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Yan, F., Xiao, Y., Chen, B., Li, L., Zhang, X., & Liu, Q. Cell Secretome from Mesenchymal Stem Cells for Periodontal Regeneration. Regenerative Medicine and Dentistry. 2024. doi: https://doi.org/10.53941/rmd.2024.100004

Review

Cell Secretome from Mesenchymal Stem Cells for Periodontal Regeneration

Bin Chen 1,, Lili Li 1,, Xiaoxin Zhang 2, Qing Liu 1, Yin Xiao 3,* and Fuhua Yan 1,*

1 Department of Periodontology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing 210008, China

2 Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing 210008, China

3 School of Medicine and Dentistry & Institute for Biomedicine and Glycomics, Griffith University, Gold Coast, QLD 4222, Australia

* Correspondence: yin.xiao@griffith.edu.au (Y.X.); yanfh@nju.edu.cn (F.Y.)

† These authors contributed equally to this work.

Received: 6 November 2024; Revised: 12 December 2024; Accepted: 16 December 2024; Published: 23 December 2024

 

Abstract: Periodontitis affects approximately 50% of the global adult population and results in varying degrees of periodontal destruction. The regeneration of periodontal tissue is in great demand but is currently difficult to achieve. The cell secretome from mesenchymal stem cells (CSmsc) has shown promise in promoting periodontal regeneration and is a translational alternative for mesenchymal stem cell (MSC)-based therapy. The practical components of CSmsc are soluble secretions and extracellular vesicles. The mechanisms of CSmsc-induced tissue regeneration may lie in its regulation of the local microenvironment, modulating immune cells such as macrophages and stimulating local host MSCs, a cell population with a direct effect on tissue regeneration. Therefore, CSmsc has been suggested as a promising cell-based product for future periodontal regenerative therapy. Hence, more studies should be conducted to analyse the effective components of the MSC secretome, explore the underlying mechanisms, and obtain functional CSmsc for clinical translation in periodontal regeneration.

Keywords:

mesenchymal stem cells periodontal regeneration secretome extracellular vesicles cell-free therapy

