Extracellular vesicles: potential roles in regenerative medicine

Olivier G De Jong, Bas W M Van Balkom, Raymond M Schiffelers, Carlijn V C Bouten, Marianne C Verhaar, Olivier G De Jong, Bas W M Van Balkom, Raymond M Schiffelers, Carlijn V C Bouten, Marianne C Verhaar

Abstract

Extracellular vesicles (EV) consist of exosomes, which are released upon fusion of the multivesicular body with the cell membrane, and microvesicles, which are released directly from the cell membrane. EV can mediate cell-cell communication and are involved in many processes, including immune signaling, angiogenesis, stress response, senescence, proliferation, and cell differentiation. The vast amount of processes that EV are involved in and the versatility of manner in which they can influence the behavior of recipient cells make EV an interesting source for both therapeutic and diagnostic applications. Successes in the fields of tumor biology and immunology sparked the exploration of the potential of EV in the field of regenerative medicine. Indeed, EV are involved in restoring tissue and organ damage, and may partially explain the paracrine effects observed in stem cell-based therapeutic approaches. The function and content of EV may also harbor information that can be used in tissue engineering, in which paracrine signaling is employed to modulate cell recruitment, differentiation, and proliferation. In this review, we discuss the function and role of EV in regenerative medicine and elaborate on potential applications in tissue engineering.

Keywords: exosomes; extracellular vesicles; microvesicles; regenerative medicine; tissue engineering.

Figures

Figure 1
Figure 1
Bio-activated artificial scaffolds. Electrospinning allows formation of constructs with a variety in shapes, sizes, and tissue strength. This allows the production of constructs for a variety of tissues (left). Electrospun fibers (middle) can be bio-activated by coating of the fibers with proteins or peptides (right, red). Incorporation of bio-active components into the fibers will result in gradual release during fiber degradation (right, green). After electrospinning, fibers can also be pre-seeded with appropriate cell populations to induce ECM production, angiogenesis, or immunomodulation (right, yellow).
Figure 2
Figure 2
EV formation (left) and intercellular communication (right). After endocytosis, intraluminal vesicle formation occurs in the late endosome, resulting in the formation of the multivesicular body (MVB). The MVB can either fuse with the lysosome, resulting in breakdown and recycling of its contents, or fuse with the plasma membrane, resulting in the release of the intraluminal vesicles, which are then deemed exosomes. Microvesicles shed directly from the plasma membrane. Intercellular communication can occur through three major processes: (1) direct interaction of ligands expressed on the surface of EV with receptors on the cell membrane, (2) direct fusion of the EV with the cell membrane, resulting in the release of the content of the EV, or (3) internalization through the endocytotic pathway, which can result in (A) fusion of the EV with membrane of the endosome, resulting in content release, (B) transcytosis, or (C) degradation through the lysosomal pathway.
Figure 3
Figure 3
Applications of EV in regenerative medicine. After isolation (A), EV could be utilized in regenerative medicine through a number of methods, either separately or in combination with cells or other therapeutics. (B) Direct injection into tissue or circulation. (C) Mixing of EV in hydrogels. (D) Coating electrospun fibers indirectly via chemical linkers, antibodies, or specific tags engineered on to the EV. (E) Coating of electrospun fibers with bio-degradable gels such as fibrin, resulting in gradual release during gel degradation.

References

    1. Harrison JH, Merrill JP, Murray JE. Renal homotransplantation in identical twins. Surg Forum (1956) 6:432–6.
    1. Lexer E. The use of free osteoplasty together with trials on arthrodesis and joint transplantation. Archiv fur klin Chirurgie. 1908;86(4):939-954. Clin Orthop Relat Res (2008) 466(8):1771–610.1007/s11999-008-0314-4
    1. Zirm EK. Eine erfolgreiche totale Keratoplastik (A successful total keratoplasty). 1906. Refract Corneal Surg (1989) 5(4):258–61.
