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Mesenchymal Stem Cell-Derived Extracellular Vesicles: The Novel Therapeutic Option for Regenerative Dentistry

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Abstract

Dental mesenchymal stem cells (MSCs) are characterized by unlimited self-renewal ability and high multidirectional differentiation potential. Since dental MSCs can be easily isolated and exhibit a high capability to differentiate into odontogenic cells, they are considered as attractive therapeutic agents in regenerative dentistry. Recently, MSC-derived extracellular vesicles (MSC-EVs) have attracted widespread attention as carriers for cell-free therapy due to their potential functions. Many studies have shown that MSC-EVs can mediate microenvironment at tissue damage site, and coordinate the regeneration process. Additionally, MSC-EVs can mediate intercellular communication, thus affecting the phenotypes and functions of recipient cells. In this review, we mainly summarized the types of MSCs that could be potentially applied in regenerative dentistry, the possible molecular cargos of MSC-EVs, and the major effects of MSC-EVs on the therapeutic induction of osteogenic differentiation.

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References

  1. Tatullo, M., Marrelli, M., & Paduano, F. (2015). The regenerative medicine in oral and maxillofacial surgery: The most important innovations in the clinical application of mesenchymal stem cells. International Journal of Medical Sciences, 12(1), 72–77.

    Article  CAS  Google Scholar 

  2. Mao, A. S., & Mooney, D. J. (2015). Regenerative medicine: Current therapies and future directions. Proc Natl Acad Sci U S A, 112(47), 14452–14459.

    Article  CAS  Google Scholar 

  3. Wu, V., et al. (2019). Bone Tissue Regeneration in the Oral and Maxillofacial Region: A Review on the Application of Stem Cells and New Strategies to Improve Vascularization. Stem Cells Int, 2019, 6279721.

    Article  Google Scholar 

  4. Amrollahi, P., et al. (2016). Recent advancements in regenerative dentistry: A review. Materials Science & Engineering, C: Materials for Biological Applications, 69, 1383–1390.

    Article  CAS  Google Scholar 

  5. Oldershaw, R. A. (2012). Cell sources for the regeneration of articular cartilage: The past, the horizon and the future. International Journal of Experimental Pathology, 93(6), 389–400.

    CAS  Google Scholar 

  6. Weatherholt, A.M., R.K. Fuchs, and S.J. Warden, Specialized connective tissue: bone, the structural framework of the upper extremity. J Hand Ther, 2012. 25(2): p. 123–31; quiz 132.

  7. 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.

    Article  CAS  Google Scholar 

  8. Chang, J., et al. (2009). Inhibition of osteoblastic bone formation by nuclear factor-kappaB. Nature Medicine, 15(6), 682–689.

    Article  CAS  Google Scholar 

  9. Moerman, E. J., et al. (2004). Aging activates adipogenic and suppresses osteogenic programs in mesenchymal marrow stroma/stem cells: The role of PPAR-gamma2 transcription factor and TGF-beta/BMP signaling pathways. Aging Cell, 3(6), 379–389.

    Article  CAS  Google Scholar 

  10. Yuan, Z., et al. (2016). PPARgamma and Wnt Signaling in Adipogenic and Osteogenic Differentiation of Mesenchymal Stem Cells. Current Stem Cell Research & Therapy, 11(3), 216–225.

    Article  CAS  Google Scholar 

  11. Liu, S., et al. (2015). MSC Transplantation Improves Osteopenia via Epigenetic Regulation of Notch Signaling in Lupus. Cell Metabolism, 22(4), 606–618.

    Article  CAS  Google Scholar 

  12. Wu, Q., et al. (2018). Therapeutic antibody directed osteogenic differentiation of induced pluripotent stem cell derived MSCs. Acta Biomaterialia, 74, 222–235.

    Article  CAS  Google Scholar 

  13. Um, S., Lee, J. H., & Seo, B. M. (2018). TGF-beta2 downregulates osteogenesis under inflammatory conditions in dental follicle stem cells. International Journal of Oral Science, 10(3), 29.

    Article  Google Scholar 

  14. Wang, S., et al. (2012). Insulin-like growth factor 1 can promote the osteogenic differentiation and osteogenesis of stem cells from apical papilla. Stem Cell Res, 8(3), 346–356.

    Article  CAS  Google Scholar 

  15. Li, B., et al. (2012). Basic fibroblast growth factor inhibits osteogenic differentiation of stem cells from human exfoliated deciduous teeth through ERK signaling. Oral Diseases, 18(3), 285–292.

    Article  CAS  Google Scholar 

  16. Kinane, D. F., Stathopoulou, P. G., & Papapanou, P. N. (2017). Periodontal diseases. Nat Rev Dis Primers, 3, 17038.

    Article  Google Scholar 

  17. Liu, Y., et al. (2011). MiR-17 modulates osteogenic differentiation through a coherent feed-forward loop in mesenchymal stem cells isolated from periodontal ligaments of patients with periodontitis. Stem Cells, 29(11), 1804–1816.

