Future Perspectives of Bone Tissue Engineering with Special Emphasis on Extracellular Vesicles

  • Sippy KaurEmail author
  • Bettina Mannerström
  • Karin Ekström
  • Riitta Seppänen-Kaijansinkko


Therapeutic effects of mesenchymal stem cells in bone tissue engineering are known to facilitate via paracrine factors such as extracellular vesicles (EVs). These lipid membranous, small heterogeneous vesicles contain wide variety of functional mRNA, miRNA, proteins, and lipids. EVs are involved in several biological processes, such as mediating intercellular communication, cell differentiation, regulation of immune response, and organ remodeling. From tissue engineering point of view, all these features are considered promising in restoring the functions of the injured tissues. Additionally, due to their stability, bioavailability, and low immunogenicity, EVs can be used to develop cell-free therapy for regenerative medicine. Therefore, a paradigm shift in the field of bone tissue engineering is beginning to emerge with stem-derived EV-based therapy. Scientific evidence regarding the application of stem cell-derived EVs in regenerative medicine is still in its infancy, and the challenges and progress made in the diagnostic and therapeutic applications of EVs are summarized in this chapter. Despite the promise they hold for future diagnostic and therapy, their heterogeneity and molecular complexity demand extensive research and high-resolution technology advancement to fully explore the potential of the EVs.


Extracellular vesicles Mesenchymal stem cells Bone tissue engineering Scaffolds Extracellular vesicles applications 


  1. 1.
    Huey DJ, Hu JC, Athanasiou KA. Unlike bone, cartilage regeneration remains elusive. Science. 2012;338(6109):917–21. Scholar
  2. 2.
    Bianco P, Cao X, Frenette PS, et al. The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nat Med. 2013;19(1):35–42. Scholar
  3. 3.
    Fennema EM, Tchang LAH, Yuan H, et al. Ectopic bone formation by aggregated mesenchymal stem cells from bone marrow and adipose tissue: a comparative study. J Tissue Eng Regen Med. 2018;12(1):e150–8. Scholar
  4. 4.
    Eggenhofer E, Luk F, Dahlke MH, Hoogduijn MJ. The life and fate of mesenchymal stem cells. Front Immunol. 2014;5:148. Scholar
  5. 5.
    Gnecchi M, He H, Liang OD, et al. Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med. 2005;11(4):367–8. nm0405–367 [pii].CrossRefGoogle Scholar
  6. 6.
    Timmers L, Lim SK, Arslan F, et al. Reduction of myocardial infarct size by human mesenchymal stem cell conditioned medium. Stem Cell Res. 2007;1(2):129–37. Scholar
  7. 7.
    El Andaloussi S, Lakhal S, Mager I, Wood MJ. Exosomes for targeted siRNA delivery across biological barriers. Adv Drug Deliv Rev. 2013;65(3):391–7. Scholar
  8. 8.
    Yanez-Mo M, Siljander PR, Andreu Z, et al. Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles. 2015;4:27066. Scholar
  9. 9.
    Vader P, Breakefield XO, Wood MJ. Extracellular vesicles: emerging targets for cancer therapy. Trends Mol Med. 2014;20(7):385–93. Scholar
  10. 10.
    Willis GR, Kourembanas S, Mitsialis SA. Toward exosome-based therapeutics: isolation, heterogeneity, and fit-for-purpose potency. Front Cardiovasc Med. 2017;4:63. Scholar
  11. 11.
    Willis GR, Fernandez-Gonzalez A, Anastas J, et al. Mesenchymal stromal cell exosomes ameliorate experimental bronchopulmonary dysplasia and restore lung function through macrophage immunomodulation. Am J Respir Crit Care Med. 2018;197(1):104–16. Scholar
  12. 12.
    Lee C, Mitsialis SA, Aslam M, et al. Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension. Circulation. 2012;126(22):2601–11. Scholar
  13. 13.
    Aliotta JM, Pereira M, Wen S, et al. Exosomes induce and reverse monocrotaline-induced pulmonary hypertension in mice. Cardiovasc Res. 2016;110(3):319–30. Scholar
  14. 14.
