Abstract
The broad clinical applications of Mesenchymal Stem Cells (MSCs) in the regenerative medicine field is attributed to their ability to self-renew and differentiate into multiple cellular lineages. Nowadays, MSCs can be derived from a variety of adult and fetal tissues including bone marrow, adipose tissue, umbilical cord and placenta. The difficulties associated with the isolation of MSCs from certain tissues such as bone marrow promoted the search for alternative tissues which are easily accessible. Oral derived MSCs include dental pulp stem cells (DPSCs), dental follicle progenitor cells (DFPC), and periodontal ligament stem cells (PDLSC). Being abundant and easily accessible, oral derived MSCs represent an interesting alternative MSC type to be employed in regenerative medicine. Human periapical cyst-mesenchymal stem cells (hPCy–MSCs) correspond to a newly discovered and characterized MSC subtype. Interestingly, hPCy–MSCs are collected from periapical cysts, which are a biological waste, without any influence on the other healthy tissues in oral cavity. hPCy–MSCs exhibit cell surface marker profile similar to that of other oral derived MSCs, show high proliferative potency, and possess the potential to differentiate into different cell types such as osteoblasts, adipocytes and neurons-like cells. hPCy–MSCs, therefore, represent a novel promising MSCs type to be applied in regenerative medicine domain. In this review, we will compare the different types of dental derived MSCs, we will highlight the isolation technique, the characteristics, and the therapeutic potential of hPCy–MSCs.
Similar content being viewed by others
References
Phinney DG, Prockop DJ (2007) Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair—current views. Stem Cells 25(11):2896–2902
Lennon DP, Caplan AI (2006) Isolation of human marrow-derived mesenchymal stem cells. Exp Hematol 34(11):1604–1605
Suchanek J et al (2007) Human dental pulp stem cells–isolation and long term cultivation. Acta Medica (Hradec Kralove) 50(3):195–201
Bieback K et al (2004) Critical parameters for the isolation of mesenchymal stem cells from umbilical cord blood. Stem Cells 22(4):625–634
Zuk PA et al (2002) Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 13(12):4279–4295
Gronthos S et al (2000) Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci USA 97(25):13625–13630
Chamberlain G et al (2007) Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells 25(11):2739–2749
Dominici M et al (2006) Minimal criteria for defining multipotent mesenchymal stromal cells: the international society for cellular therapy position statement. Cytotherapy 8(4):315–317
Mahla RS (2016) Stem cells applications in regenerative medicine and disease therapeutics. Int J Cell Biol 2016:6940283
Koussoulakou DS, Margaritis LH, Koussoulakos SL (2009) A curriculum vitae of teeth: evolution, generation, regeneration. Int J Biol Sci 5(3):226–243
Stanko P et al (2014) Comparison of human mesenchymal stem cells derived from dental pulp, bone marrow, adipose tissue, and umbilical cord tissue by gene expression. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 158(3):373–377
Hollands P, Aboyeji D, Orcharton M (2018) Dental pulp stem cells in regenerative medicine. Br Dent J 224:747–750
Miura M et al (2003) SHED: stem cells from human exfoliated deciduous teeth. Proc Natl Acad Sci USA 100(10):5807–5812
Kerkis I et al (2006) Isolation and characterization of a population of immature dental pulp stem cells expressing OCT-4 and other embryonic stem cell markers. Cells Tissues Organs 184(3–4):105–116
Seo BM et al (2004) Investigation of multipotent postnatal stem cells from human periodontal ligament. Lancet 364(9429):149–155
Morsczeck C et al (2005) Isolation of precursor cells (PCs) from human dental follicle of wisdom teeth. Matrix Biol 24(2):155–165
Sonoyama W et al (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
Marrelli M, Paduano F, Tatullo M (2013) Cells isolated from human periapical cysts express mesenchymal stem cell-like properties. Int J Biol Sci 9(10):1070–1078
