The Efficacy of Stem Cells Secretome Application in Osteoarthritis: A Systematic Review of In Vivo Studies

Abstract

Purpose

Mesenchymal stem cells (MSCs) have appeared as a promising regenerative cell-based therapeutic, for degenerative conditions, such as OA, while the beneficial results from the application of MSCs have been attributed to the MSCs-derived secretome, which is the sum of cytoprotective factors produced by the MSCs. Aim of this study was to systematically review the literature in order to assess whether stem cell secretome (conditioned medium-CM, exosome-Exos or microvesicles-MV)(CM/Exos/MVs) treatment reduces inflammation and enhances cartilage regeneration in preclinical studies of experimental arthritis.

Materials and Methods

An extensive electronic search was conducted by 2 independent reviewers by using the PubMed, Cochrane Library, Web of Science, and Scopus database, as well as Google Scholar, in order to identify the studies that met our inclusion criteria until August 2019. Included studies were assessed for quality and Risk of Bias (RoB) using the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines and a modification of Systematic Review Centre for Laboratory animal Experimentation (SYRCLE) RoB tool for animal studies, respectively.

Results

The initial search provided 525 records, with 28 fulfilling the inclusion criteria. The included studies presented great heterogeneity regarding the stem cells used, the preparation of therapeutic agent as well as the animal models used for testing. In addition, most studies presented with an unclear or high risk bias.

Conclusion

In summary, the positive results of CM/Exos/MVs application in preclinical models of experimentally induced OA in terms of resolution of inflammation and cartilage regeneration are highlighted in this review, presenting a promising therapeutic solution for OA.

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Fig. 1

References

  1. 1.

    Aspden, R. M., & Saunders, F. R. (2019). Osteoarthritis as an organ disease: From the cradle to the grave. European Cells and Materials, 37, 74–87. https://doi.org/10.22203/eCM.v037a06.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Cisternas, M. G., Murphy, L., Sacks, J. J., Solomon, D. H., Pasta, D. J., & Helmick, C. G. (2016). Alternative methods for defining osteoarthritis and the impact on estimating prevalence in a US population-based survey. Arthritis Care and Research, 68(5), 574–580. https://doi.org/10.1002/acr.22721.

    Article  PubMed  Google Scholar 

  3. 3.

    Torio, C. M., & Moore, B. J. (2016). Statistical brief #204 national inpatient hospital costs: The most expensive conditions by payer, 2013. Hcup, 204, 1–15. https://doi.org/10.1377/hlthaff.2015.1194.3.

    Article  Google Scholar 

  4. 4.

    Raman, S., Fitzgerald, U., Murphy, J. M., & Murphy, J. M. (2018). interplay of inflammatory mediators with epigenetics and cartilage modifications in osteoarthritis. Frontiers in Bioengineering and Biotechnology, 6(March, 1–9. https://doi.org/10.3389/fbioe.2018.00022.

    Article  Google Scholar 

  5. 5.

    Loeser, R. F., Collins, J. A., & Diekman, B. O. (2016). Ageing and the pathogenesis of osteoarthritis. Nature Reviews Rheumatology, 12(7), 412–420. https://doi.org/10.1038/nrrheum.2016.65.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Millerand, M., Berenbaum, F., & Jacques, C. (2019). Danger signals and inflammaging in osteoarthritis. Clinical and experimental rheumatology, 37(Suppl 120(5)), 48–56.

    PubMed  Google Scholar 

  7. 7.

    Feng, J. E., Novikov, D., Anoushiravani, A. A., & Schwarzkopf, R. (2018). Total knee arthroplasty: Improving outcomes with a multidisciplinary approach. Journal of Multidisciplinary Healthcare, 11, 63–73. https://doi.org/10.2147/JMDH.S140550.

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Mamidi, M. K., Das, A. K., Zakaria, Z., & Bhonde, R. (2016). Mesenchymal stromal cells for cartilage repair in osteoarthritis. Osteoarthritis and Cartilage, 24(8), 1307–1316. https://doi.org/10.1016/j.joca.2016.03.003.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    McKinney, J. M., Doan, T. N., Wang, L., Deppen, J., Reece, D. S., Pucha, K. A., et al. (2019). Therapeutic efficacy of intra-articular delivery of encapsulated human mesenchymal stem cells on early stage osteoarthritis. European Cells & Materials, 37, 42–59. https://doi.org/10.22203/eCM.v037a04.

