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Mesenchymal Stromal Cells and Extracellular Vesicles

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Early Osteoarthritis

Abstract

Current treatment strategies for osteoarthritis (OA) are generally palliative, with the goal of alleviating pain and inflammation rather than addressing underlying pathology or slowing OA progression. The presence of clinical symptoms and radiographic changes are indicative of irreversible damage. It is becoming clear that the earlier we intervene, the better the likelihood of preserving cartilage and preventing or delaying end-stage disease. Due to the paucity of effective treatment options for OA, regenerative medicine strategies have recently generated considerable excitement. Therapeutic strategies based on mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (EVs) have rapidly emerged as the most promising approaches for preserving articular cartilage and slowing OA disease progression. Despite the considerable momentum to explore novel regenerative approaches for OA, research is still in the early stages, and paradigms continue to rapidly evolve. This chapter examines current knowledge regarding the biological aspects of MSCs and MSC-derived EVs, their potential mechanisms of action, and promising therapeutic approaches being explored in the context of early OA.

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References

  1. Arden N, Blanco FJ, Cooper C, Guermazi A, Hayashi D, Hunter Kassim Javaid DM, Rannou F, Reginster J-Y, Roemer FW. Atlas of osteoarthritis. Berlin: Springer; 2014. www.springerhealthcare.com.

    Book  Google Scholar 

  2. Kong L, Zheng LZ, Qin L, Ho KKW. Role of mesenchymal stem cells in osteoarthritis treatment. J Orthop Transl. 2017;9:89–103. https://doi.org/10.1016/j.jot.2017.03.006.

    Article  Google Scholar 

  3. Berenbaum F. Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!). Osteoarthr Cartil. 2013;21(1):16–21. https://doi.org/10.1016/j.joca.2012.11.012.

    Article  CAS  Google Scholar 

  4. Sokolove J, Lepus CM. Role of inflammation in the pathogenesis of osteoarthritis: latest findings and interpretations. Ther Adv Musculoskelet Dis. 2013;5(2):77–94. https://doi.org/10.1177/1759720X12467868.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Loeser RF, Goldring SR, Scanzello CR, Goldring MB. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum. 2012;64(6):1697–707. https://doi.org/10.1002/art.34453.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Liu-Bryan R, Terkeltaub R. Emerging regulators of the inflammatory process in osteoarthritis. Nat Rev Rheumatol. 2015;11(1):35–44. https://doi.org/10.1038/nrrheum.2014.162.

    Article  CAS  PubMed  Google Scholar 

  7. Goldring MB, Otero M. Inflammation in osteoarthritis. Curr Opin Rheumatol. 2011;23(5):471–8. https://doi.org/10.1097/BOR.0b013e328349c2b1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Licastro F, Candore G, Lio D, Porcellini E, Colonna-Romano G, Franceschi C, Caruso C. Innate immunity and inflammation in ageing: a key for understanding age-related diseases. Immun Ageing. 2005;2:8. https://doi.org/10.1186/1742-4933-2-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Loeser RF. Aging and osteoarthritis. Curr Opin Rheumatol. 2011;23(5):492–6. https://doi.org/10.1097/BOR.0b013e3283494005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sohn DH, Sokolove J, Sharpe O, Erhart JC, Chandra PE, Lahey LJ, Lindstrom TM, Hwang I, Boyer KA, Andriacchi TP, Robinson WH. Plasma proteins present in osteoarthritic synovial fluid can stimulate cytokine production via Toll-like receptor 4. Arthritis Res Ther. 2012;14(1). https://doi.org/10.1186/ar3555.

  11. Gobezie R, Kho A, Krastins B, Sarracino DA, Thornhill TS, Chase M, Millett PJ, Lee DM. High abundance synovial fluid proteome: distinct profiles in health and osteoarthritis. Arthritis Res Ther. 2007;9(2):R36. https://doi.org/10.1186/ar2172.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Scanzello CR, Goldring SR. The role of synovitis in osteoarthritis pathogenesis. Bone. 2012;51(2):249–57. https://doi.org/10.1016/j.bone.2012.02.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Robinson WH, Lepus CM, Wang Q, Raghu H, Mao R, Lindstrom TM, Sokolove J. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat Rev Rheumatol. 2016;12(10):580–92. https://doi.org/10.1038/nrrheum.2016.136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Guilak F. Biomechanical factors in osteoarthritis. Best Pract Res Clin Rheumatol. 2011;25(6):815–23. https://doi.org/10.1016/j.berh.2011.11.013.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Servin-Vences MR, Moroni M, Lewin GR, Poole K. Direct measurement of TRPV4 and PIEZO1 activity reveals multiple mechanotransduction pathways in chondrocytes. ELife. 2017;6:e21074. https://doi.org/10.7554/eLife.21074.

    Article  PubMed  Google Scholar 

  16. Clark AL, Votta BJ, Kumar S, Liedtke W, Guilak F. Chondroprotective role of the osmotically sensitive ion channel transient receptor potential vanilloid 4: age- and sex-dependent progression of osteoarthritis in Trpv4-deficient mice. Arthritis Rheum. 2010;62(10):2973–83. https://doi.org/10.1002/art.27624.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lee W, Guilak F, Liedtke W. Role of piezo channels in joint health and injury. Curr Top Membr. 2017;79:263–73. https://doi.org/10.1016/bs.ctm.2016.10.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Phan MN, Leddy HA, Votta BJ, Kumar S, Levy DS, Lipshutz DB, Suk HL, Liedtke W, Guilak F. Functional characterization of TRPV4 as an osmotically sensitive ion channel in porcine articular chondrocytes. Arthritis Rheum. 2009;60(10):3028–37. https://doi.org/10.1002/art.24799.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Stevens AL, Wishnok JS, White FM, Grodzinsky AJ, Tannenbaum SR. Mechanical injury and cytokines cause loss of cartilage integrity and upregulate proteins associated with catabolism, immunity, inflammation, and repair. Mol Cell Proteomics. 2009;8(7):1475–89. https://doi.org/10.1074/mcp.M800181-MCP200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chow YY, Chin K-Y. The role of inflammation in the pathogenesis of osteoarthritis. Mediators Inflamm. 2020;2020:8293921. https://doi.org/10.1155/2020/8293921.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cheng DS, Visco CJ. Pharmaceutical therapy for osteoarthritis. PM&R. 2012;4(5 Suppl):82–8. https://doi.org/10.1016/j.pmrj.2012.02.009.

    Article  Google Scholar 

  22. Gallagher B, Tjoumakaris FP, Harwood MI, Good RP, Ciccotti MG, Freedman KB. Chondroprotection and the prevention of osteoarthritis progression of the knee: a systematic review of treatment agents. Am J Sports Med. 2015;43(3):734–44. https://doi.org/10.1177/0363546514533777.

    Article  PubMed  Google Scholar 

  23. Barry F, Murphy M. Mesenchymal stem cells in joint disease and repair. Nat Rev Rheumatol. 2013;9(10):584–94. https://doi.org/10.1038/nrrheum.2013.109.

    Article  CAS  PubMed  Google Scholar 

  24. Nelson AE, Allen KD, Golightly YM, Goode AP, Jordan JM. A systematic review of recommendations and guidelines for the management of osteoarthritis: the Chronic Osteoarthritis Management Initiative of the U.S. Bone and Joint Initiative. Semin Arthritis Rheum. 2014;43(6):701–12. https://doi.org/10.1016/j.semarthrit.2013.11.012.

    Article  PubMed  Google Scholar 

  25. Nöth U, Steinert AF, Tuan RS. Technology insight: adult mesenchymal stem cells for osteoarthritis therapy. Nat Clin Pract Rheumatol. 2008;4(7):371–80. https://doi.org/10.1038/ncprheum0816.

