Stem Cells-based and Molecular-based Approaches in Regenerative Dentistry: A Topical Review

Author(s): Marco Tatullo*, Bruna Codispoti, Jamal Sied, Irina Makeeva, Francesco Paduano, Massimo Marrelli, Gianrico Spagnuolo.

Journal Name: Current Stem Cell Research & Therapy

Volume 14 , Issue 7 , 2019

Become EABM
Become Reviewer


Background: Regenerative medicine is a growing branch of medicine aimed to treat damaged or lost tissues, to promote tissue formation and to restore both aesthetics and function. In the last years, several scientific articles have been focused on the regenerative procedures aimed to increase the survival rate of compromised teeth; the most effective approaches have been based on molecularbased and on cellular-based protocols; however, to date, both these techniques have not been carefully analysed and discussed, to know in details the advantages of each of them.

Methods: A literature search was undertaken on three electronic scientific databases: Medline via PubMed, EMBASE and Google Scholar. Authors aimed to select such articles published in the time span from January 1961 until December 2017. The authors screened the titles and the abstracts including the following keywords combinations: “Pulp AND Therapy”, “Regenerative AND Endodontic”, and “Endodontics AND Tissue engineering”. After the exclusion of any not related articles, the full text of such papers related to the topics was included in this review.

Results: Following the removal of duplicate articles and of other types of publications (such as erratum and corrigendum), 621 articles were selected to be included and analysed in our topical review. The articles were analysed into the following sections: cellular-based approaches for dental regeneration, molecular-based and combined cellular/molecular-based approaches for dental regeneration, and translational applications of regenerative dentistry.

Conclusion: This topical review has been focused on the main, the most promising and the most innovative strategies for achieving the regeneration of dental pulp or dental tissues. The main and surprising “take-home message” is related to the great interest towards the dental-derived stem cells, characterized by a high angiogenic and neurogenic commitment. Future challenges will be focused on the development of biological-friendly regenerative strategies: the new approaches should overcome the current biological limitations, to promote the combined cellular and molecular-based treatments, able to ensure predictable clinical evidence, with the achievement of the regeneration/repairing of the compromised dental pulp and of the entire tooth structure.

Keywords: Regenerative dentistry, bone regeneration, dental stem cells, tissue engineering, regenerative medicine, osteogenic cells.

