Abstract
Teeth develop as result of sequential and reciprocal interactions between oral epithelium and cranial neural crest-derived cells. Signaling molecules and specific transcription factors constitute a unique molecular imprint for odontogenesis and contribute to the generation of teeth with various and function-specific shapes. Teeth are vulnerable to external harmful agents, injuries, and pathologies that compromise their integrity and function. Although stem cells guarantee dental tissue repair and regeneration after injury or pathology, the natural regenerative capacity of dental tissues is limited, thus making unable the entire restoration of damaged teeth. In such cases, cell-based therapeutic approaches that consist of in vitro manipulation of stem cells and their consequent administration to patients are attractive alternatives to current dental treatments.
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Mitsiadis TA, Luder HU (2011) Genetic basis for tooth malformations: from mice to men and back again. Clin Genet 80(4):319–329
Cobourne MT, Mitsiadis T (2006) Neural crest cells and patterning of the mammalian dentition. J Exp Zool B Mol Dev Evol 306(3):251–260
Anderson DJ (1993) Molecular control of cell fate in the neural crest: the sympathoadrenal lineage. Annu Rev Neurosci 16:129–158
Weissman IL, Anderson DJ, Gage F (2001) Stem and progenitor cells: origins, phenotypes, lineage commitments, and transdifferentiations. Annu Rev Cell Dev Biol 17:387–403
Imai H, Osumi-Yamashita N, Ninomiya Y, Eto K (1996) Contribution of early-emigrating midbrain crest cells to the dental mesenchyme of mandibular molar teeth in rat embryos. Dev Biol 176(2):151–165
Chai Y, Jiang X, Ito Y, Bringas P Jr, Han J, Rowitch DH, Soriano P, McMahon AP, Sucov HM (2000) Fate of the mammalian cranial neural crest during tooth and mandibular morphogenesis. Development 127(8):1671–1679
Diep L, Matalova E, Mitsiadis TA, Tucker AS (2009) Contribution of the tooth bud mesenchyme to alveolar bone. J Exp Zool B Mol Dev Evol 312B(5):510–517
Lumsden AG (1988) Spatial organization of the epithelium and the role of neural crest cells in the initiation of the mammalian tooth germ. Dev Suppl 103:155–169
Mina M, Kollar EJ (1987) The induction of odontogenesis in non-dental mesenchyme combined with early murine mandibular arch epithelium. Arch Oral Biol 32(2):123–127
Kollar EJ, Fisher C (1980) Tooth induction in chick epithelium: expression of quiescent genes for enamel synthesis. Science 207(4434):993–995
Bluteau G, Luder HU, De Bari C, Mitsiadis TA (2008) Stem cells for tooth engineering. Eur Cell Mater 16:1–9
Mitsiadis T, Papagerakis P (2013) Development and structure of teeth and periodontal tissues. In: Rosen CJ (ed) Primer on the metabolic bone diseases and disorders of mineral metabolism. Wiley-Blackwell, New Jersey (United States), pp 904–913
Sire JY, Davit-Beal T, Delgado S, Gu X (2007) The origin and evolution of enamel mineralization genes. Cells Tissues Organs 186(1):25–48
Mitsiadis TA, Rahiotis C (2004) Parallels between tooth development and repair: conserved molecular mechanisms following carious and dental injury. J Dent Res 83(12):896–902
Dorsky RI, Moon RT, Raible DW (2000) Environmental signals and cell fate specification in premigratory neural crest. Bioessays 22(8):708–716
Moss EG (2007) Heterochronic genes and the nature of developmental time. Curr Biol 17(11):R425–R434
Mitsiadis TA, Graf D (2009) Cell fate determination during tooth development and regeneration. Birth Defects Res C Embryo Today 87(3):199–211
Mitsiadis TA, Mucchielli ML, Raffo S, Proust JP, Koopman P, Goridis C (1998) Expression of the transcription factors Otlx2, Barx1 and Sox9 during mouse odontogenesis. Eur J Oral Sci 106(Suppl 1):112–116
Mucchielli ML, Mitsiadis TA, Raffo S, Brunet JF, Proust JP, Goridis C (1997) Mouse Otlx2/RIEG expression in the odontogenic epithelium precedes tooth initiation and requires mesenchyme-derived signals for its maintenance. Dev Biol 189(2):275–284