    Article  CAS  PubMed  Google Scholar 

  26. Harrell CR, Markovic BS, Fellabaum C, Arsenijevic A, Volarevic V. Mesenchymal stem cell-based therapy of osteoarthritis: current knowledge and future perspectives. Biomed Pharmacother. 2019;109:2318–26. https://doi.org/10.1016/j.biopha.2018.11.099.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  Google Scholar 

  28. Toh WS, Lai RC, Hui JHP, Lim SK. MSC exosome as a cell-free MSC therapy for cartilage regeneration: implications for osteoarthritis treatment. Semin Cell Dev Biol. 2017;67:56–64. https://doi.org/10.1016/j.semcdb.2016.11.008.

    Article  CAS  PubMed  Google Scholar 

  29. McIntyre JA, Jones IA, Han B, Vangsness CT. Intra-articular mesenchymal stem cell therapy for the human joint: a systematic review. Am J Sports Med. 2018;46(14):3550–63. https://doi.org/10.1177/0363546517735844.

    Article  PubMed  Google Scholar 

  30. Diekman BO, Guilak F. Stem cell-based therapies for osteoarthritis: challenges and opportunities. Curr Opin Rheumatol. 2013;25(1):119–26. https://doi.org/10.1097/BOR.0b013e32835aa28d.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Jevotovsky DS, Alfonso AR, Einhorn TA, Chiu ES. Osteoarthritis and stem cell therapy in humans: a systematic review. Osteoarthr Cartil. 2018;26(6):711–29. https://doi.org/10.1016/j.joca.2018.02.906.

    Article  CAS  Google Scholar 

  32. Hsu YC, Wu YT, Yu TH, Wei YH. Mitochondria in mesenchymal stem cell biology and cell therapy: from cellular differentiation to mitochondrial transfer. Semin Cell Dev Biol. 2016;52:119–31. https://doi.org/10.1016/j.semcdb.2016.02.011.

    Article  CAS  PubMed  Google Scholar 

  33. Mo M, Wang S, Zhou Y, Li H, Wu Y. Mesenchymal stem cell subpopulations: phenotype, property and therapeutic potential. Cell Mol Life Sci. 2016;73(17):3311–21. https://doi.org/10.1007/s00018-016-2229-7.

    Article  CAS  PubMed  Google Scholar 

  34. Hall PA, Watt FM. Stem cells: the generation and maintenance of cellular diversity. Development. 1989;106:619–33.

    Article  CAS  PubMed  Google Scholar 

  35. Spencer ND, Gimble JM, Lopez MJ. Mesenchymal stromal cells: past, present, and future. Vet Surg. 2011;40(2):129–39. https://doi.org/10.1111/j.1532-950X.2010.00776.x.

    Article  PubMed  Google Scholar 

  36. Wilson A, Webster A, Genever P. Nomenclature and heterogeneity: consequences for the use of mesenchymal stem cells in regenerative medicine. Regen Med. 2019;14(6):595–611. https://doi.org/10.2217/rme-2018-0145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Horwitz EM, Le Blanc K, Dominici M, Mueller I, Slaper-Cortenbach I, Marini FC, Deans RJ, Krause DS, Keating A. Clarification of the nomenclature for MSC: the International Society for Cellular Therapy position statement. Cytotherapy. 2005;7(5):393–5. https://doi.org/10.1080/14653240500319234.

    Article  CAS  PubMed  Google Scholar 

  38. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini FC, Krause DS, Deans RJ, Keating A, Prockop DJ, Horwitz EM. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–7. https://doi.org/10.1080/14653240600855905.

    Article  CAS  PubMed  Google Scholar 

  39. Mafi P. Adult mesenchymal stem cells and cell surface characterization—a systematic review of the literature. Open Orthop J. 2011;5(1):253–60. https://doi.org/10.2174/1874325001105010253.

    Article  Google Scholar 

  40. Maleki M, Ghanbarvand F, Behvarz MR, Ejtemaei M, Ghadirkhomi E. Comparison of mesenchymal stem cell markers in multiple human adult stem cells. Int J Stem Cells. 2014;7(2):118–26. https://doi.org/10.15283/ijsc.2014.7.2.118.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Lv F-J, Tuan RS, Cheung KMC, Leung VYL. Concise review: the surface markers and identity of human mesenchymal stem cells. Stem Cells. 2014;32(6):1408–19. https://doi.org/10.1002/stem.1681.

    Article  CAS  PubMed  Google Scholar 

  42. Samsonraj RM, Rai B, Sathiyanathan P, Puan KJ, Rötzschke O, Hui JH, Raghunath M, Stanton LW, Nurcombe V, Cool SM. Establishing criteria for human mesenchymal stem cell potency. Stem Cells. 2015;33(6):1878–91. https://doi.org/10.1002/stem.1982.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Parekkadan B, Milwid JM. Mesenchymal stem cells as therapeutics. Annu Rev Biomed Eng. 2010;12(1):87–117. https://doi.org/10.1146/annurev-bioeng-070909-105309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Caplan AI, Koutroupas S. The control of muscle and cartilage development in the chick limb: the role of differential vascularization. J Embroyl Exp Morph. 1973;29(3):571–83.

    CAS  Google Scholar 

  45. Quarto R, Mastrogiacomo M, Cancedda R, Kutepov SM, Mukhachev V, Lavroukov A, Kon E, Marcacci M. Repair of large bone defects with the use of autologous bone marrow stromal cells. N Engl J Med. 2001;344(5):385–6. https://doi.org/10.1056/NEJM200102013440516.

    Article  CAS  PubMed  Google Scholar 

  46. Lv F, Lu M, Cheung KMC, Leung VYL, Zhou G. Intrinsic properties of mesemchymal stem cells from human bone marrow, umbilical cord and umbilical cord blood comparing the different sources of MSC. Curr Stem Cell Res Ther. 2012;7(6):389–99. https://doi.org/10.2174/157488812804484611.

    Article  CAS  PubMed  Google Scholar 

  47. Al Faqeh H, Nor Hamdan BMY, Chen HC, Aminuddin BS, Ruszymah BHI. The potential of intra-articular injection of chondrogenic-induced bone marrow stem cells to retard the progression of osteoarthritis in a sheep model. Exp Gerontol. 2012;47(6):458–64. https://doi.org/10.1016/j.exger.2012.03.018.

    Article  PubMed  Google Scholar 

  48. Garay-Mendoza D, Villarreal-Martínez L, Garza-Bedolla A, Pérez-Garza DM, Acosta-Olivo C, Vilchez-Cavazos F, Diaz-Hutchinson C, Gómez-Almaguer D, Jaime-Pérez JC, Mancías-Guerra C. The effect of intra-articular injection of autologous bone marrow stem cells on pain and knee function in patients with osteoarthritis. Int J Rheum Dis. 2018;21(1):140–7. https://doi.org/10.1111/1756-185X.13139.

    Article  CAS  PubMed  Google Scholar 

  49. Nguyen PD, Tran TD-X, Nguyen HT-N, Vu HT, Le PT-B, Phan NL-C, Vu NB, Phan NK, Van Pham P. Comparative clinical observation of arthroscopic microfracture in the presence and absence of a stromal vascular fraction injection for osteoarthritis. Stem Cells Transl Med. 2017;6(1):187–95. https://doi.org/10.5966/sctm.2016-0023.

    Article  PubMed  Google Scholar 

  50. Al-Nbaheen M, Vishnubalaji R, Ali D, Bouslimi A, Al-Jassir F, Megges M, Prigione A, Adjaye J, Kassem M, Aldahmash A. Human stromal (mesenchymal) stem cells from bone marrow, adipose tissue and skin exhibit differences in molecular phenotype and differentiation potential. Stem Cell Rev Rep. 2013;9(1):32–43. https://doi.org/10.1007/s12015-012-9365-8.

    Article  CAS  PubMed  Google Scholar 

  51. De Ugarte DA, Morizono K, Elbarbary A, Alfonso Z, Zuk PA, Zhu M, Dragoo JL, Ashjian P, Thomas B, Benhaim P, Chen I, Fraser J, Hedrick MH. Comparison of multi-lineage cells from human adipose tissue and bone marrow. Cells Tissues Organs. 2003;174(3):101–9. https://doi.org/10.1159/000071150.

