More Than Tiny Sacks: Stem Cell Exosomes as Cell-Free Modality for Cardiac Repair

Circulation Research

Volumn 118, Issue 2, 2016, Pages 330-343

  Kishore, Raj ^a   Khan, Mohsin ^a  

^a TEMPLE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

cardiac regeneration; cardiovascular diseases; exosomes; miRNAs; stem cells

Indexed keywords

CARDIAC REGENERATION; CARDIOVASCULAR DISEASE; CELL COMMUNICATION; CELL CYCLE PROGRESSION; CELL FREE SYSTEM; CELL TRANSDIFFERENTIATION; EMBRYONIC STEM CELL; ENDOTHELIAL PROGENITOR CELL; EXOSOME; HEART FUNCTION; HUMAN; IMMUNOMODULATION; IMMUNOREGULATION; INFLAMMATION; MESENCHYMAL STROMA CELL; META ANALYSIS (TOPIC); MULTICENTER STUDY (TOPIC); NEOVASCULARIZATION (PATHOLOGY); NONHUMAN; PARACRINE SIGNALING; PLURIPOTENT STEM CELL; PRIORITY JOURNAL; REVIEW; STEM CELL TRANSPLANTATION; TISSUE REGENERATION; ADVERSE EFFECTS; ANIMAL; CARDIAC MUSCLE; GENETICS; GENOTYPE; HEART DISEASES; METABOLISM; PATHOLOGY; PATHOPHYSIOLOGY; PHENOTYPE; PROCEDURES; REGENERATION; REGENERATIVE MEDICINE; TRANSPLANTATION;

ANIMALS; CELL TRANSDIFFERENTIATION; EXOSOMES; GENOTYPE; HEART DISEASES; HUMANS; MYOCARDIUM; PARACRINE COMMUNICATION; PHENOTYPE; REGENERATION; REGENERATIVE MEDICINE; STEM CELL TRANSPLANTATION;

EID: 84955301496     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.115.307654     Document Type: Review

References (139)

1. Pagani FD, DerSimonian H, Zawadzka A, Wetzel K, Edge AS, Jacoby DB, Dinsmore JH, Wright S, Aretz TH, Eisen HJ, Aaronson KD., Autologous skeletal myoblasts transplanted to ischemia-damaged myocardium in humans. Histological analysis of cell survival and differentiation. J Am Coll Cardiol 2003;41:879-888
2. Menasché P, Hagège AA, Scorsin M, Pouzet B, Desnos M, Duboc D, Schwartz K, Vilquin JT, Marolleau JP., Myoblast transplantation for heart failure. Lancet 2001;357:279-280. doi: 10.1016/S0140-6736(00)03617-5.
3. Al Attar N, Carrion C, Ghostine S, Garcin I, Vilquin JT, Hagège AA, Menasché P., Long-term (1 year) functional and histological results of autologous skeletal muscle cells transplantation in rat. Cardiovasc Res 2003;58:142-148
4. Menasché P, Alfieri O, Janssens S, McKenna W, Reichenspurner H, Trinquart L, Vilquin JT, Marolleau JP, Seymour B, Larghero J, Lake S, Chatellier G, Solomon S, Desnos M, Hagège AA., The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation. Circulation 2008;117:1189-1200. doi: 10.1161/CIRCULATIONAHA.107.734103.
5. Herreros J, Prósper F, Perez A, Gavira JJ, Garcia-Velloso MJ, Barba J, Sánchez PL, Cañizo C, Rábago G, Martí-Climent JM, Hernández M, López-Holgado N, González-Santos JM, Martín-Luengo C, Alegria E., Autologous intramyocardial injection of cultured skeletal muscle-derived stem cells in patients with non-acute myocardial infarction. Eur Heart J 2003;24:2012-2020
6. Menasché P, Hagège AA, Vilquin JT, Desnos M, Abergel E, Pouzet B, Bel A, Sarateanu S, Scorsin M, Schwartz K, Bruneval P, Benbunan M, Marolleau JP, Duboc D., Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. J Am Coll Cardiol 2003;41:1078-1083
7. Smits PC, van Geuns RJ, Poldermans D, Bountioukos M, Onderwater EE, Lee CH, Maat AP, Serruys PW., Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure: clinical experience with six-month follow-up. J Am Coll Cardiol 2003;42:2063-2069
8. Lee RH, Kim B, Choi I, Kim H, Choi HS, Suh K, Bae YC, Jung JS., Characterization and expression analysis of mesenchymal stem cells from human bone marrow and adipose tissue. Cell Physiol Biochem 2004;14:311-324. doi: 10.1159/000080341.
9. Giordano A, Galderisi U, Marino IR., From the laboratory bench to the patient's bedside: an update on clinical trials with mesenchymal stem cells. J Cell Physiol 2007;211:27-35. doi: 10.1002/jcp.20959.
10. Schächinger V, Erbs S, Elsässer A, Haberbosch W, Hambrecht R, Hölschermann H, Yu J, Corti R, Mathey DG, Hamm CW, Süselbeck T, Assmus B, Tonn T, Dimmeler S, Zeiher AM, REPAIR-AMI Investigators Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med 2006;355:1210-1221. doi: 10.1056/NEJMoa060186.