He L, Kim SG, Gong Q, et al. Regenerative endodontics for adult patients. J Endod 2017; 43(9S): S57-64.
Seale NS, Coll JA. Vital pulp therapy for the primary dentition. Gen Dent 2010; 58(3): 194-200.
Rossman LE. American association of endodontists. J Am Coll Dent 2009; 76(1): 4-8.
Barthel CR, Rosenkranz B, Leuenberg A, Roulet JF. Pulp capping of carious exposures: treatment outcome after 5 and 10 years: A retrospective study. J Endod 2000; 26(9): 525-8.
Saoud TM, Martin G, Chen YH, et al. Treatment of mature permanent teeth with necrotic pulps and apical periodontitis using regenerative endodontic procedures: A case series. J Endod 2016; 42(1): 57-65.
Trope M. Regenerative potential of dental pulp. J Endod 2008; 34(7)(Suppl.): S13-7.
Ostby BN. The role of the blood clot in endodontic therapy. An experimental histologic study. Acta Odontol Scand 1961; 19: 324-53.
Nygaard-Ostby B, Hjortdal O. Tissue formation in the root canal following pulp removal. Scand J Dent Res 1971; 79(5): 333-49.
Murray PE, Garcia-Godoy F, Hargreaves KM. Regenerative endodontics: A review of current status and a call for action. J Endod 2007; 33(4): 377-90.
Seghi RR, Nasrin S, Draney J, Katsube N. Root fortification. J Endod 2013; 39(3)(Suppl.): S57-62.
Nosrat A, Nekoofar MH, Bolhari B, Dummer PM. Unintentional extrusion of mineral trioxide aggregate: a report of three cases. Int Endod J 2012; 45(12): 1165-76.
Lin LM, Shimizu E, Gibbs JL, Loghin S, Ricucci D. Histologic and histobacteriologic observations of failed revascularization/revitalization therapy: A case report. J Endod 2014; 40(2): 291-5.
Saoud TM, Mistry S, Kahler B, Sigurdsson A, Lin LM. Regenerative endodontic procedures for traumatized teeth after horizontal root fracture, avulsion, and perforating root resorption. J Endod 2016; 42(10): 1476-82.
Corbella S, Ferrara G, El Kabbaney A, Taschieri S. Apexification, apexogenesis and regenerative endodontic procedures: a review of the literature. Minerva Stomatol 2014; 63(11-12): 375-89.
Saoud TM, Huang GT, Gibbs JL, Sigurdsson A, Lin LM. Management of teeth with persistent apical periodontitis after root canal treatment using regenerative endodontic therapy. J Endod 2015; 41(10): 1743-8.
Haapasalo M, Shen Y, Qian W, Gao Y. Irrigation in endodontics. Dent Clin North Am 2010; 54(2): 291-312.
Diogenes AR, Ruparel NB, Teixeira FB, Hargreaves KM. Translational science in disinfection for regenerative endodontics. J Endod 2014; 40(4)(Suppl.): S52-7.
Ruparel NB, Teixeira FB, Ferraz CC, Diogenes A. Direct effect of intracanal medicaments on survival of stem cells of the apical papilla. J Endod 2012; 38(10): 1372-5.
Palasuk J, Kamocki K, Hippenmeyer L, et al. Bimix antimicrobial scaffolds for regenerative endodontics. J Endod 2014; 40(11): 1879-84.
Huang GT, Sonoyama W, Liu Y, Liu H, Wang S, Shi S. The hidden treasure in apical papilla: the potential role in pulp/dentin regeneration and bioroot engineering. J Endod 2008; 34(6): 645-51.
Kim JH, Kim Y, Shin SJ, Park JW, Jung IY. Tooth discoloration of immature permanent incisor associated with triple antibiotic therapy: A case report. J Endod 2010; 36(6): 1086-91.
Couve E, Osorio R, Schmachtenberg O. The amazing odontoblast: activity, autophagy, and aging. J Dent Res 2013; 92(9): 765-72.
Smith AJ, Smith JG, Shelton RM, Cooper PR. Harnessing the natural regenerative potential of the dental pulp. Dent Clin North Am 2012; 56(3): 589-601.
Ricucci D, Loghin S, Lin LM, Spångberg LS, Tay FR. Is hard tissue formation in the dental pulp after the death of the primary odontoblasts a regenerative or a reparative process? J Dent 2014; 42(9): 1156-70.
Aguilar P, Linsuwanont P. Vital pulp therapy in vital permanent teeth with cariously exposed pulp: a systematic review. J Endod 2011; 37(5): 581-7.
Kaida H, Hamachi T, Anan H, Maeda K. Wound healing process of injured pulp tissues with emdogain gel. J Endod 2008; 34(1): 26-30.
Ricucci D, Loghin S, Siqueira JF Jr. Correlation between clinical and histologic pulp diagnoses. J Endod 2014; 40(12): 1932-9.
Gruber R, Karreth F, Kandler B, et al. Platelet-released supernatants increase migration and proliferation, and decrease osteogenic differentiation of bone marrow-derived mesenchymal progenitor cells under in vitro conditions. Platelets 2004; 15(1): 29-35.