    Article  CAS  Google Scholar 

  18. Li, H., et al. (2019). Immunomodulatory Functions of Mesenchymal Stem Cells in Tissue Engineering. Stem Cells Int, 2019, 9671206.

    Google Scholar 

  19. 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.

    Article  Google Scholar 

  20. Toh, W. S., et al. (2014). Advances in mesenchymal stem cell-based strategies for cartilage repair and regeneration. Stem Cell Rev Rep, 10(5), 686–696.

    Article  CAS  Google Scholar 

  21. Bagno, L., et al. (2018). Mesenchymal Stem Cell-Based Therapy for Cardiovascular Disease: Progress and Challenges. Molecular Therapy, 26(7), 1610–1623.

    Article  CAS  Google Scholar 

  22. Han, C., et al. (2016). Exosomes and Their Therapeutic Potentials of Stem Cells. Stem Cells Int, 2016, 7653489.

    Article  Google Scholar 

  23. Huang, C. C., et al. (2020). Evaluating the Endocytosis and Lineage-Specification Properties of Mesenchymal Stem Cell Derived Extracellular Vesicles for Targeted Therapeutic Applications. Frontiers in Pharmacology, 11, 163.

    Article  CAS  Google Scholar 

  24. Lai, R. C., et al. (2010). Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res, 4(3), 214–222.

    Article  CAS  Google Scholar 

  25. Valadi, H., et al. (2007). Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nature Cell Biology, 9(6), 654–659.

    Article  CAS  Google Scholar 

  26. Konala, V. B., et al. (2016). The current landscape of the mesenchymal stromal cell secretome: A new paradigm for cell-free regeneration. Cytotherapy, 18(1), 13–24.

    Article  CAS  Google Scholar 

  27. Pomatto, M., et al., Differential Therapeutic Effect of Extracellular Vesicles Derived by Bone Marrow and Adipose Mesenchymal Stem Cells on Wound Healing of Diabetic Ulcers and Correlation to Their Cargoes. Int J Mol Sci, 2021. 22(8).

  28. Tuz, H. H., et al. (2019). Reconstruction and Implant-Supported Rehabilitation of an Iatrogenically Caused Maxillary Alveolar Defect. Implant Dentistry, 28(5), 510–513.

    Article  Google Scholar 

  29. Dimitriou, R., et al. (2011). Bone regeneration: Current concepts and future directions. BMC Medicine, 9, 66.

    Article  Google Scholar 

  30. Stern, A., & Barzani, G. (2015). Autogenous bone harvest for implant reconstruction. Dental Clinics of North America, 59(2), 409–420.

    Article  Google Scholar 

  31. Khojasteh, A., et al. (2017). Guided Bone Regeneration for the Reconstruction of Alveolar Bone Defects. Ann Maxillofac Surg, 7(2), 263–277.

    Article  Google Scholar 

  32. Stegen, S., van Gastel, N., & Carmeliet, G. (2015). Bringing new life to damaged bone: The importance of angiogenesis in bone repair and regeneration. Bone, 70, 19–27.

    Article  CAS  Google Scholar 

  33. Hughes, F. J., et al. (2000). Effects of growth factors and cytokines on osteoblast differentiation. Periodontology, 2006(41), 48–72.

    Google Scholar 

  34. Panetta, N. J., Gupta, D. M., & Longaker, M. T. (2010). Bone regeneration and repair. Current Stem Cell Research & Therapy, 5(2), 122–128.

    Article  CAS  Google Scholar 

  35. Del Fattore, A., et al. (2014). An experimental therapy to improve skeletal growth and prevent bone loss in a mouse model overexpressing IL-6. Osteoporosis International, 25(2), 681–692.

    Article  Google Scholar 

  36. Rao, S. S., et al. (2018). Omentin-1 prevents inflammation-induced osteoporosis by downregulating the pro-inflammatory cytokines. Bone Res, 6, 9.

    Article  Google Scholar 

  37. Fliefel, R., et al. (2016). Mesenchymal stem cell proliferation and mineralization but not osteogenic differentiation are strongly affected by extracellular pH. Journal of Cranio-Maxillo-Facial Surgery, 44(6), 715–724.

    Article  Google Scholar 

  38. Hu, L., et al., Mesenchymal Stem Cells: Cell Fate Decision to Osteoblast or Adipocyte and Application in Osteoporosis Treatment. Int J Mol Sci, 2018. 19(2).

  39. Botelho, J., et al. (2017). Dental stem cells: Recent progresses in tissue engineering and regenerative medicine. Annals of Medicine, 49(8), 644–651.

    Article  Google Scholar 

  40. Kumar, A., et al. (2017). Secretome Cues Modulate the Neurogenic Potential of Bone Marrow and Dental Stem Cells. Molecular Neurobiology, 54(6), 4672–4682.

    Article  CAS  Google Scholar 

  41. Fujii, Y., et al. (2018). Bone regeneration by human dental pulp stem cells using a helioxanthin derivative and cell-sheet technology. Stem Cell Research & Therapy, 9(1), 24.