11. Assmus B, Schächinger V, Teupe C, Britten M, Lehmann R, Döbert N, Grünwald F, Aicher A, Urbich C, Martin H, Hoelzer D, Dimmeler S, Zeiher AM., Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation 2002;106:3009-3017
12. Assmus B, Fischer-Rasokat U, Honold J, Seeger FH, Fichtlscherer S, Tonn T, Seifried E, Schächinger V, Dimmeler S, Zeiher AM, TOPCARE-CHD Registry Transcoronary transplantation of functionally competent BMCs is associated with a decrease in natriuretic peptide serum levels and improved survival of patients with chronic postinfarction heart failure: results of the TOPCARE-CHD Registry. Circ Res 2007;100:1234-1241. doi: 10.1161/01.RES.0000264508.47717.6b.
13. Heldman AW, DiFede DL, Fishman JE, Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT randomized trial. JAMA 2014;311:62-73. doi: 10.1001/jama.2013.282909.
14. Hare JM, Fishman JE, Gerstenblith G, Comparison of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA 2012;308:2369-2379. doi: 10.1001/jama.2012.25321.
15. Bartunek J, Behfar A, Dolatabadi D, Cardiopoietic stem cell therapy in heart failure: the C-CURE (Cardiopoietic stem Cell therapy in heart failURE) multicenter randomized trial with lineage-specified biologics. J Am Coll Cardiol 2013;61:2329-2338. doi: 10.1016/j.jacc.2013.02.071.
16. Makkar RR, Smith RR, Cheng K, Malliaras K, Thomson LE, Berman D, Czer LS, Marbán L, Mendizabal A, Johnston PV, Russell SD, Schuleri KH, Lardo AC, Gerstenblith G, Marbán E., Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet 2012;379:895-904. doi: 10.1016/S0140-6736(12)60195-0.
17. Bolli R, Chugh AR, D'Amario D, Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet 2011;378:1847-1857. doi: 10.1016/S0140-6736(11)61590-0.
18. Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, Pickel J, McKay R, Nadal-Ginard B, Bodine DM, Leri A, Anversa P., Bone marrow cells regenerate infarcted myocardium. Nature 2001;410:701-705. doi: 10.1038/35070587.
19. Orlic D, Kajstura J, Chimenti S, Bodine DM, Leri A, Anversa P., Transplanted adult bone marrow cells repair myocardial infarcts in mice. Ann N Y Acad Sci 2001;938:221-229; discussion 229
20. Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S, Kasahara H, Rota M, Musso E, Urbanek K, Leri A, Kajstura J, Nadal-Ginard B, Anversa P., Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 2003;114:763-776
21. Schuleri KH, Feigenbaum GS, Centola M, Weiss ES, Zimmet JM, Turney J, Kellner J, Zviman MM, Hatzistergos KE, Detrick B, Conte JV, McNiece I, Steenbergen C, Lardo AC, Hare JM., Autologous mesenchymal stem cells produce reverse remodelling in chronic ischaemic cardiomyopathy. Eur Heart J 2009;30:2722-2732. doi: 10.1093/eurheartj/ehp265.
22. Gomez-Mauricio RG, Acarregui A, Sánchez-Margallo FM, Crisóstomo V, Gallo I, Hernández RM, Pedraz JL, Orive G, Martín-Cancho MF., A preliminary approach to the repair of myocardial infarction using adipose tissue-derived stem cells encapsulated in magnetic resonance-labelled alginate microspheres in a porcine model. Eur J Pharm Biopharm 2013;84:29-39. doi: 10.1016/j.ejpb.2012.11.028.
23. Vrtovec B, Poglajen G, Lezaic L, Sever M, Domanovic D, Cernelc P, Socan A, Schrepfer S, Torre-Amione G, Haddad F, Wu JC., Effects of intracoronary CD34+ stem cell transplantation in nonischemic dilated cardiomyopathy patients: 5-year follow-up. Circ Res 2013;112:165-173. doi: 10.1161/CIRCRESAHA.112.276519.
24. Tang XL, Rokosh G, Sanganalmath SK, Intracoronary administration of cardiac progenitor cells alleviates left ventricular dysfunction in rats with a 30-day-old infarction. Circulation 2010;121:293-305. doi: 10.1161/CIRCULATIONAHA.109.871905.
25. Gnecchi M, He H, Noiseux N, Liang OD, Zhang L, Morello F, Mu H, Melo LG, Pratt RE, Ingwall JS, Dzau VJ., Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J 2006;20:661-669. doi: 10.1096/fj.05-5211com.
26. Haider HKh, Jiang S, Idris NM, Ashraf M., IGF-1-overexpressing mesenchymal stem cells accelerate bone marrow stem cell mobilization via paracrine activation of SDF-1alpha/CXCR4 signaling to promote myocardial repair. Circ Res 2008;103:1300-1308. doi: 10.1161/CIRCRESAHA.108.186742.
27. Sahoo S, Klychko E, Thorne T, Misener S, Schultz KM, Millay M, Ito A, Liu T, Kamide C, Agrawal H, Perlman H, Qin G, Kishore R, Losordo DW., Exosomes from human CD34(+) stem cells mediate their proangiogenic paracrine activity. Circ Res 2011;109:724-728. doi: 10.1161/CIRCRESAHA.111.253286.
28. Pan BT, Johnstone RM., Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell 1983;33:967-978
29. Théry C, Ostrowski M, Segura E., Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 2009;9:581-593. doi: 10.1038/nri2567.
