Concise review: Extracellular vesicles from mesenchymal stem cells as cellular therapy

Main Article Content

Phuc Van Pham http://orcid.org/0000-0001-7254-0717

Abstract

Extracellular vesicles (EVs) from mesenchymal stem cells (MSCs) are microvesicles produced from cells throughout their life. From research over recent years, there has been greater understanding about EVs, including their physiological characteristics and the role they play in cell targets. Indeed, EVs carry information (in the form of RNA, DNA and protein) to cell targets. Some of their main biological properties include angiogenesis and immune-modulation. Therefore, these properties can be exploited to treat various diseases, including bone disorders, spinal cord injury and diabetes mellitus. Recently, new methods have been developed to isolate and enrich EVs with high performance and low-toxicity. Thus, EVs have emerged as the new generation of stem cell therapy. This concise review aims to highlight some recent achievements of EVs in preclinical and clinical applications.

Peer Review Details

  • Peer review method: Single-Blind (Peer-reviewers: 03) Peer-review policy
  • Plagiarism software screening?: Yes
  • Date of Original Submission: 10 July 2017
  • Date accepted: 24 August 2017
  • Peer reviewers approved by: Dr. Lili Hami
  • Editor who approved publication: Dr. Lili Hami

 

References


  1. Abdi, R., Fiorina, P., Adra, C. N., Atkinson, M., & Sayegh, M. H. (2008). Immunomodulation by mesenchymal stem cells: A potential therapeutic strategy for type 1 diabetes. Diabetes, 57(7), 1759–1767. https://doi.org/10.2337/db08-0180

  2. Baglio, S. R., Pegtel, D. M., & Baldini, N. (2012). Mesenchymal stem cell secreted vesicles provide novel opportunities in (stem) cell-free therapy. Frontiers in Physiology, 3, 359. https://doi.org/10.3389/fphys.2012.00359

  3. Biancone, L., Bruno, S., Deregibus, M. C., Tetta, C., & Camussi, G. (2012). Therapeutic potential of mesenchymal stem cell-derived microvesicles. Nephrology, Dialysis, Transplantation, 27(8), 3037–3042. https://doi.org/10.1093/ndt/gfs168

  4. Blazquez, R., Sanchez-Margallo, F. M., de la Rosa, O., Dalemans, W., Álvarez, V., Tarazona, R., & Casado, J. G. (2014). Immunomodulatory potential of human adipose mesenchymal stem cells derived exosomes on in vitro stimulated T cells. Frontiers in Immunology, 5, 556. https://doi.org/10.3389/fimmu.2014.00556

  5. Bongso, A., & Lee, E. H. (2005). Stem cells: from bench to bedside. World Scientific. https://doi.org/10.1142/5729

  6. Boomsma, R. A., & Geenen, D. L. (2012). Mesenchymal stem cells secrete multiple cytokines that promote angiogenesis and have contrasting effects on chemotaxis and apoptosis. PLoS One, 7(4), e35685. https://doi.org/10.1371/journal.pone.0035685

  7. Börger, V., Bremer, M., Ferrer-Tur, R., Gockeln, L., Stambouli, O., Becic, A., & Giebel, B. (2017). Mesenchymal Stem/Stromal Cell-Derived Extracellular Vesicles and Their Potential as Novel Immunomodulatory Therapeutic Agents. International Journal of Molecular Sciences, 18(7), 18.

  8. Budoni, M., Fierabracci, A., Luciano, R., Petrini, S., Di Ciommo, V., & Muraca, M. (2013). The immunosuppressive effect of mesenchymal stromal cells on B lymphocytes is mediated by membrane vesicles. Cell Transplantation, 22(2), 369–379.

  9. Camussi, G., Deregibus, M.-C., Bruno, S., Grange, C., Fonsato, V., & Tetta, C. (2011). Exosome/microvesicle-mediated epigenetic reprogramming of cells. American Journal of Cancer Research, 1(1), 98–110.