    Article  CAS  Google Scholar 

  42. Bakopoulou, A., & About, I. (2016). Stem Cells of Dental Origin: Current Research Trends and Key Milestones towards Clinical Application. Stem Cells Int, 2016, 4209891.

    Article  Google Scholar 

  43. Chalisserry, E. P., et al. (2017). Therapeutic potential of dental stem cells. J Tissue Eng, 8, 2041731417702531.

    Article  Google Scholar 

  44. Huang, G.T., S. Gronthos, and S. Shi, (2009). Mesenchymal stem cells derived from dental tissues vs. those from other sources: their biology and role in regenerative medicine. J Dent Res, 88(9):792–806.

  45. Peng, L., Ye, L., & Zhou, X. D. (2009). Mesenchymal stem cells and tooth engineering. International Journal of Oral Science, 1(1), 6–12.

    Article  Google Scholar 

  46. Hu, L., Liu, Y., & Wang, S. (2018). Stem cell-based tooth and periodontal regeneration. Oral Diseases, 24(5), 696–705.

    Article  CAS  Google Scholar 

  47. Aydin, S., & Sahin, F. (2019). Stem Cells Derived from Dental Tissues. Advances in Experimental Medicine and Biology, 1144, 123–132.

    Article  CAS  Google Scholar 

  48. Gronthos, S., et al. (2000). Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci U S A, 97(25), 13625–13630.

    Article  CAS  Google Scholar 

  49. Gronthos, S., et al. (2002). Stem cell properties of human dental pulp stem cells. Journal of Dental Research, 81(8), 531–535.

    Article  CAS  Google Scholar 

  50. Pisciotta, A., et al. (2015). Human dental pulp stem cells (hDPSCs): Isolation, enrichment and comparative differentiation of two sub-populations. BMC Developmental Biology, 15, 14.

    Article  Google Scholar 

  51. Gopinath, V. K., Soumya, S., & Jayakumar, M. N. (2020). Osteogenic and odontogenic differentiation potential of dental pulp stem cells isolated from inflamed dental pulp tissues (I-DPSCs) by two different methods. Acta Odontologica Scandinavica, 78(4), 281–289.

    Article  CAS  Google Scholar 

  52. Hossein-Khannazer, N., et al. (2019). Study of the immunomodulatory effects of osteogenic differentiated human dental pulp stem cells. Life Sciences, 216, 111–118.

    Article  CAS  Google Scholar 

  53. Tomasello, L., et al. (2017). Mesenchymal stem cells derived from inflamed dental pulpal and gingival tissue: A potential application for bone formation. Stem Cell Research & Therapy, 8(1), 179.

    Article  Google Scholar 

  54. Qin, Z., et al. (2015). High dose of TNF-alpha suppressed osteogenic differentiation of human dental pulp stem cells by activating the Wnt/beta-catenin signaling. Journal of Molecular Histology, 46(4–5), 409–420.

    Article  CAS  Google Scholar 

  55. Feng, G., et al. (2016). SIRT1 was involved in TNF-alpha-promoted osteogenic differentiation of human DPSCs through Wnt/beta-catenin signal. In Vitro Cellular and Developmental Biology. Animal, 52(10), 1001–1011.

    Article  CAS  Google Scholar 

  56. Cui, Y. M., et al. (2017). TNF-alpha was involved in calcium hydroxide-promoted osteogenic differentiation of human DPSCs through NF-kappaB/p38MAPK/Wnt pathway. Die Pharmazie, 72(6), 329–333.

    CAS  Google Scholar 

  57. Chen, L., et al. (2016). Calcium Hydroxide-induced Proliferation, Migration, Osteogenic Differentiation, and Mineralization via the Mitogen-activated Protein Kinase Pathway in Human Dental Pulp Stem Cells. Journal of Endodontia, 42(9), 1355–1361.

    Article  Google Scholar 

  58. Winning, L., El Karim, I. A., & Lundy, F. T. (2019). A Comparative Analysis of the Osteogenic Potential of Dental Mesenchymal Stem Cells. Stem Cells Dev, 28(15), 1050–1058.

    Article  CAS  Google Scholar 

  59. Wang, H., et al. (2018). Comparative characterization of SHED and DPSCs during extended cultivation in vitro. Molecular Medicine Reports, 17(5), 6551–6559.

    CAS  Google Scholar 

  60. Jin, Q., et al. (2019). Comparative characterization of mesenchymal stem cells from human dental pulp and adipose tissue for bone regeneration potential. Artif Cells Nanomed Biotechnol, 47(1), 1577–1584.

    Article  CAS  Google Scholar 

  61. Jarmalaviciute, A., et al. (2015). Exosomes from dental pulp stem cells rescue human dopaminergic neurons from 6-hydroxy-dopamine-induced apoptosis. Cytotherapy, 17(7), 932–939.