30. Ratajczak J, Miekus K, Kucia M, Zhang J, Reca R, Dvorak P, Ratajczak MZ., Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia 2006 20,847-856. doi: 10.1038/sj.leu.2404132.
31. Yuan A, Farber EL, Rapoport AL, Tejada D, Deniskin R, Akhmedov NB, Farber DB., Transfer of microRNAs by embryonic stem cell microvesicles. PLoS One 2009;4 e4722. doi: 10.1371/journal.pone.0004722.
32. Peters PJ, Geuze HJ, Van der Donk HA, Slot JW, Griffith JM, Stam NJ, Clevers HC, Borst J., Molecules relevant for T cell-target cell interaction are present in cytolytic granules of human T lymphocytes. Eur J Immunol 1989:19;1469-1475. doi: 10.1002/eji.1830190819.
33. Zitvogel L, Regnault A, Lozier A, Wolfers J, Flament C, Tenza D, Ricciardi-Castagnoli P, Raposo G, Amigorena S., Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat Med 1998;4 594:600
34. Raposo G, Tenza D, Mecheri S, Peronet R, Bonnerot C, Desaymard C., Accumulation of major histocompatibility complex class II molecules in mast cell secretory granules and their release upon degranulation. Mol Biol Cell 1997-8 2631 2645
35. Wolfers J, Lozier A, Raposo G, Regnault A, Théry C, Masurier C, Flament C, Pouzieux S, Faure F, Tursz T, Angevin E, Amigorena S, Zitvogel L., Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming. Nat Med 2001;7-297-303. doi: 10.1038/85438.
36. Sullivan R, Saez F, Girouard J, Frenette G., Role of exosomes in sperm maturation during the transit along the male reproductive tract. Blood Cells Mol Dis 2005-35 1 10. doi: 10.1016/j.bcmd.2005.03.005.
37. Stein JM, Luzio JP., Ectocytosis caused by sublytic autologous complement attack on human neutrophils. The sorting of endogenous plasma-membrane proteins and lipids into shed vesicles. Biochem J 1991;274:pt 2-381 386
38. Vrijsen KR, Sluijter JP, Schuchardt MW, van Balkom BW, Noort WA, Chamuleau SA, Doevendans PA., Cardiomyocyte progenitor cell-derived exosomes stimulate migration of endothelial cells. J Cell Mol Med 2010;14:1064-1070. doi: 10.1111/j.1582-4934.2010.01081.x.
39. Xin H, Li Y, Liu Z, Wang X, Shang X, Cui Y, Zhang ZG, Chopp M., MiR-133b promotes neural plasticity and functional recovery after treatment of stroke with multipotent mesenchymal stromal cells in rats via transfer of exosome-enriched extracellular particles. Stem Cells 2013;31:2737-2746. doi: 10.1002/stem.1409.
40. Stoorvogel W, Strous GJ, Geuze HJ, Oorschot V, Schwartz AL., Late endosomes derive from early endosomes by maturation. Cell 1991;65:417-427
41. Novikoff AB, Essner E, Quintana N., Golgi apparatus and Lysosomes. Fed Proc 1964;23:1010-1022
42. Johnstone RM, Bianchini A, Teng K., Reticulocyte maturation and exosome release: transferrin receptor containing exosomes shows multiple plasma membrane functions. Blood 1989;74:1844-1851
43. Clayton A, Turkes A, Navabi H, Mason MD, Tabi Z., Induction of heat shock proteins in B-cell exosomes. J Cell Sci 2005;118:3631-3638. doi: 10.1242/jcs.02494.
44. Simons M, Raposo G., Exosomes-vesicular carriers for intercellular communication. Curr Opin Cell Biol 2009;21:575-581. doi: 10.1016/j.ceb.2009.03.007.
45. Mathivanan S, Ji H, Simpson RJ., Exosomes: extracellular organelles important in intercellular communication. J Proteomics 2010;73:1907-1920. doi: 10.1016/j.jprot.2010.06.006.
46. Simpson RJ, Lim JW, Moritz RL, Mathivanan S., Exosomes: proteomic insights and diagnostic potential. Expert Rev Proteomics 2009;6-267-283. doi: 10.1586/epr.09.17.
47. Kobayashi T, Gu F, Gruenberg J., Lipids, lipid domains and lipid-protein interactions in endocytic membrane traffic. Semin Cell Dev Biol 1998-9 517 526. doi: 10.1006/scdb.1998.0257.
48. Subra C, Laulagnier K, Perret B, Record M., Exosome lipidomics unravels lipid sorting at the level of multivesicular bodies. Biochimie 2007;89:205-212. doi: 10.1016/j.biochi.2006.10.014.
49. Mittelbrunn M, Gutiérrez-Vázquez C, Villarroya-Beltri C, González S, Sánchez-Cabo F, González MÁ Bernad A, Sánchez-Madrid F., Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat Commun 2011;2 282. doi: 10.1038/ncomms1285.
50. Pegtel DM, Cosmopoulos K, Thorley-Lawson DA, van Eijndhoven MA, Hopmans ES, Lindenberg JL, de Gruijl TD, Würdinger T, Middeldorp JM., Functional delivery of viral miRNAs via exosomes. Proc Natl Acad Sci USA 2010,107,6328-6333. doi: 10.1073/pnas.0914843107.