Gruber R, Kandler B, Agis H, Fischer MB, Watzek G. Bone cell responsiveness to growth and differentiation factors under hypoxia in vitro. Int J Oral Maxillofac Implants 2008; 23(3): 417-26.
Li L, Zhu YQ, Jiang L, Peng W, Ritchie HH. Hypoxia promotes mineralization of human dental pulp cells. J Endod 2011; 37(6): 799-802.
Yuan C, Wang P, Zhu L, et al. Coculture of stem cells from apical papilla and human umbilical vein endothelial cell under hypoxia increases the formation of three-dimensional vessel-like structures in vitro. Tissue Eng Part A 2015; 21(5-6): 1163-72.
Niklas A, Proff P, Gosau M, Römer P. The role of hypoxia in orthodontic tooth movement. Int J Dent 2013.2013841840
Janjić K, Edelmayer M, Moritz A, Agis H. L-mimosine and hypoxia can increase angiogenin production in dental pulp-derived cells. BMC Oral Health 2017; 17(1): 87.
Babb R, Chandrasekaran D, Carvalho Moreno Neves V, Sharpe PT. Axin2-expressing cells differentiate into reparative odontoblasts via autocrine Wnt/β-catenin signaling in response to tooth damage. Sci Rep 2017; 7(1): 3102.
Tatullo M, Marrelli M, Paduano F. The regenerative medicine in oral and maxillofacial surgery: the most important innovations in the clinical application of mesenchymal stem cells. Int J Med Sci 2015; 12(1): 72-7.
Namour M, Theys S. Pulp revascularization of immature permanent teeth: a review of the literature and a proposal of a new clinical protocol. ScientificWorldJournal 2014; 2014737503
Tatullo M, Marrelli M, Shakesheff KM, White LJ. Dental pulp stem cells: Function, isolation and applications in regenerative medicine. J Tissue Eng Regen Med 2015; 9(11): 1205-16.
Huang GT, Yamaza T, Shea LD, 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 Part A 2010; 16(2): 605-15.
Sakai VT, Cordeiro MM, Dong Z, Zhang Z, Zeitlin BD, Nör JE. Tooth slice/scaffold model of dental pulp tissue engineering. Adv Dent Res 2011; 23(3): 325-32.
Rosa V, Zhang Z, Grande RH, Nör JE. Dental pulp tissue engineering in full-length human root canals. J Dent Res 2013; 92(11): 970-5.
Baylan N, Bhat S, Ditto M, Lawrence JG, Lecka-Czernik B, Yildirim-Ayan E. Polycaprolactone nanofiber interspersed collagen type-I scaffold for bone regeneration: a unique injectable osteogenic scaffold. Biomed Mater 2013; 8(4)045011
Bottino MC, Yassen GH, Platt JA, et al. A novel three-dimensional scaffold for regenerative endodontics: materials and biological characterizations. J Tissue Eng Regen Med 2015; 9(11): E116-23.
Athirasala A, Lins F, Tahayeri A, et al. A novel strategy to engineer pre-vascularized full-length dental pulp-like tissue constructs. Sci Rep 2017; 7(1): 3323.
Paduano F, Marrelli M, White LJ, Shakesheff KM, Tatullo M. Odontogenic differentiation of human dental pulp stem cells on hydrogel scaffolds derived from decellularized bone extracellular matrix and collagen type i. PLoS One 2016; 11(2)e0148225
Paduano F, Marrelli M, Alom N, et al. Decellularized bone extracellular matrix and human dental pulp stem cells as a construct for bone regeneration. J Biomater Sci Polym Ed 2017; 28(8): 730-48.
Matsui M, Kobayashi T, Tsutsui TW. CD146 positive human dental pulp stem cells promote regeneration of dentin/pulp-like structures. Hum Cell 2018; 31(2): 127-38.
Ishizaka R, Iohara K, Murakami M, Fukuta O, Nakashima M. Regeneration of dental pulp following pulpectomy by fractionated stem/progenitor cells from bone marrow and adipose tissue. Biomaterials 2012; 33(7): 2109-18.
Ishizaka R, Hayashi Y, Iohara K, et al. Stimulation of angiogenesis, neurogenesis and regeneration by side population cells from dental pulp. Biomaterials 2013; 34(8): 1888-97.
Marrelli M, Paduano F, Tatullo M. Cells isolated from human periapical cysts express mesenchymal stem cell-like properties. Int J Biol Sci 2013; 9(10): 1070-8.
Marrelli M, Paduano F, Tatullo M. Human periapical cyst-mesenchymal stem cells differentiate into neuronal cells. J Dent Res 2015; 94(6): 843-52.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [607 - 616]
Pages: 10
DOI: 10.2174/1574888X14666190626111154
Price: $65

Article Metrics

PDF: 34