    1. Drury JL, Mooney DJ. Hydrogels for tissue engineering: scaffold design variables and applications. Biomaterials (2003) 24(24):4337–51.10.1016/S0142-9612(03)00340-5
    1. Mol A, Driessen NJ, Rutten MC, Hoerstrup SP, Bouten CV, Baaijens FP. Tissue engineering of human heart valve leaflets: a novel bioreactor for a strain-based conditioning approach. Ann Biomed Eng (2005) 33(12):1778–88.10.1007/s10439-005-8025-4
    1. Wagers AJ, Sherwood RI, Christensen JL, Weissman IL. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science (2002) 297(5590):2256–9.10.1126/science.1074807
    1. Murry CE, Soonpaa MH, Reinecke H, Nakajima H, Nakajima HO, Rubart M, et al. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature (2004) 428(6983):664–8.10.1038/nature02446
    1. Den Haan MC, Grauss RW, Smits AM, Winter EM, van Tuyn J, Pijnappels DA, et al. Cardiomyogenic differentiation-independent improvement of cardiac function by human cardiomyocyte progenitor cell injection in ischaemic mouse hearts. J Cell Mol Med (2012) 16(7):1508–21.10.1111/j.1582-4934.2011.01468.x
    1. Van Koppen A, Joles JA, Bongartz LG, van den Brandt J, Reichardt HM, Goldschmeding R, et al. Healthy bone marrow cells reduce progression of kidney failure better than CKD bone marrow cells in rats with established chronic kidney disease. Cell Transplant (2012) 21(10):2299–312.10.3727/096368912X636795
    1. Janowska-Wieczorek A, Wysoczynski M, Kijowski J, Marquez-Curtis L, Machalinski B, Ratajczak J, et al. Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer. Int J Cancer (2005) 113(5):752–60.10.1002/ijc.20657
    1. Mu W, Rana S, Zoller M. Host matrix modulation by tumor exosomes promotes motility and invasiveness. Neoplasia (2013) 15(8):875–87.10.1593/neo.13786
    1. Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, et al. B lymphocytes secrete antigen-presenting vesicles. J Exp Med (1996) 183(3):1161–72.10.1084/jem.183.3.1161
    1. Van Balkom BW, de Jong OG, Smits M, Brummelman J, den Ouden K, de Bree PM, et al. Endothelial cells require miR-214 to secrete exosomes that suppress senescence and induce angiogenesis in human and mouse endothelial cells. Blood (2013) 121(19):3997–4006.10.1182/blood-2013-02-478925
    1. Thomas ED, Lochte HL, Jr, Lu WC, Ferrebee JW. Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy. N Engl J Med (1957) 257(11):491–610.1056/NEJM195709122571102
    1. Blundell J. Experiments on the transfusion of blood by the syringe. Med Chir Trans (1818) 9(Pt 1):56–92.
    1. Slaper-Cortenbach IC. Current regulations for the production of multipotent mesenchymal stromal cells for clinical application. Transfus Med Hemother (2008) 35(4):295–8.10.1159/000144043
    1. Nishida K, Yamato M, Hayashida Y, Watanabe K, Yamamoto K, Adachi E, et al. Corneal reconstruction with tissue-engineered cell sheets composed of autologous oral mucosal epithelium. N Engl J Med (2004) 351(12):1187–96.10.1056/NEJMoa040455
    1. Bartlett W, Skinner JA, Gooding CR, Carrington RW, Flanagan AM, Briggs TW, et al. Autologous chondrocyte implantation versus matrix-induced autologous chondrocyte implantation for osteochondral defects of the knee: a prospective, randomised study. J Bone Joint Surg Br (2005) 87(5):640–5.10.1302/0301-620X.87B5.15905
    1. Schwarz TM, Leicht SF, Radic T, Rodriguez-Araboalaza I, Hermann PC, Berger F, et al. Vascular incorporation of endothelial colony-forming cells is essential for functional recovery of murine ischemic tissue following cell therapy. Arterioscler Thromb Vasc Biol (2012) 32(2):e13–21.10.1161/ATVBAHA.111.239822
    1. Beltrami AP, Cesselli D, Beltrami CA. Stem cell senescence and regenerative paradigms. Clin Pharmacol Ther (2012) 91(1):21–9.10.1038/clpt.2011.262
