The Potential of Stem Cells and Stem Cell-Derived Exosomes in Treating Cardiovascular Diseases

  • Jing Ni
  • Yuxi Sun
  • Zheng LiuEmail author
Review Article


In recent years, the cardiac protective mechanisms of stem cells have become a research focus. Increasing evidence has suggested that stem cells release vesicles, including exosomes and micro-vesicles. The content of these vesicles relies on an extracellular stimulus, and active ingredients are extensively being studied. Previous studies have confirmed that stem cell-derived exosomes have a cardiac protective function similar to that of stem cells, and promote angiogenesis, decrease apoptosis, and respond to stress. Compared to stem cells, exosomes are more stable without aneuploidy and immune rejection, and may be a promising and effective therapy for cardiovascular diseases. In this review, the biological functions and molecular mechanisms of stem cells and stem cell-derived exosomes are discussed.


Cardiovascular diseases Exosomes Stem cells 



Acute myocardial infarction


Adult stem cell


Bone marrow stem cell


Cardiac progenitor cell


CPC-derived exosomes


Cardiac stem cell


Cardiovascular diseases


2-Methyl sulfoxide


Embryonic stem cell


Extracellular vesicle


Heart failure


High-density lipoprotein


Hematopoietic stem cell


Induced pluripotent stem cell


Induced pluripotent stem cell-derived exosomes




Messenger RNA


Mesenchymal stem cell


MSC-derived exosome


Small interfering RNA



This study was supported by grants from the National Natural Science Foundation of China (Nos. 81570303 and 81370297).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

This study does not involve human participants or animals.