References

  1. Peres, M.A.; Macpherson, L.M.D.; Weyant, R.J.; et al. Oral diseases: A global public health challenge. Lancet 2019, 394, 249–260. https://doi.org/10.1016/s0140-6736(19)31146-8.
  2. Tassi, S.A.; Sergio, N.Z.; Misawa, M.Y.O.; et al. Efficacy of stem cells on periodontal regeneration: Systematic review of pre-clinical studies. J. Periodontal Res. 2017, 52, 793–812. https://doi.org/10.1111/jre.12455.
  3. d’Aquino, R.; De Rosa, A.; Lanza, V.; et al. Human mandible bone defect repair by the grafting of dental pulp stem/progenitor cells and collagen sponge biocomplexes. Eur. Cells Mater. 2009, 18, 75–83. https://doi.org/10.22203/ecm.v018a07.
  4. Zanwar, K.; Kumar Ganji, K.; Bhongade, M.L. Efficacy of Human Umbilical Stem Cells Cultured on Polylactic/ Polyglycolic Acid Membrane in the Treatment of Multiple Gingival Recession Defects: A Randomized Controlled Clinical Study. J. Dent. 2017, 18, 95–103.
  5. Yan, X.Z.; Yang, F.; Jansen, J.A.; 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, 411–426. https://doi.org/10.1089/ten.TEB.2015.0049.
  6. Sreeparvathy, R.; Belludi, S.A.; Prabhu, A. Platelet Rich Fibrin Matrix (PRFM) and Peripheral Blood Mesenchymal Stem Cells (PBMSCs) in the management of intraosseous defects–A randomized clinical trial. J. Appl. Oral. Sci. Rev. FOB 2024, 32, e20230442. https://doi.org/10.1590/1678-7757-2023-0442.
  7. 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, 1–12. https://doi.org/10.1111/jre.12684.
  8. Pharoun, J.; Berro, J.; Sobh, J.; et al. Mesenchymal stem cells biological and biotechnological advances: Implications for clinical applications. Eur. J. Pharmacol. 2024, 977, 176719. https://doi.org/10.1016/j.ejphar.2024.176719.
  9. Zanwar, K.; Laxmanrao Bhongade, M.; Kumar Ganji, K.; et al. Comparative evaluation of efficacy of stem cells in combination with PLA/PGA membrane versus sub-epithelial connective tissue for the treatment of multiple gingival recession defects: A clinical study. J. Stem Cells 2014, 9, 253–267.
  10. Köseoğlu, S.; Duran, İ.; Sağlam, M.; et al. Efficacy of collagen membrane seeded with autologous gingival fibroblasts in gingival recession treatment: A randomized, controlled pilot study. J. Periodontol. 2013, 84, 1416–1424. https://doi.org/10.1902/jop.2012.120529.
  11. Chen, F.M.; Gao, L.N.; Tian, B.M.; et al. Treatment of periodontal intrabony defects using autologous periodontal ligament stem cells: A randomized clinical trial. Stem Cell Res. Ther. 2016, 7, 33. https://doi.org/10.1186/s13287-016-0288-1.
  12. Ferrarotti, F.; Romano, F.; Gamba, M.N.; et al. Human intrabony defect regeneration with micrografts containing dental pulp stem cells: A randomized controlled clinical trial. J. Clin. Periodontol. 2018, 45, 841–850. https://doi.org/10.1111/jcpe.12931.
  13. Shalini, H.S.; Vandana, K.L. Direct application of autologous periodontal ligament stem cell niche in treatment of periodontal osseous defects: A randomized controlled trial. J. Indian. Soc. Periodontol. 2018, 22, 503–512. https://doi.org/10.4103/jisp.jisp_92_18.
  14. Abdal-Wahab, M.; Abdel Ghaffar, K.A.; Ezzatt, O.M.; et al. Regenerative potential of cultured gingival fibroblasts in treatment of periodontal intrabony defects (randomized clinical and biochemical trial). J. Periodontal Res. 2020, 55, 441–452. https://doi.org/10.1111/jre.12728.
  15. Sánchez, N.; Fierravanti, L.; Núñez, J.; et al. Periodontal regeneration using a xenogeneic bone substitute seeded with autologous periodontal ligament-derived mesenchymal stem cells: A 12-month quasi-randomized controlled pilot clinical trial. J. Clin. Periodontol. 2020, 47, 1391–1402. https://doi.org/10.1111/jcpe.13368.
  16. Apatzidou, D.A.; Bakopoulou, A.A.; Kouzi-Koliakou, K.; et al. A tissue-engineered biocomplex for periodontal reconstruction. A proof-of-principle randomized clinical study. J. Clin. Periodontol. 2021, 48, 1111–1125. https://doi.org/10.1111/jcpe.13474.
  17. Cubuk, S.; Oduncuoglu, B.F.; Alaaddinoglu, E.E. The effect of dental pulp stem cells and L-PRF when placed into the extraction sockets of impacted mandibular third molars on the periodontal status of adjacent second molars: A split-mouth, randomized, controlled clinical trial. Oral. Maxillofac. Surg. 2023, 27, 59–68. https://doi.org/10.1007/s10006-022-01045-2.
  18. Jepsen, K.; Sculean, A.; Jepsen, S. Complications and treatment errors related to regenerative periodontal surgery. Periodontology 2023, 92, 120–134. https://doi.org/10.1111/prd.12504.