Iohara K et al (2006) Side population cells isolated from porcine dental pulp tissue with self-renewal and multipotency for dentinogenesis, chondrogenesis, adipogenesis, and neurogenesis. Stem Cells 24(11):2493–2503
Ishkitiev N et al (2010) Deciduous and permanent dental pulp mesenchymal cells acquire hepatic morphologic and functional features in vitro. J Endod 36(3):469–474
Reynolds AJ, Jahoda CA (2004) Cultured human and rat tooth papilla cells induce hair follicle regeneration and fiber growth. Differentiation 72(9–10):566–575
Yang R et al (2010) Clones of ectopic stem cells in the regeneration of muscle defects in vivo. PLoS ONE 5(10):e13547
Lima RL et al (2017) Human dental follicle cells express embryonic, mesenchymal and neural stem cells markers. Arch Oral Biol 73:121–128
Tanaka Y et al (2018) Suppression of AKT-mTOR signal pathway enhances osteogenic/dentinogenic capacity of stem cells from apical papilla. Stem Cell Res Ther 9(1):334
Sonoyama W et al (2006) Mesenchymal stem cell-mediated functional tooth regeneration in swine. PLoS ONE 1:e79
Li Y et al (2014) 17beta-estradiol promotes the odonto/osteogenic differentiation of stem cells from apical papilla via mitogen-activated protein kinase pathway. Stem Cell Res Ther 5(6):125
Siqueira J, Moap J, Essential endodontology. (2008) Oxford. Blackwell, UK
Peters E, Lau M (2003) Histopathologic examination to confirm diagnosis of periapical lesions: a review. J Can Dent Assoc 69(9):598–600
Babal P et al (1989) Cellular composition of periapical granulomas and its function: histological, immunohistochemical and electronmicroscopic study. Czech Med 12(4):193–215
Holland R et al (2017) Factors affecting the periapical healing process of endodontically treated teeth. J Appl Oral Sci 25(5):465–476
Patel J et al (2010) Foreign body-induced granulation tissue is a source of adult stem cells. Transl Res 155(4):191–199
Liao J et al (2011) Cells isolated from inflamed periapical tissue express mesenchymal stem cell markers and are highly osteogenic. J Endod 37(9):1217–1224
Huang GT et al (2006) In vitro characterization of human dental pulp cells: various isolation methods and culturing environments. Cell Tissue Res 324(2):225–236
Martin MJ et al (2005) Human embryonic stem cells express an immunogenic nonhuman sialic acid. Nat Med 11(2):228–232
Aldahmash A et al (2011) Human serum is as efficient as fetal bovine serum in supporting proliferation and differentiation of human multipotent stromal (mesenchymal) stem cells in vitro and in vivo. Stem Cell Rev Rep 7(4):860–868
Tatullo M et al (2018) Human periapical cysts-mesenchymal stem cells cultured with allogenic human serum are a “clinical-grade” construct alternative to bovine fetal serum and indicated in the regeneration of endo-periodontal tissues. Giornale Italiano di Endodonzia 32:36–41
Russell KC et al (2010) In vitro high-capacity assay to quantify the clonal heterogeneity in trilineage potential of mesenchymal stem cells reveals a complex hierarchy of lineage commitment. Stem Cells 28(4):788–798
Paduano F et al (2016) CD146 Expression influences periapical cyst mesenchymal stem cell properties. Stem Cell Rev 12(5):592–603
Zhu W et al (2013) Comparison of the properties of human CD146+ and CD146- periodontal ligament cells in response to stimulation with tumour necrosis factor alpha. Arch Oral Biol 58(12):1791–1803
Estrela C et al (2019) Mesenchymal Stem Cell Marker Expression in Periapical Abscess. J Endod 45(6):716–723
Tatullo M et al (2015) Dental pulp stem cells and human periapical cyst mesenchymal stem cells in bone tissue regeneration: comparison of basal and osteogenic differentiated gene expression of a newly discovered mesenchymal stem cell lineage. J Biol Regul Homeost Agents 29(3):713–718
Marrelli M, Paduano F, Tatullo M (2015) Human periapical cyst-mesenchymal stem cells differentiate into neuronal cells. J Dent Res 94(6):843–852
Sieber-Blum M et al (2006) Characterization of epidermal neural crest stem cell (EPI-NCSC) grafts in the lesioned spinal cord. Mol Cell Neurosci 32(1–2):67–81
Venkatesh K et al (2013) In vitro differentiation of cultured human CD34+ cells into astrocytes. Neurol India 61(4):383–388