  10. Camussi, G., Deregibus, M. C., Bruno, S., Cantaluppi, V., & Biancone, L. (2010). Exosomes/microvesicles as a mechanism of cell-to-cell communication. Kidney International, 78(9), 838–848. https://doi.org/10.1038/ki.2010.278

  11. Chase, L. G., & Vemuri, M. C. (2012). Mesenchymal stem cell therapy. Springer Science & Business Media.
    Chen, W., Huang, Y., Han, J., Yu, L., Li, Y., Lu, Z., . . . Xiao, Y. (2016). Immunomodulatory effects of mesenchymal stromal cells-derived exosome. Immunologic Research, 64(4), 831–840. https://doi.org/10.1007/s12026-016-8798-6

  12. Collino, F., Deregibus, M. C., Bruno, S., Sterpone, L., Aghemo, G., Viltono, L., . . . Camussi, G. (2010). Microvesicles derived from adult human bone marrow and tissue specific mesenchymal stem cells shuttle selected pattern of miRNAs. PLoS One, 5(7), e11803. https://doi.org/10.1371/journal.pone.0011803

  13. Conforti, A., Scarsella, M., Starc, N., Giorda, E., Biagini, S., Proia, A., . . . Bernardo, M. E. (2014). Microvescicles derived from mesenchymal stromal cells are not as effective as their cellular counterpart in the ability to modulate immune responses in vitro. Stem Cells and Development, 23(21), 2591–2599. https://doi.org/10.1089/scd.2014.0091

  14. Crescitelli, R., Lässer, C., Szabó, T. G., Kittel, A., Eldh, M., Dianzani, I., . . . Lötvall, J. (2013). Distinct RNA profiles in subpopulations of extracellular vesicles: Apoptotic bodies, microvesicles and exosomes. Journal of Extracellular Vesicles, 2(1), 20677. https://doi.org/10.3402/jev.v2i0.20677

  15. 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 Reviews, 20(5-6), 419–427. https://doi.org/10.1016/j.cytogfr.2009.10.002

  16. De Luca, L., Trino, S., Laurenzana, I., Simeon, V., Calice, G., Raimondo, S., . . . Musto, P. (2016). MiRNAs and piRNAs from bone marrow mesenchymal stem cell extracellular vesicles induce cell survival and inhibit cell differentiation of cord blood hematopoietic stem cells: A new insight in transplantation. Oncotarget, 7(6), 6676–6692. https://doi.org/10.18632/oncotarget.6791

  17. Doeppner, T. R., Herz, J., Görgens, A., Schlechter, J., Ludwig, A.-K., Radtke, S., . . . Hermann, D. M. (2015). Extracellular vesicles improve post-stroke neuroregeneration and prevent postischemic immunosuppression. Stem Cells Translational Medicine, 4(10), 1131–1143. https://doi.org/10.5966/sctm.2015-0078

  18. Eirin, A., Riester, S. M., Zhu, X.-Y., Tang, H., Evans, J. M., O’Brien, D., . . . Lerman, L. O. (2014). MicroRNA and mRNA cargo of extracellular vesicles from porcine adipose tissue-derived mesenchymal stem cells. Gene, 551(1), 55–64. https://doi.org/10.1016/j.gene.2014.08.041

  19. Fafián-Labora, J., Lesende-Rodriguez, I., Fernández-Pernas, P., Sangiao-Alvarellos, S., Monserrat, L., Arntz, O. J., . . . Arufe, M. C. (2017). Effect of age on pro-inflammatory miRNAs contained in mesenchymal stem cell-derived extracellular vesicles. Scientific Reports, 7, 43923. https://doi.org/10.1038/srep43923

  20. Ginn, S. L., Alexander, I. E., Edelstein, M. L., Abedi, M. R., & Wixon, J. (2013). Gene therapy clinical trials worldwide to 2012 - an update. The Journal of Gene Medicine, 15(2), 65–77. https://doi.org/10.1002/jgm.2698

  21. Han, D., Wu, C., Xiong, Q., Zhou, L., & Tian, Y. (2015). Anti-inflammatory mechanism of bone marrow mesenchymal stem cell transplantation in rat model of spinal cord injury. Cell Biochemistry and Biophysics, 71(3), 1341–1347. https://doi.org/10.1007/s12013-014-0354-1