  19. Nibali, L.; Sultan, D.; Arena, C.; et al. Periodontal infrabony defects: Systematic review of healing by defect morphology following regenerative surgery. J. Clin. Periodontol. 2021, 48, 100–113. https://doi.org/10.1111/jcpe.13381.
  20. Tsumanuma, Y.; Iwata, T.; Washio, K.; et al. Comparison of different tissue-derived stem cell sheets for periodontal regeneration in a canine 1-wall defect model. Biomaterials 2011, 32, 5819–5825. https://doi.org/10.1016/j.biomaterials.2011.04.071.
  21. Nuñez, J.; Vignoletti, F.; Caffesse, R.G.; et al. Cellular therapy in periodontal regeneration. Periodontology 2019, 79, 107–116. https://doi.org/10.1111/prd.12250.
  22. Nagata, M.; Iwasaki, K.; Akazawa, K.; et al. Conditioned Medium from Periodontal Ligament Stem Cells Enhances Periodontal Regeneration. Tissue Eng. Part. A 2017, 23, 367–377. https://doi.org/10.1089/ten.TEA.2016.0274.
  23. Zhong, Z.; Tan, J.; Tan, L.; et al. Modifications of gut microbiota are associated with the severity of IgA nephropathy in the Chinese population. Int. Immunopharmacol. 2020, 89, 107085. https://doi.org/10.1016/j.intimp.2020.107085.
  24. Gnecchi, M.; Danieli, P.; Malpasso, G.; et al. Paracrine Mechanisms of Mesenchymal Stem Cells in Tissue Repair. Methods Mol. Biol. 2016, 1416, 123–146. https://doi.org/10.1007/978-1-4939-3584-0_7.
  25. Volarevic, V.; Gazdic, M.; Simovic Markovic, B.; et al. Mesenchymal stem cell-derived factors: Immuno-modulatory effects and therapeutic potential. Biofactors 2017, 43, 633–644. https://doi.org/10.1002/biof.1374.
  26. Katagiri, W.; Osugi, M.; Kawai, T.; et al. First-in-human study and clinical case reports of the alveolar bone regeneration with the secretome from human mesenchymal stem cells. Head. Face Med. 2016, 12, 5. https://doi.org/10.1186/s13005-016-0101-5.
  27. Lin, H.; Chen, H.; Zhao, X.; et al. Advances in mesenchymal stem cell conditioned medium-mediated periodontal tissue regeneration. J. Transl. Med. 2021, 19, 456. https://doi.org/10.1186/s12967-021-03125-5.
  28. Peshkova, M.; Korneev, A.; Suleimanov, S.; et al. MSCs’ conditioned media cytokine and growth factor profiles and their impact on macrophage polarization. Stem Cell Res. Ther. 2023, 14, 142. https://doi.org/10.1186/s13287-023-03381-w.
  29. Ng, W.H.; Umar Fuaad, M.Z.; Azmi, S.M.; et al. Guided evaluation and standardisation of mesenchymal stem cell culture conditions to generate conditioned medium favourable to cardiac c-kit cell growth. Cell Tissue Res. 2019, 375, 383–396. https://doi.org/10.1007/s00441-018-2918-7.
  30. Wang, M.; Yuan, Q.; Xie, L. Mesenchymal Stem Cell-Based Immunomodulation: Properties and Clinical Application. Stem Cells Int. 2018, 2018, 3057624. https://doi.org/10.1155/2018/3057624.
  31. Estrada, R.; Li, N.; Sarojini, H.; et al. Secretome from mesenchymal stem cells induces angiogenesis via Cyr61. J. Cell Physiol. 2009, 219, 563–571. https://doi.org/10.1002/jcp.21701.
  32. Park, C.W.; Kim, K.S.; Bae, S.; et al. Cytokine secretion profiling of human mesenchymal stem cells by antibody array. Int. J. Stem Cells 2009, 2, 59–68. https://doi.org/10.15283/ijsc.2009.2.1.59.
  33. Sze, S.K.; de Kleijn, D.P.; Lai, R.C.; et al. Elucidating the secretion proteome of human embryonic stem cell-derived mesenchymal stem cells. Mol. Cell Proteom. 2007, 6, 1680–1689. https://doi.org/10.1074/mcp.M600393-MCP200.
  34. Suh, H.N.; Ji, J.Y.; Heo, J.S. Translating proteome and transcriptome dynamics of periodontal ligament stem cell-derived secretome/conditioned medium in an in vitro model of periodontitis. BMC Oral. Health 2024, 24, 390. https://doi.org/10.1186/s12903-024-04167-z.
  35. Morand, D.N.; Davideau, J.L.; Clauss, F.; et al. Cytokines during periodontal wound healing: Potential application for new therapeutic approach. Oral. Dis. 2017, 23, 300–311. https://doi.org/10.1111/odi.12469.
  36. Sakaguchi, K.; Katagiri, W.; Osugi, M.; et al. Periodontal tissue regeneration using the cytokine cocktail mimicking secretomes in the conditioned media from human mesenchymal stem cells. Biochem. Biophys. Res. Commun. 2017, 484, 100–106. https://doi.org/10.1016/j.bbrc.2017.01.065.
  37. Danesh-Meyer, M.J. Tissue engineering in periodontics using rhBMP-2. J. N. Z. Soc. Periodontol. 2000, 85, 10–14.
  38. Carragee, E.J.; Chu, G.; Rohatgi, R.; et al. Cancer risk after use of recombinant bone morphogenetic protein-2 for spinal arthrodesis. J. Bone Jt. Surg. Am. 2013, 95, 1537–1545. https://doi.org/10.2106/JBJS.L.01483.