Kalinina NI et al (2011) Mesenchymal stem cells in tissue growth and repair. Acta Naturae 3(4):30–37
Li Z et al (2014) Immunomodulatory properties of dental tissue-derived mesenchymal stem cells. Oral Dis 20(1):25–34
Prockop DJ (2007) "Stemness" does not explain the repair of many tissues by mesenchymal stem/multipotent stromal cells (MSCs). Clin Pharmacol Ther 82(3):241–243
Kinnaird T et al (2004) Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ Res 94(5):678–685
Rubtsov Y et al (2017) Molecular mechanisms of immunomodulation properties of mesenchymal stromal cells: a new insight into the role of ICAM-1. Stem Cells Int 2017:6516854
Lopatina T et al (2011) Adipose-derived stem cells stimulate regeneration of peripheral nerves: BDNF secreted by these cells promotes nerve healing and axon growth de novo. PLoS ONE 6(3):e17899
Kumar A et al (2017) Secretome cues modulate the neurogenic potential of bone marrow and dental stem cells. Mol Neurobiol 54(6):4672–4682
Mead B et al (2014) Paracrine-mediated neuroprotection and neuritogenesis of axotomised retinal ganglion cells by human dental pulp stem cells: comparison with human bone marrow and adipose-derived mesenchymal stem cells. PLoS ONE 9(10):e109305
Yamaguchi S et al (2015) Dental pulp-derived stem cell conditioned medium reduces cardiac injury following ischemia-reperfusion. Sci Rep 5:16295
Werle SB et al (2016) The effects of hypoxia on in vitro culture of dental-derived stem cells. Arch Oral Biol 68:13–20
Shi Y et al (2012) How mesenchymal stem cells interact with tissue immune responses. Trends Immunol 33(3):136–143
Waterman RS et al (2010) A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an Immunosuppressive MSC2 phenotype. PLoS ONE 5(4):e10088
Hwang SH et al (2014) Toll like receptor 3 & 4 responses of human turbinate derived mesenchymal stem cells: stimulation by double stranded RNA and lipopolysaccharide. PLoS ONE 9(7):e101558
Mekhemar MK et al (2018) TLR-induced immunomodulatory cytokine expression by human gingival stem/progenitor cells. Cell Immunol 326:60–67
Lee DK, Song SU (2018) Immunomodulatory mechanisms of mesenchymal stem cells and their therapeutic applications. Cell Immunol 326:68–76
Tolar J et al (2010) Concise review: hitting the right spot with mesenchymal stromal cells. Stem Cells 28(8):1446–1455
Andrukhov O et al (2019) Immunomodulatory properties of dental tissue-derived mesenchymal stem cells: implication in disease and tissue regeneration. World J Stem Cells 11(9):604–617
Ozdemir AT et al (2016) The paracrine immunomodulatory interactions between the human dental pulp derived mesenchymal stem cells and CD4 T cell subsets. Cell Immunol 310:108–115
Aggarwal S, Pittenger MF (2005) Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105(4):1815–1822
Franquesa M et al (2015) Human adipose tissue-derived mesenchymal stem cells abrogate plasmablast formation and induce regulatory B cells independently of T helper cells. Stem Cells 33(3):880–891
Tatullo M et al (2017) Potential use of human periapical cyst-mesenchymal stem cells (hPCy-MSCs) as a novel stem cell source for regenerative medicine applications. Front Cell Dev Biol 5:103
Karnoub AE et al (2007) Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449(7162):557–563
Corcoran KE et al (2008) Mesenchymal stem cells in early entry of breast cancer into bone marrow. PLoS ONE 3(6):e2563
Huang WH et al (2013) Mesenchymal stem cells promote growth and angiogenesis of tumors in mice. Oncogene 32(37):4343–4354
Ljujic B et al (2013) Human mesenchymal stem cells creating an immunosuppressive environment and promote breast cancer in mice. Sci Rep 3:2298
Gjorgieva D, Zaidman N, Bosnakovski D (2013) Mesenchymal stem cells for anti-cancer drug delivery. Recent Pat Anticancer Drug Discov 8(3):310–318
Lacerda L et al (2015) Mesenchymal stem cells mediate the clinical phenotype of inflammatory breast cancer in a preclinical model. Breast Cancer Res 17:42
He N et al (2018) MSCs inhibit tumor progression and enhance radiosensitivity of breast cancer cells by down-regulating Stat3 signaling pathway. Cell Death Dis 9(10):1026