    1. Siddappa R, Licht R, van Blitterswijk C, de Boer J. Donor variation and loss of multipotency during in vitro expansion of human mesenchymal stem cells for bone tissue engineering. J Orthop Res (2007) 25(8):1029–41.10.1002/jor.20402
    1. Engler AJ, Sen S, Sweeney HL, Discher DE. Matrix elasticity directs stem cell lineage specification. Cell (2006) 126(4):677–89.10.1016/j.cell.2006.06.044
    1. Jie KE, Zaikova MA, Bergevoet MW, Westerweel PE, Rastmanesh M, Blankestijn PJ, et al. Progenitor cells and vascular function are impaired in patients with chronic kidney disease. Nephrol Dial Transplant (2010) 25(6):1875–82.10.1093/ndt/gfp749
    1. Scruggs BA, Semon JA, Zhang X, Zhang S, Bowles AC, Pandey AC, et al. Age of the donor reduces the ability of human adipose-derived stem cells to alleviate symptoms in the experimental autoimmune encephalomyelitis mouse model. Stem Cells Transl Med (2013) 2(10):797–807.10.5966/sctm.2013-0026
    1. Williamson KA, Hamilton A, Reynolds JA, Sipos P, Crocker I, Stringer SE, et al. Age-related impairment of endothelial progenitor cell migration correlates with structural alterations of heparan sulfate proteoglycans. Aging Cell (2013) 12(1):139–47.10.1111/acel.12031
    1. Hugle T, Daikeler T. Stem cell transplantation for autoimmune diseases. Haematologica (2010) 95(2):185–810.3324/haematol.2009.017038
    1. Muylaert DE, Fledderus JO, Bouten CV, Dankers PY, Verhaar MC. Combining tissue repair and tissue engineering; bioactivating implantable cell-free vascular scaffolds. Heart (2014) 100(23):1825–30.10.1136/heartjnl-2014-306092
    1. Vanden Berg-Foels WS. In situ tissue regeneration: chemoattractants for endogenous stem cell recruitment. Tissue Eng Part B Rev (2014) 20(1):28–3910.1089/ten.teb.2013.0100
    1. Badylak SF. Xenogeneic extracellular matrix as a scaffold for tissue reconstruction. Transpl Immunol (2004) 12(3–4):367–77.10.1016/j.trim.2003.12.016
    1. Knight RL, Wilcox HE, Korossis SA, Fisher J, Ingham E. The use of acellular matrices for the tissue engineering of cardiac valves. Proc Inst Mech Eng H (2008) 222(1):129–4310.1243/09544119JEIM230
    1. Borschel GH, Huang YC, Calve S, Arruda EM, Lynch JB, Dow DE, et al. Tissue engineering of recellularized small-diameter vascular grafts. Tissue Eng (2005) 11(5–6):778–8610.1089/ten.2005.11.778
    1. Baiguera S, Jungebluth P, Burns A, Mavilia C, Haag J, De Coppi P, et al. Tissue engineered human tracheas for in vivo implantation. Biomaterials (2010) 31(34):8931–8.10.1016/j.biomaterials.2010.08.005
    1. Zheng MH, Chen J, Kirilak Y, Willers C, Xu J, Wood D. Porcine small intestine submucosa (SIS) is not an acellular collagenous matrix and contains porcine DNA: possible implications in human implantation. J Biomed Mater Res B Appl Biomater (2005) 73(1):61–710.1002/jbm.b.30170
    1. Ratner BD, Bryant SJ. Biomaterials: where we have been and where we are going. Annu Rev Biomed Eng (2004) 6:41–75.10.1146/annurev.bioeng.6.040803.140027
    1. Mendelson K, Schoen FJ. Heart valve tissue engineering: concepts, approaches, progress, and challenges. Ann Biomed Eng (2006) 34(12):1799–819.10.1007/s10439-006-9163-z
    1. Mikos AG, Lyman MD, Freed LE, Langer R. Wetting of poly(L-lactic acid) and poly(DL-lactic-co-glycolic acid) foams for tissue culture. Biomaterials (1994) 15(1):55–8.10.1016/0142-9612(94)90197-X
    1. Whang K, Thomas CH, Healy KE, Nuber G. A novel method to fabricate bioabsorbable scaffolds. Polymer (1995) 36(4):837–4210.1016/0032-3861(95)93115-3