  39. Kalluri, R.; LeBleu, V.S. The biology, function, and biomedical applications of exosomes. Science 2020, 367, aau6977. https://doi.org/10.1126/science.aau6977.
  40. Théry, C.; Witwer, K.W.; Aikawa, E.; et al. 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 2018, 7, 1535750. https://doi.org/10.1080/20013078.2018.1535750.
  41. Kalluri, R. The biology and function of extracellular vesicles in immune response and immunity. Immunity 2024, 57, 1752–1768. https://doi.org/10.1016/j.immuni.2024.07.009.
  42. Kumar, M.A.; Baba, S.K.; Sadida, H.Q.; et al. Extracellular vesicles as tools and targets in therapy for diseases. Signal Transduct. Target. Ther. 2024, 9, 27. https://doi.org/10.1038/s41392-024-01735-1.
  43. Witwer, K.W.; Goberdhan, D.C.; O’Driscoll, L.; et al. Updating MISEV: Evolving the minimal requirements for studies of extracellular vesicles. J. Extracell. Vesicles 2021, 10, e12182. https://doi.org/10.1002/jev2.12182.
  44. Mathieu, M.; Névo, N.; Jouve, M.; et al. Specificities of exosome versus small ectosome secretion revealed by live intracellular tracking of CD63 and CD9. Nat. Commun. 2021, 12, 4389. https://doi.org/10.1038/s41467-021-24384-2.
  45. Raghu Kalluri, K.M.M. The role of extracellular vesicles in cancer. Cell 2023, 186, 1610–1626, doi:doi.org/10.1016/j.cell.2023.03.010.
  46. Russell, A.E.; Sneider, A.; Witwer, K.W.; et al. Biological membranes in EV biogenesis, stability, uptake, and cargo transfer: An ISEV position paper arising from the ISEV membranes and EVs workshop. J. Extracell. Vesicles 2019, 8, 1684862. https://doi.org/10.1080/20013078.2019.1684862.
  47. Stenmark, H. Rab GTPases as coordinators of vesicle traffic. Nat. Rev. Mol. Cell Biol. 2009, 10, 513–525. https://doi.org/10.1038/nrm2728.
  48. Phinney, D.G.; Di Giuseppe, M.; Njah, J.; et al. Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat. Commun. 2015, 6, 8472. https://doi.org/10.1038/ncomms9472.
  49. Borcherding, N.; Brestoff, J.R. The power and potential of mitochondria transfer. Nature 2023, 623, 283–291. https://doi.org/10.1038/s41586-023-06537-z.
  50. Soekmadji, C.; Li, B.; Huang, Y.; et al. The future of Extracellular Vesicles as Theranostics–an ISEV meeting report. J. Extracell. Vesicles 2020, 9, 1809766. https://doi.org/10.1080/20013078.2020.1809766.
  51. Qiu, G.; Zheng, G.; Ge, M.; et al. Functional proteins of mesenchymal stem cell-derived extracellular vesicles. Stem Cell Res. Ther. 2019, 10, 359. https://doi.org/10.1186/s13287-019-1484-6.
  52. Verweij, F.J.; Revenu, C.; Arras, G.; et al. Live Tracking of Inter-organ Communication by Endogenous Exosomes In Vivo. Dev. Cell 2019, 48, 573–589 e574. https://doi.org/10.1016/j.devcel.2019.01.004.
  53. Marcoux, G.; Magron, A.; Sut, C.; et al. Platelet-derived extracellular vesicles convey mitochondrial DAMPs in platelet concentrates and their levels are associated with adverse reactions. Transfusion 2019, 59, 2403–2414. https://doi.org/10.1111/trf.15300.
  54. Tsilioni, I.; Theoharides, T.C. Extracellular vesicles are increased in the serum of children with autism spectrum disorder, contain mitochondrial DNA, and stimulate human microglia to secrete IL-1beta. J. Neuroinflammation 2018, 15, 239. https://doi.org/10.1186/s12974-018-1275-5.
  55. Rosina, M.; Ceci, V.; Turchi, R.; et al. Ejection of damaged mitochondria and their removal by macrophages ensure efficient thermogenesis in brown adipose tissue. Cell Metab. 2022, 34, 533–548 e512. https://doi.org/10.1016/j.cmet.2022.02.016.
  56. Deng, H.; Wu, L.; Liu, M.; et al. Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Attenuate LPS-Induced ARDS by Modulating Macrophage Polarization Through Inhibiting Glycolysis in Macrophages. Shock. 2020, 54, 828–843. https://doi.org/10.1097/SHK.0000000000001549.
  57. Liu, L.; Guo, S.; Shi, W.; et al. Bone Marrow Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Promote Periodontal Regeneration. Tissue Eng. Part. A 2021, 27, 962–976. https://doi.org/10.1089/ten.TEA.2020.0141.
  58. 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, 43. https://doi.org/10.1038/s41368-021-00150-4.
  59. Huang, Y.; Liu, Q.; Liu, L.; et al. Lipopolysaccharide-Preconditioned Dental Follicle Stem Cells Derived Small Extracellular Vesicles Treating Periodontitis via Reactive Oxygen Species/Mitogen-Activated Protein Kinase Signaling-Mediated Antioxidant Effect. Int. J. Nanomed. 2022, 17, 799–819. https://doi.org/10.2147/IJN.S350869.