Green J (2002) Morphogen gradients, positional information, and Xenopus: interplay of theory and experiment. Dev Dyn 225(4):392–408
Mitsiadis TA, Smith MM (2006) How do genes make teeth to order through development? J Exp Zool B Mol Dev Evol 306(3):177–182
Mikkola ML (2008) TNF superfamily in skin appendage development. Cytokine Growth Factor Rev 19(3–4):219–230
Neubuser A, Peters H, Balling R, Martin GR (1997) Antagonistic interactions between FGF and BMP signaling pathways: a mechanism for positioning the sites of tooth formation. Cell 90(2):247–255
Jimenez-Rojo L, Granchi Z, Graf D, Mitsiadis TA (2012) Stem cell fate determination during development and regeneration of ectodermal organs. Front Physiol 3:107
Mitsiadis TA, Henrique D, Thesleff I, Lendahl U (1997) Mouse Serrate-1 (Jagged-1): expression in the developing tooth is regulated by epithelial-mesenchymal interactions and fibroblast growth factor-4. Development 124(8):1473–1483
Mitsiadis TA, Hirsinger E, Lendahl U, Goridis C (1998) Delta-notch signaling in odontogenesis: correlation with cytodifferentiation and evidence for feedback regulation. Dev Biol 204(2):420–431
Mitsiadis TA, Lardelli M, Lendahl U, Thesleff I (1995) Expression of Notch 1, 2 and 3 is regulated by epithelial-mesenchymal interactions and retinoic acid in the developing mouse tooth and associated with determination of ameloblast cell fate. J Cell Biol 130(2):407–418
Mitsiadis TA, Regaudiat L, Gridley T (2005) Role of the Notch signalling pathway in tooth morphogenesis. Arch Oral Biol 50(2):137–140
Mitsiadis TA, Graf D, Luder H, Gridley T, Bluteau G (2010) BMPs and FGFs target Notch signalling via jagged 2 to regulate tooth morphogenesis and cytodifferentiation. Development 137(18):3025–3035
Caton J, Luder HU, Zoupa M, Bradman M, Bluteau G, Tucker AS, Klein O, Mitsiadis TA (2009) Enamel-free teeth: Tbx1 deletion affects amelogenesis in rodent incisors. Dev Biol 328(2):493–505
Jerome LA, Papaioannou VE (2001) DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nat Genet 27(3):286–291
Kettunen P, Laurikkala J, Itaranta P, Vainio S, Itoh N, Thesleff I (2000) Associations of FGF-3 and FGF-10 with signaling networks regulating tooth morphogenesis. Dev Dyn 219(3):322–332
Mitsiadis TA, Tucker AS, De Bari C, Cobourne MT, Rice DP (2008) A regulatory relationship between Tbx1 and FGF signaling during tooth morphogenesis and ameloblast lineage determination. Dev Biol 320(1):39–48
Caton J, Bostanci N, Remboutsika E, De Bari C, Mitsiadis TA (2011) Future dentistry: cell therapy meets tooth and periodontal repair and regeneration. J Cell Mol Med 15(5):1054–1065
Mitsiadis TA, De Bari C, About I (2008) Apoptosis in developmental and repair-related human tooth remodeling: a view from the inside. Exp Cell Res 314(4):869–877
Ferracane JL (2011) Resin composite: state of the art. Dent Mater 27(1):29–38
Pashley DH, Tay FR, Breschi L, Tjaderhane L, Carvalho RM, Carrilho M, Tezvergil-Mutluay A (2011) State of the art etch-and-rinse adhesives. Dent Mater 27(1):1–16
Lehmann N, Debret R, Romeas A, Magloire H, Degrange M, Bleicher F, Sommer P, Seux D (2009) Self-etching increases matrix metalloproteinase expression in the dentin-pulp complex. J Dent Res 88(1):77–82
Breschi L, Mazzoni A, Ruggeri A, Cadenaro M, Di Lenarda R, De Stefano DE (2008) Dental adhesion review: aging and stability of the bonded interface. Dent Mater 24(1):90–101
Castellan CS, Bedran-Russo AK, Karol S, Pereira PN (2011) Long-term stability of dentin matrix following treatment with various natural collagen cross-linkers. J Mech Behav Biomed Mater 4(7):1343–1350
Bedran-Russo AK, Castellan CS, Shinohara MS, Hassan L, Antunes A (2011) Characterization of biomodified dentin matrices for potential preventive and reparative therapies. Acta Biomater 7(4):1735–1741
Fuks AB (2008) Vital pulp therapy with new materials for primary teeth: new directions and treatment perspectives. J Endod 34(7 Suppl):S18–S24
Dammaschke T (2008) The history of direct pulp capping. J Hist Dent 56(1):9–23