51. Goldie BJ, Dun MD, Lin M, Smith ND, Verrills NM, Dayas CV, Cairns MJ., Activity-associated miRNA are packaged in Map1b-enriched exosomes released from depolarized neurons. Nucleic Acids Res 2014;42:9195-9208. doi: 10.1093/nar/gku594.
52. Skog J, Würdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, Curry WT Jr, Carter BS, Krichevsky AM, Breakefield XO., Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 2008;10:1470-1476. doi: 10.1038/ncb1800.
53. Guduric-Fuchs J, O'Connor A, Camp B, O'Neill CL, Medina RJ, Simpson DA., Selective extracellular vesicle-mediated export of an overlapping set of microRNAs from multiple cell types. BMC Genomics 2012;13:357. doi: 10.1186/1471-2164-13-357.
54. Squadrito ML, Baer C, Burdet F, Maderna C, Gilfillan GD, Lyle R, Ibberson M, De Palma M., Endogenous RNAs modulate microRNA sorting to exosomes and transfer to acceptor cells. Cell Rep 2014-8 1432 1446. doi: 10.1016/j.celrep.2014.07.035.
55. Kosaka N, Iguchi H, Hagiwara K, Yoshioka Y, Takeshita F, Ochiya T., Neutral sphingomyelinase 2 (nSMase2)-dependent exosomal transfer of angiogenic microRNAs regulate cancer cell metastasis. J Biol Chem 2013;288:10849-10859. doi: 10.1074/jbc.M112.446831.
56. Villarroya-Beltri C, Gutiérrez-Vázquez C, Sánchez-Cabo F, Pérez-Hernández D, Vázquez J, Martin-Cofreces N, Martinez-Herrera DJ, Pascual-Montano A, Mittelbrunn M, Sánchez-Madrid F., Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat Commun 2013;4 2980. doi: 10.1038/ncomms3980.
57. Koppers-Lalic D, Hackenberg M, Bijnsdorp IV, van Eijndhoven MA, Sadek P, Sie D, Zini N, Middeldorp JM, Ylstra B, de Menezes RX, Würdinger T, Meijer GA, Pegtel DM., Nontemplated nucleotide additions distinguish the small RNA composition in cells from exosomes. Cell Rep 2014:8;1649-1658. doi: 10.1016/j.celrep.2014.08.027.
58. Frank F, Sonenberg N, Nagar B., Structural basis for 5'-nucleotide base-specific recognition of guide RNA by human AGO2. Nature 2010;465:818-822. doi: 10.1038/nature09039.
59. Hood JL, Pan H, Lanza GM, Wickline SA, Consortium for Translational Research in Advanced Imaging and Nanomedicine (C-TRAIN) Paracrine induction of endothelium by tumor exosomes. Lab Invest 2009;89:1317-1328. doi: 10.1038/labinvest.2009.94.
60. Higginbotham JN, Demory Beckler M, Gephart JD, Franklin JL, Bogatcheva G, Kremers GJ, Piston DW, Ayers GD, McConnell RE, Tyska MJ, Coffey RJ., Amphiregulin exosomes increase cancer cell invasion. Curr Biol 2011;21:779-786. doi: 10.1016/j.cub.2011.03.043.
61. Garcia E, Pion M, Pelchen-Matthews A, Collinson L, Arrighi JF, Blot G, Leuba F, Escola JM, Demaurex N, Marsh M, Piguet V., HIV-1 trafficking to the dendritic cell-T-cell infectious synapse uses a pathway of tetraspanin sorting to the immunological synapse. Traffic 2005;6;488-501. doi: 10.1111/j.1600-0854.2005.00293.x.
62. Von Bartheld CS, Altick AL., Multivesicular bodies in neurons: distribution, protein content, and trafficking functions. Prog Neurobiol 2011-93 313 340. doi: 10.1016/j.pneurobio.2011.01.003.
63. Dai S, Wan T, Wang B, Zhou X, Xiu F, Chen T, Wu Y, Cao X., More efficient induction of HLA-A∗0201-restricted and carcinoembryonic antigen (CEA)-specific CTL response by immunization with exosomes prepared from heat-stressed CEA-positive tumor cells. Clin Cancer Res 2005;11:7554-7563. doi: 10.1158/1078-0432.CCR-05-0810.
64. Clayton A, Mitchell JP, Court J, Linnane S, Mason MD, Tabi Z., Human tumor-derived exosomes down-modulate NKG2D expression. J Immunol 2008;180:7249-7258
65. Korkut C, Ataman B, Ramachandran P, Ashley J, Barria R, Gherbesi N, Budnik V., Trans-synaptic transmission of vesicular Wnt signals through Evi/Wntless. Cell 2009;139:393-404. doi: 10.1016/j.cell.2009.07.051.
66. Chairoungdua A, Smith DL, Pochard P, Hull M, Caplan MJ., Exosome release of β-catenin: a novel mechanism that antagonizes Wnt signaling. J Cell Biol 2010;190:1079-1091. doi: 10.1083/jcb.201002049.
67. Söderberg A, Barral AM, Söderström M, Sander B, Rosén A., Redox-signaling transmitted in trans to neighboring cells by melanoma-derived TNF-containing exosomes. Free Radic Biol Med 2007;43:90-99. doi: 10.1016/j.freeradbiomed.2007.03.026.
68. Cowan CA, Atienza J, Melton DA, Eggan K., Nuclear reprogramming of somatic cells after fusion with human embryonic stem cells. Science 2005;309:1369-1373. doi: 10.1126/science.1116447.