    Article  PubMed  Google Scholar 

  52. Afizah H, Yang Z, Hui JHP, Ouyang HW, Lee EH. A comparison between the chondrogenic potential of human bone marrow stem cells (BMSCs) and adipose-derived stem cells (ADSCs) taken from the same donors. Tissue Eng. 2007;13(4):659–66. https://doi.org/10.1089/ten.2006.0118.

    Article  CAS  PubMed  Google Scholar 

  53. Filardo G, Madry H, Jelic M, Roffi A, Cucchiarini M, Kon E. Mesenchymal stem cells for the treatment of cartilage lesions: from preclinical findings to clinical application in orthopaedics. Knee Surg Sports Traumatol Arthrosc. 2013;21(8):1717–29. https://doi.org/10.1007/s00167-012-2329-3.

    Article  PubMed  Google Scholar 

  54. Churchman SM, Boxall SA, McGonagle D, Jones EA. Predicting the remaining lifespan and cultivation-related loss of osteogenic capacity of bone marrow multipotential stromal cells applicable across a broad donor age range. Stem Cells Int. 2017;2017:6129596. https://doi.org/10.1155/2017/6129596. Epub 2017 Feb 19. PMID: 28298930; PMCID: PMC5337353.

  55. Ganguly P, El-Jawhari JJ, Giannoudis PV, Burska AN, Ponchel F, Jones EA. Age-related changes in bone marrow mesenchymal stromal cells: a potential impact on osteoporosis and osteoarthritis development. Cell Transplant. 2017;26(9):1520–9. https://doi.org/10.1177/0963689717721201.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Schäffler A, Büchler C. Concise review: adipose tissue-derived stromal cells-basic and clinical implications for novel cell-based therapies. Stem Cells. 2007;25(4):818–27. https://doi.org/10.1634/stemcells.2006-0589.

    Article  CAS  PubMed  Google Scholar 

  57. Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, Alfonso ZC, Fraser JK, Benhaim P, Hedrick MH. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell. 2002;13(12):4279–95. https://doi.org/10.1091/mbc.E02-02-0105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Strioga M, Viswanathan S, Darinskas A, Slaby O, Michalek J. Same or not the same? comparison of adipose tissue-derived versus bone marrow-derived mesenchymal stem and stromal cells. Stem Cells Dev. 2012;21(14):2724–52. https://doi.org/10.1089/scd.2011.0722.

    Article  CAS  PubMed  Google Scholar 

  59. Dufrane D. Impact of age on human adipose stem cells for bone tissue engineering. Cell Transpl. 2017;26(9):1496–504. https://doi.org/10.1177/0963689717721203.

    Article  Google Scholar 

  60. Reumann MK, Linnemann C, Aspera-Werz RH, Arnold S, Held M, Seeliger C, Nussler AK, Ehnert S. Donor site location is critical for proliferation, stem cell capacity, and osteogenic differentiation of adipose mesenchymal stem/stromal cells: implications for bone tissue engineering. Int J Mol Sci. 2018;19(7):1868. https://doi.org/10.3390/ijms19071868.

    Article  CAS  PubMed Central  Google Scholar 

  61. Jayaram P, Ikpeama U, Rothenberg JB, Malanga GA. Bone marrow–derived and adipose-derived mesenchymal stem cell therapy in primary knee osteoarthritis: a narrative review. PM&R. 2019;11(2):177–91. https://doi.org/10.1016/j.pmrj.2018.06.019.

    Article  Google Scholar 

  62. Sakaguchi Y, Sekiya I, Yagishita K, Muneta T. Comparison of human stem cells derived from various mesenchymal tissues: superiority of synovium as a cell source. Arthritis Rheum. 2005;52(8):2521–9. https://doi.org/10.1002/art.21212.

    Article  PubMed  Google Scholar 

  63. De Bari C, Dell’Accio F, Karystinou A, Guillot PV, Fisk NM, Jones EA, McGonagle D, Khan IM, Archer CW, Mitsiadis TA, Donaldson AN, Luyten FP, Pitzalis C. A biomarker-based mathematical model to predict bone-forming potency of human synovial and periosteal mesenchymal stem cells. Arthritis Rheum. 2008;58(1):240–50. https://doi.org/10.1002/art.23143.

    Article  CAS  PubMed  Google Scholar 

  64. Saw KY, Anz A, Merican S, Tay YG, Ragavanaidu K, Jee CSY, McGuire DA. Articular cartilage regeneration with autologous peripheral blood progenitor cells and hyaluronic acid after arthroscopic subchondral drilling: a report of 5 cases with histology. Arthroscopy. 2011;27(4):493–506. https://doi.org/10.1016/j.arthro.2010.11.054.

    Article  PubMed  Google Scholar 

  65. Turajane T, Chaweewannakorn U, Larbpaiboonpong V, Aojanepong J, Thitiset T, Honsawek S, Fongsarun J, Papadopoulos KI. Combination of intra-articular autologous activated peripheral blood stem cells with growth factor addition/preservation and hyaluronic acid in conjunction with arthroscopic microdrilling mesenchymal cell stimulation improves quality of life and regenerates articular cartilage in early osteoarthritic knee disease. J Med Assoc Thailand. 2013;96(5):580–88. https://pubmed.ncbi.nlm.nih.gov/23745314/.

  66. Hopper N, Wardale J, Brooks R, Power J, Rushton N, Henson F. Peripheral blood mononuclear cells enhance cartilage repair in in vivo osteochondral defect model. PLoS One. 2015;10(8):e0133937. https://doi.org/10.1371/journal.pone.0133937.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. He Q, Wan C, Li G. Concise review: multipotent mesenchymal stromal cells in blood. Stem Cells. 2007;25(1):69–77. https://doi.org/10.1634/stemcells.2006-0335.

    Article  CAS  PubMed  Google Scholar 

  68. Ng J, Little CB, Lee FY, Gronthos S, Worthley DL, Woods S, Whittle S, Mukherjee S, Hunter DJ. Stem cell directed therapies for osteoarthritis: the promise and the practice: concise review. Stem Cells. 2020;38(4):477–86. https://doi.org/10.1002/stem.3139.

    Article  PubMed  Google Scholar 

  69. Yubo M, Yanyan L, Li L, Tao S, Bo L, Lin C. Clinical efficacy and safety of mesenchymal stem cell transplantation for osteoarthritis treatment: a meta-analysis. PLoS One. 2017;12(4):e0175449. https://doi.org/10.1371/journal.pone.0175449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Freitag J, Bates D, Boyd R, Shah K, Barnard A, Huguenin L, Tenen A. Mesenchymal stem cell therapy in the treatment of osteoarthritis: reparative pathways, safety and efficacy—a review. BMC Musculoskelet Disord. 2016;17(1):1–13. https://doi.org/10.1186/s12891-016-1085-9.

    Article  CAS  Google Scholar 

  71. Lukomska B, Stanaszek L, Zuba-Surma E, Legosz P, Sarzynska S, Drela K. Challenges and controversies in human mesenchymal stem cell therapy. Stem Cells Int. 2019;2019:9628536. https://doi.org/10.1155/2019/9628536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Mautner K, Carr D, Whitley J, Bowers R. Allogeneic versus autologous injectable mesenchymal stem cells for knee osteoarthritis: review and current status. Tech Orthop. 2019;34(4):244–56. https://doi.org/10.1097/BTO.0000000000000357.

    Article  Google Scholar 

  73. Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringdén O. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol. 2003;31(10):890–6. https://doi.org/10.1016/S0301-472X(03)00110-3.

    Article  CAS  PubMed  Google Scholar 

  74. Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood. 2007;110(10):3499–506. https://doi.org/10.1182/blood-2007-02-069716.

