Table of Contents Author Guidelines Submit a Manuscript
Stem Cells International
Volume 2015, Article ID 765846, 10 pages
http://dx.doi.org/10.1155/2015/765846
Review Article

A New Paradigm in Cardiac Regeneration: The Mesenchymal Stem Cell Secretome

Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, Orbassano, 10043 Turin, Italy

Received 19 December 2014; Revised 9 March 2015; Accepted 12 March 2015

Academic Editor: Mohsin Khan

Copyright © 2015 Clara Gallina et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. A. S. Go, D. Mozaffarian, V. L. Roger et al., “Heart disease and stroke statistics–2014 update: a report from the American Heart Association,” Circulation, vol. 129, no. 3, pp. e28–e292, 2014. View at Publisher · View at Google Scholar · View at Scopus
  2. M. Crisan, S. Yap, L. Casteilla et al., “A perivascular origin for mesenchymal stem cells in multiple human organs,” Cell Stem Cell, vol. 3, no. 3, pp. 301–313, 2008. View at Publisher · View at Google Scholar · View at Scopus
  3. M. Dominici, K. Le Blanc, I. Mueller et al., “Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement,” Cytotherapy, vol. 8, no. 4, pp. 315–317, 2006. View at Publisher · View at Google Scholar · View at Scopus
  4. R. R. Sharma, K. Pollock, A. Hubel, and D. McKenna, “Mesenchymal stem or stromal cells: a review of clinical applications and manufacturing practices,” Transfusion, vol. 54, no. 5, pp. 1418–1437, 2014. View at Publisher · View at Google Scholar · View at Scopus
  5. R. Mingliang, Z. Bo, and W. Zhengguo, “Stem cells for cardiac repair: status, mechanisms, and new strategies,” Stem Cells International, vol. 2011, Article ID 310928, 8 pages, 2011. View at Publisher · View at Google Scholar · View at Scopus
  6. C. Bearzi, M. Rota, T. Hosoda et al., “Human cardiac stem cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 35, pp. 14068–14073, 2007. View at Publisher · View at Google Scholar · View at Scopus
  7. A. Leri, J. Kajstura, and P. Anversa, “Cardiac stem cells and mechanisms of myocardial regeneration,” Physiological Reviews, vol. 85, no. 4, pp. 1373–1416, 2005. View at Publisher · View at Google Scholar · View at Scopus
  8. H. Xu, B. A. Yi, and K. R. Chien, “Shortcuts to making cardiomyocytes,” Nature Cell Biology, vol. 13, no. 3, pp. 191–193, 2011. View at Publisher · View at Google Scholar · View at Scopus
  9. K. C. Wollert and H. Drexler, “Cell therapy for the treatment of coronary heart disease: a critical appraisal,” Nature Reviews Cardiology, vol. 7, no. 4, pp. 204–215, 2010. View at Publisher · View at Google Scholar · View at Scopus
  10. E. Chavakis, M. Koyanagi, and S. Dimmeler, “Enhancing the outcome of cell therapy for cardiac repair: progress from bench to bedside and back,” Circulation, vol. 121, no. 2, pp. 325–335, 2010. View at Publisher · View at Google Scholar · View at Scopus
  11. J. M. Hare, J. H. Traverse, T. D. Henry et al., “A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction,” Journal of the American College of Cardiology, vol. 54, no. 24, pp. 2277–2286, 2009. View at Publisher · View at Google Scholar · View at Scopus
  12. K. E. Hatzistergos, H. Quevedo, B. N. Oskouei et al., “Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation,” Circulation Research, vol. 107, no. 7, pp. 913–922, 2010. View at Publisher · View at Google Scholar · View at Scopus
  13. Y. Iso, J. L. Spees, C. Serrano et al., “Multipotent human stromal cells improve cardiac function after myocardial infarction in mice without long-term engraftment,” Biochemical and Biophysical Research Communications, vol. 354, no. 3, pp. 700–706, 2007. View at Publisher · View at Google Scholar · View at Scopus