    CAS  Article  Google Scholar 

  10. 10.

    Colombini, A., Perucca Orfei, C., Kouroupis, D., Ragni, E., De Luca, P., ViganÒ, M., et al. (2019). Mesenchymal stem cells in the treatment of articular cartilage degeneration: New biological insights for an old-timer cell. Cytotherapy, 21(12), 1179–1197. https://doi.org/10.1016/j.jcyt.2019.10.004.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Home - ClinicalTrials.gov. (n.d.). Retrieved January 19, 2020, from https://clinicaltrials.gov/.

  12. 12.

    Ha, C. W., Park, Y. B., Kim, S. H., & Lee, H. J. (2019). Intra-articular Mesenchymal stem cells in osteoarthritis of the knee: A systematic review of clinical outcomes and evidence of cartilage repair. Arthroscopy - Journal of Arthroscopic and Related Surgery, 35(1), 277.e2–288.e2. https://doi.org/10.1016/j.arthro.2018.07.028.

    Article  Google Scholar 

  13. 13.

    Murphy, J. M., Dixon, K., Beck, S., Fabian, D., Feldman, A., & Barry, F. (2002). Reduced chondrogenic and adipogenic activity of mesenchymal stem cells from patients with advanced osteoarthritis. Arthritis and Rheumatism, 46(3), 704–713. https://doi.org/10.1002/art.10118.

    Article  PubMed  Google Scholar 

  14. 14.

    Barry, F., & Murphy, M. (2013). Mesenchymal stem cells in joint disease and repair. Nature Reviews Rheumatology, 9(10), 584–594. https://doi.org/10.1038/nrrheum.2013.109.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Veronesi, F., Borsari, V., Sartori, M., Orciani, M., Mattioli-Belmonte, M., & Fini, M. (2018). The use of cell conditioned medium for musculoskeletal tissue regeneration. Journal of Cellular Physiology, 233(6), 4423–4442. https://doi.org/10.1002/jcp.26291.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Yuan, Q. L., Zhang, Y. G., & Chen, Q. (2019). Mesenchymal Stem Cell (MSC)-Derived Extracellular Vesicles: Potential Therapeutics as MSC Trophic Mediators in Regenerative Medicine. Anatomical Record, (June 2018). https://doi.org/10.1002/ar.24186.

  17. 17.

    Doyle, M. L., & Wang, Z. M. (2019). Overview of extracellular vesicles, their origin, composition, purpose, and methods for exosome isolation and analysis. Cells, 8(7), 727. https://doi.org/10.1016/b978-0-12-386050-7.50008-3.

    CAS  Article  PubMed Central  Google Scholar 

  18. 18.

    Pourakbari, R., Khodadadi, M., Aghebati-Maleki, A., Aghebati-Maleki, L., & Yousefi, M. (2019). The potential of exosomes in the therapy of the cartilage and bone complications; emphasis on osteoarthritis. Life Sciences, 236(September, 116861. https://doi.org/10.1016/j.lfs.2019.116861.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Théry, C., Witwer, K. W., Aikawa, E., Alcaraz, M. J., Anderson, J. D., Andriantsitohaina, R., 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. Journal of Extracellular Vesicles, 7(1), 1535750. https://doi.org/10.1080/20013078.2018.1535750.

    Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Witwer, K. W., Van Balkom, B. W. M., Bruno, S., Choo, A., Dominici, M., Gimona, M., et al. (2019). Defining mesenchymal stromal cell (MSC)-derived small extracellular vesicles for therapeutic applications. Journal of Extracellular Vesicles, 8(1). https://doi.org/10.1080/20013078.2019.1609206.

  21. 21.

    Moher, D., Liberati, A., Tetzlaff, J., Altman, G. D., & The PRISMA group. (2014). Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement David. Physical Therapy, 89(9), 1–5. https://doi.org/10.1371/journal.pmed.1000097.

    Article  Google Scholar 

  22. 22.

    Kilkenny, C., Browne, W. J., Cuthill, I. C., Emerson, M., & Altman, D. G. (2010). Improving bioscience research reporting: The ARRIVE guidelines for reporting animal research, 8(6), 6–10. https://doi.org/10.1371/journal.pbio.1000412.

