Role of Mesenchymal Stem Cells—Derived Exosomes in Osteoarthritis Treatment

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Exosomes are nanovesicles that are involved in inter-cellular communication and are secreted by many types of cells. Exosomes secreted by stem cells can effectively transport bioactive proteins, messenger ribonucleic acids (mRNAs) and microribonucleic acids (miRNAs) organelles and play important roles in intercellular communication and the regulation of tissue regeneration. This transfer of bioactive molecules plays a main role in: tumor invasion and metastasis, immune and inflammation modulation, epithelial-mesenchymal transition and neurobiology. Mesenchymal Stem Cells (MSC) exosomes provide new perspectives for the development of an off-the-shelf and cell-free MSC therapy for the treatment of cartilage injuries and osteoarthritis. This report describes the progress in exosome studies and potential clinical use for osteoarthritis treatment.

1. Admyre, C., Grunewald, J., Thyberg, J., Gripenbäck, S., Tornling G., Eklund A., 2003: Exosomes with major histo-compatibility complex class II and co-stimulatory molecules are present in human BAL fluid. Eur. Respir. J., 22, 578—583.

2. Bruno, S., Grange, C., Deregibus, M. C., 2009: Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J. Am. Soc. Nephrol., 20, 1053—1067.

3. Caby, M. P., Lankar, D., Vincendeau-Scherrer, C., Raposo, G., Bonnerot, C., 2005: Exosomal-like vesicles are present in human blood plasma. Int. Immunol., 17, 879—887.

4. Clayton, A., Al-Taei, S., Webber, J., Mason, M. D., Tabi, Z., 2011: Cancer exosomes express CD39 and CD73, which suppress t cells through adenosine production. J. Immunol., 187, 676—683.

5. Cosenza, S., Ruiz, M., Toupet, K., Jorgensen, Ch., Noël, D., 2017: Mesenchymal stem cells derived exosomes and microparticles protect cartilage and bone from degradation in osteoarthritis. Scientific Reports, 7, 16214.

6. De Bari, C., Roelofs, A. J., 2018: Stem cell-based therapeutic strategies for cartilage defects and osteoarthritis. Current Opinion in Pharmacology, 40, 74—80.

7. De Gassart, A., Geminard, C., Fevrier, B., Raposo, G., Vidal, M., 2003: Lipid raft-associated protein sorting in exosomes. Blood, 102, 4336—4344.

8. Duijvesz, D., Luider, T., Bangma, C. H., Jenster, G., 2011: Exosomes as biomarker treasure chests for prostate cancer. Eur. Urol., 59, 823—831.

9. Fevrier, B., Vilette, D., Archer, F., Loew, D., Faigle, W., Vidal, M., 2004: Cells release prions in association with exosomes. Proc. Natl. Acad. Sci. USA, 101, 9683—9688.

10. Ge, Z., Hu, Y., Heng, B. C., Yang, Z., Ouyang, H., Lee, E. H., et al., 2006: Osteoarthritis and therapy. Arthritis Care Res., 55, 493—500.

11. Heijnen, H. F., Schiel, A. E., Fijnheer, R., Geuze, H.., Sixma, J. J., 1999: Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules. Blood, 94, 3791—3799.

12. Hu, G. W., Li, Q., Niu, X., Hu, B., Liu, J., Zhou, S. M., et al., 2015: Exosomes secreted by human-induced pluripotent stem cell-derived mesenchymal stem cells attenuate limb ischemia by promoting angiogenesis in mice. Stem Cell Res. Ther., 6, 10.

13. Lai, R. C., Arslan, F., Lee, M. M., 2010: Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res., 4, 214—222.

14. Lai, R. C., Chen, T. S., Lim, S. K., 2011: Mesenchymal stem cell exosome: a novel stem cell-based therapy for cardiovascular disease. Regen. Med., 6, 481—492.

15. Lai, R. C., Yeo, R. W., Lim, S. K., 2015: Mesenchymal stem cell exosomes. Semin. Cell Dev. Biol., 40, 82e88.

16. Lai, R. C., Yeo, R. W., Tan, K. H., Lim, S. K., 2013: Exosomes for drug delivery — a novel application for the mesenchymal stem cell. Biotechnology Advances, 31, 543—551.

17. Lee, C., Mitsialis, S. A., Aslam, M., 2012: Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension. Circulation, 126, 2601—2611.

18. Liu, X., Li, Q., Niu, X., Hu, B., Chen, S., Song, W., et al., 2017: Exosomes secreted from human-induced pluripotent stem cell-derived mesenchymal stem cells prevent osteonecrosis of the femoral head by promoting angiogenesis. Int. J. Biol. Sci., 13, 232—244.

19. Loeser, R. F., Goldring, S. R., Scanzello, C. R., Goldring, M. B., 2012: Osteoarthritis: A disease of the joint as an organ. Arthritis Rheum., 64, 1697—1707.

20. Mamidi, M. K., Das, A. K., Zakaria, Z., Bhonde, R., 2016: Mesenchymal stromal cells for cartilage repair in osteoarthritis. Osteoarthritis and Cartilage, 24, 1307e1316.

21. Maumus, M., Jorgensen, C., Noël, D., 2013: Mesenchymal stem cells in regenerative medicine applied to rheumatic diseases: Role of secretome and exosomes. Biochemie, 95, 2229e2234.