69. Do JT, Schöler HR., Nuclei of embryonic stem cells reprogram somatic cells. Stem Cells 2004;22:941-949. doi: 10.1634/stemcells.22-6-941.
70. Jeong D, Jo W, Yoon J, Kim J, Gianchandani S, Gho YS, Park J., Nanovesicles engineered from ES cells for enhanced cell proliferation. Biomaterials 2014;35:9302-9310. doi: 10.1016/j.biomaterials.2014.07.047.
71. Katsman D, Stackpole EJ, Domin DR, Farber DB., Embryonic stem cell-derived microvesicles induce gene expression changes in Müller cells of the retina. PLoS One 2012;7 e50417. doi: 10.1371/journal.pone.0050417.
72. Reis LA, Carbonel AAF, Maganhin CC, Simones MDJ, Schor N., Effects of exosomes (exos) dervied by renal pluripotent stem cells (rpscs) on the cisplatin (cis) nephrotoxicity in mice. Microsc Mircoanal 2014,20:1426-1427
73. Hong KU, Li QH, Guo Y, Patton NS, Moktar A, Bhatnagar A, Bolli R., A highly sensitive and accurate method to quantify absolute numbers of c-kit+ cardiac stem cells following transplantation in mice. Basic Res Cardiol 2013;108:346. doi: 10.1007/s00395-013-0346-0.
74. Sanganalmath SK, Bolli R., Cell therapy for heart failure: a comprehensive overview of experimental and clinical studies, current challenges, and future directions. Circ Res 2013-113 810 834. doi: 10.1161/CIRCRESAHA.113.300219.
75. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR., Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143-147
76. Dennis JE, Merriam A, Awadallah A, Yoo JU, Johnstone B, Caplan AI., A quadripotential mesenchymal progenitor cell isolated from the marrow of an adult mouse. J Bone Miner Res 1999;14:700-709. doi: 10.1359/jbmr.1999.14.5.700.
77. Karp JM, Leng Teo GS., Mesenchymal stem cell homing: the devil is in the details. Cell Stem Cell 2009;4,206-216. doi: 10.1016/j.stem.2009.02.001.
78. Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler PD., Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation 2002-105 93 98
79. Lai RC, Arslan F, Lee MM, Sze NS, Choo A, Chen TS, Salto-Tellez M, Timmers L, Lee CN, El Oakley RM, Pasterkamp G, de Kleijn DP, Lim SK., Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res 2010;4;214-222. doi: 10.1016/j.scr.2009.12.003.
80. Yeo RW, Lai RC, Zhang B, Tan SS, Yin Y, Teh BJ, Lim SK., Mesenchymal stem cell: an efficient mass producer of exosomes for drug delivery. Adv Drug Deliv Rev 2013-65 336 341. doi: 10.1016/j.addr.2012.07.001.
81. Lai RC, Tan SS, Teh BJ, Sze SK, Arslan F, de Kleijn DP, Choo A, Lim SK., Proteolytic potential of the MSC exosome proteome: implications for an exosome-mediated delivery of therapeutic proteasome. Int J Proteomics 2012;2012:971907. doi: 10.1155/2012/971907.
82. Mokarizadeh A, Delirezh N, Morshedi A, Mosayebi G, Farshid AA, Mardani K., Microvesicles derived from mesenchymal stem cells: potent organelles for induction of tolerogenic signaling. Immunol Lett 2012-147 47 54. doi: 10.1016/j.imlet.2012.06.001.
83. Zhang B, Yin Y, Lai RC, Tan SS, Choo AB, Lim SK., Mesenchymal stem cells secrete immunologically active exosomes. Stem Cells Dev 2014;23:1233-1244. doi: 10.1089/scd.2013.0479.
84. Zhu W, Huang L, Li Y, Zhang X, Gu J, Yan Y, Xu X, Wang M, Qian H, Xu W., Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth in vivo. Cancer Lett 2012;315:28-37. doi: 10.1016/j.canlet.2011.10.002.
85. Zhu W, Huang L, Li Y, Qian H, Shan X, Yan Y, Mao F, Wu X, Xu WR., Mesenchymal stem cell-secreted soluble signaling molecules potentiate tumor growth. Cell Cycle 2011;10:3198-3207
86. Xin H, Li Y, Buller B, Katakowski M, Zhang Y, Wang X, Shang X, Zhang ZG, Chopp M., Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells 2012;30:1556-1564. doi: 10.1002/stem.1129.
87. Xin H, Li Y, Cui Y, Yang JJ, Zhang ZG, Chopp M., Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J Cereb Blood Flow Metab 2013;33:1711-1715. doi: 10.1038/jcbfm.2013.152.
88. Katsuda T, Tsuchiya R, Kosaka N, Yoshioka Y, Takagaki K, Oki K, Takeshita F, Sakai Y, Kuroda M, Ochiya T., Human adipose tissue-derived mesenchymal stem cells secrete functional neprilysin-bound exosomes. Sci Rep 2013;3 1197. doi: 10.1038/srep01197.
89. Deregibus MC, Cantaluppi V, Calogero R, Lo Iacono M, Tetta C, Biancone L, Bruno S, Bussolati B, Camussi G., Endothelial progenitor cell derived microvesicles activate an angiogenic program in endothelial cells by a horizontal transfer of mRNA. Blood 2007:110-2440 2448. doi: 10.1182/blood-2007-03-078709.