  23. 23.

    Helgeland, E., Shanbhag, S., Pedersen, T. O., Mustafa, K., & Rosén, A. (2018). Scaffold-based Temporomandibular joint tissue regeneration in experimental animal models: A systematic review. Tissue Engineering - Part B: Reviews, 24(4), 300–316. https://doi.org/10.1089/ten.teb.2017.0429.

    Article  Google Scholar 

  24. 24.

    Hooijmans, C. R., Rovers, M. M., de Vries, R. B., Leenaars, M., Ritskes-Hoitinga, M. L., & M. W. (2014). SYRCLE’s risk of bias tool for animal studies. BMC Medical Research Methodology, 14(10), 1281–1285. https://doi.org/10.7507/1672-2531.20140206.

    Article  Google Scholar 

  25. 25.

    Zhang, S., Chu, W. C., Lai, R. C., Lim, S. K., Hui, J. H. P., & Toh, W. S. (2016). Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration. Osteoarthritis and Cartilage, 24(12), 2135–2140. https://doi.org/10.1016/j.joca.2016.06.022.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Tao, S.-C., Yuan, T., Zhang, Y.-L., Yin, W.-J., Guo, S.-C., & Zhang, C.-Q. (2017). Exosomes derived from miR-140-5p-overexpressing human synovial mesenchymal stem cells enhance cartilage tissue regeneration and prevent osteoarthritis of the knee in a rat model. Theranostics, 7(1), 180–195. https://doi.org/10.7150/thno.17133.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Liu, Y., Zou, R., Wang, Z., Wen, C., Zhang, F., & Lin, F. (2018). Exosomal KLF3-AS1 from hMSCs promoted cartilage repair and chondrocyte proliferation in osteoarthritis. Biochemical Journal, 475(22), 3629–3638. https://doi.org/10.1042/BCJ20180675.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Wang, R., Xu, B., & Xu, H. (2018). TGF-β1 promoted chondrocyte proliferation by regulating Sp1 through MSC-exosomes derived miR-135b. Cell Cycle, 17(24), 2756–2765. https://doi.org/10.1080/15384101.2018.1556063.

    CAS  Article  PubMed Central  Google Scholar 

  29. 29.

    Zhang, S., Chuah, S. J., Lai, R. C., Hui, J. H. P., Lim, S. K., & Toh, W. S. (2018). MSC exosomes mediate cartilage repair by enhancing proliferation, attenuating apoptosis and modulating immune reactivity. Biomaterials, 156, 16–27. https://doi.org/10.1016/j.biomaterials.2017.11.028.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Zhang, S., Teo, K. Y. W., Chuah, S. J., Lai, R. C., Lim, S. K., & Toh, W. S. (2019). MSC exosomes alleviate temporomandibular joint osteoarthritis by attenuating inflammation and restoring matrix homeostasis. Biomaterials, 200(January), 35–47. https://doi.org/10.1016/j.biomaterials.2019.02.006.

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Chen, W., Sun, Y., Gu, X., Hao, Y., Liu, X., Lin, J., Chen, J., & Chen, S. (2019). Conditioned medium of mesenchymal stem cells delays osteoarthritis progression in a rat model by protecting subchondral bone, maintaining matrix homeostasis, and enhancing autophagy. Journal of Tissue Engineering and Regenerative Medicine, 13, 1618–1628. https://doi.org/10.1002/term.2916.

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Nazemian, V., Nasseri, B., Manaheji, H., & Zaringhalam, J. (2016). Effects of mesenchymal stem cells conditioned medium on behavioral aspects of inflammatory arthritic pain induced by CFA adjuvant. Journal of Cellular and Molecular Anesthesia, 1(2), 47–55. https://doi.org/10.22037/jcma.v1i2.11429.

    Article  Google Scholar 

  33. 33.

    Nazemian, V., Manaheji, H., Sharifi, A. M., & Zaringhalam, J. (2018). Long term treatment by mesenchymal stem cells conditioned medium modulates cellular, molecular and behavioral aspects of adjuvant-induced arthritis. Cellular and Molecular Biology, 64(1), 19–26. https://doi.org/10.14715/cmb/2018.64.2.5.