  14. M. Leiker, G. Suzuki, V. S. Iyer, J. M. Canty Jr., and T. Lee, “Assessment of a nuclear affinity labeling method for tracking implanted mesenchymal stem cells,” Cell Transplantation, vol. 17, no. 8, pp. 911–922, 2008. View at Publisher · View at Google Scholar · View at Scopus
  15. C. Toma, M. F. Pittenger, K. S. Cahill, B. J. Byrne, and P. D. Kessler, “Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart,” Circulation, vol. 105, no. 1, pp. 93–98, 2002. View at Publisher · View at Google Scholar · View at Scopus
  16. R. Mazhari and J. M. Hare, “Mechanisms of action of mesenchymal stem cells in cardiac repair: potential influences on the cardiac stem cell niche,” Nature Clinical Practice Cardiovascular Medicine, vol. 4, no. 1, pp. S21–S26, 2007. View at Publisher · View at Google Scholar · View at Scopus
  17. R. H. Lee, A. A. Pulin, M. J. Seo et al., “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, vol. 5, no. 1, pp. 54–63, 2009. View at Publisher · View at Google Scholar · View at Scopus
  18. M. Rodrigues, L. G. Griffith, and A. Wells, “Growth factor regulation of proliferation and survival of multipotential stromal cells,” Stem Cell Research and Therapy, vol. 1, no. 4, article 32, 2010. View at Publisher · View at Google Scholar · View at Scopus
  19. F. S. Loffredo, M. L. Steinhauser, J. Gannon, and R. T. Lee, “Bone marrow-derived cell therapy stimulates endogenous cardiomyocyte progenitors and promotes cardiac repair,” Cell Stem Cell, vol. 8, no. 4, pp. 389–398, 2011. View at Publisher · View at Google Scholar · View at Scopus
  20. M. Gnecchi, H. He, O. D. Liang et al., “Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells,” Nature Medicine, vol. 11, no. 4, pp. 367–368, 2005. View at Publisher · View at Google Scholar · View at Scopus
  21. H. Song, M.-J. Cha, B.-W. Song et al., “Reactive oxygen species inhibit adhesion of mesenchymal stem cells implanted into ischemic myocardium via interference of focal adhesion complex,” Stem Cells, vol. 28, no. 3, pp. 555–563, 2010. View at Publisher · View at Google Scholar · View at Scopus
  22. H. Skalnikova, J. Motlik, S. J. Gadher, and H. Kovarova, “Mapping of the secretome of primary isolates of mammalian cells, stem cells and derived cell lines,” Proteomics, vol. 11, no. 4, pp. 691–708, 2011. View at Publisher · View at Google Scholar · View at Scopus
  23. A. I. Caplan, “Adult mesenchymal stem cells for tissue engineering versus regenerative medicine,” Journal of Cellular Physiology, vol. 213, no. 2, pp. 341–347, 2007. View at Publisher · View at Google Scholar · View at Scopus
  24. M. Takahashi, T.-S. Li, R. Suzuki et al., “Cytokines produced by bone marrow cells can contribute to functional improvement of the infarcted heart by protecting cardiomyocytes from ischemic injury,” The American Journal of Physiology—Heart and Circulatory Physiology, vol. 291, no. 2, pp. H886–H893, 2006. View at Publisher · View at Google Scholar · View at Scopus
  25. M. Gnecchi, H. He, N. Noiseux et al., “Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement,” The FASEB Journal, vol. 20, no. 6, pp. 661–669, 2006. View at Publisher · View at Google Scholar · View at Scopus
  26. J. Bartunek, M. Vanderheyden, B. Vandekerckhove et al., “Intracoronary injection of CD133-positive enriched bone marrow progenitor cells promotes cardiac recovery after recent myocardial infarction: feasibility and safety,” Circulation, vol. 112, no. 9, pp. I178–I183, 2005. View at Publisher · View at Google Scholar · View at Scopus
  27. M. Mirotsou, Z. Zhang, A. Deb et al., “Secreted frizzled related protein 2 (Sfrp2) is the key Akt-mesenchymal stem cell-released paracrine factor mediating myocardial survival and repair,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 5, pp. 1643–1648, 2007. View at Publisher · View at Google Scholar · View at Scopus
