Cell Therapy Based on Mesenchymal Stromal Cells and Their Derivatives in the Comprehensive Treatment of Chronic Periodontitis



Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

Chronic periodontitis is a widespread infectious inflammatory disease that leads to the destruction of the connective tissue and bony structures of the periodontium and is a primary cause of tooth loss in the adult population. Analysis of published data confirms the increasing incidence of periodontitis worldwide, regardless of age and sex, necessitating the development of not only early diagnostic methods but also effective treatment and preventive approaches. Conventional treatments aimed at controlling infection and inflammation cannot achieve complete regeneration of destroyed tissues. Consequently, a promising area of research involves investigating the potential of cell therapy using mesenchymal stromal cells. This review summarizes current data on the role of mesenchymal stromal cells from various origins (dental pulp, periodontal ligament, bone marrow, gingiva) in the pathogenesis and treatment of periodontitis. It examines both direct mechanisms (differentiation into osteoblasts and cementoblasts) and paracrine effects, including pronounced immunomodulation (restoration of the Th17/Treg cell balance, macrophage polarization), effects on angiogenesis, as well as the secretion of extracellular vesicles and exosomes. The results of preclinical studies on the efficacy of both mesenchymal stromal cells and their secretome in in vivo and in vitro models were analyzed. Particular attention was paid to the molecular mechanisms regulating the osteogenic differentiation of these cells under inflammatory conditions, including the role of long non-coding RNAs, microRNAs, and key signaling pathways in the pathogenesis of chronic periodontitis. The review also addresses the impact of systemic factors such as diabetes mellitus and aging on the regenerative potential of mesenchymal stromal cells. Based on a systematic analysis of the available data, it can be concluded that these cells and their derivatives possess high therapeutic potential for periodontal regeneration, opening new horizons for their application in clinical practice.

About the authors

Zhanna V. Dzampaeva

North Ossetian State University after K.L. Khetagurov; North Ossetian State Medical Academy

Author for correspondence.
Email: dzhanaeva_1991@mail.ru
ORCID iD: 0000-0002-0778-5117
SPIN-code: 4402-3614