    Article  PubMed  Google Scholar 

  34. 34.

    Cheng, X., Zhang, G., Zhang, L., Hu, Y., Zhang, K., Sun, X., Zhao, C., Li, H., Li, Y. M., & Zhao, J. (2018). Mesenchymal stem cells deliver exogenous miR-21 via exosomes to inhibit nucleus pulposus cell apoptosis and reduce intervertebral disc degeneration. Journal of Cellular and Molecular Medicine, 22(1), 261–276. https://doi.org/10.1111/jcmm.13316.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Soetjahjo, B., Hidayat, M., Sujuti, H., & Fibrianto, Y. H. (2018). The significant effect of conditioned medium of umbilical cord mesenchymal stem cells in histological improvement of cartilage defect in Wistar rats. Turkish Journal of Immunology, 6(2), 57–64. https://doi.org/10.25002/tji.2018.682.

    Article  Google Scholar 

  36. 36.

    Miranda, J. P., Camões, S. P., Gaspar, M. M., Rodrigues, J. S., Carvalheiro, M., Bárcia, R. N., et al. (2019). The secretome derived from 3D-cultured umbilical cord tissue MSCS counteracts manifestations typifying rheumatoid arthritis. Frontiers in Immunology, 10, 18. https://doi.org/10.3389/fimmu.2019.00018.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Kay, A. G., Long, G., Tyler, G., Stefan, A., Broadfoot, S. J., Piccinini, A. M., Middleton, J., & Kehoe, O. (2017). Mesenchymal stem cell-conditioned medium reduces disease severity and immune responses in inflammatory arthritis. Scientific Reports, 7(1), 18019. https://doi.org/10.1038/s41598-017-18144-w.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Wang, Y., Yu, D., Liu, Z., Zhou, F., Dai, J., Wu, B., Zhou, J., Heng, B. C., Zou, X. H., Ouyang, H., & Liu, H. (2017). Exosomes from embryonic mesenchymal stem cells alleviate osteoarthritis through balancing synthesis and degradation of cartilage extracellular matrix. Stem Cell Research and Therapy, 8(1), 189. https://doi.org/10.1186/s13287-017-0632-0.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Cosenza, S., Ruiz, M., Toupet, K., Jorgensen, C., & Noël, D. (2017). Mesenchymal stem cells derived exosomes and microparticles protect cartilage and bone from degradation in osteoarthritis. Scientific Reports, 7(1), 16214. https://doi.org/10.1038/s41598-017-15376-8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Khatab, S., van Osch, G. J. V. M., Kops, N., Bastiaansen-Jenniskens, Y. M., Bos, P. K., Verhaar, J. A. N., et al. (2018). Mesenchymal stem cell secretome reduces pain and prevents cartilage damage in a murine osteoarthritis model. European Cells and Materials, 36, 218–230. https://doi.org/10.22203/eCM.v036a16.

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Wu, J., Kuang, L., Chen, C., Yang, J., Zeng, W.-N., Li, T., Chen, H., Huang, S., Fu, Z., Li, J., Liu, R., Ni, Z., Chen, L., & Yang, L. (2019). miR-100-5p-abundant exosomes derived from infrapatellar fat pad MSCs protect articular cartilage and ameliorate gait abnormalities via inhibition of mTOR in osteoarthritis. Biomaterials, 206, 87–100. https://doi.org/10.1016/j.biomaterials.2019.03.022.

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Ishikawa, J., Takahashi, N., Matsumoto, T., Yoshioka, Y., Yamamoto, N., Nishikawa, M., Hibi, H., Ishigro, N., Ueda, M., Furukawa, K., & Yamamoto, A. (2016). Factors secreted from dental pulp stem cells show multifaceted benefits for treating experimental rheumatoid arthritis. Bone, 83, 210–219. https://doi.org/10.1016/j.bone.2015.11.012.

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Chen, Z., Wang, H., Xia, Y., Yan, F., & Lu, Y. (2018). Therapeutic potential of mesenchymal cell-derived miRNA-150-5p-expressing exosomes in rheumatoid arthritis mediated by the modulation of MMP14 and VEGF. Journal of Immunology, 201(8), 2472–2482. https://doi.org/10.4049/jimmunol.1800304.

