Exosomes: Fundamental Biology and Roles in Cardiovascular Physiology

Annual Review of Physiology

Volumn 78, Issue , 2016, Pages 67-83

  Ibrahim, Ahmed ^a   Marbán, Eduardo ^b  

^a Capricor Therapeutics   (United States)

^b CEDARS SINAI MEDICAL CENTER   (United States)

Author keywords

Cardiovascular disease; Extracellular vesicles; Intracellular communication; MicroRNA; Regenerative medicine; Stem cells

Indexed keywords

CD63 ANTIGEN; CD81 ANTIGEN; CD9 ANTIGEN; ESCRT PROTEIN; HEAT SHOCK PROTEIN 20; HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN; LONG UNTRANSLATED RNA; LYSOSOME ASSOCIATED MEMBRANE PROTEIN 1; LYSOSOME ASSOCIATED MEMBRANE PROTEIN 2; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 2; MICRORNA; MICRORNA 126; MICRORNA 146A; PIWI INTERACTING RNA; STAT3 PROTEIN;

CARDIAC STEM CELL; CARDIOMYOPATHY; CARDIOVASCULAR DISEASE; CARDIOVASCULAR FUNCTION; CELL COMMUNICATION; CELL MEMBRANE; ENDOPLASMIC RETICULUM; EXOSOME; EXTRACELLULAR SPACE; HEART ARRHYTHMIA; HEART LEFT VENTRICLE FAILURE; HEART PROTECTION; HEART VENTRICLE HYPERTROPHY; HUMAN; LIPID COMPOSITION; MEMBRANE VESICLE; MESENCHYMAL STEM CELL; MULTIVESICULAR BODY; NONHUMAN; ORGANELLE BIOGENESIS; PARTICLE SIZE; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; THERAPY EFFECT; ANIMAL; GENETICS; METABOLISM; PHYSIOLOGY; TRANSPORT AT THE CELLULAR LEVEL;

ANIMALS; BIOLOGICAL TRANSPORT; CARDIOVASCULAR PHYSIOLOGICAL PHENOMENA; EXOSOMES; HUMANS; MICRORNAS;

EID: 84958645302     PISSN: 00664278     EISSN: 15451585     Source Type: Book Series    
DOI: 10.1146/annurev-physiol-021115-104929     Document Type: Review

References (116)

