Stem Cell Reviews and Reports

, Volume 11, Issue 1, pp 150–160 | Cite as

A Systematic Review of Preclinical Studies on the Therapeutic Potential of Mesenchymal Stromal Cell-Derived Microvesicles

  • Celine Akyurekli
  • Yevgeniya Le
  • Richard B. Richardson
  • Dean Fergusson
  • Jason Tay
  • David S. AllanEmail author



The therapeutic potential of mesenchymal stromal cells (MSCs) may be largely mediated by paracrine factors contained in microvesicles (MV) released from intracellular endosomes. A systematic review of controlled interventional animal studies was performed to identify models of organ injury where clinical translation of MSC-derived microvesicle therapy appears most promising as regenerative therapy.


A total of 190 published articles were identified in our systematic search of electronic databases (MEDLINE, EMBASE, PUBMED). After screening for eligibility, a total of 17 controlled studies testing MSC-derived MVs as therapeutic interventions in animal models of disease underwent comprehensive review, quality assessment, and data extraction.


Thirteen studies addressed the regenerative potential following organ injury. Six studies were included on acute kidney injury, 4 on myocardial infarction and reperfusion injury, 1 on hind limb ischemia, 1 on liver injury, and 1 on hypoxic lung injury. Four studies addressed immunological effects of MSC-derived MVs on inhibiting tumor growth. Twelve studies (71 %) provided explicit information regarding the number of animals allocated to treatment or control groups. Five studies (29 %) randomly assigned animals to treatment or control groups and only 1 study (6 %) reported on blinding. Therapeutic intervention involved isolation of exosomes (40–100 nm) in eight studies, while nine studies tested unfractionated microvesicles (<1,000 nm). In studies of tissue regeneration, all 13 reported that treatment with MSC-derived MVs improved at least one major/clinical parameter associated with organ dysfunction. Three of 4 studies evaluating the inhibition of tumor growth reported benefit.


In preclinical studies, the use of MSC-derived MVs is strongly associated with improved organ function following injury and may be useful for inhibiting tumor growth. Improved preclinical study quality in terms of treatment allocation reporting, randomization and blinding will accelerate needed progress towards clinical trials that should assess feasibility and safety of this therapeutic approach in humans.


Mesenchymal stromal cells Microvesicles Exosomes Preclinical Animal models Systematic review 



We wish to acknowledge the expertise and assistance of Risa Shorr from the library at The Ottawa Hospital for help with design and execution of the systematic search. Funding support for CA was provided by The Ottawa Hospital Foundation Research Fund for Hematology and Blood and Marrow Transplantation. Salary support from a New Investigator Award (DSA) and Mentorship Award in Clinical Trials (JT) was generously provided by Canadian Institutes of Health Research. An endowed Chair in Clinical Epidemiology (DF) from the University of Ottawa (U of O) and Ottawa Hospital Research Institute is gratefully acknowledged. DSA and JT are supported in part by the Department of Medicine at U of O. Part of this work was undertaken as part of the Science and Technology program of the Canadian Government, AECL Project 1.4.4-8 Improving Occupational Dosimetry.


The authors indicate no potential conflicts of interest.