90. Cantaluppi V, Biancone L, Figliolini F, Beltramo S, Medica D, Deregibus MC, Galimi F, Romagnoli R, Salizzoni M, Tetta C, Segoloni GP, Camussi G., Microvesicles derived from endothelial progenitor cells enhance neoangiogenesis of human pancreatic islets. Cell Transplant 2012;21:1305-1320. doi: 10.3727/096368911X627534.
91. Ranghino A, Cantaluppi V, Grange C, Vitillo L, Fop F, Biancone L, Deregibus MC, Tetta C, Segoloni GP, Camussi G., Endothelial progenitor cell-derived microvesicles improve neovascularization in a murine model of hindlimb ischemia. Int J Immunopathol Pharmacol 2012;25:75-85
92. Wang J, Chen S, Ma X, Cheng C, Xiao X, Chen J, Liu S, Zhao B, Chen Y., Effects of endothelial progenitor cell-derived microvesicles on hypoxia/reoxygenation-induced endothelial dysfunction and apoptosis. Oxid Med Cell Longev 2013;2013:572729. doi: 10.1155/2013/572729.
93. van Balkom BW, de Jong OG, Smits M, Brummelman J, den Ouden K, de Bree PM, van Eijndhoven MA, Pegtel DM, Stoorvogel W, Würdinger T, Verhaar MC., Endothelial cells require miR-214 to secrete exosomes that suppress senescence and induce angiogenesis in human and mouse endothelial cells. Blood 2013;121:3997-4006, S1. doi: 10.1182/blood-2013-02-478925.
94. Sluijter JP, Verhage V, Deddens JC, van den Akker F, Doevendans PA., Microvesicles and exosomes for intracardiac communication. Cardiovasc Res 2014;102:302-311. doi: 10.1093/cvr/cvu022.
95. Fischer KM, Cottage CT, Wu W, Din S, Gude NA, Avitabile D, Quijada P, Collins BL, Fransioli J, Sussman MA., Enhancement of myocardial regeneration through genetic engineering of cardiac progenitor cells expressing Pim-1 kinase. Circulation 2009;120:2077-2087. doi: 10.1161/CIRCULATIONAHA.109.884403.
96. Barile L, Lionetti V, Cervio E, Matteucci M, Gherghiceanu M, Popescu LM, Torre T, Siclari F, Moccetti T, Vassalli G., Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction. Cardiovasc Res 2014;103:530-541. doi: 10.1093/cvr/cvu167.
97. Malliaras K, Makkar RR, Smith RR, Cheng K, Wu E, Bonow RO, Marbán L, Mendizabal A, Cingolani E, Johnston PV, Gerstenblith G, Schuleri KH, Lardo AC, Marbán E., 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 2014;63:110-122. doi: 10.1016/j.jacc.2013.08.724.
98. Tang YL, Zhu W, Cheng M, Chen L, Zhang J, Sun T, Kishore R, Phillips MI, Losordo DW, Qin G., Hypoxic preconditioning enhances the benefit of cardiac progenitor cell therapy for treatment of myocardial infarction by inducing CXCR4 expression. Circ Res 2009;104:1209-1216. doi: 10.1161/CIRCRESAHA.109.197723.
99. Chimenti I, Smith RR, Li TS, Gerstenblith G, Messina E, Giacomello A, Marbán E., Relative roles of direct regeneration versus paracrine effects of human cardiosphere-derived cells transplanted into infarcted mice. Circ Res 2010;106:971-980. doi: 10.1161/CIRCRESAHA.109.210682.
100. Chen L, Wang Y, Pan Y, Zhang L, Shen C, Qin G, Ashraf M, Weintraub N, Ma G, Tang Y., Cardiac progenitor-derived exosomes protect ischemic myocardium from acute ischemia/reperfusion injury. Biochem Biophys Res Commun 2013;431:566-571. doi: 10.1016/j.bbrc.2013.01.015.
101. Gray WD, French KM, Ghosh-Choudhary S, Maxwell JT, Brown ME, Platt MO, Searles CD, Davis ME., Identification of therapeutic covariant microRNA clusters in hypoxia-treated cardiac progenitor cell exosomes using systems biology. Circ Res 2015;116:255-263. doi: 10.1161/CIRCRESAHA.116.304360.
102. Ong SG, Lee WH, Huang M, Dey D, Kodo K, Sanchez-Freire V, Gold JD, Wu JC., Cross talk of combined gene and cell therapy in ischemic heart disease: role of exosomal microRNA transfer. Circulation 2014;130:S60-S69. doi: 10.1161/CIRCULATIONAHA.113.007917.
103. Gupta S, Knowlton AA., HSP60 trafficking in adult cardiac myocytes: role of the exosomal pathway. Am J Physiol Heart Circ Physiol 2007;292:H3052-H3056. doi: 10.1152/ajpheart.01355.2006.
104. Malik ZA, Kott KS, Poe AJ, Kuo T, Chen L, Ferrara KW, Knowlton AA., Cardiac myocyte exosomes: stability, HSP60, and proteomics. Am J Physiol Heart Circ Physiol 2013;304:H954-H965. doi: 10.1152/ajpheart.00835.2012.