  28. L. Huang, W. Ma, Y. Ma, D. Feng, H. Chen, and B. Cai, “Exosomes in mesenchymal stem cells, a new therapeutic strategy for cardiovascular diseases?” International Journal of Biological Sciences, vol. 11, no. 2, pp. 238–245, 2015. View at Publisher · View at Google Scholar
  29. M. L. Kelly, M. Wang, P. R. Crisostomo et al., “TNF receptor 2, not TNF receptor 1, enhances mesenchymal stem cell-mediated cardiac protection following acute ischemia,” Shock, vol. 33, no. 6, pp. 602–607, 2010. View at Publisher · View at Google Scholar · View at Scopus
  30. B.-K. Nguyen, S. Maltais, L. P. Perrault et al., “Improved function and myocardial repair of infarcted heart by intracoronary injection of mesenchymal stem cell-derived growth factors,” Journal of Cardiovascular Translational Research, vol. 3, no. 5, pp. 547–558, 2010. View at Publisher · View at Google Scholar · View at Scopus
  31. X.-H. Liu, C.-G. Bai, Z.-Y. Xu et al., “Therapeutic potential of angiogenin modified mesenchymal stem cells: angiogenin improves mesenchymal stem cells survival under hypoxia and enhances vasculogenesis in myocardial infarction,” Microvascular Research, vol. 76, no. 1, pp. 23–30, 2008. View at Publisher · View at Google Scholar · View at Scopus
  32. J. Tang, J. Wang, L. Guo et al., “Mesenchymal stem cells modified with stromal cell-derived factor 1 alpha improve cardiac remodeling via paracrine activation of hepatocyte growth factor in a rat model of myocardial infarction,” Molecules and Cells, vol. 29, no. 1, pp. 9–19, 2010. View at Publisher · View at Google Scholar · View at Scopus
  33. P. J. Psaltis, S. Paton, F. See et al., “Enrichment for STRO-1 expression enhances the cardiovascular paracrine activity of human bone marrow-derived mesenchymal cell populations,” Journal of Cellular Physiology, vol. 223, no. 2, pp. 530–540, 2010. View at Publisher · View at Google Scholar · View at Scopus
  34. H. Sarojini, R. Estrada, H. Lu et al., “PEDF from mouse mesenchymal stem cell secretome attracts fibroblasts,” Journal of Cellular Biochemistry, vol. 104, no. 5, pp. 1793–1802, 2008. View at Publisher · View at Google Scholar · View at Scopus
  35. R. Estrada, N. Li, H. Sarojini, J. An, M.-J. Lee, and E. Wang, “Secretome from mesenchymal stem cells induces angiogenesis via Cyr61,” Journal of Cellular Physiology, vol. 219, no. 3, pp. 563–571, 2009. View at Publisher · View at Google Scholar · View at Scopus
  36. T. Brade, J. Männer, and M. Kühl, “The role of Wnt signalling in cardiac development and tissue remodelling in the mature heart,” Cardiovascular Research, vol. 72, no. 2, pp. 198–209, 2006. View at Publisher · View at Google Scholar · View at Scopus
  37. J. G. J. Huang, M. Mirotsou, H. Mu, L. Zhang, and Z. Zhang, “Novel Stem cell paracrine factor protects cardiomyocytes through protein kinase C epsilon selective mechanism,” Circulation, vol. 120, 2009. View at Google Scholar
  38. H. K. Haider, S. Jiang, N. M. Idris, and M. Ashraf, “IGF-1-overexpressing mesenchymal stem cells accelerate bone marrow stem cell mobilization via paracrine activation of SDF-1alpha/CXCR4 signaling to promote myocardial repair,” Circulation Research, vol. 103, no. 11, pp. 1300–1308, 2008. View at Publisher · View at Google Scholar · View at Scopus
  39. T. Kinnaird, E. Stabile, M. S. Burnett et al., “Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms,” Circulation Research, vol. 94, no. 5, pp. 678–685, 2004. View at Publisher · View at Google Scholar · View at Scopus
  40. A. Shabbir, D. Zisa, G. Suzuki, and T. Lee, “Heart failure therapy mediated by the trophic activities of bone marrow mesenchymal stem cells: a noninvasive therapeutic regimen,” The American Journal of Physiology—Heart and Circulatory Physiology, vol. 296, no. 6, pp. H1888–H1897, 2009. View at Publisher · View at Google Scholar · View at Scopus