  1. 1.
    Yan, R., Li, W., Yin, L., Wang, Y., Bo, J., & Investigators, P. C. (2017). Cardiovascular diseases and risk-factor burden in urban and rural communities in high-, middle-, and low-income regions of China: a large community-based epidemiological study. Journal of the American Heart Association, 6(2), e004445.Google Scholar
  2. 2.
    Benjamin, E. J., Blaha, M. J., Chiuve, S. E., Cushman, M., Das, S. R., Deo, R., et al. (2017). Heart disease and stroke statistics—2017 update: a report from the American Heart Association. Circulation, 135, e146–e603.Google Scholar
  3. 3.
    Cahill, T. J., Choudhury, R. P., & Riley, P. R. (2017). Heart regeneration and repair after myocardial infarction: translational opportunities for novel therapeutics. Nature Reviews Drug Discovery, 16(10), 699–717.Google Scholar
  4. 4.
    Jeevanantham, V., Butler, M., Saad, A., Abdel-Latif, A., Zuba-Surma, E. K., & Dawn, B. (2012). Adult bone marrow cell therapy improves survival and induces long-term improvement in cardiac parameters: a systematic review and meta-analysis. Circulation, 126(5), 551–568.Google Scholar
  5. 5.
    Jackson, R., Tilokee, E. L., Latham, N., Mount, S., Rafatian, G., Strydhorst, J., et al. (2015). Paracrine engineering of human cardiac stem cells with insulin-like growth factor 1 enhances myocardial repair. Journal of the American Heart Association, 4(9), e002104.Google Scholar
  6. 6.
    Rossaint, J., Kuhne, K., Skupski, J., Van Aken, H., Looney, M. R., Hidalgo, A., et al. (2016). Directed transport of neutrophil-derived extracellular vesicles enables platelet-mediated innate immune response. Nature Communications, 7, 13464.Google Scholar
  7. 7.
    Barile, L., Lionetti, V., Cervio, E., Matteucci, M., Gherghiceanu, M., Popescu, L. M., et al. (2014). Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction. Cardiovascular Research, 103(4), 530–541.Google Scholar
  8. 8.
    Choi, W. Y., Gemberling, M., Wang, J., Holdway, J. E., Shen, M. C., Karlstrom, R. O., et al. (2013). In vivo monitoring of cardiomyocyte proliferation to identify chemical modifiers of heart regeneration. Development, 140(3), 660–666.Google Scholar
  9. 9.
    Asahara, T., Kalka, C., & Isner, J. M. (2000). Stem cell therapy and gene transfer for regeneration. Gene Therapy, 7(6), 451–457.Google Scholar
  10. 10.
    Yabut, O., & Bernstein, H. S. (2011). The promise of human embryonic stem cells in aging-associated diseases. Aging, 3(5), 494–508.Google Scholar
  11. 11.
    Riolobos, L., Hirata, R. K., Turtle, C. J., Wang, P., Gornalusse, G. G., Zavajlevski, M., et al. (2013). HLA engineering of human pluripotent stem cells. Molecular Therapy, 21(6), 1232–1241.Google Scholar
  12. 12.
    Martin, G. R. (1981). Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proceedings of the National Academy of Sciences of the United States of America, 78(12), 7634–7638.Google Scholar
  13. 13.
    Evans, M. J., & Kaufman, M. H. (1981). Establishment in culture of pluripotential cells from mouse embryos. Nature, 292, 154–156.Google Scholar
  14. 14.
    Thomson, J. A., Itskovitzeldor, J., Shapiro, S. S., Waknitz, M. A., Swiergiel, J. J., Marshall, V. S., et al. (1998). Embryonic stem cell lines derived from human blastocysts. Science, 282(5391), 1145–1147.Google Scholar
  15. 15.
    Sartiani, L., Bettiol, E., Stillitano, F., Mugelli, A., Cerbai, E., & Jaconi, M. E. (2007). Developmental changes in cardiomyocytes differentiated from human embryonic stem cells: a molecular and electrophysiological approach. Stem Cells, 25(5), 1136–1144.Google Scholar
  16. 16.
    Fang, H., Cong, L., Zhi, Y., Xu, H., Jia, X., & Peng, S. (2016). T-2 toxin inhibits murine ES cells cardiac differentiation and mitochondrial biogenesis by ROS and p-38 MAPK-mediated pathway. Toxicology Letters, 258, 259–266.Google Scholar
  17. 17.
    Iglesias-García, O., Baumgartner, S., Macrí-Pellizzeri, L., Rodriguez-Madoz, J. R., Abizanda, G., Guruceaga, E., et al. (2014). Neuregulin-1β induces mature ventricular cardiac differentiation from induced pluripotent stem cells contributing to cardiac tissue repair. Stem Cells and Development, 24(4), 484–496.Google Scholar