  60. Shi, W.; Guo, S.; Liu, L.; et al. Small Extracellular Vesicles from Lipopolysaccharide-Preconditioned Dental Follicle Cells Promote Periodontal Regeneration in an Inflammatory Microenvironment. ACS Biomater. Sci. Eng. 2020, 6, 5797–5810. https://doi.org/10.1021/acsbiomaterials.0c00882.
  61. Chew, J.R.J.; Chuah, S.J.; Teo, K.Y.W.; et al. Mesenchymal stem cell exosomes enhance periodontal ligament cell functions and promote periodontal regeneration. Acta Biomater. 2019, 89, 252–264. https://doi.org/10.1016/j.actbio.2019.03.021.
  62. Mohammed, E.; Khalil, E.; Sabry, D. Effect of Adipose-Derived Stem Cells and Their Exo as Adjunctive Therapy to Nonsurgical Periodontal Treatment: A Histologic and Histomorphometric Study in Rats. Biomolecules 2018, 8, 167. https://doi.org/10.3390/biom8040167.
  63. Liu, J.; Qiu, X.; Lv, Y.; et al. Apoptotic bodies derived from mesenchymal stem cells promote cutaneous wound healing via regulating the functions of macrophages. Stem Cell Res. Ther. 2020, 11, 507. https://doi.org/10.1186/s13287-020-02014-w.
  64. Li, J.; Wei, C.; Yang, Y.; et al. Apoptotic bodies extracted from adipose mesenchymal stem cells carry microRNA-21-5p to induce M2 polarization of macrophages and augment skin wound healing by targeting KLF6. Burns 2022, 48, 1893–1908. https://doi.org/10.1016/j.burns.2021.12.010.
  65. Liu, J.; Chen, B.; Bao, J.; et al. Macrophage polarization in periodontal ligament stem cells enhanced periodontal regeneration. Stem Cell Res. Ther. 2019, 10, 320. https://doi.org/10.1186/s13287-019-1409-4.
  66. Ma, J.; Zhao, Y.; Sun, L.; et al. Exosomes Derived from Akt-Modified Human Umbilical Cord Mesenchymal Stem Cells Improve Cardiac Regeneration and Promote Angiogenesis via Activating Platelet-Derived Growth Factor D. Stem Cells Transl. Med. 2017, 6, 51–59. https://doi.org/10.5966/sctm.2016-0038.
  67. Huang, P.; Wang, L.; Li, Q.; et al. Atorvastatin enhances the therapeutic efficacy of mesenchymal stem cells-derived exosomes in acute myocardial infarction via up-regulating long non-coding RNA H19. Cardiovasc. Res. 2020, 116, 353–367. https://doi.org/10.1093/cvr/cvz139.
  68. Sil, S.; Dagur, R.S.; Liao, K.; et al. Strategies for the use of Extracellular Vesicles for the Delivery of Therapeutics. J. Neuroimmune Pharmacol. 2020, 15, 422–442. https://doi.org/10.1007/s11481-019-09873-y.
  69. Zhang, J.; Chen, L.; Yu, J.; et al. Advances in the roles and mechanisms of mesenchymal stem cell derived microRNAs on periodontal tissue regeneration. Stem Cell Res. Ther. 2024, 15, 393. https://doi.org/10.1186/s13287-024-03998-5.
  70. Mias, C.; Lairez, O.; Trouche, E.; et al. Mesenchymal stem cells promote matrix metalloproteinase secretion by cardiac fibroblasts and reduce cardiac ventricular fibrosis after myocardial infarction. Stem Cells 2009, 27, 2734–2743. https://doi.org/10.1002/stem.169.
  71. Zhu, S.; Chen, W.; Masson, A.; et al. Cell signaling and transcriptional regulation of osteoblast lineage commitment, differentiation, bone formation, and homeostasis. Cell Discov. 2024, 10, 71. https://doi.org/10.1038/s41421-024-00689-6.
  72. Wei, X.; Liu, F.; Zhang, S.; et al. Human Umbilical Cord Mesenchymal Stem Cell-Derived Conditioned Medium Promotes Human Endometrial Cell Proliferation through Wnt/β-Catenin Signaling. Biomed. Res. Int. 2022, 2022, 8796093. https://doi.org/10.1155/2022/8796093.
  73. Wang, S.; Yang, B.; Mu, H.; et al. PTX3 promotes cementum formation and cementoblast differentiation via HA/ITGB1/FAK/YAP1 signaling pathway. Bone 2024, 187, 117199. https://doi.org/10.1016/j.bone.2024.117199.
  74. Maacha, S.; Sidahmed, H.; Jacob, S.; et al. Paracrine Mechanisms of Mesenchymal Stromal Cells in Angiogenesis. Stem Cells Int. 2020, 2020, 4356359. https://doi.org/10.1155/2020/4356359.
  75. Zimta, A.A.; Baru, O.; Badea, M.; et al. The Role of Angiogenesis and Pro-Angiogenic Exosomes in Regenerative Dentistry. Int. J. Mol. Sci. 2019, 20, 406. https://doi.org/10.3390/ijms20020406.
  76. Qiu, J.; Wang, X.; Zhou, H.; et al. Enhancement of periodontal tissue regeneration by conditioned media from gingiva-derived or periodontal ligament-derived mesenchymal stem cells: A comparative study in rats. Stem Cell Res. Ther. 2020, 11, 42. https://doi.org/10.1186/s13287-019-1546-9.