    Article  CAS  PubMed  Google Scholar 

  75. Shah K, Zhao AG, Sumer H. New approaches to treat osteoarthritis with mesenchymal stem cells. Stem Cells Int. 2018;2018:5373294. https://doi.org/10.1155/2018/5373294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Zangi L, Margalit R, Reich-Zeliger S, Bachar-Lustig E, Beilhack A, Negrin R, Reisner Y. Direct imaging of immune rejection and memory induction by allogeneic mesenchymal stromal cells. Stem Cells. 2009;27(11):2865–74. https://doi.org/10.1002/stem.217.

    Article  CAS  PubMed  Google Scholar 

  77. Zhang J, Huang X, Wang H, Liu X, Zhang T, Wang Y, Hu D. The challenges and promises of allogeneic mesenchymal stem cells for use as a cell-based therapy. Stem Cell Res Ther. 2015;6(1):234. https://doi.org/10.1186/s13287-015-0240-9.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Trounson A, McDonald C. Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell. 2015;17(1):11–22. https://doi.org/10.1016/j.stem.2015.06.007.

    Article  CAS  PubMed  Google Scholar 

  79. Phinney DG. Functional heterogeneity of mesenchymal stem cells: implications for cell therapy. J Cell Biochem. 2012;113(9):2806–12. https://doi.org/10.1002/jcb.24166.

    Article  CAS  PubMed  Google Scholar 

  80. Russell KC, Phinney DG, Lacey MR, Barrilleaux BL, Meyertholen KE, O’Connor KC. In vitro high-capacity assay to quantify the clonal heterogeneity in trilineage potential of mesenchymal stem cells reveals a complex hierarchy of lineage commitment. Stem Cells. 2010;28(4):788–98. https://doi.org/10.1002/stem.312.

    Article  CAS  PubMed  Google Scholar 

  81. Colter DC, Sekiya I, Prockop DJ. Identification of a subpopulation of rapidly self-renewing and multipotential adult stem cells in colonies of human marrow stromal cells. Proc Natl Acad Sci U S A. 2001;98(14):7841–5. https://doi.org/10.1073/pnas.141221698.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Prockop DJ, Sekiya I, Colter DC. Isolation and characterization of rapidly self-renewing stem cells from cultures of human marrow stromal cells. Cytotherapy. 2001;3(5):393–6. https://doi.org/10.1080/146532401753277229.

    Article  CAS  PubMed  Google Scholar 

  83. Muraglia A, Cancedda R, Quarto R. Clonal mesenchymal progenitors from human bone marrow differentiate in vitro according to a hierarchical model. J Cell Sci. 2000;113(Pt 7):1161–6.

    Article  CAS  PubMed  Google Scholar 

  84. Wang AT, Feng Y, Jia HH, Zhao M, Yu H. Application of mesenchymal stem cell therapy for the treatment of osteoarthritis of the knee: a concise review. World J Stem Cells. 2019;11(4):222–35. https://doi.org/10.4252/wjsc.v11.i4.222.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Cui GH, Wang YY, Li CJ, Shi CH, Wang WS. Efficacy of mesenchymal stem cells in treating patients with osteoarthritis of the knee: a meta-analysis. Exp Ther Med. 2016;12(5):3390–400. https://doi.org/10.3892/etm.2016.3791.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Xu S, Liu H, Xie Y, Sang L, Liu J, Chen B. Effect of mesenchymal stromal cells for articular cartilage degeneration treatment: a meta-analysis. Cytotherapy. 2015;17(10):1342–52. https://doi.org/10.1016/j.jcyt.2015.05.005.

    Article  CAS  PubMed  Google Scholar 

  87. Murphy JM, Fink DJ, Hunziker EB, Barry FP. Stem cell therapy in a caprine model of osteoarthritis. Arthritis Rheum. 2003;48(12):3464–74. https://doi.org/10.1002/art.11365.

    Article  PubMed  Google Scholar 

  88. Jeong SY, Kim DH, Ha J, Jin HJ, Kwon SJ, Chang JW, Choi SJ, Oh W, Yang YS, Kim G, Kim JS, Yoon JR, Cho DH, Jeon HB. Thrombospondin-2 secreted by human umbilical cord blood-derived mesenchymal stem cells promotes chondrogenic differentiation. Stem Cells. 2013;31(10):2136–48. https://doi.org/10.1002/stem.1471.

    Article  CAS  PubMed  Google Scholar 

  89. Pers Y-M, Rackwitz L, Ferreira R, Pullig O, Delfour C, Barry F, Sensebe L, Casteilla L, Fleury S, Bourin P, Noël D, Canovas F, Cyteval C, Lisignoli G, Schrauth J, Haddad D, Domergue S, Noeth U, Jorgensen C. Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: a phase I dose-escalation trial. Stem Cells Transl Med. 2016;5(7):847–56. https://doi.org/10.5966/sctm.2015-0245.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Jo CH, Lee YG, Shin WH, Kim H, Chai JW, Jeong EC, Kim JE, Shim H, Shin JS, Shin IS, Ra JC, Oh S, Yoon KS. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial. Stem Cells. 2014;32(5):1254–66. https://doi.org/10.1002/stem.1634.

    Article  CAS  PubMed  Google Scholar 

  91. Pintat J, Silvestre A, Magalon G, Gadeau AP, Pesquer L, Perozziello A, Peuchant A, Mounayer C, Dallaudière B. Intra-articular injection of mesenchymal stem cells and platelet-rich plasma to treat patellofemoral osteoarthritis: preliminary results of a long-term pilot study. J Vasc Interv Radiol. 2017;28(12):1708–13. https://doi.org/10.1016/j.jvir.2017.08.004.

    Article  PubMed  Google Scholar 

  92. Xie X, Wang Y, Zhao C, Guo S, Liu S, Jia W, Tuan RS, Zhang C. Comparative evaluation of MSCs from bone marrow and adipose tissue seeded in PRP-derived scaffold for cartilage regeneration. Biomaterials. 2012;33(29):7008–18. https://doi.org/10.1016/j.biomaterials.2012.06.058.

    Article  CAS  PubMed  Google Scholar 

  93. Shi WJ, Tjoumakaris FP, Lendner M, Freedman KB. Biologic injections for osteoarthritis and articular cartilage damage: can we modify disease? Physician Sportsmed. 2017;45(3):203–23. https://doi.org/10.1080/00913847.2017.1357421.

    Article  Google Scholar 

  94. Xia P, Wang X, Lin Q, Li X. Efficacy of mesenchymal stem cells injection for the management of knee osteoarthritis: a systematic review and meta-analysis. Int Orthop. 2015;39(12):2363–72. https://doi.org/10.1007/s00264-015-2785-8.

    Article  PubMed  Google Scholar 

  95. Delco ML, Goodale M, Talts JF, Pownder SL, Koff MF, Miller AD, Nixon B, Bonassar LJ, Lundgren-Åkerlund E, Fortier LA. Integrin α10β1-selected mesenchymal stem cells mitigate the progression of osteoarthritis in an equine talar impact model. Am J Sports Med. 2020;48(3):612–23. https://doi.org/10.1177/0363546519899087.

    Article  PubMed  Google Scholar 

  96. Minas T. Autologous chondrocyte implantation for focal chondral defects of the knee. Clin Orthop Related Res. 2001;(391 Suppl):S349–61. https://doi.org/10.1097/00003086-200110001-00032.

  97. De Bari C, Roelofs AJ. Stem cell-based therapeutic strategies for cartilage defects and osteoarthritis. Curr Opin Pharmacol. 2018;40:74–80. https://doi.org/10.1016/j.coph.2018.03.009.

    Article  CAS  PubMed  Google Scholar 

  98. Dai W, Hale SL, Martin BJ, Kuang JQ, Dow JS, Wold LE, Kloner RA. Allogeneic mesenchymal stem cell transplantation in postinfarcted rat myocardium: short- and long-term effects. Circulation. 2005;112(2):214–23. https://doi.org/10.1161/CIRCULATIONAHA.104.527937.