    Zhu YG, Feng XM, Abbott J, et al. Human mesenchymal stem cell microvesicles for treatment of escherichia coli endotoxin-induced acute lung injury in mice. Stem Cells. 2014;32(1):116–25. Scholar
  15. 15.
    Phinney DG, Pittenger MF. Concise review: MSC-derived exosomes for cell-free therapy. Stem Cells. 2017;35(4):851–8. Scholar
  16. 16.
    Monsel A, Zhu YG, Gennai S, et al. Therapeutic effects of human mesenchymal stem cell-derived microvesicles in severe pneumonia in mice. Am J Respir Crit Care Med. 2015;192(3):324–36. Scholar
  17. 17.
    Yu B, Kim HW, Gong M, et al. Exosomes secreted from GATA-4 overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection. Int J Cardiol. 2015;182:349–60. Scholar
  18. 18.
    Teng X, Chen L, Chen W, Yang J, Yang Z, Shen Z. Mesenchymal stem cell-derived exosomes improve the microenvironment of infarcted myocardium contributing to angiogenesis and anti-inflammation. Cell Physiol Biochem. 2015;37(6):2415–24. Scholar
  19. 19.
    Bian S, Zhang L, Duan L, Wang X, Min Y, Yu H. Extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis in a rat myocardial infarction model. J Mol Med (Berl). 2014;92(4):387–97. Scholar
  20. 20.
    Lai RC, Arslan F, Lee MM, et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res. 2010;4(3):214–22. Scholar
  21. 21.
    Arslan F, Lai RC, Smeets MB, et al. Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury. Stem Cell Res. 2013;10(3):301–12. Scholar
  22. 22.
    Kim DK, Nishida H, An SY, Shetty AK, Bartosh TJ, Prockop DJ. Chromatographically isolated CD63+CD81+ extracellular vesicles from mesenchymal stromal cells rescue cognitive impairments after TBI. Proc Natl Acad Sci U S A. 2016;113(1):170–5. Scholar
  23. 23.
    Yu B, Shao H, Su C, et al. Exosomes derived from MSCs ameliorate retinal laser injury partially by inhibition of MCP-1. Sci Rep. 2016;6:34562. Scholar
  24. 24.
    Mead B, Tomarev S. Bone marrow-derived mesenchymal stem cells-derived exosomes promote survival of retinal ganglion cells through miRNA-dependent mechanisms. Stem Cells Transl Med. 2017;6(4):1273–85. Scholar
  25. 25.
    Doeppner TR, Herz J, Gorgens A, et al. Extracellular vesicles improve post-stroke neuroregeneration and prevent postischemic immunosuppression. Stem Cells Transl Med. 2015;4(10):1131–43. Scholar
  26. 26.
    Xin H, Li Y, Cui Y, Yang JJ, Zhang ZG, Chopp M. Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J Cereb Blood Flow Metab. 2013;33(11):1711–5. Scholar
  27. 27.
    Lo Sicco C, Reverberi D, Balbi C, et al. Mesenchymal stem cell-derived extracellular vesicles as mediators of anti-inflammatory effects: endorsement of macrophage polarization. Stem Cells Transl Med. 2017;6(3):1018–28. Scholar
  28. 28.
    Tan CY, Lai RC, Wong W, Dan YY, Lim SK, Ho HK. Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models. Stem Cell Res Ther. 2014;5(3):76. Scholar
  29. 29.
    Li T, Yan Y, Wang B, et al. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis. Stem Cells Dev. 2013;22(6):845–54. Scholar
  30. 30.
    Yang J, Liu XX, Fan H, et al. Extracellular vesicles derived from bone marrow mesenchymal stem cells protect against experimental colitis via attenuating colon inflammation, oxidative stress and apoptosis. PLoS One. 2015;10(10):e0140551. Scholar
  31. 31.
    Fang S, Xu C, Zhang Y, et al. Umbilical cord-derived mesenchymal stem cell-derived exosomal MicroRNAs suppress myofibroblast differentiation by inhibiting the transforming growth factor-beta/SMAD2 pathway during wound healing. Stem Cells Transl Med. 2016;5(10):1425–39. sctm.2015–0367 [pii].CrossRefGoogle Scholar
  32. 32.