22. Meirelles, L. S., Fontes, A. M., Covas, D. T., Caplan, A. I., 2009: Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev., 20, 419—427.

23. Morishita, M., Takahashi, Y., Nishikawa, M., Takakura, Y., 2017: Pharmacokinetics of exosomes – an important factor for elucidating the biological roles of exosomes and for the development of exosome-based therapeutics. J. Pharm. Sci., 106, 2265—2269.

24. Pan, B. T., Johnstone, R. M., 1983: Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell, 33, 967—978.

25. Peters, P. J., Geuze, H. J., Van Der Donk, H. A., Slot, J. W., Griffith, J. M., Stam, N. J., 1989: Molecules relevant for T cell-target cell interaction are present in cytolytic granules of human T lymphocytes. Eur. J. Immunol., 19, 1469—1475.

26. Pisitkun, T., Shen, R. F., Knepper, M. A., 2004: Identification and proteomic profiling of exosomes in human urine. Proc. Natl. Acad. Sci. U S A, 101, 13368—13373.

27. Rabinowits, G., Gerçel-Taylor, C., Day, J. M., Taylor, D. D., Kloecker, G. H., 2009: Exosomal microRNA: a diagnostic marker for lung cancer. Clin. Lung Cance., 10, 42—46.

28. Raposo, G., Nijman, H., Stoorvogel, W., Liejendekker,., Harding, C. V., Melief, C. J., 1996: B lymphocytes secrete antigen-presenting vesicles. J. Exp. Med., 183, 1161—1172.

29. Raposo, G., Tenza, D., Mecheri, S., Peronet, R., Bonnerot, C., Desaymard, C., 1997: Accumulation of major histocompatibility complex class II molecules in mast cell secretory granules and their release upon degranulation. Mol. Biol. Cell., 8, 2631—2645.

30. Sampson, S., Botto-van Bemden, A., Aufieroet, D., 2015: Stem cell therapies for treatment of cartilage and bone disorders: Osteoarthritis, avascular necrosis, and non-union fractures. PMR, 7, S26—S32.

31. Skog, J., Wurdinger, T., Van Rijn, S., Meijer, D. H., Gainche, L., Curry, W. T., 2008: Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat. Cell. Biol., 10, 1470—1476.

32. Sokolova, V., Ludwig, A. K., Hornung, S., Rotan, O., Horn, P. A., Epple, M., 2011: Characterisation of exosomes derived from human cells by nanoparticle tracking analysis and scanning electron microscopy. Colloids Surf B Biointerfaces, 87, 146—150.

33. Sullivan, R., Saez, F., Girouard, J., Frenette, G., 2005: Role of exosomes in sperm maturation during the transit along the male reproductive tract. Blood Cells Mol. Dis., 35, 1—10.

34. Tao, S., Yuan, T., Zhang, Y., Yin, W., Guo, S., Zhang, Ch., 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, 180—195.

35. Thery, C., Ostrowski, M., Segura, E., 2009: Membrane vesicles as conveyors of immune responses. Nat. Rev. Immunol., 9, 581—593.

36. Toha, W. S., Lai, R. C., Huib, J. H. P., Limd, S. K., 2017: MSC exosome as a cell-free MSC therapy for cartilage regeneration: Implications for osteoarthritis treatment. Seminars in Cell and Developmental Biology, 67, 56—64.

37. Wolfers, J., Lozier, A., Raposo, G., Regnault, A., Théry, C., Masurier, C., 2001: Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming. Nat. Med., 7, 297—303.

38. Wu, L., Prins, H.-J., Helder, M. N., van Blitterswijk, C. A., Karperien, M., 2012: Trophic effects of mesenchymal stem cells in chondrocyte co-cultures are independent of culture conditions and cell sources. Tissue Eng. A., 18, 1542—1551.

39. Wu, L., Leijten, J. C. H., Georgi, N., Post, J. N., van Blitterswijk, C. A. Karperien, M., 2011: Trophic effects of mesenchymal stem cells increase chondrocyte proliferation and matrix formation. Tissue Eng. A., 17, 1425—1436.

40. Wubbolts, R., Leckie, R. S., Veenhuizen, P. T., Schwarz-mann, G., Mobius, W., Hoernschemeyer, J., 2003: Proteomic and biochemical analyses of human B cell-derived exosomes. J. Biol. Chem., 278, 10963—10972.

41. Xin, H., Li, Y., Buller, B., 2012: Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells, 30, 1556—1564.

42. Zhang, S., Chuah, S. J., Lai, R. C., Hui, S. K., Toh, W. S., 2018: MSC exosomes mediate cartilage by enhancing proliferation, attenuating apoptosis and modulating immune reactivity. Biomaterials, 156, 16—27.

43. Zhang, S., Chu, W. C., Lai, R. C., Lim, S. K., Hui, J. H., Toh, W. S., 2016: Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration. Osteoarthr. Cartil., 24, 2135e2140.

44. Zhu, Y., Wang, Y., Zhao, B., Niu, X., Hu, B., Li, Q., et al., 2017: Comparison of exosomes secreted by induced pluripo-tent stem cell-derived mesenchymal stem cells and synovial membrane-derived mesenchymal stem cells for the treatment of osteoarthritis. Stem Cell Research and Therapy, 8, 64.

45. Zitvogel, L., Regnault, A., Lozier, A., Wolfers, J., Flament, C., Tenza, D., 1998: Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat. Med., 4, 594—600.

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