  22. Hu, L., Wang, J., Zhou, X., Xiong, Z., Zhao, J., Yu, R., . . . Chen, L. (2016). Exosomes derived from human adipose mensenchymal stem cells accelerates cutaneous wound healing via optimizing the characteristics of fibroblasts. Scientific Reports, 6(1), 32993. https://doi.org/10.1038/srep32993

  23. Kastelowitz, N., & Yin, H. (2014). Exosomes and microvesicles: Identification and targeting by particle size and lipid chemical probes. ChemBioChem, 15(7), 923–928. https://doi.org/10.1002/cbic.201400043

  24. Kilroy, G. E., Foster, S. J., Wu, X., Ruiz, J., Sherwood, S., Heifetz, A., . . . Gimble, J. M. (2007). Cytokine profile of human adipose-derived stem cells: Expression of angiogenic, hematopoietic, and pro-inflammatory factors. Journal of Cellular Physiology, 212(3), 702–709. https://doi.org/10.1002/jcp.21068

  25. Kordelas, L., Rebmann, V., Ludwig, A. K., Radtke, S., Ruesing, J., Doeppner, T. R., . . . Giebel, B. (2014). MSC-derived exosomes: A novel tool to treat therapy-refractory graft-versus-host disease. Leukemia, 28(4), 970–973.

  26. Kumar, L., Verma, S., Vaidya, B., & Gupta, V. (2015). Exosomes: Natural carriers for siRNA delivery. Current Pharmaceutical Design, 21(31), 4556–4565. https://doi.org/10.2174/138161282131151013190112
    Lai, R.C., Yeo, R.W.Y., and Lim, S.K. (2015). Mesenchymal stem cell exosomes. Paper presented at: Seminars in Cell & Developmental Biology (Elsevier). https://doi.org/10.1016/j.semcdb.2015.03.001

  27. Lespagnol, A., Duflaut, D., Beekman, C., Blanc, L., Fiucci, G., Marine, J. C., . . . Telerman, A. (2008). Exosome secretion, including the DNA damage-induced p53-dependent secretory pathway, is severely compromised in TSAP6/Steap3-null mice. Cell Death and Differentiation, 15(11), 1723–1733. https://doi.org/10.1038/cdd.2008.104

  28. Liu, X., Li, Q., Niu, X., Hu, B., Chen, S., Song, W., . . . Wang, Y. (2017). Exosomes Secreted from Human-Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Prevent Osteonecrosis of the Femoral Head by Promoting Angiogenesis. International Journal of Biological Sciences, 13(2), 232–244. https://doi.org/10.7150/ijbs.16951

  29. Livingston, M. J., & Wei, Q. (2016). MicroRNAs in extracellular vesicles protect kidney from ischemic injury: From endothelial to tubular epithelial. Kidney International, 90(6), 1150–1152. https://doi.org/10.1016/j.kint.2016.08.032

  30. Lo Sicco, C., Reverberi, D., Balbi, C., Ulivi, V., Principi, E., Pascucci, L., . . . Tasso, R. (2017). Mesenchymal Stem Cell-Derived Extracellular Vesicles as Mediators of Anti-Inflammatory Effects: Endorsement of Macrophage Polarization. Stem Cells Translational Medicine, 6(3), 1018–1028. https://doi.org/10.1002/sctm.16-0363

  31. Meehan, B., Rak, J., & Di Vizio, D. (2016). Oncosomes - large and small: What are they, where they came from? Journal of Extracellular Vesicles, 5(1), 33109. https://doi.org/10.3402/jev.v5.33109

  32. Mokarizadeh, A., Delirezh, N., Morshedi, A., Mosayebi, G., Farshid, A.-A., & Mardani, K. (2012). Microvesicles derived from mesenchymal stem cells: Potent organelles for induction of tolerogenic signaling. Immunology Letters, 147(1-2), 47–54. https://doi.org/10.1016/j.imlet.2012.06.001

  33. Nawaz, M., Fatima, F., Vallabhaneni, K. C., Penfornis, P., Valadi, H., Ekström, K., . . . Camussi, G. (2016). Extracellular Vesicles: Evolving Factors in Stem Cell Biology. Stem Cells International, 2016, 1073140. https://doi.org/10.1155/2016/1073140

  34. Ostrowski, M., Carmo, N.B., Krumeich, S., Fanget, I., Raposo, G., Savina, A., Moita, C.F., Schauer, K., Hume, A.N., Freitas, R.P., et al. (2010). Rab27a and Rab27b control different steps of the exosome secretion pathway. Nature cell biology 12, 19-30; sup pp 11-13.