    Zhang J, Guan J, Niu X, et al. Exosomes released from human induced pluripotent stem cells-derived MSCs facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis. J Transl Med. 2015;13:49. Scholar
  33. 33.
    Zou X, Zhang G, Cheng Z, et al. Microvesicles derived from human Wharton’s jelly mesenchymal stromal cells ameliorate renal ischemia-reperfusion injury in rats by suppressing CX3CL1. Stem Cell Res Ther. 2014;5(2):40. Scholar
  34. 34.
    Bruno S, Grange C, Collino F, et al. Microvesicles derived from mesenchymal stem cells enhance survival in a lethal model of acute kidney injury. PLoS One. 2012;7(3):e33115. Scholar
  35. 35.
    Fatima F, Ekstrom K, Nazarenko I, et al. Non-coding RNAs in mesenchymal stem cell-derived extracellular vesicles: deciphering regulatory roles in stem cell potency, inflammatory resolve, and tissue regeneration. Front Genet. 2017;8:161. Scholar
  36. 36.
    Hu L, Wang J, Zhou X, et al. Exosomes derived from human adipose mesenchymal stem cells accelerates cutaneous wound healing via optimizing the characteristics of fibroblasts. Sci Rep. 2016;6:32993. Scholar
  37. 37.
    Kaur S, Singh SP, Elkahloun AG, Wu W, Abu-Asab MS, Roberts DD. CD47-dependent immunomodulatory and angiogenic activities of extracellular vesicles produced by T cells. Matrix Biol. 2014;37:49–59. Scholar
  38. 38.
    Zhou Y, Day A, Haykal S, Keating A, Waddell TK. Mesenchymal stromal cells augment CD4+ and CD8+ T-cell proliferation through a CCL2 pathway. Cytotherapy. 2013;15(10):1195–207. Scholar
  39. 39.
    Aslam M, Baveja R, Liang OD, et al. Bone marrow stromal cells attenuate lung injury in a murine model of neonatal chronic lung disease. Am J Respir Crit Care Med. 2009;180(11):1122–30. Scholar
  40. 40.
    Gebraad A, Kornilov R, Kaur S, et al. Monocyte-derived extracellular vesicles stimulate cytokine secretion and gene expression of matrix metalloproteinases by mesenchymal stem/stromal cells. FEBS J. 2018;285(12):2337–59. Scholar
  41. 41.
    Mannerström B, Kornilov R, Abu-Shahba AGA, Chowdhury IM, Sinha S, Seppänen-Kaijansinkko R, Kaur R. Epigenetic alterations in mesenchymal stem cells by osteosarcoma derived extracellular vesicles. Epigenetics. 2019;14(4):352–64.CrossRefGoogle Scholar
  42. 42.
    Kaur S, Abu-Shahba AGA, Paananen RO, Hiidenmaa H, Hongisto H, Skottman H, Seppänen-Kaijansinkko R, Mannerström B. Small RNA non-coding landscape of extracellular vesicles from human stem cells. Sci Rep. 2018;8(1):15503.CrossRefGoogle Scholar
  43. 43.
    Bruno S, Grange C, Deregibus MC, et al. Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol. 2009;20(5):1053–67. Scholar
  44. 44.
    Narayanan R, Huang CC, Ravindran S. Hijacking the cellular mail: exosome mediated differentiation of mesenchymal stem cells. Stem Cells Int. 2016;2016:3808674. Scholar
  45. 45.
    Xie H, Wang Z, Zhang L, et al. Extracellular vesicle-functionalized decalcified bone matrix scaffolds with enhanced pro-angiogenic and pro-bone regeneration activities. Sci Rep. 2017;7:45622. Scholar
  46. 46.
    Chen J, Liu Z, Hong MM, et al. Proangiogenic compositions of microvesicles derived from human umbilical cord mesenchymal stem cells. PLoS One. 2014;9(12):e115316. Scholar
  47. 47.