  1. 1.
    Lalu, M. M., McIntyre, L., Pugliese, C., et al. (2012). Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PloS One, 7, e47559.CrossRefPubMedCentralPubMedGoogle Scholar
  2. 2.
    Hofmann, N. A., Ortner, A., Jacamo, R. O., et al. (2012). Oxygen sensing mesenchymal progenitors promote neo-vasculogenesis in a humanized mouse model in vivo. PloS One, 7, e44468.CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Bell, G. I., Meschino, M. T., Hughes-Large, J. M., et al. (2012). Combinatorial human progenitor cell transplantation optimizes islet regeneration through secretion of paracrine factors. Stem Cells and Development, 21, 1863–1876.CrossRefPubMedGoogle Scholar
  4. 4.
    Zhao, S., Wehner, R., Bornhauser, M., et al. (2010). Immunomodulatory properties of mesenchymal stromal cells and their therapeutic consequences for immune-mediated disorders. Stem Cells and Development, 19, 607–614.CrossRefPubMedGoogle Scholar
  5. 5.
    Nauta, A. J., & Fibbe, W. E. (2007). Immunomodulatory properties of mesenchymal stromal cells. Blood, 110, 3499–3506.CrossRefPubMedGoogle Scholar
  6. 6.
    Beitnes, O., Oie, E., Shahdadfar, A., et al. (2012). Intramyocardial injections of human mesenchymal stem cells following acute myocardial infarction modulate scar formation and improve left ventricular function. Cell Transplantation, 21, 1697–1709.CrossRefGoogle Scholar
  7. 7.
    Zhu, X. Y., Lerman, A., & Lerman, L. O. (2013). Concise review: mesenchymal stem cell treatment for ischemic kidney disease. Stem Cells, 31, 1731–1736.CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    Waszak, P., Alphonse, R., Vadivel, A., et al. (2012). Preconditioning enhances the paracrine effect of mesenchymal stem cells in preventing oxygen-induced neonatal lung injury in rats. Stem Cells and Development, 21, 2789–2797.CrossRefPubMedGoogle Scholar
  9. 9.
    Ionescu, L., Byrne, R. N., van Haaften, T., et al. (2012). Stem cell conditioned medium improves acute lung injury in mice: in vivo evidence for stem cell paracrine action. American Journal of Physiology Lung Cellular and Molecular Physiology, 303, L967–L977.CrossRefPubMedCentralPubMedGoogle Scholar
  10. 10.
    Fouraschen, S. M., Pan, Q., de Ruiter, P. E., et al. (2012). Secreted factors of human-derived mesenchymal stem cells promote liver regeneration early after partial hepatectomy. Stem Cells and Development, 21, 2410–2419.CrossRefPubMedGoogle Scholar
  11. 11.
    Lai, R. C., Chen, T. S., & Lim, S. K. (2011). Mesenchymal stem cell exosome: a novel stem cell-based therapy for cardiovascular disease. Regenerative Medicine, 6, 481–492.CrossRefPubMedGoogle Scholar
  12. 12.
    Camussi, G., Deregibus, M. C., & Tetta, C. (2010). Paracrine/endocrine mechanism of stem cells on kidney repair: role of microvesicle-mediated transfer of genetic information. Current Opinion Nephrol Hypertension, 19, 7–12.CrossRefGoogle Scholar
  13. 13.
    Im, H., Shao, H., Park, Y. I., et al. (2014). Label-free detection and molecular profiling of exosomes with a nano-plasmonic sensor. Nature Biotechnology. doi: 10.1038/nbt.2886. Epub ahead of print April 20, 2014.PubMedGoogle Scholar
  14. 14.
    Robbins, P. D., & Morelli, A. E. (2014). Regulation of immune responses by extracellular vesicles. Nature Reviews Immunology, 14, 195–208.CrossRefPubMedGoogle Scholar
  15. 15.
    Lee, J. K., Park, S. R., Jung, B. K., et al. (2013). Exosomes derived from mesenchymal stem cells suppress angiogenesis by down-regulating VEGF expression in breast cancer cells. PloS One, 8, e84256.CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    Roccaro, A. M., Sacco, A., Maiso, P., et al. (2013). BM Mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression. Journal of Clinical Investigation, 123, 1542–1555.CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Looze, C., Yui, D., Leung, L., et al. (2009). Proteomic profiling of human plasma exosomes identifies PPARgamma as an exosome-associated protein. Biochemical and Biophysical Research Communications, 378, 433–438.CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Moher, D., Liberati, A., Tetzlaff, J., Altman, D. G., & PRISMA Group. (2009). Preferred reporting items for sytematic reviews and meta-analyses: the PRISMA statement. PLoS Medicine, 6, e1000097.CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    Henderson, V. C., Kimmelman, J., Fergusson, D., Grimshaw, J. M., & Hackam, D. G. (2013). Threats to validity in the design and conduct of preclinical efficacy studies: a systematic review of guidelines for in vivo animal experiments. PLoS Medicine, 10, e1001489.CrossRefPubMedCentralPubMedGoogle Scholar
  20. 20.
    Bruno, S., Grange, C., Deregibus, M. C., Calogero, R. A., Saviozzi, S., Collino, F., et al. (2009). Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. Journal of the American Society of Nephrology, 20, 1053–1067.CrossRefPubMedCentralPubMedGoogle Scholar
  21. 21.
    Bruno, S., Grange, C., Collino, F., Deregibus, M. C., Cantaluppi, V., Biancone, L., et al. (2012). Microvesicles derived from mesenchymal stem cells enhance survival in a lethal model of acute kidney injury. PloS One, 7, e33115.CrossRefPubMedCentralPubMedGoogle Scholar
  22. 22.