  18. 18.
    Ao, A., Hao, J., Hopkins, C. R., & Hong, C. C. (2012). DMH1, a novel BMP small molecule inhibitor, increases cardiomyocyte progenitors and promotes cardiac differentiation in mouse embryonic stem cells. PLoS One, 7(7), e41627.Google Scholar
  19. 19.
    Sun, X., Pang, L., Shi, M., Huang, J., & Wang, Y. (2015). HIF2α induces cardiomyogenesis via Wnt/β-catenin signaling in mouse embryonic stem cells. Journal of Translational Medicine, 13, 88.Google Scholar
  20. 20.
    Karimzadeh, F., & Opas, M. (2017). Calreticulin is required for TGF-beta-induced epithelial-to-mesenchymal transition during cardiogenesis in mouse embryonic stem cells. Stem Cell Reports, 8(5), 1299–1311.Google Scholar
  21. 21.
    Passier, R., Oostwaard, D. W., Snapper, J., Kloots, J., Hassink, R. J., Kuijk, E., et al. (2005). Increased cardiomyocyte differentiation from human embryonic stem cells in serum-free cultures. Stem Cells, 23(6), 772–780.Google Scholar
  22. 22.
    Hirashima, M., Kataoka, H., Nishikawa, S., Matsuyoshi, N., & Nishikawa, S. (1999). Maturation of embryonic stem cells into endothelial cells in an in vitro model of vasculogenesis. Blood, 93(4), 1253–1263.PubMedGoogle Scholar
  23. 23.
    Hirashima, M., Ogawa, M., Nishikawa, S., Matsumura, K., Kawasaki, K., Shibuya, M., et al. (2003). A chemically defined culture of VEGFR2+ cells derived from embryonic stem cells reveals the role of VEGFR1 in tuning the threshold for VEGF in developing endothelial cells. Blood, 101(6), 2261–2267.Google Scholar
  24. 24.
    Narazaki, G., Uosaki, H., Teranishi, M., Okita, K., Kim, B., Matsuoka, S., et al. (2008). Directed and systematic differentiation of cardiovascular cells from mouse induced pluripotent stem cells. Circulation, 118(5), 498–506.Google Scholar
  25. 25.
    Patsch, C., Meylan, L. C., Thoma, E. C., Urich, E., Heckel, T., O’Sullivan, J. F., et al. (2015). Generation of vascular endothelial and smooth muscle cells from human pluripotent stem cells. Nature Cell Biology, 17(8), 994–1003.Google Scholar
  26. 26.
    Merok, J. R., & Sherley, J. L. (2001). Breaching the kinetic barrier to in vitro somatic stem cell propagation. Journal of Biomedicine and Biotechnology, 1(1), 25–27.Google Scholar
  27. 27.
    Deuse, T., Dong, W., Stubbendorff, M., Itagaki, R., Grabosch, A., Greaves, L., et al. (2015). SCNT-derived ESCs with mismatched mitochondria trigger an immune response in allogeneic hosts. Cell Stem Cell, 16(1), 33–38.Google Scholar
  28. 28.
    Ueno, S., Weidinger, G., Osugi, T., Kohn, A. D., Golob, J. L., Pabon, L., et al. (2007). Biphasic role for Wnt/beta-catenin signaling in cardiac specification in zebrafish and embryonic stem cells. Proceedings of the National Academy of Sciences of the United States of America, 104(23), 9685–9690.Google Scholar
  29. 29.
    Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4), 663–676.Google Scholar
  30. 30.
    Maherali, N., Sridharan, R., Xie, W., Utikal, J., Eminli, S., Arnold, K., et al. (2007). Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell, 1(1), 55–70.Google Scholar
  31. 31.
    Okita, K., Ichisaka, T., & Yamanaka, S. (2007). Generation of germline-competent induced pluripotent stem cells. Nature, 448(7151), 313–317.Google Scholar
  32. 32.
    Wernig, M., Meissner, A., Foreman, R., Brambrink, T., Ku, M., Hochedlinger, K., et al. (2007). In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature, 448(7151), 318–324.Google Scholar
  33. 33.
    Wang, W. E., Chen, X., Houser, S. R., & Zeng, C. (2013). Potential of cardiac stem/progenitor cells and induced pluripotent stem cells for cardiac repair in ischaemic heart disease. Clinical Science, 125(7), 319–327.Google Scholar
  34. 34.
    Chen, G., Yuan, Q., Sun, L., Yu, M., Wang, W., Xiao, W., et al. (2013). The jagged-2/notch-1/hes-1 pathway is involved in intestinal epithelium regeneration after intestinal ischemia-reperfusion injury. PLoS One, 8(10), e76274.Google Scholar
