Abstract

This review summarizes results from in vitro and in vivo studies which provide evidence that human dental pulp stem cells (hDPSCs) might be a novel treatment strategy for nervous system injuries and neurodegenerative diseases because of their high potential for neurogenic differentiation and secretion of neuron-related trophic factors. It is also worth underlining that hDPSCs are neural crest-derived cells that possess biological properties of mesenchymal stem cells (MSCs). Induced hDPSCs have a high ability to differentiate into neuron-like cells, which show functional activity. hDPSCs express immunomodulatory factors that enhance regeneration and repair of nerve injury. These specific features of undifferentiated and differentiated hDPSCs make these cells promising for the therapy of neurodegenerative diseases, such as Alzheimer’s, Parkinson’s diseases, stroke, spinal cord injury as well as peripheral nerve injury. Recently, investigators propose that the tissue engineering technology, including scaffold, stem cells and growth factor, should provide a new strategy for spinal cord and peripheral nerve injury treatment. hDPSCs should be considered as a good choice for peripheral nerve injury therapy, because they have better potential to differentiate into neural and glial cells than stem cells coming from other sources through the expression of neuronal makers and wide range of neurotropic factors secretion. Unique properties of hDPSCs, such as high proliferation rate, trophic factors expression and stronger neuroprotective effects, indicate that these stem cells may be beneficial in neural disease therapy.

References

• 1. Ahmed Nel-M., Murakami M., Hirose Y, Nakashima M.: Therapeuticpotential of dental pulp stem cell secretome for Alzheimer’sdisease treatment: an in vitro study. Stem Cells Int. 2016;2016: 8102478
  Google Scholar
• 2. Alighae A., Boroujeni M.E., Ahmadi H., Bayat A.H., Tavirani M.R.,Abdollahifar M.A., Pooyafar M.H., Mansouri V.: Dental pulp stemcell transplantation ameliorates motor function and prevents cerebellaratrophy in rat model of cerebellar ataxia. Cell Tissue Res.,2019; 376: 179–187
  Google Scholar
• 3. Alraies A., Alaidaroos N.Y., Waddington R.J., Moseley R., SloanA.J.: Variation in human dental pulp stem cell ageing profiles reflectcontrasting proliferative and regenerative capabilities. BMCCell Biol., 2017; 18: 12
  Google Scholar
• 4. Alshehadat S.A., Thu H.A., Hamid S.S.A., Nurul A.A., Rani S.A.,Ahmad A.: Scaffolds for dental pulp tissue regeneration: A review.IDMJAR, 2016; 2: 1–12
  Google Scholar
• 5. Anitua E., Troya M., Zalduendo M.: Progress in the use of dental pulpstem cells in regenerative medicine. Cytotherapy, 2018; 20: 479–498
  Google Scholar
• 6. Arthur A., Rychkov G., Shi S., Koblar S.A., Gronthos S.: Adulthuman dental pulp stem cells differentiate toward functionallyactive neurons under appropriate environmental cues. Stem Cells,2008; 26: 1787–1795
  Google Scholar
• 7. Baldion P.A., Velandia-Romero M.L., Castellanos J.E.: Odontoblast-like cells differentiated from dental pulp stem cells retaintheir phenotype after subcultivation. Int. J. Cell Biol., 2018; 2018:6853189
  Google Scholar
• 8. Carnevale G., Pisciotta A., Riccio M., Bertoni L., De Biasi S., GibelliniL., Zordani A., Cavallini G.M., La Sala G.B., Bruzzesi G., Ferrari A.,Cossarizza A., de Pol A.: Human dental pulp stem cells expressingSTRO-1, c-kit and CD34 markers in peripheral nerve regeneration.J. Tissue Eng. Regen. Med., 2018; 12: e774–e785
  Google Scholar
• 9. Chang C.C., Chang K.C., Tsai S.J., Chang H.H., Lin C.P.: Neurogenicdifferentiation of dental pulp stem cells to neuron-like cellsin dopaminergic and motor neuronal inductive media. J. Formos.Med. Assoc., 2014; 113: 956–965