    Article  CAS  Google Scholar 

  62. Shen, Z., et al. (2020). Chitosan hydrogel incorporated with dental pulp stem cell-derived exosomes alleviates periodontitis in mice via a macrophage-dependent mechanism. Bioact Mater, 5(4), 1113–1126.

    Article  Google Scholar 

  63. Ji, L., et al. (2019). Comparison of immunomodulatory properties of exosomes derived from bone marrow mesenchymal stem cells and dental pulp stem cells. Immunologic Research, 67(4–5), 432–442.

    Article  CAS  Google Scholar 

  64. Miura, M., et al. (2003). SHED: Stem cells from human exfoliated deciduous teeth. Proc Natl Acad Sci U S A, 100(10), 5807–5812.

    Article  CAS  Google Scholar 

  65. Kashyap, R., SHED - Basic Structure for Stem Cell Research. J Clin Diagn Res, 2015. 9(3): p. ZE07–9.

  66. Brar, G. S., & Toor, R. S. (2012). Dental stem cells: Dentinogenic, osteogenic, and neurogenic differentiation and its clinical cell based therapies. Indian Journal of Dental Research, 23(3), 393–397.

    Article  Google Scholar 

  67. Zhang, N., et al. (2016). Isolation, characterization and multi-lineage differentiation of stem cells from human exfoliated deciduous teeth. Molecular Medicine Reports, 14(1), 95–102.

    Article  CAS  Google Scholar 

  68. Yamaza, T., et al. (2010). Immunomodulatory properties of stem cells from human exfoliated deciduous teeth. Stem Cell Research & Therapy, 1(1), 5.

    Article  Google Scholar 

  69. Junior, A. L., et al. (2020). Mesenchymal Stem Cells from Human Exfoliated Deciduous Teeth and the Orbicularis Oris Muscle: How Do They Behave When Exposed to a Proinflammatory Stimulus? Stem Cells Int, 2020, 3670412.

    Article  Google Scholar 

  70. Zhai, Y., et al. (2019). Activation and Biological Properties of Human beta Defensin 4 in Stem Cells Derived From Human Exfoliated Deciduous Teeth. Frontiers in Physiology, 10, 1304.

    Article  Google Scholar 

  71. Sebastian, A. A., et al. (2018). Interleukin-17A promotes osteogenic differentiation by increasing OPG/RANKL ratio in stem cells from human exfoliated deciduous teeth (SHED). Journal of Tissue Engineering and Regenerative Medicine, 12(8), 1856–1866.

    Article  CAS  Google Scholar 

  72. Novais, A., et al. (2019). Priming Dental Pulp Stem Cells from Human Exfoliated Deciduous Teeth with Fibroblast Growth Factor-2 Enhances Mineralization Within Tissue-Engineered Constructs Implanted in Craniofacial Bone Defects. Stem Cells Translational Medicine, 8(8), 844–857.

    Article  CAS  Google Scholar 

  73. Ishiy, F. A. A., et al. (2018). CD105 is regulated by hsa-miR-1287 and its expression is inversely correlated with osteopotential in SHED. Bone, 106, 112–120.

    Article  CAS  Google Scholar 

  74. Sonoyama, W., et al. (2008). Characterization of the apical papilla and its residing stem cells from human immature permanent teeth: A pilot study. Journal of Endodontia, 34(2), 166–171.

    Article  Google Scholar 

  75. Li, W., et al. (2018). Depletion of HOXA5 inhibits the osteogenic differentiation and proliferation potential of stem cells from the apical papilla. Cell Biology International, 42(1), 45–52.

    Article  CAS  Google Scholar 

  76. Gao, R. T., et al. (2015). Homeobox B7 promotes the osteogenic differentiation potential of mesenchymal stem cells by activating RUNX2 and transcript of BSP. International Journal of Clinical and Experimental Medicine, 8(7), 10459–10470.

    Google Scholar 

  77. Li, G., et al. (2018). Homeobox C10 inhibits the osteogenic differentiation potential of mesenchymal stem cells. Connective Tissue Research, 59(3), 201–211.

    CAS  Google Scholar 

  78. Zhou, M., et al. (2017). Blockade of LGR4 inhibits proliferation and odonto/osteogenic differentiation of stem cells from apical papillae. Journal of Molecular Histology, 48(5–6), 389–401.

    Article  CAS  Google Scholar 

  79. He, W., et al. (2014). Regulatory interplay between NFIC and TGF-beta1 in apical papilla-derived stem cells. Journal of Dental Research, 93(5), 496–501.

    Article  CAS  Google Scholar 

  80. Liu, C., et al. (2016). Long-term exposure to pro-inflammatory cytokines inhibits the osteogenic/dentinogenic differentiation of stem cells from the apical papilla. International Endodontic Journal, 49(10), 950–959.

    Article  CAS  Google Scholar 

  81. Seo, B. M., et al. (2004). Investigation of multipotent postnatal stem cells from human periodontal ligament. Lancet, 364(9429), 149–155.

    Article  CAS  Google Scholar 

  82. Abedian, Z., et al. (2020). A comparative study on immunophenotypic characterization and osteogenic differentiation of human mesenchymal stromal cells derived from periodontal ligament and gingiva. Journal of Periodontology, 91(9), 1194–1202.