1. Thakur BK, Zhang H, Becker A, Matei I, Huang Y, et al. 2014. Double-stranded DNA in exosomes: a novel biomarker in cancer detection. Cell Res. 24:766-69
2. Chargaff E, West R. 1946. The biological significance of the thromboplastic protein of blood. J. Biol. Chem. 166:189-97
3. Wolf P. 1967. The nature and significance of platelet products in human plasma. Br. J. Haematol. 13:269-88
4. Johnstone RM. 2006. Exosomes biological significance: a concise review. Blood Cells Mol. Dis. 36:315-21
5. Johnstone RM, AdamM, Hammond JR, Orr L, Turbide C. 1987. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J. Biol. Chem. 262:9412-20
6. Kriebel PW, Barr VA, Rericha EC, Zhang G, Parent CA. 2008. Collective cell migration requires vesicular trafficking for chemoattractant delivery at the trailing edge. J. Cell Biol. 183:949-61
7. Albuquerque PC, Nakayasu ES, Rodrigues ML, Frases S, Casadevall A, et al. 2008. Vesicular transport in Histoplasma capsulatum: an effective mechanism for trans-cell wall transfer of proteins and lipids in ascomycetes. Cell. Microbiol. 10:1695-710
8. An Q, van Bel AJ, Huckelhoven R. 2007. Do plant cells secrete exosomes derived from multivesicular bodies? Plant Signal. Behav. 2:4-7
9. Korkut C, Ataman B, Ramachandran P, Ashley J, Barria R, et al. 2009. Trans-synaptic transmission of vesicular Wnt signals through Evi/Wntless. Cell 139:393-404
10. Liégeois S, Benedetto A, Garnier JM, Schwab Y, Labouesse M. 2006. The V0-ATPase mediates apical secretion of exosomes containing Hedgehog-related proteins in Caenorhabditis elegans. J. Cell Biol. 173:949-61
11. Raposo G, StoorvogelW. 2013. Extracellular vesicles: exosomes, microvesicles, and friends. J. Cell Biol. 200:373-83
12. Street JM, Barran PE, Mackay CL, Weidt S, Balmforth C, et al. 2012. Identification and proteomic profiling of exosomes in human cerebrospinal fluid. J. Transl. Med. 10:5
13. Reinhardt TA, Lippolis JD, Nonnecke BJ, Sacco RE. 2012. Bovine milk exosome proteome. J. Proteom. 75:1486-92
14. TaylorDD,Gercel-TaylorC. 2005. Tumour-derived exosomes and their role in cancer-associated T-cell signalling defects. Br. J. Cancer 92:305-11
15. Runz S, Keller S, Rupp C, Stoeck A, Issa Y, et al. 2007. Malignant ascites-derived exosomes of ovarian carcinoma patients contain CD24 and EPCAM. Gynecol. Oncol. 107:563-71
16. Fernandez-Llama P, Khositseth S, Gonzales PA, Star RA, Pisitkun T, Knepper MA. 2010. Tamm-Horsfall protein and urinary exosome isolation. Kidney Int. 77:736-42
17. Chen C, Skog J, Hsu CH, Lessard RT, Balaj L, et al. 2010. Microfluidic isolation and transcriptome analysis of serum microvesicles. Lab Chip 10:505-11
18. Admyre C, Johansson SM, Qazi KR, Filen JJ, Lahesmaa R, et al. 2007. Exosomes with immune modulatory features are present in human breast milk. J. Immunol. 179:1969-78
19. Levanen B, Bhakta NR, Torregrosa Paredes P, Barbeau R,Hiltbrunner S, et al. 2013. AlteredmicroRNA profiles in bronchoalveolar lavage fluid exosomes in asthmatic patients. J. Allergy Clin. Immunol. 131:894-903
20. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. 2007. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9:654-59
21. Record M, Carayon K, Poirot M, Silvente-Poirot S. 2014. Exosomes as new vesicular lipid transporters involved in cell-cell communication and various pathophysiologies. Biochim. Biophys. Acta 1841:108-20
22. EL Andaloussi S,Mäger I, Breakefield XO,Wood MJ. 2013. Extracellular vesicles: biology and emerging therapeutic opportunities. Nat. Rev. Drug Discov. 12:347-57
23. Xu L, Yang BF, Ai J. 2013. MicroRNA transport: a new way in cell communication. J. Cell Physiol. 228:1713-19
24. Wittmann J, Jack HM. 2010. Serum microRNAs as powerful cancer biomarkers. Biochim. Biophys. Acta 1806:200-7
25. Rao P, Benito E, Fischer A. 2013. MicroRNAs as biomarkers for CNS disease. Front. Mol. Neurosci. 6:39
26. Oikonomou E, Siasos G, Tousoulis D, Kokkou E, Genimata V, et al. 2013. Diagnostic and therapeutic potentials of microRNAs in heart failure. Curr. Top. Med. Chem. 13:1548-58