  41. M. P. Alfaro, A. Vincent, S. Saraswati et al., “sFRP2 suppression of bone morphogenic protein (BMP) and Wnt signaling mediates mesenchymal stem cell (MSC) self-renewal promoting engraftment and myocardial repair,” Journal of Biological Chemistry, vol. 285, no. 46, pp. 35645–35653, 2010. View at Publisher · View at Google Scholar · View at Scopus
  42. W. He, L. Zhang, A. Ni et al., “Exogenously administered secreted frizzled related protein 2 (Sfrp2) reduces fibrosis and improves cardiac function in a rat model of myocardial infarction,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 49, pp. 21110–21115, 2010. View at Publisher · View at Google Scholar · View at Scopus
  43. H. Yagi, A. Soto-Gutierrez, N. Navarro-Alvarez et al., “Reactive bone marrow stromal cells attenuate systemic inflammation via sTNFR1,” Molecular Therapy, vol. 18, no. 10, pp. 1857–1864, 2010. View at Publisher · View at Google Scholar · View at Scopus
  44. S. Kanki, V. F. M. Segers, W. Wu et al., “Stromal cell-derived factor-1 retention and cardioprotection for ischemic myocardium,” Circulation: Heart Failure, vol. 4, no. 4, pp. 509–518, 2011. View at Publisher · View at Google Scholar · View at Scopus
  45. B. Yu, H. W. Kim, M. Gong et al., “Exosomes secreted from GATA-4 overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection,” International Journal of Cardiology, vol. 182, pp. 349–360, 2015. View at Publisher · View at Google Scholar
  46. Y. Feng, W. Huang, M. Wani, X. Yu, and M. Ashraf, “Ischemic preconditioning potentiates the protective effect of stem cells through secretion of exosomes by targeting Mecp2 via miR-22,” PLoS ONE, vol. 9, no. 2, Article ID e88685, 2014. View at Publisher · View at Google Scholar · View at Scopus
  47. R. C. Lai, S. S. Tan, B. J. Teh et al., “Proteolytic potential of the MSC exosome proteome: implications for an exosome-mediated delivery of therapeutic proteasome,” International Journal of Proteomics, vol. 2012, pp. 1–14, 2012. View at Publisher · View at Google Scholar
  48. C. Salomon, J. Ryan, L. Sobrevia et al., “Exosomal signaling during hypoxia mediates microvascular endothelial cell migration and vasculogenesis,” PLoS ONE, vol. 8, no. 7, Article ID e68451, 2013. View at Publisher · View at Google Scholar · View at Scopus
  49. T. Lopatina, S. Bruno, C. Tetta, N. Kalinina, M. Porta, and G. Camussi, “Platelet-derived growth factor regulates the secretion of extracellular vesicles by adipose mesenchymal stem cells and enhances their angiogenic potential,” Cell Communication and Signaling, vol. 12, no. 1, article 26, 2014. View at Publisher · View at Google Scholar · View at Scopus
  50. W. Zhu, L. Huang, Y. Li et al., “Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth in vivo,” Cancer Letters, vol. 315, no. 1, pp. 28–37, 2012. View at Publisher · View at Google Scholar · View at Scopus
  51. F. Arslan, R. C. Lai, M. B. Smeets 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 Research, vol. 10, no. 3, pp. 301–312, 2013. View at Publisher · View at Google Scholar · View at Scopus
  52. C. Lee, S. A. Mitsialis, M. Aslam et al., “Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension,” Circulation, vol. 126, no. 22, pp. 2601–2611, 2012. View at Publisher · View at Google Scholar · View at Scopus
  53. B. Yu, M. Gong, Y. Wang et al., “Cardiomyocyte protection by GATA-4 gene engineered mesenchymal stem cells is partially mediated by translocation of miR-221 in microvesicles,” PLoS ONE, vol. 8, no. 8, Article ID e73304, 2013. View at Publisher · View at Google Scholar · View at Scopus