    CAS  Article  Google Scholar 

  44. 44.

    Cosenza, S., Toupet, K., Maumus, M., Luz-Crawford, P., Blanc-Brude, O., Jorgensen, C., & Noël, D. (2018). Mesenchymal stem cells-derived exosomes are more immunosuppressive than microparticles in inflammatory arthritis. Theranostics, 8(5), 1399–1410. https://doi.org/10.7150/thno.21072.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Zhu, Y., Wang, Y., Zhao, B., Niu, X., Hu, B., Li, Q., Zhang, J., Ding, J., Chen, Y., & Wang, Y. (2017). Comparison of exosomes secreted by induced pluripotent stem cell-derived mesenchymal stem cells and synovial membrane-derived mesenchymal stem cells for the treatment of osteoarthritis. Stem Cell Research and Therapy, 8(1), 64. https://doi.org/10.1186/s13287-017-0510-9.

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Mao, G., Zhang, Z., Hu, S., Zhang, Z., Chang, Z., Huang, Z., Liao, W., & Kang, Y. (2018). Exosomes derived from miR-92a-3poverexpressing human mesenchymal stem cells enhance chondrogenesis and suppress cartilage degradation via targeting WNT5A. Stem Cell Research and Therapy, 9(1), 1–13. https://doi.org/10.1186/s13287-018-1004-0.

    CAS  Article  Google Scholar 

  47. 47.

    Liu, X., Yang, Y., Li, Y., Niu, X., Zhao, B., Wang, Y., Bao, C., Xie, Z., Lin, Q., & Zhu, L. (2017). Integration of stem cell-derived exosomes with in situ hydrogel glue as a promising tissue patch for articular cartilage regeneration. Nanoscale, 9(13), 4430–4438. https://doi.org/10.1039/c7nr00352h.

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Veronesi, F., Desando, G., Fini, M., Parrilli, A., Lolli, R., Maglio, M., Martini, L., Giavaresi, G., Bartolotti, I., Grigolo, B., & Sartori, M. (2019). Bone marrow concentrate and expanded mesenchymal stromal cell surnatants as cell-free approaches for the treatment of osteochondral defects in a preclinical animal model. International Orthopaedics, 43(1), 25–34. https://doi.org/10.1007/s00264-018-4202-6.

    Article  PubMed  Google Scholar 

  49. 49.

    Chen, P., Zheng, L., Wang, Y., Tao, M., Xie, Z., Xia, C., Gu, C., Chen, J., Qiu, P., Mei, S., Ning, L., Shi, Y., Fang, C., Fan, S., & Lin, X. (2019). Desktop-stereolithography 3D printing of a radially oriented extracellular matrix/mesenchymal stem cell exosome bioink for osteochondral defect regeneration. Theranostics, 9(9), 2439–2459. https://doi.org/10.7150/thno.31017.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Xia, C., Zeng, Z., Fang, B., Tao, M., Gu, C., Zheng, L., Wang, Y., Shi, Y., Fang, C., Mei, S., Chen, Q., Zhao, J., Lin, X., Fan, S., Jin, Y., & Chen, P. (2019). Mesenchymal stem cell-derived exosomes ameliorate intervertebral disc degeneration via anti-oxidant and anti-inflammatory effects. Free Radical Biology and Medicine, 143(July), 1–15. https://doi.org/10.1016/j.freeradbiomed.2019.07.026.

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Sabry, D., Shamaa, A., Amer, M., El-Tookhy, O., Abdallah, A., Abd El Hassib, D. M., et al. (2018). The effect of mesenchymal stem cell derived microvesicles in repair of femoral chondral defects in dogs. Journal of Musculoskeletal Research, 21(2), 1–12. https://doi.org/10.1142/S0218957718500069.

    Article  Google Scholar 

  52. 52.

    Casado, J. G., Blázquez, R., Vela, F. J., Álvarez, V., Tarazona, R., & Sánchez-Margallo, F. M. (2017). Mesenchymal stem cell-derived exosomes: Immunomodulatory evaluation in an antigen-induced synovitis porcine model. Frontiers in Veterinary Science, 4(MAR). https://doi.org/10.3389/fvets.2017.00039.

  53. 53.