Salehi H et al (2018) Dental pulp stem cells used to deliver the anticancer drug paclitaxel. Stem Cell Res Ther 9(1):103
Dogan A et al (2017) Dental pulp stem cells (DPSCs) increase prostate cancer cell proliferation and migration under in vitro conditions. Tissue Cell 49(6):711–718
Rodriguez-Lozano FJ et al (2011) Mesenchymal stem cells derived from dental tissues. Int Endod J 44(9):800–806
Gimble JM (2003) Adipose tissue-derived therapeutics. Expert Opin Biol Ther 3(5):705–713
Rosenbaum AJ, Grande DA, Dines JS (2008) The use of mesenchymal stem cells in tissue engineering: a global assessment. Organogenesis 4(1):23–27
Figueroa FE et al (2012) Mesenchymal stem cell treatment for autoimmune diseases: a critical review. Biol Res 45(3):269–277
Kim SH et al (2009) Alveolar bone regeneration by transplantation of periodontal ligament stem cells and bone marrow stem cells in a canine peri-implant defect model: a pilot study. J Periodontol 80(11):1815–1823
Paduano F et al (2017) Decellularized bone extracellular matrix and human dental pulp stem cells as a construct for bone regeneration. J Biomater Sci Polym Ed 28(8):730–748
Paduano F et al (2016) Odontogenic differentiation of human dental pulp stem cells on hydrogel scaffolds derived from decellularized bone extracellular matrix and collagen type I. PLoS ONE 11(2):e0148225
Tatullo M et al (2019) PLA-based mineral-doped scaffolds seeded with human periapical cyst-derived MSCs: a promising tool for regenerative healing in dentistry. Materials (Basel) 12(4):597
Corrado C et al (2013) Exosomes as intercellular signaling organelles involved in health and disease: basic science and clinical applications. Int J Mol Sci 14(3):5338–5366
Tatullo M et al (2019) Human periapical cyst-derived stem cells can be a smart "Lab-on-A-Cell" to investigate neurodegenerative diseases and the related alteration of the exosomes' content. Brain Sci 9(12):358
Del Fabbro M et al (2016) Endodontic procedures for retreatment of periapical lesions. Cochrane Database Syst Rev 10:CD00511
Maeda H et al (2004) Human periapical granulation tissue contains osteogenic cells. Cell Tissue Res 315(2):203–208
Agha-Hosseini F et al (2010) In vitro isolation of stem cells derived from human dental pulp. Clin Transplant 24(2):E23–E28
Yamada Y et al (2010) A feasibility of useful cell-based therapy by bone regeneration with deciduous tooth stem cells, dental pulp stem cells, or bone-marrow-derived mesenchymal stem cells for clinical study using tissue engineering technology. Tissue Eng A 16(6):1891–1900
Ferroni L et al (2015) A hyaluronan-based scaffold for the in vitro construction of dental pulp-like tissue. Int J Mol Sci 16(3):4666–4681
Almeida PN et al (2018) Increased extracellular matrix deposition during chondrogenic differentiation of dental pulp stem cells from individuals with neurofibromatosis type 1: an in vitro 2D and 3D study. Orphanet J Rare Dis 13(1):98
Feng X et al (2014) 3D porous chitosan scaffolds suit survival and neural differentiation of dental pulp stem cells. Cell Mol Neurobiol 34(6):859–870
Navabazam AR et al (2013) Characterization of mesenchymal stem cells from human dental pulp, preapical follicle and periodontal ligament. Iran J Reprod Med 11(3):235–242
Wang J et al (2010) The odontogenic differentiation of human dental pulp stem cells on nanofibrous poly(L-lactic acid) scaffolds in vitro and in vivo. Acta Biomater 6(10):3856–3863
Arthur A et al (2008) Adult human dental pulp stem cells differentiate toward functionally active neurons under appropriate environmental cues. Stem Cells 26(7):1787–1795
Karaoz E et al (2010) Isolation and in vitro characterisation of dental pulp stem cells from natal teeth. Histochem Cell Biol 133(1):95–112
Gosau M et al (2013) Comparison of the differentiation potential of neural crest derived progenitor cells from apical papilla (dNC-PCs) and stem cells from exfoliated deciduous teeth (SHED) into mineralising cells. Arch Oral Biol 58(6):699–706
Jarmalaviciute A et al (2013) A new experimental model for neuronal and glial differentiation using stem cells derived from human exfoliated deciduous teeth. J Mol Neurosci 51:307–317