27. Schageman J, Zeringer E, Li M, Barta T, Lea K, et al. 2013. The complete exosome workflow solution: from isolation to characterization of RNA cargo. Biomed Res. Int. 2013:253957
28. Pant S, Hilton H, Burczynski ME. 2012. The multifaceted exosome: biogenesis, role in normal and aberrant cellular function, and frontiers for pharmacological and biomarker opportunities. Biochem. Pharmacol. 83:1484-94
29. Hanson PI, Shim S, Merrill SA. 2009. Cell biology of the ESCRT machinery. Curr. Opin. Cell Biol. 21:568-74
30. Mayers JR, Audhya A. 2012. Vesicle formation within endosomes: An ESCRT marks the spot. Commun. Integr. Biol. 5:50-56
31. Alcazar O, Hawkridge AM, CollierTS, Cousins SW, Bhattacharya SK, et al. 2009. Proteomics characterization of cell membrane blebs in human retinal pigment epithelium cells. Mol. Cell. Proteom. 8:2201-11
32. Eskelinen EL. 2006. Roles of LAMP-1 and LAMP-2 in lysosome biogenesis and autophagy. Mol. Aspects Med. 27:495-502
33. NIH Office of Strategic Coordination. 2011. Extracellular RNA communication. https://commonfund. nih.gov/Exrna/index
34. Futter CE, Pearse A, Hewlett LJ, Hopkins CR. 1996. Multivesicular endosomes containing internalized EGF-EGF receptor complexes mature and then fuse directly with lysosomes. J. Cell Biol. 132:1011-23
35. Möbius W, Ohno-Iwashita Y, van Donselaar EG, Oorschot VM, et al. 2002. Immunoelectron microscopic localization of cholesterol using biotinylated and non-cytolytic perfringolysin O. J. Histochem. Cytochem. 50:43-55
36. RaiborgC, StenmarkH. 2009. The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins. Nature 458:445-52
37. Hurley JH. 2010. The ESCRT complexes. Crit. Rev. Biochem. Mol. Biol. 45:463-87
38. Hurley JH, Hanson PI. 2010. Membrane budding and scission by the ESCRT machinery: It's all in the neck. Nat. Rev. Mol. Cell Biol. 11:556-66
39. White IJ, Bailey LM, Aghakhani MR,Moss SE, Futter CE. 2006. EGF stimulates annexin 1-dependent inward vesiculation in a multivesicular endosome subpopulation. EMBO J. 25:1-12
40. Mathivanan S, Fahner CJ, Reid GE, Simpson RJ. 2012. ExoCarta 2012: database of exosomal proteins, RNA and lipids. Nucleic Acids Res. 40:D1241-44
41. Subra C, Grand D, Laulagnier K, Stella A, Lambeau G, et al. 2010. Exosomes account for vesiclemediated transcellular transport of activatable phospholipases and prostaglandins. J. Lipid Res. 51:2105-20
42. Trajkovic K, Hsu C, Chiantia S, Rajendran L, Wenzel D, et al. 2008. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319:1244-47
43. Zakharova L, Svetlova M, Fomina AF. 2007. T cell exosomes induce cholesterol accumulation in human monocytes via phosphatidylserine receptor. J. Cell. Physiol. 212:174-81
44. HendersonMC, Azorsa DO. 2012. The genomic and proteomic content of cancer cell-derived exosomes. Front. Oncol. 2:38
45. Huang X, YuanT,TschannenM, Sun Z, JacobH, et al. 2013. Characterization of human plasma-derived exosomal RNAs by deep sequencing. BMC Genomics 14:319
46. Chekanova JA, Gregory BD, Reverdatto SV, Chen H, Kumar R, et al. 2007. Genome-wide highresolution mapping of exosome substrates reveals hidden features in the Arabidopsis transcriptome. Cell 131:1340-53
47. Lotvall J, Valadi H. 2007. Cell to cell signalling via exosomes through esRNA. Cell Adh. Migr. 1:156-58
48. Mittelbrunn M, Gutierrez-Vazquez C, Villarroya-Beltri C, Gonzalez S, Sanchez-Cabo F, et al. 2011. Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat. Commun. 2:282
49. Hessvik NP, Phuyal S, Brech A, Sandvig K, Llorente A. 2012. Profiling of microRNAs in exosomes released from PC-3 prostate cancer cells. Biochim. Biophys. Acta 1819:1154-63
50. Bellingham SA, Coleman BM, Hill AF. 2012. Small RNA deep sequencing reveals a distinct miRNA signature released in exosomes from prion-infected neuronal cells. Nucleic Acids Res. 40:10937-49
51. Villarroya-Beltri C, Gutierrez-Vazquez C, Sanchez-Madrid F, Mittelbrunn M. 2013. Analysis of microRNA and protein transfer by exosomes during an immune synapse. Meth. Mol. Biol. 1024:41-51