    Gatti, S., Bruno, S., Deregibus, M. C., Sordi, A., Cantaluppi, V., Tetta, C., et al. (2011). Microvesicles derived from human adult mesenchymal stem cells protect against ischaemia-reperfusion-induced acute and chronic kidney injury. Nephrology Dialysis Transplantation, 26, 1474–1483.CrossRefGoogle Scholar
  23. 23.
    He, J., Wang, Y., Sun, S., Yu, M., Wang, C., Pei, X., et al. (2012). Bone marrow stem cells-derived microvesicles protect against renal injury in the mouse remnant kidney model. Nephrology, 17, 493–500.CrossRefPubMedGoogle Scholar
  24. 24.
    Reis, L. A., Borges, F. T., Simoes, M. J., Borges, A. A., Sinigaglia-Coimbra, R., & Schor, N. (2012). Bone marrow-derived mesenchymal stem cells repaired but did not prevent gentamicin-induced acute kidney injury through paracrine effects in rats. PloS One, 7, e44092.CrossRefPubMedCentralPubMedGoogle Scholar
  25. 25.
    Zhou, Y., Xu, H., Xu, W., Wang, B., Wu, H., Tao, Y., et al. (2013). 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 Research Therapy, 4, 34.CrossRefPubMedCentralPubMedGoogle Scholar
  26. 26.
    Arslan, F., Lai, R. C., Smeets, M. B., Akeroyd, L., Choo, A., Aguor, E. N. E., et al. (2013). 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 Research, 10, 301–312.CrossRefPubMedGoogle Scholar
  27. 27.
    Lai, R. C., Arslan, F., Lee, M. M., Sze, N. S. K., Choo, A., Chen, T. S., et al. (2010). Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Research, 4, 214–222.CrossRefPubMedGoogle Scholar
  28. 28.
    Lai, R. C., Arslan, F., Tan, S. S., Tan, B., Choo, A., Lee, M. M., et al. (2010). Derivation and characterization of human fetal MSCs: an alternative cell source for large-scale production of cardioprotective microparticles. Journal of Molecular and Cellular Cardiology, 48, 1215–1224.CrossRefPubMedGoogle Scholar
  29. 29.
    Chen, T. S., Lai, R. C., Lee, M. M., et al. (2010). Mesenchymal stem cell secretes microparticles enriched in pre-microRNAs. Nucleic Acids Research, 38, 215–224.CrossRefPubMedCentralPubMedGoogle Scholar
  30. 30.
    Zhang, H. C., Liu, X. B., Huang, S., Bi, X. Y., Wang, H. X., Xie, L. X., et al. (2012). Microvesicles derived from human umbilical cord mesenchymal stem cells stimulated by hypoxia promote angiogenesis both in vitro and in vivo. Stem Cells and Development, 21, 3289–3297.CrossRefPubMedCentralPubMedGoogle Scholar
  31. 31.
    Li, T., Yan, Y., Wang, B., Qian, H., Zhang, X., Shen, L., et al. (2013). Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis. Stem Cells and Development, 22, 845–854.CrossRefPubMedCentralPubMedGoogle Scholar
  32. 32.
    Lee, C., Mitsialis, S. A., Aslam, M., Vitali, S. H., Vergadi, E., Konstantinou, G., et al. (2012). Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension. Circulation, 126, 2601–2611.CrossRefPubMedCentralPubMedGoogle Scholar
  33. 33.
    Bruno, S., Collino, F., Deregibus, M. C., Grange, C., Tetta, C., & Camussi, G. (2013). Microvesicles derived from human bone marrow mesenchymal stem cells inhibit tumor growth. Stem Cells and Development, 22, 758–771.CrossRefPubMedGoogle Scholar
  34. 34.
    Zhu, W., Huang, L., Li, Y., Zhang, X., Gu, J., Yan, Y., et al. (2012). Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth in vivo. Cancer Letters, 315, 28–37.CrossRefPubMedGoogle Scholar
  35. 35.
    Wu, S., Ju, G. Q., Du, T., Zhu, Y. J., & Liu, G. H. (2013). Microvesicles derived from human umbilical cord Wharton’s jelly mesenchymal stem cells attenuate bladder tumor cell growth in vitro and in vivo. PloS One, 8, e61366.CrossRefPubMedCentralPubMedGoogle Scholar
  36. 36.
    Rosu-Myles M, Gillham-Eisen LA, Agbanyo FR, Ganz PR (2011) Regulatory questions in the development of blood stem cell products for regenerative therapy. In: Regenerative Therapy Using Blood-Derived Stem Cells ed. DS Allan and D Strunk, Springer Science, pp 167–190Google Scholar
  37. 37.
    Bernardo, M. E., & Fibbe, W. E. (2012). Safety and efficacy of mesenchymal stromal cell therapy in autoimmune disorders. Annals of the New York Academy of Sciences, 1266, 107–117.CrossRefPubMedGoogle Scholar
  38. 38.
    von Bahr, L., Batsis, I., Moll, G., et al. (2012). Analysis of tissues following mesenchymal stromal cell therapy in humans indicates limited long-term engraftment and no ectopic tissue formation. Stem Cells, 30, 1575–1578.CrossRefGoogle Scholar
  39. 39.
    Clark, E. A., Kalomoiris, S., Nolta, J. A., & Fierro, F. A. (2013). MicroRNA function in multipotent mesenchymal stromal cells. Stem Cells, 32, 1074–1082.CrossRefGoogle Scholar
  40. 40.
    Lavoie, J. R., & Rosu-Myles, M. (2013). Uncovering the secretes of mesenchymal stem cells. Biochimie, 95, 2212–2221.CrossRefPubMedGoogle Scholar

Copyright information

© Crown Copyright as represented by: Atomic Energy of Canada Limited 2014

Authors and Affiliations

  • Celine Akyurekli
    • 1
  • Yevgeniya Le
    • 1
    • 4
  • Richard B. Richardson
    • 4
  • Dean Fergusson
    • 2
  • Jason Tay
    • 2
    • 3
  • David S. Allan
    • 1
    • 3
    • 5
    Email author
  1. 1.Regenerative Medicine ProgramOttawa Hospital Research InstituteOttawaCanada
  2. 2.Clinical Epidemiology ProgramOttawa Hospital Research InstituteOttawaCanada
  3. 3.Department of Medicine, HematologyUniversity of OttawaOttawaCanada
  4. 4.Atomic Energy of Canada LimitedOttawaCanada
  5. 5.Ottawa Hospital Research InstituteOttawaCanada

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