example. The periodontal ligament (PDL) is a fibrous connective tissue that contains specialized cells located between the bone-like cementum and the inner wall of the alveolar bone socket that acts as a 'shock absorber' during mastication (Box 2). The PDL has long been recognized to contain a population of progenitor cells [25McCulloch C.A. Progenitor cell populations in the periodontal ligament of mice.Anat. Rec. 1985; 211: 258-262Crossref PubMed Scopus (146) Google Scholar] and recently, several studies [26Seo B.M. et al.Investigation of multipotent postnatal stem cells from human periodontal ligament.Lancet. 2004; 364: 149-155Abstract Full Text Full Text PDF PubMed Scopus (2427) Google Scholar] identified a population of stem cells from human periodontal ligament (PDLSC) capable of differentiating along mesenchymal cell lineages to produce cementoblast-like cells, adipocytes and connective tissue rich in collagen I in vitro and in vivo[26Seo B.M. et al.Investigation of multipotent postnatal stem cells from human periodontal ligament.Lancet. 2004; 364: 149-155Abstract Full Text Full Text PDF PubMed Scopus (2427) Google Scholar, 27Sonoyama W. et al.Mesenchymal stem cell-mediated functional tooth regeneration in swine.PLoS One. 2006; 1: e79Crossref PubMed Scopus (888) Google Scholar, 28Gronthos S. et al.Ovine periodontal ligament stem cells: Isolation, characterization, and differentiation potential.Calcif. Tissue Int. 2006; 79: 310-317Crossref PubMed Scopus (135) Google Scholar, 29Gault P. et al.Tissue-engineered ligament: implant constructs for tooth replacement.J. Clin. Periodontol. 2010; 37: 750-758PubMed Google Scholar]. The periodontal ligament is under constant strain from the forces of mastication, and thus PDLSC are likely to play an endogenous role in maintaining PDL cell numbers. This might explain why they are better than other dental stem cell populations at forming PDL-like structures [17Shi S. et al.The efficacy of mesenchymal stem cells to regenerate and repair dental structures.Orthod. Craniofac. Res. 2005; 8: 191-199Crossref PubMed Scopus (381) Google Scholar]. A unique population of dental stem cells known as stem cells from the root apical papilla (SCAP) is located at the tips of growing tooth roots (Box 2). The apical papilla tissue is only present during root development before the tooth erupts into the oral cavity [30Huang G.T.J. et al.The hidden treasure in apical papilla: The potential role in pulp/dentin regeneration and bioroot engineering.J. Endodont. 2008; 34: 645-651Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar]. SCAP have the capacity to differentiate into odontoblasts and adipocytes [27Sonoyama W. et al.Mesenchymal stem cell-mediated functional tooth regeneration in swine.PLoS One. 2006; 1: e79Crossref PubMed Scopus (888) Google Scholar]. These cells are CD24+ but expression is downregulated upon odontogenic differentiation in vitro coincident with alkaline phosphatase upregulation. SCAP cells exhibit higher rates of proliferation in vitro than do DPSC [27Sonoyama W. et al.Mesenchymal stem cell-mediated functional tooth regeneration in swine.PLoS One. 2006; 1: e79Crossref PubMed Scopus (888) Google Scholar]. By co-transplanting SCAP cells (to form a root) and PDLSC (to form a periodontal ligament) into tooth sockets of mini pigs, dentine and periodontal ligament was formed. These findings suggest that this population of cells, together with PDLSC, could be used to create a biological root that could be used in a similar way as a metal implant, by capping with an artificial dental crown. Most human tissues from early in their development are not clinically available for stem cell isolation; however, because roots develop postnatally, the root apical papilla is accessible in dental clinical practice from extracted wisdom teeth. Thus, a very active source of stem cells with embryonic-like properties (i.e., in the process of development) can be readily obtained. Further experiments on the properties of these cells obtained from human teeth following expansion in culture are needed. The dental follicle is a loose ectomesenchyme-derived connective tissue sac surrounding the enamel organ and the dental papilla of the developing tooth germ before eruption [31Ten Cate A.R. Oral Histology – Development, Structure, and Function.5th ed. Mosby-Year Book, Inc. Mosby Elsevier, St Louis, MO1998Google Scholar]. It is believed to contain progenitors for cementoblasts, PDL and osteoblasts. Dental follicle cells (DFC) form the PDL by differentiating into PDL fibroblasts that secrete collagen and interact with fibres on the surfaces of adjacent bone and cementum. DFC can form cementoblast-like cells after transplantation into SCID mice [32Handa K. et al.Progenitor cells from dental follicle are able to form cementum matrix in vivo.Connect. Tissue Res. 2002; 43: 