  77. Chen, B.; Ni, Y.; Liu, J.; et al. Bone Marrow-Derived Mesenchymal Stem Cells Exert Diverse Effects on Different Macrophage Subsets. Stem Cells Int. 2018, 2018, 8348121. https://doi.org/10.1155/2018/8348121.
  78. Wang, J.; Xia, J.; Huang, R.; et al. Mesenchymal stem cell-derived extracellular vesicles alter disease outcomes via endorsement of macrophage polarization. Stem Cell Res. Ther. 2020, 11, 424. https://doi.org/10.1186/s13287-020-01937-8.
  79. Wang, N.; Ma, Y.; Liu, Z.; et al. Hydroxytyrosol prevents PM2.5-induced adiposity and insulin resistance by restraining oxidative stress related NF-kappaB pathway and modulation of gut microbiota in a murine model. Free Radic. Biol. Med. 2019, 141, 393–407. https://doi.org/10.1016/j.freeradbiomed.2019.07.002.
  80. Gratchev, A. TGF-β signalling in tumour associated macrophages. Immunobiology 2017, 222, 75–81. https://doi.org/10.1016/j.imbio.2015.11.016.
  81. Wheeler, K.C.; Jena, M.K.; Pradhan, B.S.; et al. VEGF may contribute to macrophage recruitment and M2 polarization in the decidua. PLoS ONE 2018, 13, e0191040. https://doi.org/10.1371/journal.pone.0191040.
  82. Spinosa, M.; Lu, G.; Su, G.; et al. Human mesenchymal stromal cell-derived extracellular vesicles attenuate aortic aneurysm formation and macrophage activation via microRNA-147. FASEB J. 2018, 2018, fj201701138RR. https://doi.org/10.1096/fj.201701138RR.
  83. Song, Y.; Dou, H.; Li, X.; et al. Exosomal miR-146a Contributes to the Enhanced Therapeutic Efficacy of Interleukin-1beta-Primed Mesenchymal Stem Cells Against Sepsis. Stem Cells 2017, 35, 1208–1221. https://doi.org/10.1002/stem.2564.
  84. Zhao, J.; Li, X.; Hu, J.; et al. Mesenchymal stromal cell-derived exosomes attenuate myocardial ischaemia-reperfusion injury through miR-182-regulated macrophage polarization. Cardiovasc. Res. 2019, 115, 1205–1216. https://doi.org/10.1093/cvr/cvz040.
  85. Li, J.W.; Wei, L.; Han, Z.; et al. Mesenchymal stromal cells-derived exosomes alleviate ischemia/reperfusion injury in mouse lung by transporting anti-apoptotic miR-21-5p. Eur. J. Pharmacol. 2019, 852, 68–76. https://doi.org/10.1016/j.ejphar.2019.01.022.
  86. Gong, X.H.; Liu, H.; Wang, S.J.; et al. Exosomes derived from SDF1-overexpressing mesenchymal stem cells inhibit ischemic myocardial cell apoptosis and promote cardiac endothelial microvascular regeneration in mice with myocardial infarction. J. Cell Physiol. 2019, 234, 13878–13893. https://doi.org/10.1002/jcp.28070.
  87. Wang, J.; Huang, R.; Xu, Q.; et al. Mesenchymal Stem Cell-Derived Extracellular Vesicles Alleviate Acute Lung Injury Via Transfer of miR-27a-3p. Crit. Care Med. 2020, 48, e599–e610. https://doi.org/10.1097/CCM.0000000000004315.
  88. Morrison, T.J.; Jackson, M.V.; Cunningham, E.K.; et al. Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer. Am. J. Respir. Crit. Care Med. 2017, 196, 1275–1286. https://doi.org/10.1164/rccm.201701-0170OC.
  89. Rubio, C.; Puerto, M.; Garcia-Rodriquez, J.J.; et al. Impact of global PTP1B deficiency on the gut barrier permeability during NASH in mice. Mol. Metab. 2020, 35, 100954. https://doi.org/10.1016/j.molmet.2020.01.018.
  90. Chaubey, S.; Thueson, S.; Ponnalagu, D.; et al. Early gestational mesenchymal stem cell secretome attenuates experimental bronchopulmonary dysplasia in part via exosome-associated factor TSG-6. Stem Cell Res. Ther. 2018, 9, 173. https://doi.org/10.1186/s13287-018-0903-4.
  91. Théry, C.; Ostrowski, M.; Segura, E. Membrane vesicles as conveyors of immune responses. Nat. Rev. Immunol. 2009, 9, 581–593. https://doi.org/10.1038/nri2567.
  92. Jackson, M.V.; Morrison, T.J.; Doherty, D.F.; et al. Mitochondrial Transfer via Tunneling Nanotubes is an Important Mechanism by Which Mesenchymal Stem Cells Enhance Macrophage Phagocytosis in the In Vitro and In Vivo Models of ARDS. Stem Cells 2016, 34, 2210–2223. https://doi.org/10.1002/stem.2372.
  93. Yuan, Y.; Yuan, L.; Li, L.; et al. Mitochondrial transfer from mesenchymal stem cells to macrophages restricts inflammation and alleviates kidney injury in diabetic nephropathy mice via PGC-1α activation. Stem Cells 2021, 39, 913–928. https://doi.org/10.1002/stem.3375.
  94. Wang, J. Neutrophils in tissue injury and repair. Cell Tissue Res. 2018, 371, 531–539. https://doi.org/10.1007/s00441-017-2785-7.
  95. Bosurgi, L.; Cao, Y.G.; Cabeza-Cabrerizo, M.; et al. Macrophage function in tissue repair and remodeling requires IL-4 or IL-13 with apoptotic cells. Science 2017, 356, 1072–1076. https://doi.org/10.1126/science.aai8132.