  35. 35.
    Merino, H., & Singla, D. K. (2014). Notch-1 mediated cardiac protection following embryonic and induced pluripotent stem cell transplantation in doxorubicin-induced heart failure. PLoS One, 9(7), e101024.Google Scholar
  36. 36.
    Kawamura, M., Miyagawa, S., Miki, K., Saito, A., Fukushima, S., Higuchi, T., et al. (2012). Feasibility, safety, and therapeutic efficacy of human induced pluripotent stem cell-derived cardiomyocyte sheets in a porcine ischemic cardiomyopathy model. Circulation, 126, S29–S37.Google Scholar
  37. 37.
    Kawamura, M., Miyagawa, S., Fukushima, S., Saito, A., Miki, K., Ito, E., et al. (2013). Enhanced survival of transplanted human induced pluripotent stem cell-derived cardiomyocytes by the combination of cell sheets with the pedicled omental flap technique in a porcine heart. Circulation, 128(11 Suppl 1), S87–S94.Google Scholar
  38. 38.
    Bearzi, C., Gargioli, C., Baci, D., Fortunato, O., Shapira-Schweitzer, K., Kossover, O., et al. (2014). PlGF-MMP9-engineered iPS cells supported on a PEG-fibrinogen hydrogel scaffold possess an enhanced capacity to repair damaged myocardium. Cell Death and Disease, 5, e1053.Google Scholar
  39. 39.
    Hielscher, A., McGuire, T., Weisenburger, D., & Sharp, J. G. (2013). Matrigel modulates a stem cell phenotype and promotes tumor formation in a mantle cell lymphoma cell line. Stem Cell Discovery, 3(3), 167–179.Google Scholar
  40. 40.
    Massa, M., Rosti, V., Ramajoli, I., Campanelli, R., Pecci, A., Viarengo, G., et al. (2005). Circulating CD34+, CD133+, and vascular endothelial growth factor receptor 2-positive endothelial progenitor cells in myelofibrosis with myeloid metaplasia. Journal of Clinical Oncology, 23(24), 5688–5695.Google Scholar
  41. 41.
    Borlongan, C. V., Glover, L. E., Tajiri, N., Kaneko, Y., & Freeman, T. B. (2011). The great migration of bone marrow-derived stem cells toward the ischemic brain: therapeutic implications for stroke and other neurological disorders. Progress in Neurobiology, 95(2), 213–228.Google Scholar
  42. 42.
    Tolani, S., Pagler, T. A., Murphy, A. J., Bochem, A. E., Abramowicz, S., Welch, C., et al. (2013). Hypercholesterolemia and reduced HDL-C promote hematopoietic stem cell proliferation and monocytosis: studies in mice and FH children. Atherosclerosis, 229(1), 79–85.Google Scholar
  43. 43.
    Tie, G., Messina, K. E., Yan, J., Messina, J. A., & Messina, L. M. (2014). Hypercholesterolemia induces oxidant stress that accelerates the ageing of hematopoietic stem cells. Journal of the American Heart Association, 3(1), e000241.Google Scholar
  44. 44.
    Fukata, M., Ishikawa, F., Najima, Y., Yamauchi, T., Saito, Y., Takenaka, K., et al. (2013). Contribution of bone marrow-derived hematopoietic stem/progenitor cells to the generation of donor-marker+ cardiomyocytes in vivo. PLoS One, 8(5), e62506.Google Scholar
  45. 45.
    Balsam, L., Wagers, A., Christensen, J., Kofidis, T., Weissman, I., & Robbins, R. (2004). Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature, 428(6983), 668–673.Google Scholar
  46. 46.
    Azab, N. I., Kholy, A. F. A., Salem, R. F., Gabr, H., & Abd, A. M. E. (2011). Comparison between bone marrow derived mesenchymal stem cells and hematopoietic stem cells in Β-islet transdifferentiation. Stem Cell, 2(1), 1–10.Google Scholar
  47. 47.
    Nygren, J. M., Jovinge, S., Breitbach, M., Sawen, P., Roll, W., Hescheler, J., et al. (2004). Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation. Nature Medicine, 10(5), 494–501.Google Scholar
  48. 48.
    Friedenstein, A. J., Deriglasova, U. F., Kulagina, N. N., Panasuk, A. F., Rudakowa, S. F., Luriá, E. A., et al. (1974). Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. Experimental Hematology, 2(2), 83–92.PubMedGoogle Scholar
  49. 49.
    Friedenstein, A. J., Gorskaja, J. F., & Kulagina, N. N. (1976). Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Experimental Hematology, 4(5), 267–274.PubMedGoogle Scholar
  50. 50.