    Liu, Y., Zou, R., Wang, Z., Wen, C., Zhang, F., & Lin, F. (2018). Exosomal KLF3-AS1 from hMSCs promoted cartilage repair and chondrocyte proliferation in osteoarthritis. Biochemical Journal, 475(22), 3629–3638. https://doi.org/10.1042/BCJ20180675.

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Wang, R., Xu, B., & Xu, H. (2018). TGF-β1 promoted chondrocyte proliferation by regulating Sp1 through MSC-exosomes derived miR-135b. Cell Cycle, 17(24), 2756–2765. https://doi.org/10.1080/15384101.2018.1556063.

    CAS  Article  PubMed Central  Google Scholar 

  55. 55.

    Vizoso, F. J., Eiro, N., Cid, S., Schneider, J., & Perez-Fernandez, R. (2017). Mesenchymal stem cell secretome: Toward cell-free therapeutic strategies in regenerative medicine. International Journal of Molecular Sciences, 18(9). https://doi.org/10.3390/ijms18091852.

  56. 56.

    Praveen, K. L., Sangeetha, K., Ranjita, M., Vijayalakshmi, S., Rajagopal, K., & Rama, S. V. (2019). The mesenchymal stem cell secretome: A new paradigm towards cell-free therapeutic mode in regenerative medicine. Cytokine and Growth Factor Reviews. Elsevier., 46, 1–9. https://doi.org/10.1016/j.cytogfr.2019.04.002.

  57. 57.

    Konoshenko, M. Y., Lekchnov, E. A., Vlassov, A. V, & Laktionov, P. P. (2018). Isolation of extracellular vesicles: General methodologies and latest trends. BioMed Research International. Hindawi. https://doi.org/10.1155/2018/8545347.

  58. 58.

    Chen, Y. C., Chang, Y. W., Tan, K. P., Shen, Y. S., Wang, Y. H., & Chang, C. H. (2018). Can mesenchymal stem cells and their conditioned medium assist inflammatory chondrocytes recovery? PLoS One, 13(11), 1–16. https://doi.org/10.1371/journal.pone.0205563.

    CAS  Article  Google Scholar 

  59. 59.

    Harrell, C. R., Fellabaum, C., Jovicic, N., Djonov, V., Arsenijevic, N., & Volarevic, V. (2019). Molecular mechanisms responsible for therapeutic potential of Mesenchymal stem cell-derived Secretome. Cells, 8(5), 467. https://doi.org/10.3390/cells8050467.

    CAS  Article  PubMed Central  Google Scholar 

  60. 60.

    Bright, J. J., Kerr, L. D., & Sriram, S. (1997). TGF-beta inhibits IL-2-induced tyrosine phosphorylation and activation of Jak-1 and Stat 5 in T lymphocytes. Journal of immunology (Baltimore, Md.: 1950), 159(1), 175–183 Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9200453.

    CAS  Google Scholar 

  61. 61.

    Toh, W. S., Lai, R. C., Zhang, B., & Lim, S. K. (2018). MSC exosome works through a protein-based mechanism of action. Biochemical Society Transactions, 46, 843–853. https://doi.org/10.1042/BST20180079.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Bradley, E. W., & Drissi, M. H. (2010). WNT5A regulates chondrocyte differentiation through differential use of the CaN/NFAT and IKK/NF-κB pathways. Molecular Endocrinology, 24(8), 1581–1593. https://doi.org/10.1210/me.2010-0037.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Bradley, E. W., & Drissi, M. H. (2011). Wnt5b regulates mesenchymal cell aggregation and chondrocyte differentiation through the planar cell polarity pathway. Journal of Cellular Physiology, 226(6), 1683–1693. https://doi.org/10.1002/jcp.22499.

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Fang, W., & Vangsness, C. T. (2020). Implications of anti-inflammatory nature of exosomes in knee arthritis. Cartilage. https://doi.org/10.1177/1947603520904766.

  65. 65.

    Tan, S. H. S., Tjio, C. K. E., Wong, J. R. Y., Wong, K. L., Chew, J. R. J., Hui, J. H. P., & Toh, W. S. (2020). A systematic review of Mesenchymal stem cell Exosomes for cartilage repair and regeneration. Tissue Engineering Part B: Reviews, 1–43. https://doi.org/10.1089/ten.teb.2019.0326.

  66. 66.