  54. H.-C. Zhang, X.-B. Liu, S. Huang et al., “Microvesicles derived from human umbilical cord mesenchymal stem cells stimulated by hypoxia promote angiogenesis both in vitro and in vivo,” Stem Cells and Development, vol. 21, no. 18, pp. 3289–3297, 2012. View at Publisher · View at Google Scholar · View at Scopus
  55. H. Li, S. Zuo, Z. He et al., “Paracrine factors released by GATA-4 overexpressed mesenchymal stem cells increase angiogenesis and cell survival,” The American Journal of Physiology—Heart and Circulatory Physiology, vol. 299, no. 6, pp. H1772–H1781, 2010. View at Publisher · View at Google Scholar · View at Scopus
  56. F. Huang, X. Zhu, X.-Q. Hu et al., “Mesenchymal stem cells modified with miR-126 release angiogenic factors and activate Notch ligand Delta-like-4, enhancing ischemic angiogenesis and cell survival,” International Journal of Molecular Medicine, vol. 31, no. 2, pp. 484–492, 2013. View at Publisher · View at Google Scholar · View at Scopus
  57. L. Timmers, S. K. Lim, I. E. Hoefer et al., “Human mesenchymal stem cell-conditioned medium improves cardiac function following myocardial infarction,” Stem Cell Research, vol. 6, no. 3, pp. 206–214, 2011. View at Publisher · View at Google Scholar · View at Scopus
  58. J. R. Lavoie and M. Rosu-Myles, “Uncovering the secretes of mesenchymal stem cells,” Biochimie, vol. 95, no. 12, pp. 2212–2221, 2013. View at Publisher · View at Google Scholar · View at Scopus
  59. K. Nemeth, A. Keane-Myers, J. M. Brown et al., “Bone marrow stromal cells use TGF-β to suppress allergic responses in a mouse model of ragweed-induced asthma,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 12, pp. 5652–5657, 2010. View at Publisher · View at Google Scholar · View at Scopus
  60. L. A. Ortiz, M. DuTreil, C. Fattman et al., “Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 26, pp. 11002–11007, 2007. View at Publisher · View at Google Scholar · View at Scopus
  61. A. van Koppen, J. A. Joles, B. W. M. van Balkom et al., “Human embryonic mesenchymal stem cell-derived conditioned medium rescues kidney function in rats with established chronic kidney disease,” PLoS ONE, vol. 7, no. 6, Article ID e38746, 2012. View at Publisher · View at Google Scholar · View at Scopus
  62. P. Waszak, R. Alphonse, A. Vadivel, L. Ionescu, F. Eaton, and B. Thébaud, “Preconditioning enhances the paracrine effect of mesenchymal stem cells in preventing oxygen-induced neonatal lung injury in rats,” Stem Cells and Development, vol. 21, no. 15, pp. 2789–2797, 2012. View at Publisher · View at Google Scholar · View at Scopus
  63. D. van Poll, B. Parekkadan, C. H. Cho et al., “Mesenchymal stem cell-derived molecules directly modulate hepatocellular death and regeneration in vitro and in vivo,” Hepatology, vol. 47, no. 5, pp. 1634–1643, 2008. View at Publisher · View at Google Scholar · View at Scopus
  64. C. Nakanishi, M. Yamagishi, K. Yamahara et al., “Activation of cardiac progenitor cells through paracrine effects of mesenchymal stem cells,” Biochemical and Biophysical Research Communications, vol. 374, no. 1, pp. 11–16, 2008. View at Publisher · View at Google Scholar · View at Scopus
  65. B. György, T. G. Szabó, M. Pásztói et al., “Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles,” Cellular and Molecular Life Sciences, vol. 68, no. 16, pp. 2667–2688, 2011. View at Publisher · View at Google Scholar
  66. P. Wolf, “The nature and significance of platelet products in human plasma,” British Journal of Haematology, vol. 13, no. 3, pp. 269–288, 1967. View at Publisher · View at Google Scholar · View at Scopus
  67. C. Théry, M. Ostrowski, and E. Segura, “Membrane vesicles as conveyors of immune responses,” Nature Reviews Immunology, vol. 9, no. 8, pp. 581–593, 2009. View at Publisher · View at Google Scholar · View at Scopus