  Google Scholar
• 10. Cho Y.A., Kim D.S., Song M., Bae W.J., Lee S., Kim E.C.: Proteininteracting with never in mitosis A-1 induces glutamatergic andGABAergic neuronal differentiation in human dental pulp stemcells. J. Endod., 2016; 42: 1055–1061
  Google Scholar
• 11. Chun S.Y., Soker S., Jang Y.J., Kwon T.G., Yoo E.S.: Differentiationof human dental pulp stem cells into dopaminergic neuronlikecells in vitro. J. Korean Med. Sci., 2016; 31: 171–177
  Google Scholar
• 12. d’Aquino R., De Rosa A., Lanza V., Tirino V., Laino L., GrazianoA., Desiderio V., Laino G., Papaccio G.: Human mandible bone defectrepair by the grafting of dental pulp stem/progenitor cells andcollagen sponge biocomplexes. Eur. Cells Mater., 2009; 18: 75–83
  Google Scholar
• 13. Dominici M., Le Blanc K., Mueller I., Slaper-Cortenbach, I.,Marini F.C., Krause D.S., Deans R.J., Keating A., Prockop D.J., HorwitzE.M.: Minimal criteria for defining multipotent mesenchymalstromal cells. The International Society for Cellular Therapy positionstatement. Cytotherapy, 2006; 8: 315–317
  Google Scholar
• 14. Faroni A., Mobasseri S.A., Kingham P.J., Reid A.J.: Peripheralnerve regeneration: experimental strategies and future perspectives.Adv. Drug Deliv. Rev., 2015; 82–83: 160–167
  Google Scholar
• 15. Földes A., Kádár K., Kerémi B., Zsembery Á., Gyires K., ZádoriZ.S., Varga G.: Mesenchymal stem cells of dental origin-their potentialfor antiinflammatory and regenerative actions in brain andgut damage. Curr. Neuropharmacol., 2016; 14: 914–934
  Google Scholar
• 16. Gärtner A., Pereira T., Alves M.G., Armada-da-Silva P.A.,Amorim I., Gomes R., Ribeiro J., França M.L., Lopes C., CarvalhoR.A., Socorro S., Oliveira P.F., Porto B., Sousa R., Bombaci A., et al.:Use of poly(DL-lactide-ε-caprolactone) membranes and mesenchymalstem cells from the Wharton’s jelly of the umbilical cordfor promoting nerve regeneration in axonotmesis: in vitro and invivo analysis. Differentiation, 2012; 84: 355–365
  Google Scholar
• 17. Geng Y.W., Zhang Z., Liu M.Y., Hu W.P.: Differentiation of humandental pulp stem cells into neuronal by resveratrol. Cell Biol.Int., 2017; 41: 1391–1398
  Google Scholar
• 18. Gervois P., Struys T., Hilkens P., Bronckaers A., Ratajczak J., PolitisC., Brône B., Lambrichts I., Martenset W.: Neurogenic maturationof human dental pulp stem cells following neurosphere generationinduces morphological and electrophysiological characteristics offunctional neurons. Stem Cells Dev., 2015; 24: 296–311
  Google Scholar
• 19. Giuliani A., Manesco A., Langer M., Rustichelli F., DesiderioV., Paino F., De Rosa A., Laino., d’Aquino R., Tirino V., Papaccio G.:Three years after transplants in human mandibles, histologicaland in-line holotomography revealed that stem cells regenerateda compact rather than a spongy bone: biological and clinical implications.Stem Cells Transl. Med., 2013; 2: 316–324
  Google Scholar
• 20. Gnanasegaran N., Govindasamy V., Abu Kasim N.H.: Differentiationof stem cells derived from carious teeth into dopaminergiclikecells. Int. Endod. J., 2016; 49: 937-949
  Google Scholar
• 21. Gnanasegaran N., Govindasamy V., Kathirvaloo P., Musa S., AbuKasim N.H.: Effect of cells cycle phases on the induction of dentalpulp cells toward dopaminergic-like cells. J. Tissue Eng. RegenerativeMed., 2018; 2: e881–e893
  Google Scholar
• 22. Gnanasegaran N., Govindasamy V., Mani V., Abu Kasim N.H.:Neuroimmunomodulatory properties of DPSCs in an in vitro modelof Parkinson’s disease. IUBMB Life, 2017; 69: 689–699
  Google Scholar
• 23. Gonmanee T., Thonabulsombat C., Vongsavan K., SritanaudomchaiH.: Differentiation of stem cells from human deciduousand permanent teeth into spiral ganglion neuron-like cells. Arch.Oral Biol., 2018; 88: 34–41
  Google Scholar