    Article  PubMed  Google Scholar 

  99. Iso Y, Spees JL, Serrano C, Bakondi B, Pochampally R, Song YH, Sobel BE, Delafontaine P, Prockop DJ. Multipotent human stromal cells improve cardiac function after myocardial infarction in mice without long-term engraftment. Biochem Biophys Res Commun. 2007;354(3):700–6. https://doi.org/10.1016/j.bbrc.2007.01.045.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Lee RH, Pulin AA, Seo MJ, Kota DJ, Ylostalo J, Larson BL, Semprun-Prieto L, Delafontaine P, Prockop DJ. Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell. 2009;5(1):54–63. https://doi.org/10.1016/j.stem.2009.05.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Lee RH, Seo MJ, Pulin AA, Gregory CA, Ylostalo J, Prockop DJ. The CD34-like protein PODXL and ά6-integrin (CD49f) identify early progenitor MSCs with increased clonogenicity and migration to infarcted heart in mice. Blood. 2009;113(4):816–26. https://doi.org/10.1182/blood-2007-12-128702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Mokbel AN, El Tookhy OS, Shamaa AA, Rashed LA, Sabry D, El Sayed AM. Homing and reparative effect of intra-articular injection of autologus mesenchymal stem cells in osteoarthritic animal model. BMC Musculoskelet Disord. 2011;12:259. https://doi.org/10.1186/1471-2474-12-259.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem. 2006;98(5):1076–84. https://doi.org/10.1002/jcb.20886.

    Article  CAS  PubMed  Google Scholar 

  104. Spees JL, Lee RH, Gregory CA. Mechanisms of mesenchymal stem/stromal cell function. Stem Cell Res Ther. 2016;7(1):1–13. https://doi.org/10.1186/s13287-016-0363-7.

    Article  CAS  Google Scholar 

  105. Weiss ARR, Dahlke MH. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Murakami S, Lefebvre V, De Crombrugghe B. Potent inhibition of the master chondrogenic factor Sox9 gene by interleukin-1 and tumor necrosis factor-α. J Biol Chem. 2000;275(5):3687–92. https://doi.org/10.1074/jbc.275.5.3687.

    Article  CAS  PubMed  Google Scholar 

  107. Kuroda K, Kabata T, Hayashi K, Maeda T, Kajino Y, Iwai S, Fujita K, Hasegawa K, Inoue D, Sugimoto N, Tsuchiya H. The paracrine effect of adipose-derived stem cells inhibits osteoarthritis progression orthopedics and biomechanics. BMC Musculoskelet Disord. 2015;16(1):236. https://doi.org/10.1186/s12891-015-0701-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Volarevic V, Al-Qahtani A, Arsenijevic N, Pajovic S, Lukic ML. Interleukin-1 receptor antagonist (IL-1Ra) and IL-1Ra producing mesenchymal stem cells as modulators of diabetogenesis. Autoimmunity. 2010;43(4):255–63. https://doi.org/10.3109/08916930903305641.

    Article  CAS  PubMed  Google Scholar 

  109. Tabera S, Pérez-Simón JA, Díez-Campelo M, Sánchez-Abarca LI, Blanco B, López A, Benito A, Ocio E, Sánchez-Guijo FM, Cañizo C, San Miguel JF. The effect of mesenchymal stem cells on the viability, proliferation and differentiation of B-lymphocytes. Haematologica. 2008;93(9):1301–9. https://doi.org/10.3324/haematol.12857.

    Article  CAS  PubMed  Google Scholar 

  110. Ge W, Jiang J, Arp J, Liu W, Garcia B, Wang H. Regulatory T-cell generation and kidney allograft tolerance induced by mesenchymal stem cells associated with indoleamine 2,3-dioxygenase expression. Transplantation. 2010;90(12):1312–20. https://doi.org/10.1097/TP.0b013e3181fed001.

    Article  CAS  PubMed  Google Scholar 

  111. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005;105(4):1815–22. https://doi.org/10.1182/blood-2004-04-1559.

    Article  CAS  PubMed  Google Scholar 

  112. Chang CL, Leu S, Sung HC, Zhen YY, Cho CL, Chen A, Tsai TH, Chung SY, Chai HT, Sun CK, Yen CH, Yip HK. Impact of apoptotic adipose-derived mesenchymal stem cells on attenuating organ damage and reducing mortality in rat sepsis syndrome induced by cecal puncture and ligation. J Transl Med. 2012;10(1):244. https://doi.org/10.1186/1479-5876-10-244.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Gonçalves FDC, Luk F, Korevaar SS, Bouzid R, Paz AH, López-Iglesias C, Baan CC, Merino A, Hoogduijn MJ. Membrane particles generated from mesenchymal stromal cells modulate immune responses by selective targeting of pro-inflammatory monocytes. Sci Rep. 2017;7(1):12100. https://doi.org/10.1038/s41598-017-12121-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Luk F, De Witte SFH, Korevaar SS, Roemeling-Van Rhijn M, Franquesa M, Strini T, Van Den Engel S, Gargesha M, Roy D, Dor FJMF, Horwitz EM, De Bruin RWF, Betjes MGH, Baan CC, Hoogduijn MJ. Inactivated mesenchymal stem cells maintain immunomodulatory capacity. Stem Cells Dev. 2016;25(18):1342–54. https://doi.org/10.1089/scd.2016.0068.

    Article  CAS  PubMed  Google Scholar 

  115. Alcaraz MJ, Compañ A, Guillén MI. Extracellular vesicles from mesenchymal stem cells as novel treatments for musculoskeletal diseases. Cells. 2020;9(1):98. https://doi.org/10.3390/cells9010098.

    Article  CAS  Google Scholar 

  116. Mancuso P, Raman S, Glynn A, Barry F, Murphy JM. Mesenchymal stem cell therapy for osteoarthritis: the critical role of the cell secretome. Front Bioeng Biotechnol. 2019;7:1–9. https://doi.org/10.3389/fbioe.2019.00009.

    Article  Google Scholar 

  117. Noronha Nc NDC, Mizukami A, Caliári-Oliveira C, Cominal JG, Rocha JLM, Covas DT, Swiech K, Malmegrim KCR. Priming approaches to improve the efficacy of mesenchymal stromal cell-based therapies. Stem Cell Res Ther. 2019;10(1):131. https://doi.org/10.1186/s13287-019-1224-y.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Colombini A, Perucca Orfei C, Kouroupis D, Ragni E, De Luca P, ViganÒ M, Correa D, de Girolamo L. Mesenchymal stem cells in the treatment of articular cartilage degeneration: new biological insights for an old-timer cell. Cytotherapy. 2019;21(12):1179–97. https://doi.org/10.1016/j.jcyt.2019.10.004.

    Article  CAS  PubMed  Google Scholar 

  119. Saldaña L, Bensiamar F, Vallés G, Mancebo FJ, García-Rey E, Vilaboa N. Immunoregulatory potential of mesenchymal stem cells following activation by macrophage-derived soluble factors. Stem Cell Res Ther. 2019;10(1):58. https://doi.org/10.1186/s13287-019-1156-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Najar M, Raicevic G, Kazan HF, de Bruyn C, Bron D, Toungouz M, Lagneaux L. Immune-related antigens, surface molecules and regulatory factors in human-derived mesenchymal stromal cells: the expression and impact of inflammatory priming. Stem Cell Rev Rep. 2012;8(4):1188–98. https://doi.org/10.1007/s12015-012-9408-1.

    Article  CAS  PubMed  Google Scholar 

  121. Bartell LR, Fortier LA, Bonassar LJ, Szeto HH, Cohen I, Delco ML. Mitoprotective therapy prevents rapid, strain-dependent mitochondrial dysfunction after articular cartilage injury. J Orthop Res. 2019;38(6):1257–67. https://doi.org/10.1002/jor.24567.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Delco ML, Bonnevie ED, Bonassar LJ, Fortier LA. Mitochondrial dysfunction is an acute response of articular chondrocytes to mechanical injury. J Orthop Res. 2018;36(2):739–50. https://doi.org/10.1002/jor.23651.