DeRosa TA (2006) A retrospective evaluation of pulpotomy as an alternative to extraction. Gen Dent 54(1):37–40
Bishop BG, Woollard GW (2002) Modern endodontic therapy for an incompletely developed tooth. Gen Dent 50(3):252–256, quiz 257–258
Nosrat A, Asgary S (2010) Apexogenesis treatment with a new endodontic cement: a case report. J Endod 36(5):912–914
Ricketts D (2001) Management of the deep carious lesion and the vital pulp dentine complex. Br Dent J 191(11):606–610
Goto Y, Ceyhan J, Chu SJ (2009) Restorations of endodontically treated teeth: new concepts, materials, and aesthetics. Pract Proced Aesthet Dent 21(2):81–89
Esposito M, Grusovin MG, Maghaireh H, Worthington HV (2013) Interventions for replacing missing teeth: different times for loading dental implants. Cochrane Database Syst Rev 3, CD003878
Temmerman A, Keestra JA, Coucke W, Teughels W, Quirynen M (2015) The outcome of oral implants placed in bone with limited bucco-oral dimensions: a 3-year follow-up study. J Clin Periodontol 42(3):311–318
Esposito M, Murray-Curtis L, Grusovin MG, Coulthard P, Worthington HV (2007) Interventions for replacing missing teeth: different types of dental implants. Cochrane Database Syst Rev 4, CD003815
Variola F, Brunski JB, Orsini G, Tambasco de Oliveira P, Wazen R, Nanci A (2011) Nanoscale surface modifications of medically relevant metals: state-of-the art and perspectives. Nanoscale 3(2):335–353
Singh P (2011) Understanding peri-implantitis: a strategic review. J Oral Implantol 37(5):622–626
Pilipchuk SP, Plonka AB, Monje A, Taut AD, Lanis A, Kang B, Giannobile WV (2015) Tissue engineering for bone regeneration and osseointegration in the oral cavity. Dent Mater 31(4):317–338
Lynch SE, Buser D, Hernandez RA, Weber HP, Stich H, Fox CH, Williams RC (1991) Effects of the platelet-derived growth factor/insulin-like growth factor-I combination on bone regeneration around titanium dental implants. Results of a pilot study in beagle dogs. J Periodontol 62(11):710–716
Becker W, Lynch SE, Lekholm U, Becker BE, Caffesse R, Donath K, Sanchez R (1992) A comparison of ePTFE membranes alone or in combination with platelet-derived growth factors and insulin-like growth factor-I or demineralized freeze-dried bone in promoting bone formation around immediate extraction socket implants. J Periodontol 63(11):929–940
Windisch P, Stavropoulos A, Molnar B, Szendroi-Kiss D, Szilagyi E, Rosta P, Horvath A, Capsius B, Wikesjo UM, Sculean A (2012) A phase IIa randomized controlled pilot study evaluating the safety and clinical outcomes following the use of rhGDF-5/beta-TCP in regenerative periodontal therapy. Clin Oral Investig 16(4):1181–1189
Kitamura M, Akamatsu M, Machigashira M, Hara Y, Sakagami R, Hirofuji T, Hamachi T, Maeda K, Yokota M, Kido J, Nagata T, Kurihara H, Takashiba S, Sibutani T, Fukuda M, Noguchi T, Yamazaki K, Yoshie H, Ioroi K, Arai T, Nakagawa T, Ito K, Oda S, Izumi Y, Ogata Y, Yamada S, Shimauchi H, Kunimatsu K, Kawanami M, Fujii T, Furuichi Y, Furuuchi T, Sasano T, Imai E, Omae M, Yamada S, Watanuki M, Murakami S (2011) FGF-2 stimulates periodontal regeneration: results of a multi-center randomized clinical trial. J Dent Res 90(1):35–40
Bashutski JD, Eber RM, Kinney JS, Benavides E, Maitra S, Braun TM, Giannobile WV, McCauley LK (2010) Teriparatide and osseous regeneration in the oral cavity. N Engl J Med 363(25):2396–2405
Huang YC, Simmons C, Kaigler D, Rice KG, Mooney DJ (2005) Bone regeneration in a rat cranial defect with delivery of PEI-condensed plasmid DNA encoding for bone morphogenetic protein-4 (BMP-4). Gene Ther 12(5):418–426
Cirelli JA, Park CH, MacKool K, Taba M Jr, Lustig KH, Burstein H, Giannobile WV (2009) AAV2/1-TNFR:Fc gene delivery prevents periodontal disease progression. Gene Ther 16(3):426–436
Pelegrine AA, da Costa CE, Correa ME, Marques JF Jr (2010) Clinical and histomorphometric evaluation of extraction sockets treated with an autologous bone marrow graft. Clin Oral Implants Res 21(5):535–542