  35. Pols, M. S., & Klumperman, J. (2009). Trafficking and function of the tetraspanin CD63. Experimental Cell Research, 315(9), 1584–1592. https://doi.org/10.1016/j.yexcr.2008.09.020

  36. Prockop, D. J., & Oh, J. Y. (2012). Mesenchymal stem/stromal cells (MSCs): Role as guardians of inflammation. Molecular Therapy, 20(1), 14–20. https://doi.org/10.1038/mt.2011.211

  37. Qin, Y., Wang, L., Gao, Z., Chen, G., & Zhang, C. (2016). Bone marrow stromal/stem cell-derived extracellular vesicles regulate osteoblast activity and differentiation in vitro and promote bone regeneration in vivo. Scientific Reports, 6(1), 21961. https://doi.org/10.1038/srep21961

  38. Rak, J. (2013). Extracellular vesicles - biomarkers and effectors of the cellular interactome in cancer. Frontiers in Pharmacology, 4, 21. https://doi.org/10.3389/fphar.2013.00021

  39. Rani, S., Ryan, A. E., Griffin, M. D., & Ritter, T. (2015). Mesenchymal stem cell-derived extracellular vesicles: Toward cell-free therapeutic applications. Molecular Therapy, 23(5), 812–823. https://doi.org/10.1038/mt.2015.44

  40. Raposo, G., & Stoorvogel, W. (2013). Extracellular vesicles: Exosomes, microvesicles, and friends. The Journal of Cell Biology, 200(4), 373–383. https://doi.org/10.1083/jcb.201211138

  41. de Rivero Vaccari, J. P., Brand, F., III, Adamczak, S., Lee, S. W., Perez-Barcena, J., Wang, M. Y., . . . Keane, R. W. (2016). Exosome-mediated inflammasome signaling after central nervous system injury. Journal of Neurochemistry, 136(Suppl 1), 39–48. https://doi.org/10.1111/jnc.13036

  42. Shigemoto-Kuroda, T., Oh, J. Y., Kim, D. K., Jeong, H. J., Park, S. Y., Lee, H. J., . . . Lee, R. H. (2017). MSC-derived Extracellular Vesicles Attenuate Immune Responses in Two Autoimmune Murine Models: Type 1 Diabetes and Uveoretinitis. Stem Cell Reports, 8(5), 1214–1225. https://doi.org/10.1016/j.stemcr.2017.04.008

  43. Squillaro, T., Peluso, G., & Galderisi, U. (2016). Clinical trials with mesenchymal stem cells: An update. Cell Transplantation, 25(5), 829–848. https://doi.org/10.3727/096368915X689622

  44. Stoorvogel, W., Kleijmeer, M. J., Geuze, H. J., & Raposo, G. (2002). The biogenesis and functions of exosomes. Traffic (Copenhagen, Denmark), 3(5), 321–330. https://doi.org/10.1034/j.1600-0854.2002.30502.x

  45. Teixeira, F. G., Carvalho, M. M., Neves-Carvalho, A., Panchalingam, K. M., Behie, L. A., Pinto, L., . . . Salgado, A. J. (2015). Secretome of mesenchymal progenitors from the umbilical cord acts as modulator of neural/glial proliferation and differentiation. Stem Cell Reviews and Reports, 11(2), 288–297. https://doi.org/10.1007/s12015-014-9576-2

  46. Tomasoni, S., Longaretti, L., Rota, C., Morigi, M., Conti, S., Gotti, E., . . . Benigni, A. (2013). Transfer of growth factor receptor mRNA via exosomes unravels the regenerative effect of mesenchymal stem cells. Stem Cells and Development, 22(5), 772–780. https://doi.org/10.1089/scd.2012.0266