    Article  CAS  PubMed  Google Scholar 

  123. Delco ML, Bonnevie ED, Szeto HS, Bonassar LJ, Fortier LA. Mitoprotective therapy preserves chondrocyte viability and prevents cartilage degeneration in an ex vivo model of posttraumatic osteoarthritis. J Orthop Res. 2018;36(8):2147–56. https://doi.org/10.1002/jor.23882.

    Article  CAS  Google Scholar 

  124. Spees JL, Olson SD, Whitney MJ, Prockop DJ. Mitochondrial transfer between cells can rescue aerobic respiration. Proc Natl Acad Sci U S A. 2006;103(5):1283–8. https://doi.org/10.1073/pnas.0510511103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Cho YM, Kim JH, Kim M, Park SJ, Koh SH, Ahn HS, Kang GH, Lee JB, Park KS, Lee HK. Mesenchymal stem cells transfer mitochondria to the cells with virtually no mitochondrial function but not with pathogenic mtDNA mutations. PLoS One. 2012;7(3):e32778. https://doi.org/10.1371/journal.pone.0032778.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Lin HY, Liou CW, Der Chen S, Hsu TY, Chuang JH, Wang PW, Huang ST, Tiao MM, Chen JB, Lin TK, Chuang YC. Mitochondrial transfer from Wharton’s jelly-derived mesenchymal stem cells to mitochondria-defective cells recaptures impaired mitochondrial function. Mitochondrion. 2015;22:31–44. https://doi.org/10.1016/j.mito.2015.02.006.

    Article  CAS  PubMed  Google Scholar 

  127. Torralba D, Baixauli F, Sánchez-Madrid F. Mitochondria know no boundaries: mechanisms and functions of intercellular mitochondrial transfer. Front Cell Dev Biol. 2016;4:1–11. https://doi.org/10.3389/fcell.2016.00107.

    Article  Google Scholar 

  128. Paliwal S, Chaudhuri R, Agrawal A, Mohanty S. Regenerative abilities of mesenchymal stem cells through mitochondrial transfer. J Biomed Sci. 2018;25(1):1–12. https://doi.org/10.1186/s12929-018-0429-1.

    Article  CAS  Google Scholar 

  129. Berridge MV, McConnell MJ, Grasso C, Bajzikova M, Kovarova J, Neuzil J. Horizontal transfer of mitochondria between mammalian cells: beyond co-culture approaches. Curr Opin Genet Dev. 2016;38:75–82. https://doi.org/10.1016/j.gde.2016.04.003.

    Article  CAS  PubMed  Google Scholar 

  130. Islam MN, Das SR, Emin MT, Wei M, Sun L, Rowlands DJ, Quadri SK, Bhattacharya S. Mitochondrial transfer from bone marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med. 2013;18(5):759–65. https://doi.org/10.1038/nm.2736.Mitochondrial.

    Article  Google Scholar 

  131. Jiang D, Gao F, Zhang Y, Wong DSH, Li Q, Tse HF, Xu G, Yu Z, Lian Q. Mitochondrial transfer of mesenchymal stem cells effectively protects corneal epithelial cells from mitochondrial damage. Cell Death Disease. 2016;7(11):e2467–10. https://doi.org/10.1038/cddis.2016.358.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Margolis L, Sadovsky Y. The biology of extracellular vesicles: the known unknowns. PLoS Biol. 2019;17(7):e3000363. https://doi.org/10.1371/journal.pbio.3000363.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Bruno S, Grange C, Deregibus MC, Calogero RA, Saviozzi S, Collino F, Morando L, Busca A, Falda M, Bussolati B, Tetta C, Camussi G. Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol. 2009;20(5):1053–67. https://doi.org/10.1681/ASN.2008070798.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Herrera MB, Fonsato V, Gatti S, Deregibus MC, Sordi A, Cantarella D, Calogero R, Bussolati B, Tetta C, Camussi G. Human liver stem cell-derived microvesicles accelerate hepatic regeneration in hepatectomized rats. J Cell Mol Med. 2010;14(6B):1605–18. https://doi.org/10.1111/j.1582-4934.2009.00860.x.

    Article  CAS  PubMed  Google Scholar 

  135. Cosenza S, Ruiz M, Toupet K, Jorgensen C, Noël D. Mesenchymal stem cells derived exosomes and microparticles protect cartilage and bone from degradation in osteoarthritis. Sci Rep. 2017;7(1):1–12. https://doi.org/10.1038/s41598-017-15376-8.

    Article  CAS  Google Scholar 

  136. Colombo M, Raposo G, Théry C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol. 2014;30(1):255–89. https://doi.org/10.1146/annurev-cellbio-101512-122326.

    Article  CAS  PubMed  Google Scholar 

  137. Kalra H, Adda CG, Liem M, Ang CS, Mechler A, Simpson RJ, Hulett MD, Mathivanan S. Comparative proteomics evaluation of plasma exosome isolation techniques and assessment of the stability of exosomes in normal human blood plasma. Proteomics. 2013;13(22):3354–64. https://doi.org/10.1002/pmic.201300282.

    Article  CAS  PubMed  Google Scholar 

  138. Murphy C, Withrow J, Hunter M, Liu Y, Tang YL, Fulzele S, Hamrick MW. Emerging role of extracellular vesicles in musculoskeletal diseases. Mol Aspects Med. 2018;60:123–8. https://doi.org/10.1016/j.mam.2017.09.006.

    Article  CAS  PubMed  Google Scholar 

  139. Qin Y, Sun R, Wu C, Wang L, Zhang C. Exosome: a novel approach to stimulate bone regeneration through regulation of osteogenesis and angiogenesis. Int J Mol Sci. 2016;17(5):712. https://doi.org/10.3390/ijms17050712.

    Article  CAS  PubMed Central  Google Scholar 

  140. Lawson C, Vicencio JM, Yellon DM, Davidson SM. Microvesicles and exosomes: new players in metabolic and cardiovascular disease. J Endocrinol. 2016;228(2):R57–71.

    Article  PubMed  Google Scholar 

  141. Vishnubhatla I, Corteling R, Stevanato L, Hicks C, Sinden J. The development of stem cell-derived exosomes as a cell-free regenerative medicine. J Circulating Biomark. 2014;3:2. https://doi.org/10.5772/58597.

    Article  CAS  Google Scholar 

  142. Keller S, Sanderson MP, Stoeck A, Altevogt P. Exosomes: from biogenesis and secretion to biological function. Immunol Lett. 2006;107(2):102–8. https://doi.org/10.1016/j.imlet.2006.09.005.

    Article  CAS  PubMed  Google Scholar 

  143. Stoorvogel W, Kleijmeer MJ, Geuze HJ, Raposo G. The biogenesis and functions of exosomes. Traffic. 2002;3(5):321–30. https://doi.org/10.1034/j.1600-0854.2002.30502.x.

    Article  CAS  PubMed  Google Scholar 

  144. Calzolari A, Raggi C, Deaglio S, Sposi NM, Stafsnes M, Fecchi K, Parolini I, Malavasi F, Peschle C, Sargiacomo M, Testa U. TfR2 localizes in lipid raft domains and is released in exosomes to activate signal transduction along the MAPK pathway. J Cell Sci. 2006;119(21):4486–98. https://doi.org/10.1242/jcs.03228.

    Article  CAS  PubMed  Google Scholar 

  145. Clayton A, Turkes A, Dewitt S, Steadman R, Mason MD, Hallett MB. Adhesion and signaling by B cell-derived exosomes: the role of integrins. FASEB J. 2004;18(9):977–9. https://doi.org/10.1096/fj.03-1094fje.

    Article  CAS  PubMed  Google Scholar 

  146. Yáñez-Mó M, Siljander PRM, Andreu Z, Zavec AB, Borràs FE, Buzas EI, Buzas K, Casal E, Cappello F, Carvalho J, Colás E, Cordeiro-Da Silva A, Fais S, Falcon-Perez JM, Ghobrial IM, Giebel B, Gimona M, Graner M, Gursel I, et al. Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles. 2015;4(2015):1–60. https://doi.org/10.3402/jev.v4.27066.