• 24. Hei W.H., Kim S., Park J.C., Seo Y.K., Kim S.M., Jahng J.W., LeeJ.H.: Schwann-like cells differentiated from human dental pulpstem cells combined with a pulsed electromagnetic field can improveperipheral nerve regeneration. Bioelectromagnetics, 2016;37: 163–174
  Google Scholar
• 25. Heng B.C., Gong T., Xu J., Lim L.W., Zhang C.: Ephrin B2 signallingmodulates the neural differentiation of human dental pulpstem cells. Biomed. Rep., 2018; 9: 161–168
  Google Scholar
• 26. Jung J., Kim J.W., Moon H.J., Hong J.Y., Hyun J.K.: Characterizationof neurogenic potential of dental pulp stem cells cultured inxeno/serum-free condition: in vitro and in vivo assessment. StemCells Int., 2016; 2016: 6921097
  Google Scholar
• 27. Király M., Porcsalmy B., Pataki A., Kádár K., Jelitai M., MolnárB., Hermann P., Gera I., Grimm W.D., Ganss B., Zsembery A., VargaG.: Simultaneous PKC and cAMP activation induces differentiationof human dental pulp stem cells into functionally active neurons.Neurochem. Int., 2009; 55: 323–332
  Google Scholar
• 28. Kolar M.K., Itte V.N., Kingham P.J., Novikov L.N., Wiberg M.,Kelk P.: The neurotrophic effects of different human dental mesenchymalstem cells. Sci. Rep., 2017; 7: 12605
  Google Scholar
• 29. Kumar A., Kumar V., Rattan V., Jha V., Battacharys S.: Secretomecusemodulate the neurogenic potential of bone marrowand dental pulp stem cells. Mol. Neurobiol., 2017; 54: 4672–4682
  Google Scholar
• 30. Li R., Wu J., Lin Z., Nangle M.R., Li Y., Cai P., Liu D., Ye L., XiaoZ., He C., Ye J., Zhang H., Zhao Y., Wang J., Li X., He Y., Ye Q., XiaoJ.: Single injection of a novel nerve growth factor coacervate improvesstructural and functional regeneration after sciatic nerveinjury in adult rats. Exp. Neurol. 2017; 288: 1–10
  Google Scholar
• 31. Li Y., Zhao Sh., Nan X., Wei H., Shi J., Li A., Gou J.: Repair ofhuman periodontal bone defects by autologous grafting stem cellsderived from inflammatory dental pulp tissues. Stem Cells Res.,Ther., 2016; 7: 141–150
  Google Scholar
• 32. Liu S., Xie Y.Y., Wang B.: Role and prospects of regenerativebiomaterials in the repair of spinal cord injury. Neural Regen. Res.,2019; 14: 1352–1363
  Google Scholar
• 33. Lou L., Albashari A.A., Wang X., Jin L., Zhang Y., Zheng L., Xia J.,Xu H., Zhao Y., Xiao J., He Y., Ye Q.: Effects of transplanted heparinpoloxamerhydrogel combining dental pulp stem cells and bFGFon spinal cord injury repair. Stem Cells Int., 2018; 2018: 2398521
  Google Scholar
• 34. Luo L., He Y., Wang X., Key B., Lee B.H., Li H., Ye Q.: Potentialroles of dental pulp stem cells in neural regeneration and repair.Stem Cells Int.; 2018: 2018: 1731289
  Google Scholar
• 35. Man R.C., Sulaiman N., Idrus R.B.H., Ariffin S.H.Z., WahabR.M.A., Yazid M.D., Insights into the effects of the dental stemcell secretome on nerve regeneration: toward cell-retreatment.Stem Cells Int., 2019; 2019: 4596150
  Google Scholar
• 36. Martínez-Morales P.L., Revilla A., Ocaña I., González C., SainzP., McGuire D., Liste I.: Progress in stem cell therapy for major humanneurological disorders. Stem Cell Rev. Rep., 2013; 9: 685–699
  Google Scholar
• 37. Mead B., Logan A., Berry M., Leadbeater W., Scheven B.A.: Concisereview: Dental pulp stem cells: A novel cell therapy for retinaland central nervous system repair. Stem Cells, 2017; 35: 61–67
  Google Scholar
• 38. Monti M., Graziano A., Rizzo A., Perotti C., Del Fante C.,D’Aquino R., Redi C.A, Baena R.R.: In vitro and in vivo differentiationof progenitor stem cells obtained after mechanical digestionof human dental pulp. J. Cell Physiol., 2017; 232: 548–555
  Google Scholar
• 39. Morsczek C., Reichert T.E.: Dental stem cells in tooth regenerationand repair in the future. Expert Opin. Biol. Ther., 2018;18: 187–196
  Google Scholar