  96. Taghavi-Farahabadi, M.; Mahmoudi, M.; Mahdaviani, S.A.; et al. Improving the function of neutrophils from chronic granulomatous disease patients using mesenchymal stem cells’ exosomes. Hum. Immunol. 2020, 81, 614–624. https://doi.org/10.1016/j.humimm.2020.05.009.
  97. Mahmoudi, M.; Taghavi-Farahabadi, M.; Namaki, S.; et al. Exosomes derived from mesenchymal stem cells improved function and survival of neutrophils from severe congenital neutropenia patients in vitro. Hum. Immunol. 2019, 80, 990–998. https://doi.org/10.1016/j.humimm.2019.10.006.
  98. Mahmoudi, M.; Taghavi-Farahabadi, M.; Rezaei, N.; et al. Comparison of the effects of adipose tissue mesenchymal stromal cell-derived exosomes with conditioned media on neutrophil function and apoptosis. Int. Immunopharmacol. 2019, 74, 105689. https://doi.org/10.1016/j.intimp.2019.105689.
  99. Su, V.Y.; Lin, C.S.; Hung, S.C.; et al. Mesenchymal Stem Cell-Conditioned Medium Induces Neutrophil Apoptosis Associated with Inhibition of the NF-kappaB Pathway in Endotoxin-Induced Acute Lung Injury. Int. J. Mol. Sci. 2019, 20, 2208. https://doi.org/10.3390/ijms20092208.
  100. Taghavi-Farahabadi, M.; Mahmoudi, M.; Rezaei, N.; et al. Wharton’s Jelly Mesenchymal Stem Cells Exosomes and Conditioned Media Increased Neutrophil Lifespan and Phagocytosis Capacity. Immunol. Investig. 2021, 50, 1042–1057. https://doi.org/10.1080/08820139.2020.1801720.
  101. Rurik, J.G.; Tombacz, I.; Yadegari, A.; et al. CAR T cells produced in vivo to treat cardiac injury. Science 2022, 375, 91–96. https://doi.org/10.1126/science.abm0594.
  102. Arpaia, N.; Green, J.A.; Moltedo, B.; et al. A Distinct Function of Regulatory T Cells in Tissue Protection. Cell 2015, 162, 1078–1089. https://doi.org/10.1016/j.cell.2015.08.021.
  103. Ge, W.; Jiang, J.; Arp, J.; et al. Regulatory T-cell generation and kidney allograft tolerance induced by mesenchymal stem cells associated with indoleamine 2,3-dioxygenase expression. Transplantation 2010, 90, 1312–1320. https://doi.org/10.1097/TP.0b013e3181fed001.
  104. Weiss, A.R.R.; Dahlke, M.H. Immunomodulation by Mesenchymal Stem Cells (MSCs): Mechanisms of Action of Living, Apoptotic, and Dead MSCs. Front. Immunol. 2019, 10, 1191. https://doi.org/10.3389/fimmu.2019.01191.
  105. Davies, L.C.; Heldring, N.; Kadri, N.; et al. Mesenchymal Stromal Cell Secretion of Programmed Death-1 Ligands Regulates T Cell Mediated Immunosuppression. Stem Cells 2017, 35, 766–776. https://doi.org/10.1002/stem.2509.
  106. Liu, R.; Li, H.F.; Li, S. PD-1-mediated inhibition of T cell activation: Mechanisms and strategies for cancer combination immunotherapy. Cell Insight 2024, 3, 100146. https://doi.org/10.1016/j.cellin.2024.100146.
  107. Wen, D.; Peng, Y.; Liu, D.; et al. Mesenchymal stem cell and derived exosome as small RNA carrier and Immunomodulator to improve islet transplantation. J. Control. Release 2016, 238, 166–175. https://doi.org/10.1016/j.jconrel.2016.07.044.
  108. Court, A.C.; Le-Gatt, A.; Luz-Crawford, P.; et al. Mitochondrial transfer from MSCs to T cells induces Treg differentiation and restricts inflammatory response. EMBO Rep. 2020, 21, e48052. https://doi.org/10.15252/embr.201948052.
  109. Nemeth, K.; Leelahavanichkul, A.; Yuen, P.S.; et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat. Med. 2009, 15, 42–49. https://doi.org/10.1038/nm.1905.
  110. Benavides-Castellanos, M.P.; Garzon-Orjuela, N.; Linero, I. Effectiveness of mesenchymal stem cell-conditioned medium in bone regeneration in animal and human models: A systematic review and meta-analysis. Cell Regen. 2020, 9, 5. https://doi.org/10.1186/s13619-020-00047-3.
  111. Gunawardena, T.N.A.; Rahman, M.T.; Abdullah, B.J.J.; et al. Conditioned media derived from mesenchymal stem cell cultures: The next generation for regenerative medicine. J. Tissue Eng. Regen. Med. 2019, 13, 569–586. https://doi.org/10.1002/term.2806.
  112. Sagaradze, G.; Grigorieva, O.; Nimiritsky, P.; et al. Conditioned Medium from Human Mesenchymal Stromal Cells: Towards the Clinical Translation. Int. J. Mol. Sci. 2019, 20, 1656. https://doi.org/10.3390/ijms20071656.
  113. Kawai, T.; Katagiri, W.; Osugi, M.; et al. Secretomes from bone marrow-derived mesenchymal stromal cells enhance periodontal tissue regeneration. Cytotherapy 2015, 17, 369–381. https://doi.org/10.1016/j.jcyt.2014.11.009.