    Article  Google Scholar 

  147. Gasser O, Schifferli JA. Activated polymorphonuclear neutrophils disseminate anti-inflammatory microparticles by ectocytosis. Blood. 2004;104(8):2543–8. https://doi.org/10.1182/blood-2004-01-0361.

    Article  CAS  PubMed  Google Scholar 

  148. Morelli AE, Larregina AT, Shufesky WJ, Sullivan MLG, Stolz DB, Papworth GD, Zahorchak AF, Logar AJ, Wang Z, Watkins SC, Falo LD, Thomson AW. Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells. Blood. 2004;104(10):3257–66. https://doi.org/10.1182/blood-2004-03-0824.

    Article  CAS  PubMed  Google Scholar 

  149. Giri PK, Schorey JS. Exosomes derived from M. bovis BCG infected macrophages activate antigen-specific CD4+ and CD8+ T cells in vitro and in vivo. PLoS One. 2008;3(6):e2461. https://doi.org/10.1371/journal.pone.0002461.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Raposo G, Nijman HW, Stoorvogel W, Leijendekker R, Harding CV, Melief CJM, Geuze HJ. B lymphocytes secrete antigen-presenting vesicles. J Exp Med. 1996;183(3):1161–72. https://doi.org/10.1084/jem.183.3.1161.

    Article  CAS  PubMed  Google Scholar 

  151. Théry C, Regnault A, Garin J, Wolfers J, Zitvogel L, Ricciardi-Castagnoli P, Raposo G, Amigorena S. Molecular characterization of dendritic cell-derived exosomes: selective accumulation of the heat shock protein hsc73. J Cell Biol. 1999;147(3):599–610. https://doi.org/10.1083/jcb.147.3.599.

    Article  PubMed  PubMed Central  Google Scholar 

  152. Withrow J, Murphy C, Liu Y, Hunter M, Fulzele S, Hamrick MW. Extracellular vesicles in the pathogenesis of rheumatoid arthritis and osteoarthritis. Arthritis Res Ther. 2016;18(1):1–12. https://doi.org/10.1186/s13075-016-1178-8.

    Article  CAS  Google Scholar 

  153. Lories RJU. Joint homeostasis, restoration, and remodeling in osteoarthritis. Best Pract Res Clin Rheumatol. 2008;22(2):209–20. https://doi.org/10.1016/j.berh.2007.12.001.

    Article  CAS  PubMed  Google Scholar 

  154. Kato T, Miyaki S, Ishitobi H, Nakamura Y, Nakasa T, Lotz MK, Ochi M. Exosomes from IL-1β stimulated synovial fibroblasts induce osteoarthritic changes in articular chondrocytes. Arthritis Res Ther. 2014;16(4):R163. https://doi.org/10.1186/ar4679.

    Article  PubMed  PubMed Central  Google Scholar 

  155. Kolhe R, Hunter M, Liu S, Jadeja RN, Pundkar C, Mondal AK, Mendhe B, Drewry M, Rojiani MV, Liu Y, Isales CM, Guldberg RE, Hamrick MW, Fulzele S. Gender-specific differential expression of exosomal miRNA in synovial fluid of patients with osteoarthritis. Sci Rep. 2017;7(1):2029. https://doi.org/10.1038/s41598-017-01905-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Domenis R, Zanutel R, Caponnetto F, Toffoletto B, Cifù A, Pistis C, Di Benedetto P, Causero A, Pozzi M, Bassini F, Fabris M, Niazi KR, Soon-Shiong P, Curcio F. Characterization of the proinflammatory profile of synovial fluid-derived exosomes of patients with osteoarthritis. Mediators Inflamm. 2017;2017:4814987. https://doi.org/10.1155/2017/4814987.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. György B, Szabó TG, Turiák L, Wright M, Herczeg P, Lédeczi Z, Kittel Á, Polgár A, Tóth K, Dérfalvi B, Zelenák G, Böröcz I, Carr B, Nagy G, Vékey K, Gay S, Falus A, Buzás EI. Improved flow cytometric assessment reveals distinct microvesicle (cell-derived microparticle) signatures in joint diseases. PLoS One. 2012;7(11):e49726. https://doi.org/10.1371/journal.pone.0049726.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Li JJ, Hosseini-Beheshti E, Grau GE, Zreiqat H, Little CB. Stem cell-derived extracellular vesicles for treating joint injury and osteoarthritis. Nanomaterials. 2019;9(2):1–21. https://doi.org/10.3390/nano9020261.

    Article  CAS  Google Scholar 

  159. Bjørge IM, Kim SY, Mano JF, Kalionis B, Chrzanowski W. Extracellular vesicles, exosomes and shedding vesicles in regenerative medicine—a new paradigm for tissue repair. Biomater Sci. 2018;6(1):60–78. https://doi.org/10.1039/c7bm00479f.

    Article  CAS  Google Scholar 

  160. Lamichhane TN, Sokic S, Schardt JS, Raiker RS, Lin JW, Jay SM. Emerging roles for extracellular vesicles in tissue engineering and regenerative medicine. Tissue Eng Part B Rev. 2015;21(1):45–54. https://doi.org/10.1089/ten.teb.2014.0300.

    Article  CAS  PubMed  Google Scholar 

  161. Rani S, Ryan AE, Griffin MD, Ritter T. Mesenchymal stem cell-derived extracellular vesicles: toward cell-free therapeutic applications. Mol Ther. 2015;23(5):812–23. https://doi.org/10.1038/mt.2015.44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Vonk LA, van Dooremalen SFJ, Liv N, Klumperman J, Coffer PJ, Saris DBF, Lorenowicz MJ. Mesenchymal stromal/stem cell-derived extracellular vesicles promote human cartilage regeneration in vitro. Theranostics. 2018;8(4):906–20. https://doi.org/10.7150/thno.20746.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Seo Y, Kim H-S, Hong I-S. Stem cell-derived extracellular vesicles as immunomodulatory therapeutics. Stem Cells Int. 2019;2019:5126156. https://doi.org/10.1155/2019/5126156.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Tofiño-Vian M, Guillén MI, Pérez Del Caz MD, Silvestre A, Alcaraz MJ. Microvesicles from human adipose tissue-derived mesenchymal stem cells as a new protective strategy in osteoarthritic chondrocytes. Cell Physiol Biochem. 2018;47(1):11–25. https://doi.org/10.1159/000489739.

    Article  CAS  PubMed  Google Scholar 

  165. Wong DE, Banyard DA, Santos PJF, Sayadi LR, Evans GRD, Widgerow AD. Adipose-derived stem cell extracellular vesicles: a systematic review✰. J Plast Reconstr Aesthet Surg. 2019;72(7):1207–18. https://doi.org/10.1016/j.bjps.2019.03.008.

    Article  PubMed  Google Scholar 

  166. Zhou Y, Xu H, Xu W, Wang B, Wu H, Tao Y, Zhang B, Wang M, Mao F, Yan Y, Gao S, Gu H, Zhu W, Qian H. Exosomes released by human umbilical cord mesenchymal stem cells protect against cisplatin-induced renal oxidative stress and apoptosis in vivo and in vitro. Stem Cell Res Ther. 2013;4(2):34. https://doi.org/10.1186/scrt194.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Tofiño-Vian M, Guillén MI, Pérez Del Caz MD, Castejón MA, Alcaraz MJ. Extracellular vesicles from adipose-derived mesenchymal stem cells downregulate senescence features in osteoarthritic osteoblasts. Oxid Med Cell Longev. 2017;2017:7197598. https://doi.org/10.1155/2017/7197598.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Ham O, Song BW, Lee SY, Choi E, Cha MJ, Lee CY, Park JH, Kim IK, Chang W, Lim S, Lee CH, Kim S, Jang Y, Hwang KC. The role of microRNA-23b in the differentiation of MSC into chondrocyte by targeting protein kinase A signaling. Biomaterials. 2012;33(18):4500–7. https://doi.org/10.1016/j.biomaterials.2012.03.025.