52. Jaiswal R, Gong J, Sambasivam S, Combes V, Mathys JM, et al. 2012. Microparticle-associated nucleic acids mediate trait dominance in cancer. FASEB J. 26:420-29
53. Turturici G, Tinnirello R, Sconzo G, Geraci F. 2014. Extracellular membrane vesicles as a mechanism of cell-to-cell communication: advantages and disadvantages. Am. J. Physiol. Cell Physiol. 306:C621-33
54. Smyth T, Kullberg M, Malik N, Smith-Jones P, Graner MW, Anchordoquy TJ. 2015. Biodistribution and delivery efficiency of unmodified tumor-derived exosomes. J. Control. Release 199:145-55
55. Wiklander OP, Nordin JZ, O'Loughlin A, Gustafsson Y, Corso G, et al. 2015. Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. J. Extracell. Vesicles 4:26316
56. Roma-RodriguesC, Fernandes AR, Baptista PV. 2014. Exosome in tumour microenvironment: overview of the crosstalk between normal and cancer cells. BioMed. Res. Int. 2014:179486
57. Lopez-Verrilli MA, Court FA. 2013. Exosomes: mediators of communication in eukaryotes. Biol. Res. 46:5-11
58. Bhatnagar S, Shinagawa K, Castellino FJ, Schorey JS. 2007. Exosomes released from macrophages infected with intracellular pathogens stimulate a proinflammatory response in vitro and in vivo. Blood 110:3234-44
59. Sahoo S,LosordoDW.2014. Exosomes and cardiac repair aftermyocardial infarction. Circ. Res. 114:333-44
60. Molkentin JD, DornGW2nd. 2001. Cytoplasmic signaling pathways that regulate cardiac hypertrophy. Annu. Rev. Physiol. 63:391-426
61. Tian J, Guo X, Liu XM, Liu L, Weng QF, et al. 2013. Extracellular HSP60 induces inflammation through activating and up-regulating TLRs in cardiomyocytes. Cardiovasc. Res. 98:391-401
62. Bang C, Batkai S, Dangwal S,Gupta SK, FoinquinosA, et al. 2014. Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. J. Clin. Investig. 124:2136-46
63. Fredj S, Bescond J, Louault C, Potreau D. 2005. Interactions between cardiac cells enhance cardiomyocyte hypertrophy and increase fibroblast proliferation. J. Cell. Physiol. 202:891-99
64. Bang C, Batkai S, Dangwal S,Gupta SK, FoinquinosA, et al. 2014. Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. J. Clin. Investig. 124:2136-46
65. Queiros AM, EschenC, Fliegner D, Kararigas G, Dworatzek E, et al. 2013. Sex-and estrogen-dependent regulation of a miRNA network in the healthy and hypertrophied heart. Int. J. Cardiol. 169:331-38
66. Borges FT,Melo SA, Ozdemir BC, KatoN, Revuelta I, et al. 2013. TGF-β1-containing exosomes from injured epithelial cells activate fibroblasts to initiate tissue regenerative responses and fibrosis. J. Am. Soc. Nephrol. 24:385-92
67. Xu C, Lu Y, Pan Z, Chu W, Luo X, et al. 2007. The muscle-specific microRNAs miR-1 and miR-133 produce opposing effects on apoptosis by targeting HSP60, HSP70 and caspase-9 in cardiomyocytes. J. Cell Sci. 120:3045-52
68. Belevych AE, Sansom SE, Terentyeva R, Ho HT,Nishijima Y, et al. 2011. Microrna-1 and-133 increase arrhythmogenesis in heart failure by dissociating phosphatase activity from RyR2 complex. PLOS ONE 6:e28324
69. Elton TS, Martin MM, Sansom SE, Belevych AE, Gyorke S, Terentyev D. 2011. MiRNAs got rhythm. Life Sci. 88:373-83
70. Dempsey E, Feidhlim D, Maguire PB. 2014. Platelet derived exosomes are enriched for specific microRNAs which regulate Wnt signalling in endothelial cells. Presented at Am. Soc. Hematol. Annu. Meet., San Francisco, CA, Dec. 6-9
71. Neppl RL, Wang DZ. 2014. The myriad essential roles of microRNAs in cardiovascular homeostasis and disease. Genes Dis. 1:18-39
72. Lu Y, Zhang Y, Wang N, Pan Z, Gao X, et al. 2010. MicroRNA-328 contributes to adverse electrical remodeling in atrial fibrillation. Circulation 122:2378-87
73. Gambim MH, do Carmo Ade O,Marti L, Verissimo-Filho S, Lopes LR, JaniszewskiM. 2007. Plateletderived exosomes induce endothelial cell apoptosis through peroxynitrite generation: experimental evidence for a novel mechanism of septic vascular dysfunction. Crit. Care 11:R107
74. Wang X, HuangW, Liu G, Cai W, Millard RW, et al. 2014. Cardiomyocytes mediate anti-angiogenesis in type 2 diabetic rats through the exosomal transfer of miR-320 into endothelial cells. J. Mol. Cell. Cardiol. 74:139-50