    Friedenstein, A. J., Petrakova, K. V., Kurolesova, A. I., & Frolova, G. P. (1968). Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation, 6(2), 230–247.Google Scholar
  51. 51.
    Spaggiari, G. M., Capobianco, A., Becchetti, S., Mingari, M. C., & Moretta, L. (2006). Mesenchymal stem cell-natural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation. Blood, 107(4), 1484–1490.Google Scholar
  52. 52.
    Sotiropoulou, P. A., Perez, S. A., Gritzapis, A. D., Baxevanis, C. N., & Papamichail, M. (2006). Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells, 24(1), 74–85.Google Scholar
  53. 53.
    Gotherstrom, C., Lundqvist, A., Duprez, I. R., Childs, R., Berg, L., & le Blanc, K. (2011). Fetal and adult multipotent mesenchymal stromal cells are killed by different pathways. Cytotherapy, 13(3), 269–278.Google Scholar
  54. 54.
    Li, M., Sun, X., Kuang, X., Liao, Y., Li, H., & Luo, D. (2014). Mesenchymal stem cells suppress CD8+ T cell-mediated activation by suppressing natural killer group 2, member D protein receptor expression and secretion of prostaglandin E2, indoleamine 2, 3-dioxygenase and transforming growth factor-beta. Clinical and Experimental Immunology, 178(3), 516–524.Google Scholar
  55. 55.
    Tögel, F., & Westenfelder, C. (2011). The role of multipotent marrow stromal cells (MSCs) in tissue regeneration. Organogenesis, 7(2), 96–100.Google Scholar
  56. 56.
    Williams, A. R., Hatzistergos, K. E., Addicott, B., Mccall, F., Carvalho, D., Suncion, V., et al. (2013). Enhanced effect of combining human cardiac stem cells and bone marrow mesenchymal stem cells to reduce infarct size and to restore cardiac function after myocardial infarction. Circulation, 127(2), 213–223.Google Scholar
  57. 57.
    Yang, W., Zheng, H., Wang, Y., Lian, F., Hu, Z., & Xue, S. (2015). Nesprin-1 has key roles in the process of mesenchymal stem cell differentiation into cardiomyocyte-like cells in vivo and in vitro. Molecular Medicine Reports, 11(1), 133–142.Google Scholar
  58. 58.
    Makino, S., Fukuda, K., Miyoshi, S., Konishi, F., Kodama, H., Pan, J., et al. (1999). Cardiomyocytes can be generated from marrow stromal cells in vitro. The Journal of Clinical Investigation, 103(5), 697–705.Google Scholar
  59. 59.
    Kamihata, H., Matsubara, H., Nishiue, T., Fujiyama, S., Tsutsumi, Y., Ozono, R., et al. (2001). Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation, 104(9), 1046–1052.Google Scholar
  60. 60.
    Golpanian, S., Wolf, A., Hatzistergos, K. E., & Hare, J. M. (2016). Rebuilding the damaged heart: mesenchymal stem cells, cell-based therapy, and engineered heart tissue. Physiological Reviews, 96(3), 1127–1168.Google Scholar
  61. 61.
    Fatima, F., & Nawaz, M. (2015). Stem cell-derived exosomes: roles in stromal remodeling, tumor progression, and cancer immunotherapy. Chinese Journal of Cancer, 34(12), 541–553.PubMedGoogle Scholar
  62. 62.
    Guo, Y., Wysoczynski, M., Nong, Y., Tomlin, A., Zhu, X., Gumpert, A. M., et al. (2017). Repeated doses of cardiac mesenchymal cells are therapeutically superior to a single dose in mice with old myocardial infarction. Basic Research in Cardiology, 112, 18.Google Scholar
  63. 63.
    Zeng, L., Hu, Q., Wang, X., Mansoor, A., Lee, J., Feygin, J., et al. (2007). Bioenergetic and functional consequences of bone marrow-derived multipotent progenitor cell transplantation in hearts with postinfarction left ventricular remodeling. Circulation, 115(14), 1866–1875.Google Scholar
  64. 64.
    Ismahil, M. A., Hamid, T., Bansal, S. S., Patel, B., Kingery, J. R., & Prabhu, S. D. (2014). Remodeling of the mononuclear phagocyte network underlies chronic inflammation and disease progression in heart failure: critical importance of the cardiosplenic axis. Circulation Research, 114(2), 266–282.Google Scholar
  65. 65.
    Prabhu, S. D., & Frangogiannis, N. G. (2016). The biological basis for cardiac repair after myocardial infarction: from inflammation to fibrosis. Circulation Research, 119(1), 91–112.Google Scholar
  66. 66.
    Tzahor, E., & Poss, K. D. (2017). Cardiac regeneration strategies: Staying young at heart. Science, 356(6342), 1035–1039.Google Scholar