    1. Mooney DJ, Baldwin DF, Suh NP, Vacanti JP, Langer R. Novel approach to fabricate porous sponges of poly(D,L-lactic-co-glycolic acid) without the use of organic solvents. Biomaterials (1996) 17(14):1417–22.10.1016/0142-9612(96)87284-X
    1. Mooney DJ, Mazzoni CL, Breuer C, McNamara K, Hern D, Vacanti JP, et al. Stabilized polyglycolic acid fibre-based tubes for tissue engineering. Biomaterials (1996) 17(2):115–24.10.1016/0142-9612(96)85756-5
    1. Stankus JJ, Guan J, Wagner WR. Fabrication of biodegradable elastomeric scaffolds with sub-micron morphologies. J Biomed Mater Res A (2004) 70(4):603–14.10.1002/jbm.a.30122
    1. Li M, Mondrinos MJ, Chen X, Gandhi MR, Ko FK, Lelkes PI. Co-electrospun poly(lactide-co-glycolide), gelatin, and elastin blends for tissue engineering scaffolds. J Biomed Mater Res A (2006) 79(4):963–73.10.1002/jbm.a.30833
    1. Choi WS, Bae JW, Lim HR, Joung YK, Park JC, Kwon IK, et al. RGD peptide-immobilized electrospun matrix of polyurethane for enhanced endothelial cell affinity. Biomed Mater (2008) 3(4):044104.10.1088/1748-6041/3/4/044104
    1. Yu J, Lee AR, Lin WH, Lin CW, Wu YK, Tsai WB. Electrospun PLGA fibers incorporated with functionalized biomolecules for cardiac tissue engineering. Tissue Eng Part A (2014) 20(13–14):1896–907.10.1089/ten.tea.2013.0008
    1. Kolambkar YM, Bajin M, Wojtowicz A, Hutmacher DW, Garcia AJ, Guldberg RE. Nanofiber orientation and surface functionalization modulate human mesenchymal stem cell behavior in vitro. Tissue Eng Part A (2014) 20(1–2):398–409.10.1089/ten.tea.2012.0426
    1. Han F, Jia X, Dai D, Yang X, Zhao J, Zhao Y, et al. Performance of a multilayered small-diameter vascular scaffold dual-loaded with VEGF and PDGF. Biomaterials (2013) 34(30):7302–13.10.1016/j.biomaterials.2013.06.006
    1. Thevenot PT, Nair AM, Shen J, Lotfi P, Ko CY, Tang L. The effect of incorporation of SDF-1alpha into PLGA scaffolds on stem cell recruitment and the inflammatory response. Biomaterials (2010) 31(14):3997–4008.10.1016/j.biomaterials.2010.01.144
    1. De Visscher G, Mesure L, Meuris B, Ivanova A, Flameng W. Improved endothelialization and reduced thrombosis by coating a synthetic vascular graft with fibronectin and stem cell homing factor SDF-1alpha. Acta Biomater (2012) 8(3):1330–8.10.1016/j.actbio.2011.09.016
    1. Tsai TN, Kirton JP, Campagnolo P, Zhang L, Xiao Q, Zhang Z, et al. Contribution of stem cells to neointimal formation of decellularized vessel grafts in a novel mouse model. Am J Pathol (2012) 181(1):362–73.10.1016/j.ajpath.2012.03.021
    1. Lai RC, Arslan F, Lee MM, Sze NS, Choo A, Chen TS, et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res (2010) 4(3):214–22.10.1016/j.scr.2009.12.003
    1. Stoorvogel W, Kleijmeer MJ, Geuze HJ, Raposo G. The biogenesis and functions of exosomes. Traffic (2002) 3(5):321–30.10.1034/j.1600-0854.2002.30502.x
    1. Thery C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol (2002) 2(8):569–7910.1038/nri855
    1. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol (2007) 9(6):654–9.10.1038/ncb1596
    1. Bobrie A, Colombo M, Raposo G, Thery C. Exosome secretion: molecular mechanisms and roles in immune responses. Traffic (2011) 12(12):1659–68.10.1111/j.1600-0854.2011.01225.x
    1. Gutzeit C, Nagy N, Gentile M, Lyberg K, Gumz J, Vallhov H, et al. Exosomes derived from Burkitt’s lymphoma cell lines induce proliferation, differentiation, and class-switch recombination in B cells. J Immunol (2014) 192(12):5852–62.10.4049/jimmunol.1302068
    1. Pan BT, Johnstone RM. Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell (1983) 33(3):967–78.10.1016/0092-8674(83)90040-5
    1. Xu D, Tahara H. The role of exosomes and microRNAs in senescence and aging. Adv Drug Deliv Rev (2013) 65(3):368–7510.1016/j.addr.2012.07.010