    Article  CAS  Google Scholar 

  83. Ai, T., et al. (2018). DNA methylation profile is associated with the osteogenic potential of three distinct human odontogenic stem cells. Signal Transduction and Targeted Therapy, 3, 1.

    Article  CAS  Google Scholar 

  84. Xia, Y., et al. (2016). Cell Responses to Conditioned Media Produced by Patient-Matched Stem Cells Derived From Healthy and Inflamed Periodontal Ligament Tissues. Journal of Periodontology, 87(5), e53-63.

    Article  CAS  Google Scholar 

  85. Tang, H. N., et al. (2016). Stem cells derived from “inflamed” and healthy periodontal ligament tissues and their sheet functionalities: A patient-matched comparison. Journal of Clinical Periodontology, 43(1), 72–84.

    Article  CAS  Google Scholar 

  86. Kato, H., et al. (2014). Porphyromonas gingivalis LPS inhibits osteoblastic differentiation and promotes pro-inflammatory cytokine production in human periodontal ligament stem cells. Archives of Oral Biology, 59(2), 167–175.

    Article  CAS  Google Scholar 

  87. Li, C., et al. (2014). Lipopolysaccharide differentially affects the osteogenic differentiation of periodontal ligament stem cells and bone marrow mesenchymal stem cells through Toll-like receptor 4 mediated nuclear factor kappaB pathway. Stem Cell Research & Therapy, 5(3), 67.

    Article  Google Scholar 

  88. Albiero, M.L., et al., Osteogenic potential of periodontal ligament stem cells are unaffected after exposure to lipopolysaccharides. Braz Oral Res, 2017. 31: p. e17.

  89. Liu, H., et al., Exendin-4 regulates Wnt and NF-kappaB signaling in lipopolysaccharide-induced human periodontal ligament stem cells to promote osteogenic differentiation. Int Immunopharmacol, 2019. 75: p. 105801.

  90. Mao, C.Y., et al., Double-edged-sword effect of IL-1beta on the osteogenesis of periodontal ligament stem cells via crosstalk between the NF-kappaB, MAPK and BMP/Smad signaling pathways. Cell Death Dis, 2016. 7: p. e2296.

  91. Zhang, K., et al. (2019). Autophagy preserves the osteogenic ability of periodontal ligament stem cells under high glucose conditions in rats. Archives of Oral Biology, 101, 172–179.

    Article  CAS  Google Scholar 

  92. Kato, H., et al. (2016). High Glucose Concentrations Suppress the Proliferation of Human Periodontal Ligament Stem Cells and Their Differentiation Into Osteoblasts. Journal of Periodontology, 87(4), e44-51.

    Article  CAS  Google Scholar 

  93. Di Vito, A., et al. (2019). In Vitro Long-Term Expansion and High Osteogenic Potential of Periodontal Ligament Stem Cells: More Than a Mirage. Cell Transplantation, 28(1), 129–139.

    Article  Google Scholar 

  94. Yang, S., et al. (2018). Nitric oxide balances osteoblast and adipocyte lineage differentiation via the JNK/MAPK signaling pathway in periodontal ligament stem cells. Stem Cell Research & Therapy, 9(1), 118.

    Article  CAS  Google Scholar 

  95. Li, M., et al. (2017). Effect of cryopreservation on proliferation and differentiation of periodontal ligament stem cell sheets. Stem Cell Research & Therapy, 8(1), 77.

    Article  Google Scholar 

  96. Zhang, J., et al. (2019). Dental Follicle Stem Cells: Tissue Engineering and Immunomodulation. Stem Cells Dev, 28(15), 986–994.

    Article  Google Scholar 

  97. Shoi, K., et al. (2014). Characterization of pulp and follicle stem cells from impacted supernumerary maxillary incisors. Pediatric Dentistry, 36(3), 79–84.

    Google Scholar 

  98. Mori, G., et al. (2012). Osteogenic differentiation of dental follicle stem cells. International Journal of Medical Sciences, 9(6), 480–487.

    Article  Google Scholar 

  99. Yao, S., et al. (2013). Expression of bone morphogenetic protein-6 in dental follicle stem cells and its effect on osteogenic differentiation. Cells, Tissues, Organs, 198(6), 438–447.

    Article  CAS  Google Scholar 

  100. Rezai Rad, M., et al. (2015). The role of dentin matrix protein 1 (DMP1) in regulation of osteogenic differentiation of rat dental follicle stem cells (DFSCs). Archives of Oral Biology, 60(4), 546–556.

    Article  CAS  Google Scholar 

  101. Yao, S., et al. (2017). Expression of odontogenic ameloblast-associated protein in the dental follicle and its role in osteogenic differentiation of dental follicle stem cells. Archives of Oral Biology, 78, 6–12.