  67. 67.
    van Berlo, J. H., Kanisicak, O., Maillet, M., Vagnozzi, R. J., Karch, J., Lin, S. C., et al. (2014). c-kit+ cells minimally contribute cardiomyocytes to the heart. Nature, 509(7500), 337–341.Google Scholar
  68. 68.
    Huang, L., Ma, W., Ma, Y., Feng, D., Chen, H., & Cai, B. (2015). Exosomes in mesenchymal stem cells, a new therapeutic strategy for cardiovascular diseases? International Journal of Biological Sciences, 11(2), 238–245.Google Scholar
  69. 69.
    Yeo, R. W., Lai, R. C., Zhang, B., Tan, S. S., Yin, Y., Teh, B. J., et al. (2013). Mesenchymal stem cell: an efficient mass producer of exosomes for drug delivery. Advanced Drug Delivery Reviews, 65(3), 336–341.Google Scholar
  70. 70.
    Squadrito, M. L., Baer, C., Burdet, F., Maderna, C., Gilfillan, G. D., Lyle, R., et al. (2014). Endogenous RNAs modulate microRNA sorting to exosomes and transfer to acceptor cells. Cell Reports, 8(5), 1432–1446.Google Scholar
  71. 71.
    Barile, L., Moccetti, T., Marbán, E., & Vassalli, G. (2017). Roles of exosomes in cardioprotection. European Heart Journal, 38(18), 1372–1379.PubMedGoogle Scholar
  72. 72.
    Pan, B. T., & Johnstone, R. M. (1983). Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell, 33(3), 967–978.Google Scholar
  73. 73.
    Lee, Y., El Andaloussi, S., & Wood, M. J. (2012). Exosomes and microvesicles: extracellular vesicles for genetic information transfer and gene therapy. Human Molecular Genetics, 21(R1), R125–R134.Google Scholar
  74. 74.
    van der Pol, E., Coumans, F. A., Grootemaat, A. E., Gardiner, C., Sargent, I. L., Harrison, P., et al. (2014). Particle size distribution of exosomes and microvesicles determined by transmission electron microscopy, flow cytometry, nanoparticle tracking analysis, and resistive pulse sensing. Journal of Thrombosis and Haemostasis, 12(7), 1182–1192.Google Scholar
  75. 75.
    Kastelowitz, N., & Yin, H. (2014). Exosomes and microvesicles: identification and targeting by particle size and lipid chemical probes. Chembiochem, 15(7), 923–928.Google Scholar
  76. 76.
    Huber, H. J., & Holvoet, P. (2015). Exosomes: emerging roles in communication between blood cells and vascular tissues during atherosclerosis. Current Opinion in Lipidology, 26(5), 412–419.Google Scholar
  77. 77.
    Kooijmans, S. A., Vader, P., van Dommelen, S. M., van Solinge, W. W., & Schiffelers, R. M. (2012). Exosome mimetics: a novel class of drug delivery systems. International Journal of Nanomedicine, 7, 1525–1524.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Joyce, D. P., Glynn, C. L., Brown, J., Holian, E., Dockery, P., Kerin, M. J., et al. (2015). Exosome-mediated trafficking of microRNAs by breast cancer cells. Cancer Research, 75(9 Suppl), P4-07-05.Google Scholar
  79. 79.
    Boon, R. A., & Vickers, K. C. (2013). Intercellular transport of microRNAs. Arteriosclerosis Thrombosis and Vascular Biology, 33(2), 186–192.Google Scholar
  80. 80.
    Aoki, J., Ohashi, K., Mitsuhashi, M., Murakami, T., Oakes, M., Kobayashi, T., et al. (2014). Posttransplantation bone marrow assessment by quantifying hematopoietic cell-derived mRNAs in plasma exosomes/microvesicles. Clinical Chemistry, 60(4), 675–682.Google Scholar
  81. 81.
    Ratajczak, M. Z., Kim, C. H., Abdel-Latif, A., Schneider, G., Kucia, M., Morris, A. J., et al. (2012). A novel perspective on stem cell homing and mobilization: Review on bioactive lipids as potent chemoattractants and cationic peptides as underappreciated modulators of responsiveness to SDF-1 gradients. Leukemia, 26(1), 63–72.Google Scholar
  82. 82.
    Zhang, Y., Liu, D., Chen, X., Li, J., Li, L., Bian, Z., et al. (2010). Secreted monocytic miR-150 enhances targeted endothelial cell migration. Molecular Cell, 39(1), 133–144.Google Scholar
  83. 83.
    Atienzar-Aroca, S., Flores-Bellver, M., Serrano-Heras, G., Martinez-Gil, N., Barcia, J. M., Aparicio, S., et al. (2016). Oxidative stress in retinal pigment epithelium cells increases exosome secretion and promotes angiogenesis in endothelial cells. Journal of Cellular and Molecular Medicine, 20(8), 1457–1466.Google Scholar