    Hu L, Wang J, Zhou X, et al. Exosomes derived from human adipose mensenchymal stem cells accelerates cutaneous wound healing via optimizing the characteristics of fibroblasts. Sci Rep. 2016;6:32993. Scholar
  48. 48.
    Togliatto G, Dentelli P, Gili M, et al. Obesity reduces the pro-angiogenic potential of adipose tissue stem cell-derived extracellular vesicles (EVs) by impairing miR-126 content: impact on clinical applications. Int J Obes. 2016;40(1):102–11. Scholar
  49. 49.
    Qin Y, Wang L, Gao Z, Chen G, Zhang C. Bone marrow stromal/stem cell-derived extracellular vesicles regulate osteoblast activity and differentiation in vitro and promote bone regeneration in vivo. Sci Rep. 2016;6:21961. Scholar
  50. 50.
    Liu X, Li Q, Niu X, et al. 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. 2017;13(2):232–44. Scholar
  51. 51.
    Qi X, Zhang J, Yuan H, et al. Exosomes secreted by human-induced pluripotent stem cell-derived mesenchymal stem cells repair critical-sized bone defects through enhanced angiogenesis and osteogenesis in osteoporotic rats. Int J Biol Sci. 2016;12(7):836–49. Scholar
  52. 52.
    Tao SC, Yuan T, Zhang YL, Yin WJ, Guo SC, Zhang CQ. 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. 2017;7(1):180–95. Scholar
  53. 53.
    Furuta T, Miyaki S, Ishitobi H, et al. Mesenchymal stem cell-derived exosomes promote fracture healing in a mouse model. Stem Cells Transl Med. 2016;5(12):1620–30. sctm.2015–0285 [pii].CrossRefGoogle Scholar
  54. 54.
    Zhang J, Liu X, Li H, et al. Exosomes/tricalcium phosphate combination scaffolds can enhance bone regeneration by activating the PI3K/Akt signaling pathway. Stem Cell Res Ther. 2016;7(1):136. Scholar
  55. 55.
    Cosenza S, Ruiz M, Toupet K, Jorgensen C, Noel D. Mesenchymal stem cells derived exosomes and microparticles protect cartilage and bone from degradation in osteoarthritis. Sci Rep. 2017;7(1):16214. Scholar
  56. 56.
    Rhys HI, Dell’Accio F, Pitzalis C, Moore A, Norling LV, Perretti M. Neutrophil microvesicles from healthy control and rheumatoid arthritis patients prevent the inflammatory activation of macrophages. EBioMedicine. 2018;29:60–9. S2352-3964(18)30052-5 [pii].CrossRefGoogle Scholar
  57. 57.
    Headland SE, Jones HR, Norling LV, et al. Neutrophil-derived microvesicles enter cartilage and protect the joint in inflammatory arthritis. Sci Transl Med. 2015;7(315):315ra190. Scholar
  58. 58.
    Li W, Liu Y, Zhang P, et al. Tissue-engineered bone immobilized with human adipose stem cells-derived exosomes promotes bone regeneration. ACS Appl Mater Interfaces. 2018;10(6):5240–54. Scholar
  59. 59.
    Cui Y, Luan J, Li H, Zhou X, Han J. Exosomes derived from mineralizing osteoblasts promote ST2 cell osteogenic differentiation by alteration of microRNA expression. FEBS Lett. 2016;590(1):185–92. Scholar
  60. 60.
    Ekstrom K, Omar O, Graneli C, Wang X, Vazirisani F, Thomsen P. Monocyte exosomes stimulate the osteogenic gene expression of mesenchymal stem cells. PLoS One. 2013;8(9):e75227. Scholar
  61. 61.
    Silva AM, Almeida MI, Teixeira JH, et al. Dendritic cell-derived extracellular vesicles mediate mesenchymal stem/stromal cell recruitment. Sci Rep. 2017;7(1):1667. Scholar
  62. 62.
    Martins M, Ribeiro D, Martins A, Reis RL, Neves NM. Extracellular vesicles derived from osteogenically induced human bone marrow mesenchymal stem cells can modulate lineage commitment. Stem Cell Reports. 2016;6(3):284–91. Scholar
  63. 63.