Gonshor A, McAllister BS, Wallace SS, Prasad H (2011) Histologic and histomorphometric evaluation of an allograft stem cell-based matrix sinus augmentation procedure. Int J Oral Maxillofac Implants 26(1):123–131
Rickert D, Sauerbier S, Nagursky H, Menne D, Vissink A, Raghoebar GM (2011) Maxillary sinus floor elevation with bovine bone mineral combined with either autogenous bone or autogenous stem cells: a prospective randomized clinical trial. Clin Oral Implants Res 22(3):251–258
Sauerbier S, Rickert D, Gutwald R, Nagursky H, Oshima T, Xavier SP, Christmann J, Kurz P, Menne D, Vissink A, Raghoebar G, Schmelzeisen R, Wagner W, Koch FP (2011) Bone marrow concentrate and bovine bone mineral for sinus floor augmentation: a controlled, randomized, single-blinded clinical and histological trial--per-protocol analysis. Tissue Eng A 17(17-18):2187–2197
Schmelzeisen R, Gutwald R, Oshima T, Nagursky H, Vogeler M, Sauerbier S (2011) Making bone II: maxillary sinus augmentation with mononuclear cells--case report with a new clinical method. Br J Oral Maxillofac Surg 49(6):480–482
Mitsiadis TA, Papagerakis P (2011) Regenerated teeth: the future of tooth replacement? Regen Med 6(2):135–139
Mitsiadis TA, Harada H (2015) Regenerated teeth: the future of tooth replacement. An update. Regen Med 10(1):5–8
Mitsiadis TA, Woloszyk A, Jimenez-Rojo L (2012) Nanodentistry: combining nanostructured materials and stem cells for dental tissue regeneration. Nanomedicine (Lond) 7(11):1743–1753
Moore KA, Lemischka IR (2006) Stem cells and their niches. Science 311(5769):1880–1885
Mitsiadis TA, Feki A, Papaccio G, Caton J (2011) Dental pulp stem cells, niches, and notch signaling in tooth injury. Adv Dent Res 23(3):275–279
Pagella P, Jimenez-Rojo L, Mitsiadis TA (2014) Roles of innervation in developing and regenerating orofacial tissues. Cell Mol Life Sci 71(12):2241–2251
Pagella P, Neto E, Lamghari M, Mitsiadis TA (2015) Investigation of orofacial stem cell niches and their innervation through microfluidic devices. Eur Cell Mater 29:213–223
Betschinger J, Knoblich JA (2004) Dare to be different: asymmetric cell division in Drosophila, C. elegans and vertebrates. Curr Biol 14(16):R674–R685
Lechler T, Fuchs E (2005) Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature 437(7056):275–280
Mitsiadis TA, Barrandon O, Rochat A, Barrandon Y, De Bari C (2007) Stem cell niches in mammals. Exp Cell Res 313(16):3377–3385
Mitsiadis TA, Fried K, Goridis C (1999) Reactivation of Delta-Notch signaling after injury: complementary expression patterns of ligand and receptor in dental pulp. Exp Cell Res 246(2):312–318
Mitsiadis TA, Romeas A, Lendahl U, Sharpe PT, Farges JC (2003) Notch2 protein distribution in human teeth under normal and pathological conditions. Exp Cell Res 282(2):101–109
Gronthos S, Mankani M, Brahim J, Robey PG, Shi S (2000) Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci U S A 97(25):13625–13630
Miura M, Gronthos S, Zhao M, Lu B, Fisher LW, Robey PG, Shi S (2003) SHED: stem cells from human exfoliated deciduous teeth. Proc Natl Acad Sci U S A 100(10):5807–5812
Sonoyama W, Liu Y, Yamaza T, Tuan RS, Wang S, Shi S, Huang GT (2008) Characterization of the apical papilla and its residing stem cells from human immature permanent teeth: a pilot study. J Endod 34(2):166–171
d’Aquino R, De Rosa A, Lanza V, Tirino V, Laino L, Graziano A, Desiderio V, Laino G, Papaccio G (2009) Human mandible bone defect repair by the grafting of dental pulp stem/progenitor cells and collagen sponge biocomplexes. Eur Cell Mater 18:75–83
Harada H, Kettunen P, Jung HS, Mustonen T, Wang YA, Thesleff I (1999) Localization of putative stem cells in dental epithelium and their association with Notch and FGF signaling. J Cell Biol 147(1):105–120
Harada H, Toyono T, Toyoshima K, Yamasaki M, Itoh N, Kato S, Sekine K, Ohuchi H (2002) FGF10 maintains stem cell compartment in developing mouse incisors. Development 129(6):1533–1541
Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676