  47. Vallabhaneni, K. C., Penfornis, P., Dhule, S., Guillonneau, F., Adams, K. V., Mo, Y. Y., . . . Pochampally, R. (2015). Extracellular vesicles from bone marrow mesenchymal stem/stromal cells transport tumor regulatory microRNA, proteins, and metabolites. Oncotarget, 6(7), 4953–4967. https://doi.org/10.18632/oncotarget.3211

  48. Van Pham, P. (2016). Clinical application of stem cells: An update 2015. Biomedical Research and Therapy, 3(2), 483–489. https://doi.org/10.7603/s40730-016-0005-9

  49. Wang, J., Cen, P., Chen, J., Fan, L., Li, J., Cao, H., & Li, L. (2017). Role of mesenchymal stem cells, their derived factors, and extracellular vesicles in liver failure. Stem Cell Research & Therapy, 8(1), 137. https://doi.org/10.1186/s13287-017-0576-4

  50. Wang, L., Gu, Z., Zhao, X., Yang, N., Wang, F., Deng, A., . . . Gao, C. (2016). Extracellular vesicles released from human umbilical cord-derived mesenchymal stromal cells prevent life-threatening acute graft-versus-host disease in a mouse model of allogeneic hematopoietic stem cell transplantation. Stem Cells and Development, 25(24), 1874–1883. https://doi.org/10.1089/scd.2016.0107

  51. Yañez, R., Lamana, M. L., García-Castro, J., Colmenero, I., Ramírez, M., & Bueren, J. A. (2006). Adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graft-versus-host disease. Stem Cells (Dayton, Ohio), 24(11), 2582–2591. https://doi.org/10.1634/stemcells.2006-0228

  52. Yáñez-Mó, M., Siljander, P. R., Andreu, Z., Zavec, A. B., Borràs, F. E., Buzas, E. I., . . . De Wever, O. (2015). Biological properties of extracellular vesicles and their physiological functions. Journal of Extracellular Vesicles, 4(1), 27066. https://doi.org/10.3402/jev.v4.27066

  53. Yu, B., Zhang, X., & Li, X. (2014). Exosomes derived from mesenchymal stem cells. International Journal of Molecular Sciences, 15(3), 4142–4157. https://doi.org/10.3390/ijms15034142

  54. Yuan, Z., Kolluri, K. K., Gowers, K. H. C., & Janes, S. M. (2017). TRAIL delivery by MSC-derived extracellular vesicles is an effective anticancer therapy. Journal of Extracellular Vesicles, 6(1), 1265291. https://doi.org/10.1080/20013078.2017.1265291

  55. Zhang, B., Wang, M., Gong, A., Zhang, X., Wu, X., Zhu, Y., . . . Xu, W. (2015a). HucMSC-Exosome Mediated-Wnt4 Signaling Is Required for Cutaneous Wound Healing. Stem Cells (Dayton, Ohio), 33(7), 2158–2168. https://doi.org/10.1002/stem.1771

  56. Zhang, B., Wu, X., Zhang, X., Sun, Y., Yan, Y., Shi, H., . . . Xu, W. (2015b). Human umbilical cord mesenchymal stem cell exosomes enhance angiogenesis through the Wnt4/β-catenin pathway. Stem Cells Translational Medicine, 4(5), 513–522. https://doi.org/10.5966/sctm.2014-0267

  57. Zhang, B., Yin, Y., Lai, R. C., Tan, S. S., Choo, A. B., & Lim, S. K. (2014). Mesenchymal stem cells secrete immunologically active exosomes. Stem Cells and Development, 23(11), 1233–1244. https://doi.org/10.1089/scd.2013.0479

  58. 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. Osteoarthritis and Cartilage, 24(12), 2135–2140. https://doi.org/10.1016/j.joca.2016.06.022

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How to Cite
PHAM, Phuc Van. Concise review: Extracellular vesicles from mesenchymal stem cells as cellular therapy. Biomedical Research and Therapy, [S.l.], v. 4, n. 08, p. 1562-1573, aug. 2017. ISSN 2198-4093. Available at: <http://www.bmrat.org/index.php/BMRAT/article/view/287>. Date accessed: 25 sep. 2017. doi: https://doi.org/10.15419/bmrat.v4i08.287.
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