MD, Cand. Sci. (Medicine), Depart. of Pathological Physiology

Russian Federation, Vladikavkaz; Vladikavkaz

Agunda K. Dzlieva

North Ossetian State Medical Academy

Email: dzhanaeva_1991@mail.ru

student, Depart. of Pathological Physiology

Russian Federation, Vladikavkaz

Anna A. Khubaeva

North Ossetian State Medical Academy

Email: annkh2019@mail.ru

student, Depart. of Pathological Physiology

Russian Federation, Vladikavkaz

Maria M. Gergaulova

North Ossetian State Medical Academy

Email: gergaulovamari@mail.ru

student, Depart. of Pathological Physiology

Russian Federation, Vladikavkaz

Ludmila B. Dzaraeva

North Ossetian State Medical Academy

Email: miladzaraeva@mail.ru
ORCID iD: 0000-0001-5622-6816
SPIN-code: 4595-3410

MD, Cand. Sci. (Medicine), Assistant Professor, Depart. of Chemistry

Russian Federation, Vladikavkaz

Svetlana R. Tagaeva

North Ossetian State Medical Academy; Real clinic

Email: elenatakoeva@mail.ru
ORCID iD: 0009-0008-1924-2006

postgraduate student, Depart. of Pathological Physiology

Russian Federation, Vladikavkaz; Moscow

References

  1. Liu J, Ruan J, Weir MD, et al. Periodontal bone-ligament-cementum regeneration via scaffolds and stem cells. Cells. 2019;8(6):537. doi: 10.3390/cells8060537
  2. İyigün S, Görgülü NG, Doğan B. Changes in MMP-9, T-SOD and SIRT-1 levels after non-surgical periodontal treatment. BMC Oral Health. 2025;25(1):262. doi: 10.1186/s12903-025-05610-5 EDN: XCXAYI
  3. Novello S, Debouche A, Philippe M, et al. Clinical application of mesenchymal stem cells in periodontal regeneration: a systematic review and meta-analysis. J Periodontal Res. 2020;55(1):1–12. doi: 10.1111/jre.12684
  4. Jung J-S, Kook J-K, Park S-N, et al. Salivary microbiota reflecting changes in subgingival microbiota. Microbiol Spectr. 2024;12(11):e01030-24. doi: 10.1128/spectrum.01030-24 EDN: AKZOBD
  5. Ji S, Kook JK, Park SN, et al. Characteristics of the Salivary Microbiota in Periodontal Diseases and Potential Roles of Individual Bacterial Species to Predict the Severity of Periodontal Disease. Microbiol Spectr. 2023;11(3):e04327-22. doi: 10.1128/spectrum.04327-22 EDN: ZVFEAG
  6. Ouchi T, Nakagawa T. Mesenchymal stem cell-based tissue regeneration therapies for periodontitis. Regen Ther. 2020;14:72–78. doi: 10.1016/j.reth.2019.12.011 EDN: MCELBZ
  7. Han N, Liu Y, Du J, et al. Regulation of the Host Immune Microenvironment in Periodontitis and Periodontal Bone Remodeling. Int J Mol Sci. 2023;24(4):3158. doi: 10.3390/ijms24043158 EDN: VIJXWH
  8. Wang W, Liu W, Liu J, et al. NLRC5 modulates bone metabolism and plays a role in periodontitis. J Periodontal Res. 2022;57(4):891–903. doi: 10.1111/jre.13027 EDN: DOZADE
  9. Zhou M, Graves DT. Impact of the host response and osteoblast lineage cells on periodontal disease. Front Immunol. 2022;13:998244. doi: 10.3389/fimmu.2022.998244 EDN: XILTSL
  10. Cheng M, Yuan W, Moshaverinia A, Yu B. Rejuvenation of Mesenchymal Stem Cells to Ameliorate Skeletal Aging. Cells. 2023;12(7):998. doi: 10.3390/cells12070998 EDN: WMOELN
  11. Di Vito A, Bria J, Antonelli A, et al. A Review of Novel Strategies for Human Periodontal Ligament Stem Cell Ex Vivo Expansion: Are They an Evidence-Based Promise for Regenerative Periodontal Therapy? Int J Mol Sci. 2023;24(9):7798. doi: 10.3390/ijms24097798 EDN: ANCAME
  12. Dubuc A, Planat-Bénard V, Marty M, et al. Periodontal Cell Therapy: A Systematic Review and Meta-analysis. Adv Exp Med Biol. 2022;1373:377–397. doi: 10.1007/978-3-030-96881-6_20
  13. Zhang Y, Xiong Y, Chen X, et al. Therapeutic effect of bone marrow mesenchymal stem cells pretreated with acetylsalicylic acid on experimental periodontitis in rats. Int Immunopharmacol. 2018;54:320–328. doi: 10.1016/j.intimp.2017.11.028