    Article  CAS  PubMed  Google Scholar 

  169. Ning G, Liu X, Dai M, Meng A, Wang Q. MicroRNA-92a upholds Bmp signaling by targeting noggin3 during pharyngeal cartilage formation. Dev Cell. 2013;24(3):283–95. https://doi.org/10.1016/j.devcel.2012.12.016.

    Article  CAS  PubMed  Google Scholar 

  170. Li Z, Wang Y, Xiao K, Xiang S, Li Z, Weng X. Emerging role of exosomes in the joint diseases. Cell Physiol Biochem. 2018;47(5):2008–17. https://doi.org/10.1159/000491469.

    Article  CAS  PubMed  Google Scholar 

  171. Bellavia D, Raimondi L, Costa V, De Luca A, Carina V, Maglio M, Fini M, Alessandro R, Giavaresi G. Engineered exosomes: a new promise for the management of musculoskeletal diseases. Biochim Biophys Acta Gen Subjects. 2018;1862(9):1893–901. https://doi.org/10.1016/j.bbagen.2018.06.003.

    Article  CAS  Google Scholar 

  172. Furlani D, Ugurlucan M, Ong LL, Bieback K, Pittermann E, Westien I, Wang W, Yerebakan C, Li W, Gaebel R, Li R, Vollmar B, Steinhoff G, Ma N. Is the intravascular administration of mesenchymal stem cells safe?.Mesenchymal stem cells and intravital microscopy. Microvasc Res. 2009;77(3):370–6. https://doi.org/10.1016/j.mvr.2009.02.001.

    Article  CAS  PubMed  Google Scholar 

  173. Park KS, Bandeira E, Shelke GV, Lässer C, Lötvall J. Enhancement of therapeutic potential of mesenchymal stem cell-derived extracellular vesicles. Stem Cell Res Ther. 2019;10(1):1–15. https://doi.org/10.1186/s13287-019-1398-3.

    Article  CAS  Google Scholar 

  174. Doeppner TR, Herz J, Görgens A, Schlechter J, Ludwig A-K, Radtke S, de Miroschedji K, Horn PA, Giebel B, Hermann DM. Extracellular vesicles improve post-stroke neuroregeneration and prevent postischemic immunosuppression. Stem Cells Transl Med. 2015;4(10):1131–43. https://doi.org/10.5966/sctm.2015-0078.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Ge Q, Zhou Y, Lu J, Bai Y, Xie X, Lu Z. MiRNA in plasma exosome is stable under different storage conditions. Molecules. 2014;19(2):1568–75. https://doi.org/10.3390/molecules19021568.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  177. Colao IL, Corteling R, Bracewell D, Wall I. Manufacturing exosomes: a promising therapeutic platform. Trends Mol Med. 2018;24(3):242–56. https://doi.org/10.1016/j.molmed.2018.01.006.

    Article  CAS  PubMed  Google Scholar 

  178. Maguire G. Exosomes: smart nanospheres for drug delivery naturally produced by stem cells. In: Fabrication and self-assembly of nanobiomaterials: applications of nanobiomaterials. Amsterdam: Elsevier; 2016. p. 179–209. https://doi.org/10.1016/B978-0-323-41533-0.00007-6.

    Chapter  Google Scholar 

  179. Simons M, Raposo G. Exosomes—vesicular carriers for intercellular communication. Curr Opin Cell Biol. 2009;21(4):575–81. https://doi.org/10.1016/j.ceb.2009.03.007.

    Article  CAS  PubMed  Google Scholar 

  180. Witwer KW, Buzás EI, Bemis LT, Bora A, Lässer C, Lötvall J, Nolte-’t Hoen EN, Piper MG, Sivaraman S, Skog J, Théry C, Wauben MH, Hochberg F. Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J Extracell Ves. 2013;2(1). https://doi.org/10.3402/jev.v2i0.20360.

  181. Asghar S, Litherland GJ, Lockhart JC, Goodyear CS, Crilly A. Exosomes in intercellular communication and implications for osteoarthritis. Rheumatology. 2019;2019:57–68. https://doi.org/10.1093/rheumatology/kez462.

    Article  CAS  Google Scholar 

  182. Mathivanan S, Lim JWE, Tauro BJ, Ji H, Moritz RL, Simpson RJ. Proteomics analysis of A33 immunoaffinity-purified exosomes released from the human colon tumor cell line LIM1215 reveals a tissue-specific protein signature. Mol Cellular Proteomics. 2010;9(2):197–208. https://doi.org/10.1074/mcp.M900152-MCP200.

    Article  CAS  Google Scholar 

  183. Taylor DD, Gercel-Taylor C. MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol. 2008;110(1):13–21. https://doi.org/10.1016/j.ygyno.2008.04.033.

    Article  CAS  PubMed  Google Scholar 

  184. Atai NA, Balaj L, Van Veen H, Breakefield XO, Jarzyna PA, Van Noorden CJF, Skog J, Maguire CA. Heparin blocks transfer of extracellular vesicles between donor and recipient cells. J Neurooncol. 2013;115(3):343–51. https://doi.org/10.1007/s11060-013-1235-y.

    Article  CAS  PubMed  Google Scholar 

  185. Epple LM, Griffiths SG, Dechkovskaia AM, Dusto NL, White J, Ouellette RJ, Anchordoquy TJ, Bemis LT, Graner MW. Medulloblastoma exosome proteomics yield functional roles for extracellular vesicles. PLoS One. 2012;7(7):e42064. https://doi.org/10.1371/journal.pone.0042064.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Graner MW, Alzate O, Dechkovskaia AM, Keene JD, Sampson JH, Mitchell DA, Bigner DD. Proteomic and immunologic analyses of brain tumor exosomes. FASEB J. 2009;23(5):1541–57. https://doi.org/10.1096/fj.08-122184.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Kang D, Oh S, Ahn SM, Lee BH, Moon MH. Proteomic analysis of exosomes from human neural stem cells by flow field-flow fractionation and nanoflow liquid chromatography-tandem mass spectrometry. J Proteome Res. 2008;7(8):3475–80. https://doi.org/10.1021/pr800225z.

    Article  CAS  PubMed  Google Scholar 

  188. Kingery MT, Manjunath AK, Anil U, Strauss EJ. Bone marrow mesenchymal stem cell therapy and related bone marrow-derived orthobiologic therapeutics. Curr Rev Musculoskelet Med. 2019;12(4):451–9. https://doi.org/10.1007/s12178-019-09583-1.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Clinical Sciences, Cornell Hospital for Animals, Ithaca, NY, USA

    Michelle L. Delco

  2. Cornell Ruffian Equine Specialists, Elmont, NY, USA

    Michelle L. Delco

  3. Cornell University College of Veterinary Medicine, Ithaca, NY, USA

    Michelle L. Delco

  4. Cornell University, Ithaca, NY, USA

    Nikita Srivastava

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  1. Michelle L. Delco
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  2. Nikita Srivastava
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Correspondence to Michelle L. Delco .

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Editors and Affiliations

  1. Brigham and Women’s Hospital Harvard Medical School, Boston, MA, USA

    Christian Lattermann

  2. Zentrum fur Experimentelle Orthopädie, Universitätsklinikum des Saarlandes, Homburg, Saarland, Germany

    Henning Madry

  3. Institute for Medical Science in Sports, Osaka Health Science University, Osaka, Japan

    Norimasa Nakamura

  4. Department of Biomedical Sciences, Humanitas Research Hospital, Rozzano, Italy

    Elizaveta Kon

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Delco, M.L., Srivastava, N. (2022). Mesenchymal Stromal Cells and Extracellular Vesicles. In: Lattermann, C., Madry, H., Nakamura, N., Kon, E. (eds) Early Osteoarthritis. Springer, Cham. https://doi.org/10.1007/978-3-030-79485-9_13

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