  68. S. Pant, H. Hilton, and M. E. Burczynski, “The multifaceted exosome: biogenesis, role in normal and aberrant cellular function, and frontiers for pharmacological and biomarker opportunities,” Biochemical Pharmacology, vol. 83, no. 11, pp. 1484–1494, 2012. View at Publisher · View at Google Scholar · View at Scopus
  69. G. Raposo, H. W. Nijman, W. Stoorvogel et al., “B lymphocytes secrete antigen-presenting vesicles,” The Journal of Experimental Medicine, vol. 183, no. 3, pp. 1161–1172, 1996. View at Publisher · View at Google Scholar · View at Scopus
  70. L. Zitvogel, A. Regnault, A. Lozier et al., “Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes,” Nature Medicine, vol. 4, no. 5, pp. 594–600, 1998. View at Publisher · View at Google Scholar · View at Scopus
  71. J. Wolfers, A. Lozier, G. Raposo et al., “Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming,” Nature Medicine, vol. 7, no. 3, pp. 297–303, 2001. View at Publisher · View at Google Scholar · View at Scopus
  72. R. C. Lai, T. S. Chen, and S. K. Lim, “Mesenchymal stem cell exosome: a novel stem cell-based therapy for cardiovascular disease,” Regenerative Medicine, vol. 6, no. 4, pp. 481–492, 2011. View at Publisher · View at Google Scholar · View at Scopus
  73. C. Akyurekli, Y. Le, R. B. Richardson, D. Fergusson, J. Tay, and D. S. Allan, “A systematic review of preclinical studies on the therapeutic potential of mesenchymal stromal cell-derived microvesicles,” Stem Cell Reviews and Reports, vol. 11, no. 1, pp. 150–160, 2015. View at Publisher · View at Google Scholar
  74. S. Tomasoni, L. Longaretti, C. Rota et al., “Transfer of growth factor receptor mRNA via exosomes unravels the regenerative effect of mesenchymal stem cells,” Stem Cells and Development, vol. 22, no. 5, pp. 772–780, 2013. View at Publisher · View at Google Scholar · View at Scopus
  75. S. H. Ranganath, O. Levy, M. S. Inamdar, and J. M. Karp, “Harnessing the mesenchymal stem cell secretome for the treatment of cardiovascular disease,” Cell Stem Cell, vol. 10, no. 3, pp. 244–258, 2012. View at Publisher · View at Google Scholar · View at Scopus
  76. L. Timmers, S. K. Lim, F. Arslan et al., “Reduction of myocardial infarct size by human mesenchymal stem cell conditioned medium,” Stem Cell Research, vol. 1, no. 2, pp. 129–137, 2008. View at Publisher · View at Google Scholar · View at Scopus
  77. R. C. Lai, F. Arslan, M. M. Lee et al., “Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury,” Stem Cell Research, vol. 4, no. 3, pp. 214–222, 2010. View at Publisher · View at Google Scholar · View at Scopus
  78. I. Parolini, C. Federici, C. Raggi et al., “Microenvironmental pH is a key factor for exosome traffic in tumor cells,” The Journal of Biological Chemistry, vol. 284, no. 49, pp. 34211–34222, 2009. View at Publisher · View at Google Scholar · View at Scopus
  79. H. Kupcova Skalnikova, “Proteomic techniques for characterisation of mesenchymal stem cell secretome,” Biochimie, vol. 95, no. 12, pp. 2196–2211, 2013. View at Publisher · View at Google Scholar · View at Scopus
  80. K. J. Brown, C. A. Formolo, H. Seol et al., “Advances in the proteomic investigation of the cell secretome,” Expert Review of Proteomics, vol. 9, no. 3, pp. 337–345, 2012. View at Publisher · View at Google Scholar · View at Scopus
  81. J. A. Potian, H. Aviv, N. M. Ponzio, J. S. Harrison, and P. Rameshwar, “Veto-like activity of mesenchymal stem cells: functional discrimination between cellular responses to alloantigens and recall antigens,” Journal of Immunology, vol. 171, no. 7, pp. 3426–3434, 2003. View at Publisher · View at Google Scholar · View at Scopus
  82. Y. L. Tang, Q. Zhao, X. Qin et al., “Paracrine action enhances the effects of autologous mesenchymal stem cell transplantation on vascular regeneration in rat model of myocardial infarction,” Annals of Thoracic Surgery, vol. 80, no. 1, pp. 229–237, 2005. View at Publisher · View at Google Scholar · View at Scopus