  14. Sun L, Du X, Kuang H, et al. Stem cell-based therapy in periodontal regeneration: a systematic review and meta-analysis of clinical studies. BMC Oral Health. 2023;23(1):492. doi: 10.1186/s12903-023-03186-6 EDN: UUOCVV
  15. Mendoza AH, Balzarini D, Alves T, et al. Potential of Mesenchymal Stem Cell Sheets on Periodontal Regeneration: A Systematic Review of Pre-Clinical Studies. Curr Stem Cell Res Ther. 2023;18(7):958–978. doi: 10.2174/1574888X17666220706092520 EDN: BNIEFH
  16. Yan XZ, Yang F, Jansen JA, et al. Cell-Based Approaches in Periodontal Regeneration: A Systematic Review and Meta-Analysis of Periodontal Defect Models in Animal Experimental Work. Tissue Eng Part B Rev. 2015;21(5):411–426. doi: 10.1089/ten.TEB.2015.0049
  17. Racz GZ, Kadar K, Foldes A, et al. Immunomodulatory and potential therapeutic role of mesenchymal stem cells in periodontitis. J Physiol Pharmacol. 2014;65(3):327–339. EDN: USKIIZ
  18. Liu Y, Liu Y, Hu J, et al. Impact of allogeneic dental pulp stem cell injection on tissue regeneration in periodontitis: a multicenter randomized clinical trial. Signal Transduct Target Ther. 2025;10(1):239. doi: 10.1038/s41392-025-02320-w EDN: MDMMDE
  19. Amato M, Santonocito S, Viglianisi G, et al. Impact of Oral Mesenchymal Stem Cells Applications as a Promising Therapeutic Target in the Therapy of Periodontal Disease. Int J Mol Sci. 2022;23(21):13419. doi: 10.3390/ijms232113419 EDN: IGZJZS
  20. Zhang Y, Zhao W, Jia L, et al. The application of stem cells in tissue engineering for the regeneration of periodontal defects in randomized controlled trial: a systematic review and meta-analysis. J Evid Based Dent Pract. 2022;22(2):101713. doi: 10.1016/j.jebdp.2022.101713 EDN: EGIYXP
  21. Ando Y, Tsukasaki M, Huynh NC, et al. The neutrophil-osteogenic cell axis promotes bone destruction in periodontitis. Int J Oral Sci. 2024;16(1):18. doi: 10.1038/s41368-023-00275-8 EDN: BRNQLW
  22. Xia Y, Cheng T, Zhang C, et al. Human bone marrow mesenchymal stem cell-derived extracellular vesicles restore Th17/Treg homeostasis in periodontitis via miR-1246. FASEB J. 2023;37(11):e23226. doi: 10.1096/fj.202300674RR EDN: NLCKRN
  23. Cai XY, Zheng CX, Guo H, et al. Inflammation-triggered Gli1⁺ stem cells engage with extracellular vesicles to prime aberrant neutrophils to exacerbate periodontal immunopathology. Cell Mol Immunol. 2025;22(4):371–389. doi: 10.1038/s41423-025-01271-0 EDN: XYDUDQ
  24. Chen Y, Wang H, Ni Q, et al. B-Cell-Derived TGF-β1 Inhibits Osteogenesis and Contributes to Bone Loss in Periodontitis. J Dent Res. 2023;102(7):767–776. doi: 10.1177/00220345231161005 EDN: GVQIZE
  25. Shao B, Zhou D, Wang J, et al. A novel LncRNA SPIRE1/miR-181a-5p/PRLR axis in mandibular bone marrow-derived mesenchymal stem cells regulates the Th17/Treg immune balance through the JAK/STAT3 pathway in periodontitis. Aging. 2023;15(14):7124–7145. doi: 10.18632/aging.204895 EDN: FDFECS
  26. Su Y, Ai S, Shen Y, et al. Regulatory Effects of Three-Dimensional Cultured Lipopolysaccharide-Pretreated Periodontal Ligament Stem Cell-Derived Secretome on Macrophages. Int J Mol Sci. 2023;24(8):6981. doi: 10.3390/ijms24086981 EDN: YRNJQM
  27. Wang L, Wu F, Song Y, et al. Long noncoding RNA related to periodontitis interacts with miR-182 to upregulate osteogenic differentiation in periodontal mesenchymal stem cells of periodontitis patients. Cell Death Dis. 2016;7(8):e2327. doi: 10.1038/cddis.2016.125
  28. Huang X, Su X, Ma Q, et al. FoxO1 Agonists Promote Bone Regeneration in Periodontitis by Protecting the Osteogenesis of Periodontal Ligament Stem Cells. Stem Cells Dev. 2023;32(15–16):491–503. doi: 10.1089/scd.2023.0013 EDN: LDVZNW
  29. Hernández-Monjaraz B, Santiago-Osorio E, Ledesma-Martínez E, et al. Dental Pulp Mesenchymal Stem Cells as a Treatment for Periodontal Disease in Older Adults. Stem Cells Int. 2020;2020:8890873. doi: 10.1155/2020/8890873 EDN: OIQRFM