    Article  CAS  Google Scholar 

  102. Chen, C., et al. (2018). Nkd2 promotes the differentiation of dental follicle stem/progenitor cells into osteoblasts. International Journal of Molecular Medicine, 42(5), 2403–2414.

    CAS  Google Scholar 

  103. Rezai-Rad, M., et al. (2015). Evaluation of bone regeneration potential of dental follicle stem cells for treatment of craniofacial defects. Cytotherapy, 17(11), 1572–1581.

    Article  CAS  Google Scholar 

  104. Rezai Rad, M., et al. (2013). Activation of proliferation and differentiation of dental follicle stem cells (DFSCs) by heat stress. Cell Proliferation, 46(1), 58–66.

    Article  CAS  Google Scholar 

  105. Raposo, G., & Stoorvogel, W. (2013). Extracellular vesicles: Exosomes, microvesicles, and friends. Journal of Cell Biology, 200(4), 373–383.

    Article  CAS  Google Scholar 

  106. Harding, C., Heuser, J., & Stahl, P. (1983). Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. Journal of Cell Biology, 97(2), 329–339.

    Article  CAS  Google Scholar 

  107. Johnstone, R.M., et al. (1987). Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem, 262(19): 9412–9420.

  108. Thery, C., et al. (2018). Minimal information for studies of extracellular vesicles 2018 (MISEV2018): A position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles, 7(1), 1535750.

    Article  Google Scholar 

  109. Stoorvogel, W., et al. (2002). The biogenesis and functions of exosomes. Traffic, 3(5), 321–330.

    Article  CAS  Google Scholar 

  110. Thery, C., Zitvogel, L., & Amigorena, S. (2002). Exosomes: Composition, biogenesis and function. Nature Reviews Immunology, 2(8), 569–579.

    Article  CAS  Google Scholar 

  111. Ludwig, A. K., & Giebel, B. (2012). Exosomes: Small vesicles participating in intercellular communication. International Journal of Biochemistry & Cell Biology, 44(1), 11–15.

    Article  CAS  Google Scholar 

  112. Simons, M., & Raposo, G. (2009). Exosomes–vesicular carriers for intercellular communication. Current Opinion in Cell Biology, 21(4), 575–581.

    Article  CAS  Google Scholar 

  113. Greening, D. W., et al. (2015). A protocol for exosome isolation and characterization: Evaluation of ultracentrifugation, density-gradient separation, and immunoaffinity capture methods. Methods in Molecular Biology, 1295, 179–209.

    Article  CAS  Google Scholar 

  114. Flaherty, S. E., 3rd., et al. (2019). A lipase-independent pathway of lipid release and immune modulation by adipocytes. Science, 363(6430), 989–993.

    Article  CAS  Google Scholar 

  115. Hannafon, B. N., et al. (2019). Metastasis-associated protein 1 (MTA1) is transferred by exosomes and contributes to the regulation of hypoxia and estrogen signaling in breast cancer cells. Cell Communication and Signaling: CCS, 17(1), 13.

    Article  Google Scholar 

  116. Cabral, J., et al. (2018). Extracellular vesicles as modulators of wound healing. Advanced Drug Delivery Reviews, 129, 394–406.

    Article  CAS  Google Scholar 

  117. Riazifar, M., et al. (2019). Stem Cell-Derived Exosomes as Nanotherapeutics for Autoimmune and Neurodegenerative Disorders. ACS Nano, 13(6), 6670–6688.

    Article  CAS  Google Scholar 

  118. Chen, B., et al. (2017). Stem Cell-Derived Extracellular Vesicles as a Novel Potential Therapeutic Tool for Tissue Repair. Stem Cells Translational Medicine, 6(9), 1753–1758.

    Article  Google Scholar 

  119. Kaushik, S., & Cuervo, A. M. (2015). Proteostasis and aging. Nature Medicine, 21(12), 1406–1415.

    Article  CAS  Google Scholar 

  120. Sato-Kuwabara, Y., et al. (2015). The fusion of two worlds: Non-coding RNAs and extracellular vesicles–diagnostic and therapeutic implications (Review). International Journal of Oncology, 46(1), 17–27.

    Article  CAS  Google Scholar 

  121. Narayanan, K., et al. (2018). Lineage-specific exosomes could override extracellular matrix mediated human mesenchymal stem cell differentiation. Biomaterials, 182, 312–322.

    Article  CAS  Google Scholar 

  122. Ma, H., et al. (2018). Analysis of differentially expressed microRNA of TNF-alpha-stimulated mesenchymal stem cells and exosomes from their culture supernatant. Archives of Medical Science, 14(5), 1102–1111.

    Article  CAS  Google Scholar 

  123. Kharmate, G., et al., Epidermal Growth Factor Receptor in Prostate Cancer Derived Exosomes. PLoS One, 2016. 11(5): p. e0154967.

  124. Han, Y., et al. (2019). Exosomes from hypoxia-treated human adipose-derived mesenchymal stem cells enhance angiogenesis through VEGF/VEGF-R. International Journal of Biochemistry & Cell Biology, 109, 59–68.