  83. C. Théry, S. Amigorena, G. Raposo, and A. Clayton, “Isolation and characterization of exosomes from cell culture supernatants and biological fluids,” Current Protocols in Cell Biology, chapter 3, unit 3.22, 2006. View at Google Scholar · View at Scopus
  84. R. M. Johnstone, M. Adam, J. R. Hammond, L. Orr, and C. Turbide, “Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes),” The Journal of Biological Chemistry, vol. 262, no. 19, pp. 9412–9420, 1987. View at Google Scholar · View at Scopus
  85. H. G. Lamparski, A. Metha-Damani, J.-Y. Yao et al., “Production and characterization of clinical grade exosomes derived from dendritic cells,” Journal of Immunological Methods, vol. 270, no. 2, pp. 211–226, 2002. View at Publisher · View at Google Scholar · View at Scopus
  86. A. Clayton, J. Court, H. Navabi et al., “Analysis of antigen presenting cell derived exosomes, based on immuno-magnetic isolation and flow cytometry,” Journal of Immunological Methods, vol. 247, no. 1-2, pp. 163–174, 2001. View at Publisher · View at Google Scholar · View at Scopus
  87. D.-S. Choi, D.-K. Kim, Y.-K. Kim, and Y. S. Gho, “Proteomics, transcriptomics and lipidomics of exosomes and ectosomes,” Proteomics, vol. 13, no. 10-11, pp. 1554–1571, 2013. View at Publisher · View at Google Scholar · View at Scopus
  88. G. Camussi, M. C. Deregibus, S. Bruno, V. Cantaluppi, and L. Biancone, “Exosomes/microvesicles as a mechanism of cell-to-cell communication,” Kidney International, vol. 78, no. 9, pp. 838–848, 2010. View at Publisher · View at Google Scholar · View at Scopus
  89. T. Li, Y. Yan, B. Wang et al., “Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis,” Stem Cells and Development, vol. 22, no. 6, pp. 845–854, 2013. View at Publisher · View at Google Scholar · View at Scopus
  90. S. Bruno, C. Grange, F. Collino et al., “Microvesicles derived from mesenchymal stem cells enhance survival in a lethal model of acute kidney injury,” PLoS ONE, vol. 7, no. 3, Article ID e33115, 2012. View at Publisher · View at Google Scholar · View at Scopus
  91. F. Collino, M. C. Deregibus, S. Bruno et al., “Microvesicles derived from adult human bone marrow and tissue specific mesenchymal stem cells shuttle selected pattern of miRNAs,” PLoS ONE, vol. 5, no. 7, Article ID e11803, 2010. View at Publisher · View at Google Scholar · View at Scopus
  92. H. Valadi, K. Ekström, A. Bossios, M. Sjöstrand, J. J. Lee, and J. O. Lötvall, “Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells,” Nature Cell Biology, vol. 9, no. 6, pp. 654–659, 2007. View at Publisher · View at Google Scholar · View at Scopus
  93. A. Yuan, E. L. Farber, A. L. Rapoport et al., “Transfer of microRNAs by embryonic stem cell microvesicles,” PLoS ONE, vol. 4, no. 3, Article ID e4722, 2009. View at Publisher · View at Google Scholar · View at Scopus
  94. N. Kosaka, H. Iguchi, Y. Yoshioka, F. Takeshita, Y. Matsuki, and T. Ochiya, “Secretory mechanisms and intercellular transfer of microRNAs in living cells,” The Journal of Biological Chemistry, vol. 285, no. 23, pp. 17442–17452, 2010. View at Publisher · View at Google Scholar · View at Scopus
  95. Y. Zhang, D. Liu, X. Chen et al., “Secreted monocytic miR-150 enhances targeted endothelial cell migration,” Molecular Cell, vol. 39, no. 1, pp. 133–144, 2010. View at Publisher · View at Google Scholar · View at Scopus
  96. A. Giordano, U. Galderisi, and I. R. Marino, “From the laboratory bench to the patient's bedside: an update on clinical trials with mesenchymal stem cells,” Journal of Cellular Physiology, vol. 211, no. 1, pp. 27–35, 2007. View at Publisher · View at Google Scholar · View at Scopus