• 40. Nakajima K., Kunimatsu R., Ando K., Ando T., Hayashi Y., KiharaT., Hiraki T., Tsuka Y., Abe T., Kaku M., Nikawa H., Takata T., TanneK., Tanimoto K.: Comparison of the bone regeneration ability betweenstem cells from human exfoliated deciduous teeth, humandental pulp stem cells and human bone marrow mesenchymalstem cells. Biochem. Biophys. Res. Commun., 2018; 497: 876–882
  Google Scholar
• 41. Nakashima M., Iohara K., Murakami M., Nakamura H., SatoY., Ariji Y., Matsushita K.: Pulp regeneration by transplantation ofdental pulp stem cells in pulpitis: a pilot clinical study. Stem CellRes. Ther., 2017; 8: 61
  Google Scholar
• 42. Nito C., Sowa K., Nakajima M., Sakamoto Y., Suda S., NishiyamaY., Nakamura-Takahashi A., Nitahara-Kasahara Y., Ueda M.,Okada T., Kimura K.: Transplantation of human dental pulp stemcells ameliorates brain damage following acute cerebral ischemia.Biomed. Pharmacother., 2018; 108: 1005–1014
  Google Scholar
• 43. Pisciotta A., Bertoni L., Riccio M., Mapelli J., Bigiani A., La NoceM., Orciani M., de Pol A., Carnevale G.: Use of a 3D floating sphereculture system to maintain the neural crest-related properties ofhuman dental pulp stem cells. Front. Physiol., 2018; 9: 547
  Google Scholar
• 44. Qiao W., Lu L., Wu G., An X., Li D., Guo J.: DPSCs seeded in acellularnerve grafts processed by myroilysin improve nerve regeneration.J. Biomater. Appl., 2019; 33: 819–833
  Google Scholar
• 45. Rafiee F., Pourteymourfard-Tabrizi Z., Mahmoudian-Sani M.R.,Mehri-Ghahfarrokhi A., Soltani A., Hashemzadeh-Chaleshtori M.,Jami M.S.: Differentiation of dental pulp stem cells into neuronlikecells. Int. J. Neurosci., 2020; 130: 107–116
  Google Scholar
• 46. Saez D.M., Sasaki R.T., de Oliveira Martins D., Chacur M., KerkisJ., da Silva M.C.: Rat facial nerve regeneration with human immaturedental pulp stem cells. Cell Transplant. 2019; 28: 1573–1584
  Google Scholar
• 47. Sanen K., Martens W., Georgiou M., Ameloot M., Lambrichts I.,Phillips J.: Engineered neural tissue with Schwann cell differentiatedhuman dental pulp stem cells: potential for peripheral nerverepair? J. Tissue Eng. Regen. Med., 2017; 11: 3362–3372
  Google Scholar
• 48. San Jose L.H., Stephens P., Song B., Barrow D.: Microfluidicencapsulation supports stem cell viability, proliferation, and neuronaldifferentiation. Tissue Eng. Part. C Methods, 2018; 24: 158–170
  Google Scholar
• 49. Sasaki R., Aoki S., Yamato M., Uchiyama H., Wada K., OgiuchiH., Okano T., Ando T.: PLGA artificial nerve conduits with dentalpulp cells promote facial nerve regeneration. J. Tissue Eng. Regen.Med., 2011; 5: 823–830
  Google Scholar
• 50. Sasaki R., Matsumine H., Watanabe Y., Takeuchi Y., YamatoM., Okano T., Miyata M., Ando T.: Electrophysiologic and functionalevaluations of regenerated facial nerve defects with a tubecontaining dental pulp cells in rats. Plast. Reconstr. Surg., 2014;134: 970–978
  Google Scholar
• 51. Simon C., Gan Q.F., Kathivaloo P., Mohamad N.A., DhamodharanJ., Krishnan A., Sengodan B., Palanimuthu V.R., MarimuthuK., Rajandas H., Ravichandran M., Parimannan S.: Deciduous DPSCsameliorate MPTP-mediated neurotoxicity, sensorimotor coordinationand olfactory function in parkinsonian mice. Int. J. Mol.Sci., 2019; 20: 568
  Google Scholar
• 52. Singh M., Kakkar A., Sharma R., Kharbanda O.P., Monga N.,Kumar M., Chowdhary S., Airan B., Mohanty S.: Synergistic effectof BDNF and FGF2 in efficient generation of functional dopaminergicneurons from human mesenchymal stem cells. Sci. Rep.,2017; 7: 10378
  Google Scholar
• 53. Song M., Lee J.H., Bae J., Bu Y., Kim E.C.: Human dental pulpstem cells are more effective than human bone marrow derivedmesenchymal stem cells in cerebral ischemic injury. Cell Transplant.,2017; 26: 1001–1016
  Google Scholar