    Article  CAS  Google Scholar 

  125. Sundaram, K., et al. (2019) Plant-Derived Exosomal Nanoparticles Inhibit Pathogenicity of Porphyromonas gingivalis. iScience, 21: p. 308–327.

  126. Gnecchi, M., et al. (2016). Paracrine Mechanisms of Mesenchymal Stem Cells in Tissue Repair. Methods in Molecular Biology, 1416, 123–146.

    Article  CAS  Google Scholar 

  127. Furuta, T., et al. (2016). Mesenchymal Stem Cell-Derived Exosomes Promote Fracture Healing in a Mouse Model. Stem Cells Translational Medicine, 5(12), 1620–1630.

    Article  CAS  Google Scholar 

  128. Narayanan, R., Huang, C. C., & Ravindran, S. (2016). Hijacking the Cellular Mail: Exosome Mediated Differentiation of Mesenchymal Stem Cells. Stem Cells Int, 2016, 3808674.

    Article  Google Scholar 

  129. Wang, X., et al. (2018). Mesenchymal stem cell-derived exosomes have altered microRNA profiles and induce osteogenic differentiation depending on the stage of differentiation. PLoS One, 13(2), e0193059.

    Article  Google Scholar 

  130. Chen, S., et al. (2015). Co-culture with periodontal ligament stem cells enhanced osteoblastic differentiation of MC3T3-E1 cells and osteoclastic differentiation of RAW264.7 cells. Int J Clin Exp Pathol, 8(11), 14596–607.

    Google Scholar 

  131. Wang, M., et al. (2020). SHED-derived conditioned exosomes enhance the osteogenic differentiation of PDLSCs via Wnt and BMP signaling in vitro. Differentiation, 111, 1–11.

    Article  CAS  Google Scholar 

  132. Ekstrom, K., et al., Monocyte exosomes stimulate the osteogenic gene expression of mesenchymal stem cells. PLoS One, 2013. 8(9): p. e75227.

  133. Zheng, Y., et al. (2019). Exosomal microRNA-155-5p from PDLSCs regulated Th17/Treg balance by targeting sirtuin-1 in chronic periodontitis. Journal of Cellular Physiology, 234(11), 20662–20674.

    Article  CAS  Google Scholar 

  134. Thind, A., & Wilson, C. (2016). Exosomal miRNAs as cancer biomarkers and therapeutic targets. J Extracell Vesicles, 5, 31292.

    Article  Google Scholar 

  135. Lai, R. C., Chen, T. S., & Lim, S. K. (2011). Mesenchymal stem cell exosome: A novel stem cell-based therapy for cardiovascular disease. Regenerative Medicine, 6(4), 481–492.

    Article  Google Scholar 

  136. Vishnoi, A., & Rani, S. (2017). MiRNA Biogenesis and Regulation of Diseases: An Overview. Methods in Molecular Biology, 1509, 1–10.

    Article  CAS  Google Scholar 

  137. Deng, Y., et al. (2013). Effects of a miR-31, Runx2, and Satb2 regulatory loop on the osteogenic differentiation of bone mesenchymal stem cells. Stem Cells Dev, 22(16), 2278–2286.

    Article  CAS  Google Scholar 

  138. Fang, S., et al. (2015). MicroRNAs regulate bone development and regeneration. International Journal of Molecular Sciences, 16(4), 8227–8253.

    Article  CAS  Google Scholar 

  139. Xu, J. F., et al. (2014). Altered microRNA expression profile in exosomes during osteogenic differentiation of human bone marrow-derived mesenchymal stem cells. PLoS One, 9(12), e114627.

    Article  Google Scholar 

  140. Gallo, A., et al. (2012). The majority of microRNAs detectable in serum and saliva is concentrated in exosomes. PLoS One, 7(3), e30679.

    Article  CAS  Google Scholar 

  141. Lee, M. J., Park, D. H., & Kang, J. H. (2016). Exosomes as the source of biomarkers of metabolic diseases. Ann Pediatr Endocrinol Metab, 21(3), 119–125.

    Article  Google Scholar 

  142. Huang, Y., et al. (2021). miR-19b enhances osteogenic differentiation of mesenchymal stem cells and promotes fracture healing through the WWP1/Smurf2-mediated KLF5/beta-catenin signaling pathway. Experimental & Molecular Medicine, 53(5), 973–985.

    Article  CAS  Google Scholar 

  143. Jiang, Y., et al. (2020). Bone Marrow Mesenchymal Stem Cell-Derived Exosomal miR-25 Regulates the Ubiquitination and Degradation of Runx2 by SMURF1 to Promote Fracture Healing in Mice. Front Med (Lausanne), 7, 577578.

    Article  Google Scholar 

  144. Zuo, R., et al. (2019). Exosomes derived from human CD34(+) stem cells transfected with miR-26a prevent glucocorticoid-induced osteonecrosis of the femoral head by promoting angiogenesis and osteogenesis. Stem Cell Research & Therapy, 10(1), 321.