  30. Yan W, Li L, Ge L, et al. The cannabinoid receptor I (CB1) enhanced the osteogenic differentiation of BMSCs by rescue impaired mitochondrial metabolism function under inflammatory condition. Stem Cell Res Ther. 2022;13(1):22. doi: 10.1186/s13287-022-02702-9 EDN: DRJHRV
  31. Lin L, Li S, Hu S, et al. UCHL1 Impairs Periodontal Ligament Stem Cell Osteogenesis in Periodontitis. J Dent Res. 2023;102(1):61–71. doi: 10.1177/00220345221116031 EDN: LZKRVL
  32. Lu L, Liu Y, Zhang X, Lin J. The therapeutic role of bone marrow stem cell local injection in rat experimental periodontitis. J Oral Rehabil. 2020;47(Suppl 1):73–82. doi: 10.1111/joor.12841
  33. Lu W, Zhang L, Ji K, et al. Regulatory mechanisms of GCN5 in osteogenic differentiation of MSCs in periodontitis. Clin Exp Dent Res. 2023;9(3):464–471. doi: 10.1002/cre2.695 EDN: GFIRPY
  34. Luo J, Chen H, Wang G, et al. CGRP-Loaded Porous Microspheres Protect BMSCs for Alveolar Bone Regeneration in the Periodontitis Microenvironment. Adv Healthc Mater. 2023;12(28):e2301366. doi: 10.1002/adhm.202301366 EDN: ZMBNNS
  35. Xue P, Li B, An Y, et al. Decreased MORF leads to prolonged endoplasmic reticulum stress in periodontitis-associated chronic inflammation. Cell Death Differ. 2016;23(11):1862–1872. doi: 10.1038/cdd.2016.74
  36. Xing Y, Zhang Y, Jia L, Xu X. Lipopolysaccharide from Escherichia coli stimulates osteogenic differentiation of human periodontal ligament stem cells through Wnt/β-catenin-induced TAZ elevation. Mol Oral Microbiol. 2019;34(1):14–24. doi: 10.1111/omi.12245
  37. Wang Y, Wu H, Shen M, et al. Role of human amnion-derived mesenchymal stem cells in promoting osteogenic differentiation by influencing p38 MAPK signaling in lipopolysaccharide-induced human bone marrow mesenchymal stem cells. Exp Cell Res. 2017;350(1):41–49. doi: 10.1016/j.yexcr.2016.11.003
  38. Chen L, Zhu S, Guo S, Tian W. Mechanisms and clinical application potential of mesenchymal stem cells-derived extracellular vesicles in periodontal regeneration. Stem Cell Res Ther. 2023;14:26. doi: 10.1186/s13287-023-02509-9 EDN: YDGXMH
  39. Yue C, Cao J, Wong A, et al. Human Bone Marrow Stromal Cell Exosomes Ameliorate Periodontitis. J Dent Res. 2022;101(9):1110–1118. doi: 10.1177/00220345221084975 EDN: UIBGUF
  40. Shimizu Y, Takeda-Kawaguchi T, Kuroda I, et al. Exosomes from dental pulp cells attenuate bone loss in mouse experimental periodontitis. J Periodontal Res. 2022;57(1):162–172. doi: 10.1111/jre.12949 EDN: GZOMIB
  41. Zhou H, Qi YX, Zhu CH, et al. Mesenchymal stem cell-derived extracellular vesicles for treatment of bone loss within periodontitis in pre-clinical animal models: a meta-analysis. BMC Oral Health. 2023;23(1):701. doi: 10.1186/s12903-023-03398-w EDN: VOBMUX
  42. Xia Y, Cheng T, Zhang C, et al. Human bone marrow mesenchymal stem cell-derived extracellular vesicles restore Th17/Treg homeostasis in periodontitis via miR-1246. FASEB J. 2023;37(11):e23226. doi: 10.1096/fj.202300674RR EDN: NLCKRN
  43. Zhang Y, Chen J, Fu H, et al. Exosomes derived from 3D-cultured MSCs improve therapeutic effects in periodontitis and experimental colitis and restore the Th17 cell/Treg balance in inflamed periodontium. Int J Oral Sci. 2021;13(1):43. doi: 10.1038/s41368-021-00150-4 EDN: JPCOBI
  44. Yang H, Arecio RM, Zhou X, et al. Therapeutic effect of TSG-6 engineered iPSC-derived MSCs on experimental periodontitis in rats: a pilot study. PLoS One. 2014;9(6):e100285. doi: 10.1371/journal.pone.0100285
  45. Zhu B, Liu W, Zhang H, et al. Tissue-specific composite cell aggregates drive periodontium tissue regeneration by reconstructing a regenerative microenvironment. J Tissue Eng Regen Med. 2017;11(6):1792–1805. doi: 10.1002/term.2077