Kamao H, Mandai M, Okamoto S, Sakai N, Suga A, Sugita S, Kiryu J, Takahashi M (2014) Characterization of human induced pluripotent stem cell-derived retinal pigment epithelium cell sheets aiming for clinical application. Stem Cell Rep 2(2):205–218
Otsu K, Kumakami-Sakano M, Fujiwara N, Kikuchi K, Keller L, Lesot H, Harada H (2014) Stem cell sources for tooth regeneration: current status and future prospects. Front Physiol 5:36
Nanci A (2008) Ten cate’s oral histology: development, structure and function (Oral Anatomy), 7th edn. Mosby, St. Louis, p 411
Huang GT, Yamaza T, Shea LD, Djouad F, Kuhn NZ, Tuan RS, Shi S (2010) Stem/progenitor cell-mediated de novo regeneration of dental pulp with newly deposited continuous layer of dentin in an in vivo model. Tissue Eng A 16(2):605–615
Volponi AA, Pang Y, Sharpe PT (2010) Stem cell-based biological tooth repair and regeneration. Trends Cell Biol 20(12):715–722
Hayashi Y, Murakami M, Kawamura R, Ishizaka R, Fukuta O, Nakashima M (2015) CXCL14 and MCP1 are potent trophic factors associated with cell migration and angiogenesis leading to higher regenerative potential of dental pulp side population cells. Stem Cell Res Ther 6:111
Zheng Y, Wang XY, Wang YM, Liu XY, Zhang CM, Hou BX, Wang SL (2012) Dentin regeneration using deciduous pulp stem/progenitor cells. J Dent Res 91(7):676–682
Iohara K, Imabayashi K, Ishizaka R, Watanabe A, Nabekura J, Ito M, Matsushita K, Nakamura H, Nakashima M (2011) Complete pulp regeneration after pulpectomy by transplantation of CD105+ stem cells with stromal cell-derived factor-1. Tissue Eng A 17(15–16):1911–1920
Iohara K, Murakami M, Takeuchi N, Osako Y, Ito M, Ishizaka R, Utunomiya S, Nakamura H, Matsushita K, Nakashima M (2013) A novel combinatorial therapy with pulp stem cells and granulocyte colony-stimulating factor for total pulp regeneration. Stem Cells Transl Med 2(7):521–533
Ikeda E, Tsuji T (2008) Growing bioengineered teeth from single cells: potential for dental regenerative medicine. Expert Opin Biol Ther 8(6):735–744
Oshima M, Tsuji T (2014) Functional tooth regenerative therapy: tooth tissue regeneration and whole-tooth replacement. Odontology 102(2):123–136
Young CS, Terada S, Vacanti JP, Honda M, Bartlett JD, Yelick PC (2002) Tissue engineering of complex tooth structures on biodegradable polymer scaffolds. J Dent Res 81(10):695–700
Iwatsuki S, Honda MJ, Harada H, Ueda M (2006) Cell proliferation in teeth reconstructed from dispersed cells of embryonic tooth germs in a three-dimensional scaffold. Eur J Oral Sci 114(4):310–317
Sumita Y, Honda MJ, Ohara T, Tsuchiya S, Sagara H, Kagami H, Ueda M (2006) Performance of collagen sponge as a 3-D scaffold for tooth-tissue engineering. Biomaterials 27(17):3238–3248
Arakaki M, Ishikawa M, Nakamura T, Iwamoto T, Yamada A, Fukumoto E, Saito M, Otsu K, Harada H, Yamada Y, Fukumoto S (2012) Role of epithelial-stem cell interactions during dental cell differentiation. J Biol Chem 287(13):10590–10601
Yoshida K, Sato J, Takai R, Uehara O, Kurashige Y, Nishimura M, Chiba I, Saitoh M, Abiko Y (2014) Differentiation of mouse iPS cells into ameloblast-like cells in cultures using medium conditioned by epithelial cell rests of Malassez and gelatin-coated dishes. Med Mol Morphol 48(3):138–145
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This work was supported by funds of the University of Zurich (TAM and LJR) and the Polytechnic University of Marche (GO). The authors contributed to the planning, writing, critical reading, and editing of the present book chapter. The authors confirm that there are no conflicts of interest associated with this work.
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Mitsiadis, T.A., Orsini, G., Jimenez-Rojo, L. (2016). Dental Stem Cells for Tooth Regeneration. In: Zavan, B., Bressan, E. (eds) Dental Stem Cells: Regenerative Potential. Stem Cell Biology and Regenerative Medicine. Humana Press, Cham. https://doi.org/10.1007/978-3-319-33299-4_10
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