• 54. Spyridopoulos T., Lambropoulou M., Pagonopoulou O., BirbilisT., Tsaroucha A.K., Kouzi-Koliakou K., Botaitis S., Deftereou T.E.,Gaitanidis A., Pitiakoudis M.: Regenerated nerve defects with anerve conduit containing dental pulp stem cells in pigs: an immunohistochemicaland electrophysiological evaluation. J. Reconstr.Microsurg., 2015; 31: 516–526
  Google Scholar
• 55. Sultan M., Amin L.E., Zaher A.R., Scheven B.A., Grawish M.E.:Dental pulp stem cells:novel cells based and cell-free therapy forperipheral nerve therapy. World J. Stomatol. 2019; 1: 1–19
  Google Scholar
• 56. Tamaki T., Hirata M., Nakajima N., Saito K., Hashimoto H.,Soeda S., Uchiyama Y., Watanabe M.: A long-gap peripheral nerveinjury therapy using human skeletal muscle-derived stem cells(Sk-SCs) an achievement of significant morphological, numericaland functional recovery. PLoS One, 2016; 11: e0166639
  Google Scholar
• 57. Ullah I., Park J.M., Kang Y.H., Byun J.H., Kim D.G., Kim J.H., KangD.H., Rho G.J., Park B.W: Transplantation of human dental pulpderivedstem cells or differentiated neuronal cells from humandental pulp-derived stem cells identically enhances regenerationof the injured peripheral nerve. Stem Cells Dev., 2017; 26: 1247–1257
  Google Scholar
• 58. Wang D., Wang Y., Tian W., Pan J.: Advances of tooth-derivedstem cells in neural diseases treatments and nerve tissue regeneration.Cell Prolif., 2019; 52: e12572
  Google Scholar
• 59. Wang F., Jia Y., Liu J., Zhai J., Cao N., Yue W., He H., Pei X.:Dental pulp stem cells promote regeneration of damaged neuroncells on the cellular model of Alzheimer’s disease. Cell Biol. Int.,2017; 41: 639–650
  Google Scholar
• 60. Wang M., Yuan Q., Xie L.: Mesenchymal stem cell- based immunomodulation:Properties and clinical application. Stem CellsInt., 2018; 2018: 3057624
  Google Scholar
• 61. Xie L., Zeng X., Hu J., Chen Q.: Characterization of nestin, a selectivemarker for bone marrow derived mesenchymal stem cells.Stem Cells Int., 2015; 2015: 762098
  Google Scholar
• 62. Yamada Y., Nakamura-Yamada S., Kusano K., Baba S.: Clinicalpotential and current progress of dental pulp stem cells for varioussystemic diseases in regenerative medicine: a concise review.Int. J. Mol. Sci., 2019; 20: 1132
  Google Scholar
• 63. Yang C., Li X., Sun L., Guo W., Tian W.: Potential of human dentalstem cells in repairing the complete transection of rat spinalcord. J. Neural. Eng., 2017; 14: 026005
  Google Scholar
• 64. Yasui T., Mabuchi Y., Morikawa S., Onizawa K., Akazawa Ch.,Nakagawa T., Okano H., Matsuzaki Y.: Isolation of dental pulp stemcells with high osteogenic potential. Inflamm. Regen., 2017; 37: 8
  Google Scholar
• 65. Zhang J., Lian M., Cao P., Bao G., Xu G., Sun Y., Wang L., ChenJ., Wang Y., Feng G., Cui Z. Effect of nerve growth factor and basicfibroblast growth factor promote human dental pulp stem cellsto neural differentiation. Neurochem. Res., 2017; 42: 1015–1025
  Google Scholar
• 66. Zhang J., Lu X., Feng G., Gu Z., Sun Y., Bao G., Xu G., Lu Y., ChenJ., Xu L., Feng X., Cui Z.: Chitosan scaffolds induce human dentalpulp stem cells to neural differentiation: potential roles for spinalcord injury therapy. Cell Tissue Res., 2016; 366: 129–142
  Google Scholar
• 67. Zhang X., Zhou Y., Li H., Wang R., Yang D., Li B., Cao X., Fu J.:Transplanted dental pulp stem cells migrate to injured area andexpress neural markers in a rat model of cerebral ischemia. CellPhysiol. Biochem., 2018; 45: 258–266
  Google Scholar
• 68. Zhang X., Zhou Y., Li H., Wang R., Yang D., Li B., Fu J.: Intravenousadministration of DPSCs and BDNF improves neurologicalperformance in rats with focal cerebral ischemia. Int. J. Mol. Med.,2018; 41: 3185–3194
  Google Scholar

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