75. CDC. 2011. FastStats: leading causes of death. http://www.cdc.gov/nchs/fastats/leading-causes-ofdeath. htm
76. Thygesen K, Alpert JS, Jaffe AS, SimoonsML, Chaitman BR, White HD. 2012. Third universal definition of myocardial infarction. Nat. Rev. Cardiol. 9:620-33
77. Jhund PS, McMurray JJV. 2008. Heart failure after acute myocardial infarction: a lost battle in the war on heart failure? Circulation 118:2019-21
78. Gerbin KA, Murry CE. 2015. The winding road to regenerating the human heart. Cardiovasc. Pathol. 24:133-40
79. Kim J, Shapiro L, Flynn A. 2015. The clinical application of mesenchymal stem cells and cardiac stem cells as a therapy for cardiovascular disease. Pharmacol. Ther. 151:8-15
80. Wegener M, Bader A, Giri S. 2015. How to mend a broken heart: adult and induced pluripotent stem cell therapy for heart repair and regeneration. Drug Discov. Today 20:667-85
81. Lai RC, Arslan F, Lee MM, SzeNS, Choo A, et al. 2010. Exosome secreted byMSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res. 4:214-22
82. Arslan F, Lai RC, Smeets MB, Akeroyd L,Choo A, 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 Res. 10:301-12
83. Lee C, Mitsialis SA, Aslam M, Vitali SH, Vergadi E, et al. 2012. Exosomes mediate the cytoprotective action ofmesenchymal stromal cells on hypoxia-induced pulmonary hypertension. Circulation 126:2601-11
84. Balmer GM, Riley PR. 2012. Harnessing the potential of adult cardiac stem cells: lessons from haematopoiesis, the embryo and the niche. J. Cardiovasc. Transl. Res. 5:631-40
85. Sahoo S, Klychko E, Thorne T, Misener S, Schultz KM, et al. 2011. Exosomes from human CD34+ stem cells mediate their proangiogenic paracrine activity. Circ. Res. 109:724-28
86. Jakob P, Doerries C, Briand S, Mocharla P, Krankel N, et al. 2012. Loss of angiomiR-126 and 130a in angiogenic early outgrowth cells from patients with chronic heart failure: role for impaired in vivo neovascularization and cardiac repair capacity. Circulation 126:2962-75
87. Mocharla P, Briand S, Giannotti G, Dorries C, Jakob P, et al. 2013. AngiomiR-126 expression and secretion from circulating CD34+ and CD14+ PBMCs: role for proangiogenic effects and alterations in type 2 diabetics. Blood 121:226-36
88. Li TS, Kubo M, Ueda K, Murakami M, Mikamo A, Hamano K. 2010. Impaired angiogenic potency of bone marrow cells from patients with advanced age, anemia, and renal failure. J. Thorac. Cardiovasc. Surg. 139:459-65
89. Renault MA, Roncalli J, Tongers J, Thorne T, Klyachko E, et al. 2010. Sonic hedgehog induces angiogenesis via Rho kinase-dependent signaling in endothelial cells. J. Mol. Cell. Cardiol. 49:490-98
90. Mackie AR, Klyachko E, Thorne T, SchultzKM, Millay M, et al. 2012. Sonic hedgehog-modified human CD34+ cells preserve cardiac function after acute myocardial infarction. Circ. Res. 111:312-21
91. Marban E. 2014. Breakthroughs in cell therapy for heart disease: focus on cardiosphere-derived cells. Mayo Clin. Proc. 89:850-58
92. Song L, SuM,WangS, ZouY,WangX, et al. 2014. Mir-451 is decreased in hypertrophic cardiomyopathy and regulates autophagy by targeting TSC1. J. Cell. Mol. Med. 18:2266-74
93. Vrijsen KR, Sluijter JP, Schuchardt MW, van Balkom BW, Noort WA, et al. 2010. Cardiomyocyte progenitor cell-derived exosomes stimulate migration of endothelial cells. J. Cell. Mol. Med. 14:1064-70
94. Chen L, Wang Y, Pan Y, Zhang L, Shen C, et al. 2013. Cardiac progenitor-derived exosomes protect ischemic myocardium from acute ischemia/reperfusion injury. Biochem. Biophys. Res. Commun. 431:566-71
95. Smith RR, Barile L, Cho HC, Leppo MK, Hare JM, et al. 2007. Regenerative potential of cardiospherederived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation 115:896-908
96. Chimenti I, Smith RR, Li T-S, Gerstenblith G,Messina E, et al. 2010. Relative roles of direct regeneration versus paracrine effects of human cardiosphere-derived cells transplanted into infarcted mice. Circ. Res. 106:971-80
97. Aghila Rani KG, Kartha CC. 2010. Effects of epidermal growth factor on proliferation and migration of cardiosphere-derived cells expanded from adult human heart. Growth Factors 28:157-65