    Sabapathy, V., & Kumar, S. (2016). hiPSC-derived iMSCs: NextGen MSCs as an advanced therapeutically active cell resource for regenerative medicine. Journal of Cellular and Molecular Medicine, 20(8), 1571–1588. https://doi.org/10.1111/jcmm.12839.

    Article  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Nancarrow-Lei, R., Mafi, P., Mafi, R., & Khan, W. (2017). A systemic review of adult Mesenchymal stem cell sources and their multilineage differentiation potential relevant to musculoskeletal tissue repair and regeneration. Current Stem Cell Research & Therapy, 12, 601–610. https://doi.org/10.2174/1574888X12666170608124303.

    CAS  Article  Google Scholar 

  68. 68.

    Shafiee, A., Kabiri, M., Langroudi, L., Soleimani, M., & Ai, J. (2016). Evaluation and comparison of the in vitro characteristics and chondrogenic capacity of four adult stem/progenitor cells for cartilage cell-based repair. Journal of Biomedical Materials Research - Part A, 104(3), 600–610. https://doi.org/10.1002/jbm.a.35603.

    CAS  Article  PubMed  Google Scholar 

  69. 69.

    Pires, A. O., Mendes-Pinheiro, B., Teixeira, F. G., Anjo, S. I., Ribeiro-Samy, S., Gomes, E. D., Serra, S. C., Silva, N. A., Manadas, B., Sousa, N., & Salgado, A. J. (2016). Unveiling the differences of Secretome of human bone marrow Mesenchymal stem cells, adipose tissue-derived stem cells, and human umbilical cord perivascular cells: A proteomic analysis. Stem Cells and Development, 25(14), 1073–1083. https://doi.org/10.1089/scd.2016.0048.

    CAS  Article  PubMed  Google Scholar 

  70. 70.

    Rocha, B., Calamia, V., Casas, V., Carrascal, M., Blanco, F. J., & Ruiz-Romero, C. (2014). Secretome analysis of human Mesenchymal stem cells undergoing chondrogenic differentiation. Journal of Proteome Research, 13(2), 1045–1054. https://doi.org/10.1021/pr401030n.

    CAS  Article  PubMed  Google Scholar 

  71. 71.

    Bapat, S., Hubbard, D., Munjal, A., Hunter, M., & Fulzele, S. (2018). Pros and cons of mouse models for studying osteoarthritis. Clinical and Translational Medicine., 7, 36. https://doi.org/10.1186/s40169-018-0215-4.

    Article  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Cope, P. J., Ourradi, K., Li, Y., & Sharif, M. (2019). Models of osteoarthritis: The good, the bad and the promising. Osteoarthritis and Cartilage, 27(2), 230–239. https://doi.org/10.1016/j.joca.2018.09.016.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Baar, M. P., Perdiguero, E., Muñoz-Cánoves, P., & de Keizer, P. L. (2018). Musculoskeletal senescence: A moving target ready to be eliminated. Current Opinion in Pharmacology, 40, 147–155. https://doi.org/10.1016/J.COPH.2018.05.007.

    CAS  Article  PubMed  Google Scholar 

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Acknowledgments

This study was supported by a scholarship from the Greek State Scholarship Foundation (IKY), funded by the action “Enhancing human research potential through doctoral research” from resources of the European Program “Development of Human Potential, Education and Lifelong Learning”, 2014-2020 funded by the European Social Fund (ESF) and National Resources.

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MB: conceive the study, systematic search, screening for eligibility, data extraction, bias and quality assessment, and drafting of the manuscript. AB: systematic search, screening for eligibility and drafting the manuscript. AK: drafting the manuscript. PK: bias and quality assessment, and drafting the manuscript. All authors: interpretation of data, critical revision for important intellectual content, approval of the final version of the manuscript to be published, and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Correspondence to Maria Bousnaki.

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Bousnaki, M., Bakopoulou, A., Kritis, A. et al. The Efficacy of Stem Cells Secretome Application in Osteoarthritis: A Systematic Review of In Vivo Studies. Stem Cell Rev and Rep (2020). https://doi.org/10.1007/s12015-020-09980-x

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Keywords

  • Secretome
  • Exosomes
  • Stem cells
  • Cartilage regeneration
  • In vivo
  • Animal study