406-408Crossref PubMed Google Scholar, 33Handa K. et al.Cementum matrix formation in vivo by cultured dental follicle cells.Bone. 2002; 31: 606-611Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar]. Dental follicle progenitor cells isolated from human third molars are characterized by their rapid attachment in culture, expression of the putative stem cell markers Nestin and Notch-1, and ability to form compact calcified nodules in vitro[34Lin N.H. et al.Stem cells and periodontal regeneration.Aust. Dent. J. 2008; 53: 108-121Crossref PubMed Scopus (89) Google Scholar]. When DFC were transplanted into immunocompromised mice, however, there was little indication of cementum or bone formation [34Lin N.H. et al.Stem cells and periodontal regeneration.Aust. Dent. J. 2008; 53: 108-121Crossref PubMed Scopus (89) Google Scholar]. DFC, in common with SCAP, represent cells from a developing tissue and might thus exhibit a greater plasticity than other dental stem cells. However, also similar to SCAP, further research needs to be carried out on the properties and potential uses of these cells. There are several areas of research for which dental stem cells are currently considered to offer potential for tissue regeneration. These include the obvious uses of cells to repair damaged tooth tissues such as dentine, periodontal ligament and dental pulp [16Miura M. et al.SHED: stem cells from human exfoliated deciduous teeth.Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 5807-5812Crossref PubMed Scopus (2038) Google Scholar, 17Shi S. et al.The efficacy of mesenchymal stem cells to regenerate and repair dental structures.Orthod. Craniofac. Res. 2005; 8: 191-199Crossref PubMed Scopus (381) Google Scholar, 18Sakai V.T. et al.SHED differentiate into functional odontoblasts and endothelium.J. Dent. Res. 2010; 89: 791-796Crossref PubMed Scopus (301) Google Scholar, 19Cordeiro M.M. et al.Dental pulp tissue engineering with stem cells from exfoliated deciduous teeth.J. Endod. 2008; 34: 962-969Abstract Full Text Full Text PDF PubMed Scopus (467) Google Scholar, 32Handa K. et al.Progenitor cells from dental follicle are able to form cementum matrix in vivo.Connect. Tissue Res. 2002; 43: 406-408Crossref PubMed Google Scholar, 33Handa K. et al.Cementum matrix formation in vivo by cultured dental follicle cells.Bone. 2002; 31: 606-611Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, 34Lin N.H. et al.Stem cells and periodontal regeneration.Aust. Dent. J. 2008; 53: 108-121Crossref PubMed Scopus (89) Google Scholar, 35Hasegawa M. et al.Human periodontal ligament cell sheets can regenerate periodontal ligament tissue in an athymic rat model.Tissue Eng. 2005; 11: 469-478Crossref PubMed Scopus (232) Google Scholar, 36Huang G.T. et al.Stem/Progenitor cell-mediated de novo regeneration of dental pulp with newly deposited continuous layer of dentin in an in vivo model.Tissue Eng. 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Even enamel tissue engineering has been suggested [37Honda M.J. et al.Enamel tissue engineering using subcultured enamel organ epithelial cells in combination with dental pulp cells.Cells Tissues Organs. 2009; 189: 261-267Crossref PubMed Scopus (25) Google Scholar], as well as the use of dental stem cells as sources of cells to facilitate repair of non-dental tissues such as bone and nerves [12Graziano A. et al.Dental pulp stem cells: a promising tool for bone regeneration.Stem Cell Rev. 2008; 4: 21-26Crossref PubMed Scopus (254) Google Scholar, 13Arthur A. et al.Adult human dental pulp stem cells differentiate toward functionally active neurons under appropriate environmental cues.Stem Cells. 2008; 26: 1787-1795Crossref PubMed Scopus (456) Google Scholar, 14Arthur A. et al.Implanted adult human dental pulp stem cells induce endogenous axon guidance.Stem Cells. 2009; S27: 2229-2237Crossref Scopus (116) Google Scholar, 15Yalvac M.E. et al.Potential role of dental stem cells in the cellular therapy of cerebral ischemia.Curr. Pharm. Des. 2009; 15: 3908-3916Crossref PubMed Scopus (43) Google Scholar, 20Wang J. et al.Stem cells from human exfoliated deciduous teeth can differentiate into dopaminergic neuron-like cells.Stem Cells Dev. 2010; 19: 1375-1383Crossref PubMed Scopus (163) Google Scholar, 38D'Aquino R. et al.Human mandible bone defect repair by the grafting of dental pulp stem/progenitor cells and collagen sponge biocomplexes.Eur. Cell Mater. 2009; 18: 75-83PubMed Google Scholar, 39Seo B.M. et al.SHED repair critical-size calvarial defects in mice.Oral Dis. 2008; 14: 428-434Crossref PubMed Scopus (191) Google Scholar]. The periodontium is a set of specialized tissues that surround and support the teeth to maintain them in the jaw. Periodontitis is an inflammatory disease that affects the periodontium and results in irreversible
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