  46. Lei F, Li M, Lin T, et al. Treatment of inflammatory bone loss in periodontitis by stem cell-derived exosomes. Acta Biomater. 2022;141:333–343. doi: 10.1016/j.actbio.2021.12.035 EDN: FORDDI
  47. Aung KT, Akiyama K, Kunitomo M, et al. Aging-Affected MSC Functions and Severity of Periodontal Tissue Destruction in a Ligature-Induced Mouse Periodontitis Model. Int J Mol Sci. 2020;21(21):8103. doi: 10.3390/ijms21218103 EDN: RCAXOS
  48. Zhou J, Zhu Y, Ai D, et al. Advanced glycation end products impair bone marrow mesenchymal stem cells osteogenesis in periodontitis with diabetes via FTO-mediated N-6-methyladenosine modification of sclerostin. J Transl Med. 2023;21(1):781. doi: 10.1186/s12967-023-04630-5 EDN: XHMHLS
  49. Jung YH, Park JY, Kim HJ, et al. Regenerative Potential of Bone Morphogenetic Protein 7-Engineered Mesenchymal Stem Cells in Ligature-Induced Periodontitis. Tissue Eng Part A. 2023;29(7–8):200–210. doi: 10.1089/ten.TEA.2022.0162 EDN: TNEBYG
  50. Prasetyo EP, Juniarti DE, Kuntjoro M, et al. Mesenchymal stem cells from human umbilical cord decrease inflammation and increase vascularization of induced apical periodontitis model in diabetes mellitus rats. J Appl Oral Sci. 2024;32:e20240225. doi: 10.1590/1678-7757-2024-0225 EDN: JDZIKI
  51. Valeeva GA, Khaibullina RR, Danilko KV, et al. Treatment of chronic periodontitis using multipotent mesenchymal stem cells in an experimental study. Cathedra-Kafedra. Stomatologicheskoe obrazovanie. 2022;(81):38–40. EDN: THVRWZ
  52. Zhang Y, Zhao W, Jia L, et al. The application of stem cells in tissue engineering for the regeneration of periodontal defects in randomized controlled trial: a systematic review and meta-analysis. J Evid Based Dent Pract. 2022;22(2):101713. doi: 10.1016/j.jebdp.2022.101713 EDN: EGIYXP
  53. Patent RUS № 2791194/ 03.03.2023. Byul. № 7. Mandra IuV, Bazarnyi VV, Svetlakova EN, Fadeev FA, et al. Method of treating chronic periodontitis using adipose-derived mesenchymal stem cells. Available from: https://new.fips.ru (In Russ.)
  54. Patent RUS № 2785009/ 01.12.2022. Byul. № 34. Khaibullina RR, Danilko KV, Shangina OR, et al. Method for treating periodontitis using human dental pulp multipotent mesenchymal stem cells and an osteogenesis stimulator. Available from: https://new.fips.ru (In Russ.)
  55. Teng Y, Yang Q, Zhao Y, et al. Dental mesenchymal stem cell-derived exosomes for oral diseases: Classification, functionalization and clinical prospects. Colloids Surf B Biointerfaces. 2026;261:115431. doi: 10.1016/j.colsurfb.2026.115431
  56. Tessier S, Halgand B, Aubeux D, et al. Small Extracellular Vesicles Derived from Lipopolysaccharide-Treated Stem Cells from the Apical Papilla Modulate Macrophage Phenotypes and Inflammatory Interactions in Pulpal and Periodontal Tissues. Int J Mol Sci. 2024;26(1):297. doi: 10.3390/ijms26010297 EDN: LUWIOE
  57. Ahmad P, Estrin N, Farshidfar N, et al. Isolation methods of exosomes derived from dental stem cells. Int J Oral Sci. 2025;17(1):50. doi: 10.1038/s41368-025-00370-y EDN: DQDZJH
  58. Abd Rahman F, Azwa FN. Comparative Dental Pulp Stem Cells (DPSCs) and Periodontal Ligament Stem Cells (PDLSCs): Difference in effect of aspirin on osteoblast potential of PDLSCs and DPSCs. Tissue Cell. 2025;94:102776. doi: 10.1016/j.tice.2025.102776 EDN: QXOVVL
  59. Amriel M, Prasetyo E, Fepiosandi R, et al. Human dental pulp mesenchymal stem cells regenerative potential. Conservative Dentistry Journal. 2025;15:27–32. doi: 10.20473/cdj.v15i1.2025.27-32
  60. Fageeh HN. Preliminary Evaluation of Proliferation, Wound Healing Properties, Osteogenic and Chondrogenic Potential of Dental Pulp Stem Cells Obtained from Healthy and Periodontitis Affected Teeth. Cells. 2021;10(8):2118. doi: 10.3390/cells10082118 EDN: SORFWZ

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

© 2026 Eco-Vector

License URL: https://eco-vector.com/for_authors.php#07