  84. 84.
    Criqui, M. H., Denenberg, J. O., Ix, J. H., Mcclelland, R. L., Wassel, C. L., Rifkin, D. E., et al. (2014). Calcium density of coronary artery plaque and risk of incident cardiovascular events. JAMA, 311(3), 271–278.Google Scholar
  85. 85.
    Hutcheson, J. D., Goettsch, C., Bertazzo, S., Maldonado, N., Ruiz, J. L., Goh, W., et al. (2016). Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques. Nature Materials, 15(3), 335–343.Google Scholar
  86. 86.
    Viegas, C. S., Rafael, M. S., Enriquez, J. L., Teixeira, A., Vitorino, R., Costa, R. M., et al. (2015). Gla-rich protein acts as a calcification inhibitor in the human cardiovascular system. Arteriosclerosis Thrombosis and Vascular Biology, 35(2), 399–408.Google Scholar
  87. 87.
    Hu, G., Drescher, K. M., & Chen, X. M. (2012). Exosomal miRNAs: biological properties and therapeutic potential. Frontiers in Genetics, 3, 56.PubMedPubMedCentralGoogle Scholar
  88. 88.
    Bialek, S., Gorko, D., Zajkowska, A., Koltowski, L., Grabowski, M., Stachurska, A., et al. (2015). Release kinetics of circulating miRNA-208a in the early phase of myocardial infarction. Kardiologia Polska, 73(8), 613–619.Google Scholar
  89. 89.
    Sayed, A. S., Xia, K., Yang, T. L., & Peng, J. (2013). Circulating microRNAs: a potential role in diagnosis and prognosis of acute myocardial infarction. Disease Markers, 35(5), 561–566.Google Scholar
  90. 90.
    Corsten, M. F., Dennert, R., Jochems, S., Kuznetsova, T., Devaux, Y., Hofstra, L., et al. (2010). Circulating MicroRNA-208b and MicroRNA-499 reflect myocardial damage in cardiovascular disease. Circulation Cardiovascular Genetics, 3(6), 499–506.Google Scholar
  91. 91.
    Pereg, D., Cohen, K., Mosseri, M., Berlin, T., Steinberg, D. M., Ellis, M., et al. (2015). Incidence and expression of circulating cell free p53-related genes in acute myocardial infarction patients. Journal of Atherosclerosis and Thrombosis, 22(9), 981–998.Google Scholar
  92. 92.
    Takwi, A., & Li, Y. (2009). The p53 pathway encounters the microRNA world. Current Genomics, 10(3), 194–197.Google Scholar
  93. 93.
    Manole, C. G., Cismaşiu, V., Gherghiceanu, M., & Popescu, L. M. (2011). Experimental acute myocardial infarction: telocytes involvement in neo-angiogenesis. Journal of Cellular and Molecular Medicine, 15(11), 2284–2296.Google Scholar
  94. 94.
    Arslan, F., Lai, R. C., Smeets, M. B., Akeroyd, L., Choo, A., Aguor, E. N., 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(3), 301–312.Google Scholar
  95. 95.
    Larson, B. E., Stockwell, D. W., Boas, S., Andrews, T., Wellman, G. C., Lockette, W., et al. (2012). Cardiac reactive oxygen species after traumatic brain injury. Journal of Surgical Research, 173(2), e73–e81.Google Scholar
  96. 96.
    Bian, S., Zhang, L., Duan, L., Wang, X., Min, Y., & Yu, H. (2014). Extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis in a rat myocardial infarction model. Journal of Molecular Medicine, 92(4), 387–397.Google Scholar
  97. 97.
    Yu, B., Kim, H. W., Gong, M., Wang, J., Millard, R. W., Wang, Y., et al. (2015). Exosomes secreted from GATA-4 overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection. International Journal of Cardiology, 182, 349–360.Google Scholar
  98. 98.
    Feng, Y., Huang, W., Meng, W., Jegga, A. G., Wang, Y., Cai, W., et al. (2014). Heat shock improves Sca-1+ stem cell survival and directs ischemic cardiomyocytes toward a prosurvival phenotype via exosomal transfer: a critical role for HSF1/miR-34a/HSP70 pathway. Stem Cells, 32(2), 462–472.Google Scholar
  99. 99.
    Ong, S. G., Lee, W. H., Huang, M., Dey, D., Kodo, K., Sanchezfreire, V., et al. (2014). Cross talk of combined gene and cell therapy in ischemic heart disease: role of exosomal microRNA transfer. Circulation, 130(11 Suppl 1), S60–S69.Google Scholar
  100. 100.