105. Yu X, Deng L, Wang D, Li N, Chen X, Cheng X, Yuan J, Gao X, Liao M, Wang M, Liao Y., Mechanism of TNF-α autocrine effects in hypoxic cardiomyocytes: initiated by hypoxia inducible factor 1α presented by exosomes. J Mol Cell Cardiol 2012;53:848-857. doi: 10.1016/j.yjmcc.2012.10.002.
106. Ailawadi S, Wang X, Gu H, Fan GC., Pathologic function and therapeutic potential of exosomes in cardiovascular disease. Biochim Biophys Acta 2015;1852:1 11. doi: 10.1016/j.bbadis.2014.10.008.
107. Giricz Z, Varga ZV, Baranyai T, Sipos P, Pálóczi K, Kittel Á Buzás EI, Ferdinandy P., Cardioprotection by remote ischemic preconditioning of the rat heart is mediated by extracellular vesicles. J Mol Cell Cardiol 2014-68 75 78. doi: 10.1016/j.yjmcc.2014.01.004.
108. Li J, Rohailla S, Gelber N, Rutka J, Sabah N, Gladstone RA, Wei C, Hu P, Kharbanda RK, Redington AN., MicroRNA-144 is a circulating effector of remote ischemic preconditioning. Basic Res Cardiol 2014;109:423. doi: 10.1007/s00395-014-0423-z.
109. Fredj S, Bescond J, Louault C, Potreau D., Interactions between cardiac cells enhance cardiomyocyte hypertrophy and increase fibroblast proliferation. J Cell Physiol 2005-202 891 899. doi: 10.1002/jcp.20197.
110. LaFramboise WA, Scalise D, Stoodley P, Graner SR, Guthrie RD, Magovern JA, Becich MJ., Cardiac fibroblasts influence cardiomyocyte phenotype in vitro. Am J Physiol Cell Physiol 2007;292:C1799-C1808. doi: 10.1152/ajpcell.00166.2006.
111. Bang C, Batkai S, Dangwal S, Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. J Clin Invest 2014;124:2136-2146. doi: 10.1172/JCI70577.
112. Wang Y, Zhang L, Li Y, Chen L, Wang X, Guo W, Zhang X, Qin G, He SH, Zimmerman A, Liu Y, Kim IM, Weintraub NL, Tang Y., Exosomes/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte apoptosis in the ischemic myocardium. Int J Cardiol 2015;192:61-69. doi: 10.1016/j.ijcard.2015.05.020.
113. Arslan F, Lai RC, Smeets MB, Akeroyd L, Choo A, Aguor EN, Timmers L, van Rijen HV, Doevendans PA, Pasterkamp G, Lim SK, de Kleijn DP., 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 2013;10:301-312. doi: 10.1016/j.scr.2013.01.002.
114. Feng Y, Huang W, Wani M, Yu X, Ashraf M., Ischemic preconditioning potentiates the protective effect of stem cells through secretion of exosomes by targeting Mecp2 via miR-22. PLoS One 2014;9 e88685. doi: 10.1371/journal.pone.0088685.
115. Yu B, Kim HW, Gong M, Wang J, Millard RW, Wang Y, Ashraf M, Xu M., Exosomes secreted from GATA-4-overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection. Int J Cardiol 2015 182 349 360. doi: 10.1016/j.ijcard.2014.12.043.
116. Bian S, Zhang L, Duan L, Wang X, Min Y, Yu H., Extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis in a rat myocardial infarction model. J Mol Med (Berl) 2014;92:387-397. doi: 10.1007/s00109-013-1110-5.
117. Gu S, Zhang W, Chen J, Ma R, Xiao X, Ma X, Yao Z, Chen Y., EPC-derived microvesicles protect cardiomyocytes from Ang II-induced hypertrophy and apoptosis. PLoS One 2014;9 e85396. doi: 10.1371/journal.pone.0085396.
118. Mackie AR, Klyachko E, Thorne T, Schultz KM, Millay M, Ito A, Kamide CE, Liu T, Gupta R, Sahoo S, Misener S, Kishore R, Losordo DW., Sonic hedgehog-modified human CD34+ cells preserve cardiac function after acute myocardial infarction. Circ Res 2012:111-312 321. doi: 10.1161/CIRCRESAHA.112.266015.
119. Vicencio JM, Yellon DM, Sivaraman V, Das D, Boi-Doku C, Arjun S, Zheng Y, Riquelme JA, Kearney J, Sharma V, Multhoff G, Hall AR, Davidson SM., Plasma exosomes protect the myocardium from ischemia-reperfusion injury. J Am Coll Cardiol 2015;65:1525-1536. doi: 10.1016/j.jacc.2015.02.026.
120. Wang X, Huang W, Liu G, Cai W, Millard RW, Wang Y, Chang J, Peng T, Fan GC., Cardiomyocytes mediate anti-angiogenesis in type 2 diabetic rats through the exosomal transfer of miR-320 into endothelial cells. J Mol Cell Cardiol 2014;74:139-150. doi: 10.1016/j.yjmcc.2014.05.001.
121. Lee C, Mitsialis SA, Aslam M, Vitali SH, Vergadi E, Konstantinou G, Sdrimas K, Fernandez-Gonzalez A, Kourembanas S., Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension. Circulation 2012;126:2601-2611. doi: 10.1161/CIRCULATIONAHA.112.114173.
122. Ibrahim AG, Cheng K, Marbán E., Exosomes as critical agents of cardiac regeneration triggered by cell therapy. Stem Cell Reports 2014;2 606:619. doi: 10.1016/j.stemcr.2014.04.006.