Yamaza T et al (2010) Immunomodulatory properties of stem cells from human exfoliated deciduous teeth. Stem Cell Res Ther 1(1):5
Cordeiro MM et al (2008) Dental pulp tissue engineering with stem cells from exfoliated deciduous teeth. J Endod 34(8):962–969
Yamaza T et al (2015) In vivo hepatogenic capacity and therapeutic potential of stem cells from human exfoliated deciduous teeth in liver fibrosis in mice. Stem Cell Res Ther 6:171
Gomes JA et al (2010) Corneal reconstruction with tissue-engineered cell sheets composed of human immature dental pulp stem cells. Invest Ophthalmol Vis Sci 51(3):1408–1414
Nagatomo K et al (2006) Stem cell properties of human periodontal ligament cells. J Periodontal Res 41(4):303–310
Vasandan AB et al (2014) Functional differences in mesenchymal stromal cells from human dental pulp and periodontal ligament. J Cell Mol Med 18(2):344–354
Sowmya S et al (2015) Periodontal specific differentiation of dental follicle stem cells into osteoblast, fibroblast, and cementoblast. Tissue Eng C 21(10):1044–1058
Handa K et al (2002) Progenitor cells from dental follicle are able to form cementum matrix in vivo. Connect Tissue Res 43(2–3):406–408
Fu T et al (2019) Matrigel scaffolding enhances BMP9-induced bone formation in dental follicle stem/precursor cells. Int J Med Sci 16(4):567–575
Abe S, Yamaguchi S, Amagasa T (2007) Multilineage cells from apical pulp of human tooth with immature apex. Oral Sci Int 4(1):45–58
Abe S et al (2012) Neural crest stem cell property of apical pulp cells derived from human developing tooth. Cell Biol Int 36(10):927–936
Yuan C et al (2015) 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 A 21(5–6):1163–1172
de Almeida JF et al (2014) Stem cells of the apical papilla regulate trigeminal neurite outgrowth and targeting through a BDNF-dependent mechanism. Tissue Eng A 20(23–24):3089–3100
Bakopoulou A et al (2013) Comparative characterization of STRO-1neg/CD146pos and STRO-1pos/CD146pos apical papilla stem cells enriched with flow cytometry. Arch Oral Biol 58:1556–1568
Alongi DJ et al (2010) Stem/progenitor cells from inflamed human dental pulp retain tissue regeneration potential. Regen Med 5(4):617–631
Zhao Y et al (2012) Fas ligand regulates the immunomodulatory properties of dental pulp stem cells. J Dent Res 91(10):948–954
Barros MA et al (2015) Immature dental pulp stem cells showed renotropic and pericyte-like properties in acute renal failure in rats. Cell Med 7(3):95–108
Kerkis I et al (2008) Early transplantation of human immature dental pulp stem cells from baby teeth to golden retriever muscular dystrophy (GRMD) dogs: Local or systemic? J Transl Med 6:35
Cianci E et al (2016) Human periodontal stem cells release specialized proresolving mediators and carry immunomodulatory and prohealing properties regulated by lipoxins. Stem Cells Transl Med 5(1):20–32
Shin C et al (2017) Human periodontal ligament stem cells suppress T-cell proliferation via down-regulation of non-classical major histocompatibility complex-like glycoprotein CD1b on dendritic cells. J Periodontal Res 52(1):135–146
Genc D et al (2018) Dental follicle mesenchymal stem cells down-regulate Th2-mediated immune response in asthmatic patients mononuclear cells. Clin Exp Allergy 48(6):663–678
Zhou T et al (2019) Dental follicle cells: roles in development and beyond. Stem Cells Int 2019:9159605
Ulusoy C et al (2015) Dental follicle mesenchymal stem cell administration ameliorates muscle weakness in MuSK-immunized mice. J Neuroinflammation 12:231
Ding G et al (2010) Suppression of T cell proliferation by root apical papilla stem cells in vitro. Cells Tissues Organs 191(5):357–364
Acknowledgements
All authors are acknowledged in the authorship.
Funding
None.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declares that they have no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Ayoub, S., Berbéri, A. & Fayyad-kazan, M. An update on human periapical cyst-mesenchymal stem cells and their potential applications in regenerative medicine. Mol Biol Rep 47, 2381–2389 (2020). https://doi.org/10.1007/s11033-020-05298-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-020-05298-6