    Diomede F, Gugliandolo A, Cardelli P, et al. Three-dimensional printed PLA scaffold and human gingival stem cell-derived extracellular vesicles: a new tool for bone defect repair. Stem Cell Res Ther. 2018;9(1):104. Scholar
  64. 64.
    Gudbergsson JM, Johnsen KB, Skov MN, Duroux M. Systematic review of factors influencing extracellular vesicle yield from cell cultures. Cytotechnology. 2016;68(4):579–92. Scholar
  65. 65.
    Witwer KW, Buzas EI, Bemis LT, et al. Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J Extracell Vesicles. 2013;2 eCollection 2013.CrossRefGoogle Scholar
  66. 66.
    Yamashita T, Takahashi Y, Takakura Y. Possibility of exosome-based therapeutics and challenges in production of exosomes eligible for therapeutic application. Biol Pharm Bull. 2018;41(6):835–42. Scholar
  67. 67.
    Lai RC, Yeo RW, Tan KH, Lim SK. Exosomes for drug delivery—a novel application for the mesenchymal stem cell. Biotechnol Adv. 2013;31(5):543–51. Scholar
  68. 68.
    Nilsson J, Skog J, Nordstrand A, et al. Prostate cancer-derived urine exosomes: a novel approach to biomarkers for prostate cancer. Br J Cancer. 2009;100(10):1603–7. Scholar
  69. 69.
    Baran J, Baj-Krzyworzeka M, Weglarczyk K, et al. Circulating tumour-derived microvesicles in plasma of gastric cancer patients. Cancer Immunol Immunother. 2010;59(6):841–50. Scholar
  70. 70.
    Huttner HB, Janich P, Kohrmann M, et al. The stem cell marker prominin-1/CD133 on membrane particles in human cerebrospinal fluid offers novel approaches for studying central nervous system disease. Stem Cells. 2008;26(3):698–705. 2007–0639 [pii].CrossRefGoogle Scholar
  71. 71.
    Escudier B, Dorval T, Chaput N, et al. Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of the first phase I clinical trial. J Transl Med. 2005;3(1):10. 1479–5876-3-10 [pii].CrossRefGoogle Scholar
  72. 72.
    Morse MA, Garst J, Osada T, et al. A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer. J Transl Med. 2005;3(1):9. 1479-5876-3-9 [pii].CrossRefGoogle Scholar
  73. 73.
    Dai S, Wei D, Wu Z, et al. Phase I clinical trial of autologous ascites-derived exosomes combined with GM-CSF for colorectal cancer. Mol Ther. 2008;16(4):782–90. Scholar
  74. 74.
    Besse B, Charrier M, Lapierre V, et al. Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC. Oncoimmunology. 2015;5(4):e1071008. Scholar
  75. 75.
    Kordelas L, Rebmann V, Ludwig AK, et al. MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease. Leukemia. 2014;28(4):970–3. Scholar
  76. 76.
    Nawaz M, Camussi G, Valadi H, et al. The emerging role of extracellular vesicles as biomarkers for urogenital cancers. Nat Rev Urol. 2014;11(12):688–701. Scholar
  77. 77.
    Roy S, Hochberg FH, Jones PS. Extracellular vesicles: the growth as diagnostics and therapeutics; a survey. J Extracell Vesicles. 2018;7(1):1438720. Scholar
  78. 78.
    Gimona M, Pachler K, Laner-Plamberger S, Schallmoser K, Rohde E. Manufacturing of human extracellular vesicle-based therapeutics for clinical use. Int J Mol Sci. 2017;18(6) E1190 [pii].CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Sippy Kaur
    • 1
    Email author
  • Bettina Mannerström
    • 1
  • Karin Ekström
    • 2
  • Riitta Seppänen-Kaijansinkko
    • 1
  1. 1.Department of Oral and Maxillofacial DiseasesUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland
  2. 2.Department of Biomaterials, Institute of Clinical Sciences, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden

Personalised recommendations