    Article  Google Scholar 

  145. Chen, C., et al. (2017). Mesenchymal stem cell transplantation in tight-skin mice identifies miR-151-5p as a therapeutic target for systemic sclerosis. Cell Research, 27(4), 559–577.

    Article  CAS  Google Scholar 

  146. Lv, P. Y., et al. (2020). Osteocyte-derived exosomes induced by mechanical strain promote human periodontal ligament stem cell proliferation and osteogenic differentiation via the miR-181b-5p/PTEN/AKT signaling pathway. Stem Cell Research & Therapy, 11(1), 295.

    Article  CAS  Google Scholar 

  147. Du, W., et al. (2019). Exosomes derived from preadipocytes improve osteogenic differentiation, potentially via reduced miR223 expression. Molecular Medicine Reports, 19(2), 951–958.

    CAS  Google Scholar 

  148. Chen, S., et al. (2019). Exosomes derived from miR-375-overexpressing human adipose mesenchymal stem cells promote bone regeneration. Cell Prolif, 52(5), e12669.

    Article  Google Scholar 

  149. Hashimoto, K., et al. (2018). Cancer-secreted hsa-miR-940 induces an osteoblastic phenotype in the bone metastatic microenvironment via targeting ARHGAP1 and FAM134A. Proc Natl Acad Sci U S A, 115(9), 2204–2209.

    Article  CAS  Google Scholar 

  150. Jiang, L. B., Tian, L., & Zhang, C. G. (2018). Bone marrow stem cells-derived exosomes extracted from osteoporosis patients inhibit osteogenesis via microRNA-21/SMAD7. European Review for Medical and Pharmacological Sciences, 22(19), 6221–6229.

    Google Scholar 

  151. Yang, J. X., et al. (2020). Osteoclast-derived miR-23a-5p-containing exosomes inhibit osteogenic differentiation by regulating Runx2. Cell Signal, 70, 109504.

    Article  CAS  Google Scholar 

  152. Zhuang, X.M. and B. Zhou, Exosome secreted by human gingival fibroblasts in radiation therapy inhibits osteogenic differentiation of bone mesenchymal stem cells by transferring miR-23a. Biomed Pharmacother, 2020. 131: p. 110672.

  153. Xu, R., et al. (2018). MicroRNA-31a-5p from aging BMSCs links bone formation and resorption in the aged bone marrow microenvironment. Aging Cell, 17(4), e12794.

    Article  Google Scholar 

  154. Xu, T., et al. (2020). Exosomal miRNA-128-3p from mesenchymal stem cells of aged rats regulates osteogenesis and bone fracture healing by targeting Smad5. J Nanobiotechnology, 18(1), 47.

    Article  CAS  Google Scholar 

  155. Yang, S., et al. (2020). Exosomal miR-130a-3p regulates osteogenic differentiation of Human Adipose-Derived stem cells through mediating SIRT7/Wnt/beta-catenin axis. Cell Prolif, 53(10), e12890.

    Article  CAS  Google Scholar 

  156. Davis, C., et al. (2017). MicroRNA-183-5p Increases with Age in Bone-Derived Extracellular Vesicles, Suppresses Bone Marrow Stromal (Stem) Cell Proliferation, and Induces Stem Cell Senescence. Tissue Engineering Part A, 23(21–22), 1231–1240.

    Article  CAS  Google Scholar 

  157. Cao, F., et al. (2017). miR-214 promotes periodontal ligament stem cell osteoblastic differentiation by modulating Wnt/betacatenin signaling. Molecular Medicine Reports, 16(6), 9301–9308.

    Article  CAS  Google Scholar 

  158. Li, K. C., et al. (2017). Baculovirus-Mediated miR-214 Knockdown Shifts Osteoporotic ASCs Differentiation and Improves Osteoporotic Bone Defects Repair. Science and Reports, 7(1), 16225.

    Article  Google Scholar 

  159. Sun, Q., et al. (2013). Expression and significance of miRNA-21 and BTG2 in lung cancer. Tumour Biology, 34(6), 4017–4026.

    Article  CAS  Google Scholar 

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Funding

This work was supported by Guangdong Basic and Applied Basic Research Foundation (General Program: 2020A1515010237); Shenzhen Key Medical Discipline Construction Fund (No.SZXK039); and Special Fund for Science and Technology Development of Longgang District, Shenzhen (LGKCYLWS2021000031).

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Haiying Kong and Peiqi Liu finished the writing-original draft; Hongwen Li, Xiantao Zeng, Peiwu Xu, Xinhui Yao and Senqing Liu were involved in investigation and validation; Chak Kwong Cheng did conceptualization and editing; Jian Xu performed supervision and funding acquisition.

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Correspondence to Chak Kwong Cheng or Jian Xu.

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Kong, H., Liu, P., Li, H. et al. Mesenchymal Stem Cell-Derived Extracellular Vesicles: The Novel Therapeutic Option for Regenerative Dentistry. Stem Cell Rev and Rep 19, 46–58 (2023). https://doi.org/10.1007/s12015-022-10342-y

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