98. Gaetani R, Ledda M, Barile L, Chimenti I, De Carlo F, et al. 2009. Differentiation of human adult cardiac stem cells exposed to extremely low-frequency electromagnetic fields. Cardiovasc. Res. 82:411-20
99. Mishra R, Vijayan K, Colletti EJ, Harrington DA, Matthiesen TS, et al. 2011. Characterization and functionality of cardiac progenitor cells in congenital heart patients. Circulation 123:364-73
100. Takehara N, Tsutsumi Y, Tateishi K, Ogata T, Tanaka H, et al. 2008. Controlled delivery of basic fibroblast growth factor promotes human cardiosphere-derived cell engraftment to enhance cardiac repair for chronic myocardial infarction. J. Am. Coll. Cardiol. 52:1858-65
101. Tang YL, Zhu W, Cheng M, Chen L, Zhang J, et al. 2009. Hypoxic preconditioning enhances the benefit of cardiac progenitor cell therapy for treatment of myocardial infarction by inducing CXCR4 expression. Circ. Res. 104:1209-16
102. Zakharova L, Mastroeni D, Mutlu N, Molina M, Goldman S, et al. 2010. Transplantation of cardiac progenitor cell sheet onto infarcted heart promotes cardiogenesis and improves function. Cardiovasc. Res. 87:40-49
103. Barile L, Lionetti V, Cervio E, Matteucci M, Gherghiceanu M, et al. 2014. Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction. Cardiovasc. Res. 103:530-41
104. Makkar RR, Smith RR, Cheng K, Malliaras K, Thomson LE, et al. 2012. Intracoronary cardiospherederived cells for heart regeneration aftermyocardial infarction(CADUCEUS):a prospective, randomised phase 1 trial. Lancet 379:895-904
105. Malliaras K, Makkar RR, Smith RR, Cheng K, Wu E, et al. 2014. Intracoronary cardiosphere-derived cells after myocardial infarction: evidence of therapeutic regeneration in the final 1-year results of the CADUCEUS trial (cardiosphere-derived autologous stem cells to reverse ventricular dysfunction). J. Am. Coll. Cardiol. 63:110-22
106. Jeevanantham V, ButlerM, Saad A, Abdel-Latif A, Zuba-Surma EK, 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 126:551-68
107. Preda MB, Valen G. 2013. Evaluation of gene and cell-based therapies for cardiac regeneration. Curr. Stem Cell Res. Ther. 8:304-12
108. Chimenti I, Smith RR, Li TS,GerstenblithG,Messina E, et al. 2010. Relative roles of direct regeneration versus paracrine effects of human cardiosphere-derived cells transplanted into infarcted mice. Circ. Res. 106:971-80
109. Malliaras K, Li TS, LuthringerD, Terrovitis J, Cheng K, et al. 2012. Safety and efficacy of allogeneic cell therapy in infarcted rats transplanted with mismatched cardiosphere-derived cells. Circulation 125:100-12
110. Stastna M, Chimenti I, Marban E, Van Eyk JE. 2010. Identification and functionality of proteomes secreted by rat cardiac stem cells and neonatal cardiomyocytes. Proteomics 10:245-53
111. Ibrahim AG, Cheng K, Marban E. 2014. Exosomes as critical agents of cardiac regeneration triggered by cell therapy. Stem Cell Rep. 2:606-19
112. Tseliou E, Fouad J, Reich H, Slipczuk L, de Couto G, et al. 2015. Fibroblasts rendered antifibrotic, antiapoptotic, and angiogenic by priming with cardiosphere-derived extracellular membrane vesicles. J. Am. Coll. Cardiol. 66:599-611
113. Mu J, Zhuang X, Wang Q, Jiang H, Deng ZB, et al. 2014. Interspecies communication between plant and mouse gut host cells through edible plant derived exosome-like nanoparticles. Mol. Nutr. Food Res. 58:1561-73
114. Buck AH,Coakley G, Simbari F,McSorleyHJ, Quintana JF, et al. 2014. Exosomes secreted by nematode parasites transfer small RNAs to mammalian cells and modulate innate immunity. Nat. Commun. 5:5488
115. Villarroya-Beltri C,Gutiérrez-Vázquez C, Sánchez-Cabo F, Pérez-HernándezD, Vázquez J, et al. 2013. Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat. Commun. 4:2980
116. Gray WD, French KM, Ghosh-Choudhary S, Maxwell JT, Brown ME, et al. 2015. Identification of therapeutic covariant microRNA clusters in hypoxia-treated cardiac progenitor cell exosomes using systems biology. Circ. Res. 116:255-63