    Padin-Iruegas, M. E., Misao, Y., Davis, M. E., Segers, V. F., Esposito, G., Tokunou, T., et al. (2009). Cardiac progenitor cells and biotinylated insulin-like growth factor-1 nanofibers improve endogenous and exogenous myocardial regeneration after infarction. Circulation, 120(10), 876–887.Google Scholar
  101. 101.
    Gray, W. D., French, K. M., Ghoshchoudhary, S., Maxwell, J. T., Brown, M. E., Platt, M. O., et al. (2015). Identification of therapeutic covariant microRNA clusters in hypoxia-treated cardiac progenitor cell exosomes using systems biology. Circulation Research, 116(2), 255–263.Google Scholar
  102. 102.
    Chen, L., Wang, Y., Pan, Y., Zhang, L., Shen, C., Qin, G., et al. (2013). Cardiac progenitor-derived exosomes protect ischemic myocardium from acute ischemia/reperfusion injury. Biochemical and Biophysical Research Communications, 431(3), 566–571.Google Scholar
  103. 103.
    Cui, X. S., Shen, X. H., Sun, S. C., Cho, S. W., Heo, Y. T., Kang, Y. K., et al. (2013). Identifying microRNA and mRNA expression profiles in embryonic stem cells derived from parthenogenetic, androgenetic and fertilized blastocysts. Journal of Genetics and Genomics, 40(4), 189–200.Google Scholar
  104. 104.
    Khan, M., Nickoloff, E., Abramova, T., Johnson, J., Verma, S. K., Krishnamurthy, P., et al. (2015). Embryonic stem cell-derived exosomes promote endogenous repair mechanisms and enhance cardiac function following myocardial infarction. Circulation Research, 117(1), 52–64.Google Scholar
  105. 105.
    Camara, A. K. S., & Stowe, D. F. (2014). Reactive oxygen species (ROS) and cardiac ischemia and reperfusion injury. In I. Laher (Ed.), Systems biology of free radicals and antioxidants (pp. 889–949). Berlin: Springer.Google Scholar
  106. 106.
    Cabal-Hierro, L., & Lazo, P. S. (2012). Signal transduction by tumor necrosis factor receptors. Cellular Signalling, 24(6), 1297–1305.Google Scholar
  107. 107.
    Suzuki, T., & Inoki, K. (2011). Spatial regulation of the mTORC1 system in amino acids sensing pathway. Acta Biochimica et Biophysica Sinica, 43(9), 671–679.Google Scholar
  108. 108.
    Matsumoto, S., Sakata, Y., Suna, S., Nakatani, D., Usami, M., Hara, M., et al. (2013). Circulating p53-responsive microRNAs are predictive indicators of heart failure after acute myocardial infarction. Circulation Research, 113(3), 322–326.Google Scholar
  109. 109.
    Wang, Y., Zhang, L., Li, Y., Chen, L., Wang, X., Guo, W., et al. (2015). Exosomes/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte apoptosis in the ischemic myocardium. International Journal of Cardiology, 192, 61–69.Google Scholar
  110. 110.
    Sun, L., Xu, R., Sun, X., Duan, Y., Han, Y., Zhao, Y., et al. (2016). Safety evaluation of exosomes derived from human umbilical cord mesenchymal stromal cell. Cytotherapy, 18(3), 413–422.Google Scholar
  111. 111.
    Zhang, Y., Mignone, J., & MacLellan, W. R. (2015). Cardiac regeneration and stem cells. Physiological Reviews, 95(4), 1189–1204.Google Scholar
  112. 112.
    Wiklander, O. P. B., Nordin, J. Z., O’Loughlin, A., Gustafsson, Y., Corso, G., Mäger, I., et al. (2015). Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. Journal of Extracellular Vesicles, 4, 26316.Google Scholar
  113. 113.
    Takahashi, Y., Nishikawa, M., Shinotsuka, H., Matsui, Y., Ohara, S., Imai, T., et al. (2013). Visualization and in vivo tracking of the exosomes of murine melanoma B16-BL6 cells in mice after intravenous injection. Journal of Biotechnology, 165(2), 77–84.Google Scholar
  114. 114.
    Melzer, N., Meuth, S. G., & Wiendl, H. (2012). Neuron-directed autoimmunity in the central nervous system: entities, mechanisms, diagnostic clues, and therapeutic options. Current Opinion in Neurology, 25(3), 341–348.Google Scholar
  115. 115.
    Wang, J., Zheng, Y., & Zhao, M. (2016). Exosome-based cancer therapy: implication for targeting cancer stem cells. Frontiers in Pharmacology, 7, 533.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of CardiologyShanghai Tenth People’s HospitalShanghaiChina
  2. 2.Pan-Vascular Research Institute, Heart, Lung, and Blood CenterTongji University School of MedicineShanghaiChina

Personalised recommendations