123. Khan M, Nickoloff E, Abramova T, Embryonic stem cell-derived exosomes promote endogenous repair mechanisms and enhance cardiac function following myocardial infarction. Circ Res 2015-117 52 64. doi: 10.1161/CIRCRESAHA.117.305990.
124. Waldenström A, Gennebäck N, Hellman U, Ronquist G., Cardiomyocyte microvesicles contain DNA/RNA and convey biological messages to target cells. PLoS One 2012;7 e34653. doi: 10.1371/journal.pone.0034653.
125. Yu X, Huang C, Song B, Xiao Y, Fang M, Feng J, Wang P., CD4+CD25+ regulatory T cells-derived exosomes prolonged kidney allograft survival in a rat model. Cell Immunol 2013:285-62 68. doi: 10.1016/j.cellimm.2013.06.010.
126. Ismail N, Wang Y, Dakhlallah D, Moldovan L, Agarwal K, Batte K, Shah P, Wisler J, Eubank TD, Tridandapani S, Paulaitis ME, Piper MG, Marsh CB., Macrophage microvesicles induce macrophage differentiation and miR-223 transfer. Blood 2013;121:984-995. doi: 10.1182/blood-2011-08-374793.
127. VanWijk MJ, VanBavel E, Sturk A, Nieuwland R., Microparticles in cardiovascular diseases. Cardiovasc Res 2003;59:277-287
128. English K, Ryan JM, Tobin L, Murphy MJ, Barry FP, Mahon BP., Cell contact, prostaglandin E(2) and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4+CD25(High) forkhead box P3+ regulatory T cells. Clin Exp Immunol 2009;156:149-160. doi: 10.1111/j.1365-2249.2009.03874.x.
129. Cassatella MA, Mosna F, Micheletti A, Lisi V, Tamassia N, Cont C, Calzetti F, Pelletier M, Pizzolo G, Krampera M., Toll-like receptor-3-activated human mesenchymal stromal cells significantly prolong the survival and function of neutrophils. Stem Cells 2011;29:1001-1011. doi: 10.1002/stem.651.
130. François M, Romieu-Mourez R, Li M, Galipeau J., Human MSC suppression correlates with cytokine induction of indoleamine 2,3-dioxygenase and bystander M2 macrophage differentiation. Mol Ther 2012;20:187-195. doi: 10.1038/mt.2011.189.
131. Vandergriff AC, de Andrade JB, Tang J, Hensley MT, Piedrahita JA, Caranasos TG, Cheng K., Intravenous cardiac stem cell-derived exosomes ameliorate cardiac dysfunction in doxorubicin induced dilated cardiomyopathy. Stem Cells Int 2015;2015:960926. doi: 10.1155/2015/960926.
132. de Couto G, Liu W, Tseliou E, Sun B, Makkar N, Kanazawa H, Arditi M, Marbán E., Macrophages mediate cardioprotective cellular postconditioning in acute myocardial infarction. J Clin Invest 2015-125 3147 3162. doi: 10.1172/JCI81321.
133. Caivano A, Laurenzana I, De Luca L, La Rocca F, Simeon V, Trino S, D'Auria F, Traficante A, Maietti M, Izzo T, D'Arena G, Mansueto G, Pietrantuono G, Laurenti L, Musto P, Del Vecchio L., High serum levels of extracellular vesicles expressing malignancy-related markers are released in patients with various types of hematological neoplastic disorders. Tumour Biol 2015;36:9739-9752. doi: 10.1007/s13277-015-3741-3.
134. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ., Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 2011;29:341-345. doi: 10.1038/nbt.1807.
135. Zomer A, Maynard C, Verweij FJ, Kamermans A, Schäfer R, Beerling E, Schiffelers RM, de Wit E, Berenguer J, Ellenbroek SI, Wurdinger T, Pegtel DM, van Rheenen J., In vivo imaging reveals extracellular vesicle-mediated phenocopying of metastatic behavior. Cell 2015;161:1046-1057. doi: 10.1016/j.cell.2015.04.042.
136. Johnsen KB, Gudbergsson JM, Skov MN, Pilgaard L, Moos T, Duroux M., A comprehensive overview of exosomes as drug delivery vehicles-endogenous nanocarriers for targeted cancer therapy. Biochim Biophys Acta 2014;1846:75-87. doi: 10.1016/j.bbcan.2014.04.005.
137. Pironti G, Strachan RT, Abraham D, Mon-Wei Yu S, Chen M, Chen W, Hanada K, Mao L, Watson LJ, Rockman HA., Circulating exosomes induced by cardiac pressure overload contain functional aAngiotensin II type 1 receptors. Circulation 2015;131:2120-2130. doi: 10.1161/CIRCULATIONAHA.115.015687.
138. Kordelas L, Rebmann V, Ludwig AK, Radtke S, Ruesing J, Doeppner TR, Epple M, Horn PA, Beelen DW, Giebel B., MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease. Leukemia 2014;28:970-973. doi: 10.1038/leu.2014.41.
139. Chen TS, Arslan F, Yin Y, Tan SS, Lai RC, Choo AB, Padmanabhan J, Lee CN, de Kleijn DP, Lim SK., Enabling a robust scalable manufacturing process for therapeutic exosomes through oncogenic immortalization of human ESC-derived MSCs. J Transl Med 2011;9 47. doi: 10.1186/1479-5876-9-47.