  114. Takeuchi, R.; Katagiri, W.; Endo, S.; et al. Exosomes from conditioned media of bone marrow-derived mesenchymal stem cells promote bone regeneration by enhancing angiogenesis. PLoS ONE 2019, 14, e0225472. https://doi.org/10.1371/journal.pone.0225472.
  115. Inukai, T.; Katagiri, W.; Yoshimi, R.; et al. Novel application of stem cell-derived factors for periodontal regeneration. Biochem. Biophys. Res. Commun. 2013, 430, 763–768. https://doi.org/10.1016/j.bbrc.2012.11.074.
  116. Jin, Z.; Feng, Y.; Liu, H. Conditioned media from differentiating craniofacial bone marrow stromal cells influence mineralization and proliferation in periodontal ligament stem cells. Hum. Cell 2016, 29, 162–175. https://doi.org/10.1007/s13577-016-0144-8.
  117. Yang, Z.H.; Zhang, X.J.; Dang, N.N.; et al. Apical tooth germ cell-conditioned medium enhances the differentiation of periodontal ligament stem cells into cementum/periodontal ligament-like tissues. J. Periodontal Res. 2009, 44, 199–210. https://doi.org/10.1111/j.1600-0765.2008.01106.x.
  118. Chen, Y.; Liu, H. The differentiation potential of gingival mesenchymal stem cells induced by apical tooth germ cellconditioned medium. Mol. Med. Rep. 2016, 14, 3565–3572. https://doi.org/10.3892/mmr.2016.5726.
  119. Aiello, A.; Giannessi, F.; Percario, Z.A.; et al. An emerging interplay between extracellular vesicles and cytokines. Cytokine Growth Factor. Rev. 2020, 51, 49–60. https://doi.org/10.1016/j.cytogfr.2019.12.003.
  120. Hwang, J.H.; Shim, S.S.; Seok, O.S.; et al. Comparison of cytokine expression in mesenchymal stem cells from human placenta, cord blood, and bone marrow. J. Korean Med. Sci. 2009, 24, 547–554. https://doi.org/10.3346/jkms.2009.24.4.547.
  121. Abels, E.R.; Breakefield, X.O. Introduction to Extracellular Vesicles: Biogenesis, RNA Cargo Selection, Content, Release, and Uptake. Cell Mol. Neurobiol. 2016, 36, 301–312. https://doi.org/10.1007/s10571-016-0366-z.
  122. Li, J.Y.; Ren, K.K.; Zhang, W.J.; et al. Human amniotic mesenchymal stem cells and their paracrine factors promote wound healing by inhibiting heat stress-induced skin cell apoptosis and enhancing their proliferation through activating PI3K/AKT signaling pathway. Stem Cell Res. Ther. 2019, 10, 247. https://doi.org/10.1186/s13287-019-1366-y.
  123. Zhang, J.; Guan, J.; Qi, X.; et al. Dimethyloxaloylglycine Promotes the Angiogenic Activity of Mesenchymal Stem Cells Derived from iPSCs via Activation of the PI3K/Akt Pathway for Bone Regeneration. Int. J. Biol. Sci. 2016, 12, 639–652. https://doi.org/10.7150/ijbs.14025.
  124. Mathieu, M.; Martin-Jaular, L.; Lavieu, G.; et al. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat. Cell Biol. 2019, 21, 9–17. https://doi.org/10.1038/s41556-018-0250-9.
  125. Wang, Y.; Li, C.; Wan, Y.; et al. Quercetin-Loaded Ceria Nanocomposite Potentiate Dual-Directional Immunoregulation via Macrophage Polarization against Periodontal Inflammation. Small 2021, 17, e2101505. https://doi.org/10.1002/smll.202101505.
  126. Sun, Y.; Xue, C.; Wu, H.; et al. Genetically Modified Mesenchymal Stromal Cells in Cartilage Regeneration. Stem Cells Dev. 2023, 32, 365–378. https://doi.org/10.1089/scd.2022.0242.
  127. Su, Y.; Xu, C.; Cheng, W.; et al. Pretreated Mesenchymal Stem Cells and Their Secretome: Enhanced Immunotherapeutic Strategies. Int. J. Mol. Sci. 2023, 24, 1277. https://doi.org/10.3390/ijms24021277.
  128. Wu, Q.; Fu, X.; Li, X.; et al. Modification of adipose mesenchymal stem cells-derived small extracellular vesicles with fibrin-targeting peptide CREKA for enhanced bone repair. Bioact. Mater. 2023, 20, 208–220. https://doi.org/10.1016/j.bioactmat.2022.05.031.
  129. Ju, Y.; Hu, Y.; Yang, P.; et al. Extracellular vesicle-loaded hydrogels for tissue repair and regeneration. Mater. Today. Bio 2023, 18, 100522. https://doi.org/10.1016/j.mtbio.2022.100522.
  130. Zhang, Y.; Wu, D.; Zhou, C.; et al. Engineered extracellular vesicles for tissue repair and regeneration. Burn. Trauma 2024, 12, tkae062. https://doi.org/10.1093/burnst/tkae062.
  131. Lu, S.; Lu, L.; Liu, Y.; et al. Native and engineered extracellular vesicles for wound healing. Front. Bioeng. Biotechnol. 2022, 10, 1053217. https://doi.org/10.3389/fbioe.2022.1053217.
  132. Ryu, K.W.; Fung, T.S.; Baker, D.C.; et al. Cellular ATP demand creates metabolically distinct subpopulations of mitochondria. Nature 2024, 635, 746–754. https://doi.org/10.1038/s41586-024-08146-w.