    1. El Andaloussi S, Lakhal S, Mager I, Wood MJ. Exosomes for targeted siRNA delivery across biological barriers. Adv Drug Deliv Rev (2013) 65(3):391–7.10.1016/j.addr.2012.08.008
    1. Gould SJ, Raposo G. As we wait: coping with an imperfect nomenclature for extracellular vesicles. J Extracell Vesicles (2013) 2:20389.10.3402/jev.v2i0.20389
    1. van Balkom BW, Pisitkun T, Verhaar MC, Knepper MA. Exosomes and the kidney: prospects for diagnosis and therapy of renal diseases. Kidney Int (2011) 80(11):1138–45.10.1038/ki.2011.292
    1. Escola JM, Kleijmeer MJ, Stoorvogel W, Griffith JM, Yoshie O, Geuze HJ. Selective enrichment of tetraspan proteins on the internal vesicles of multivesicular endosomes and on exosomes secreted by human B-lymphocytes. J Biol Chem (1998) 273(32):20121–7.10.1074/jbc.273.32.20121
    1. Vader P, Breakefield XO, Wood MJ. Extracellular vesicles: emerging targets for cancer therapy. Trends Mol Med (2014) 20(7):385–93.10.1016/j.molmed.2014.03.002
    1. Cocucci E, Racchetti G, Meldolesi J. Shedding microvesicles: artefacts no more. Trends Cell Biol (2009) 19(2):43–51.10.1016/j.tcb.2008.11.003
    1. Baj-Krzyworzeka M, Szatanek R, Weglarczyk K, Baran J, Urbanowicz B, Branski P, et al. Tumour-derived microvesicles carry several surface determinants and mRNA of tumour cells and transfer some of these determinants to monocytes. Cancer Immunol Immunother (2006) 55(7):808–1810.1007/s00262-005-0075-9
    1. Ratajczak J, Wysoczynski M, Hayek F, Janowska-Wieczorek A, Ratajczak MZ. Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia (2006) 20(9):1487–95.10.1038/sj.leu.2404296
    1. Huber J, Vales A, Mitulovic G, Blumer M, Schmid R, Witztum JL, et al. Oxidized membrane vesicles and blebs from apoptotic cells contain biologically active oxidized phospholipids that induce monocyte-endothelial interactions. Arterioscler Thromb Vasc Biol (2002) 22(1):101–7.10.1161/hq0102.101525
    1. Loyer X, Vion AC, Tedgui A, Boulanger CM. Microvesicles as cell-cell messengers in cardiovascular diseases. Circ Res (2014) 114(2):345–53.10.1161/CIRCRESAHA.113.300858
    1. Zernecke A, Bidzhekov K, Noels H, Shagdarsuren E, Gan L, Denecke B, et al. Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci Signal (2009) 2(100):ra81.10.1126/scisignal.2000610
    1. Distler JH, Jungel A, Huber LC, Seemayer CA, Reich CF, III, Gay RE, et al. The induction of matrix metalloproteinase and cytokine expression in synovial fibroblasts stimulated with immune cell microparticles. Proc Natl Acad Sci U S A (2005) 102(8):2892–7.10.1073/pnas.0409781102
    1. Julich H, Willms A, Lukacs-Kornek V, Kornek M. Extracellular vesicle profiling and their use as potential disease specific biomarker. Front Immunol (2014) 5:413.10.3389/fimmu.2014.00413
    1. Kornek M, Popov Y, Libermann TA, Afdhal NH, Schuppan D. Human T cell microparticles circulate in blood of hepatitis patients and induce fibrolytic activation of hepatic stellate cells. Hepatology (2011) 53(1):230–42.10.1002/hep.23999
    1. Harding C, Heuser J, Stahl P. Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J Cell Biol (1983) 97(2):329–39.10.1083/jcb.97.2.329
    1. Johnstone RM, Mathew A, Mason AB, Teng K. Exosome formation during maturation of mammalian and avian reticulocytes: evidence that exosome release is a major route for externalization of obsolete membrane proteins. J Cell Physiol (1991) 147(1):27–3610.1002/jcp.1041470105
    1. Pegtel DM, Cosmopoulos K, Thorley-Lawson DA, van Eijndhoven MA, Hopmans ES, Lindenberg JL, et al. Functional delivery of viral miRNAs via exosomes. Proc Natl Acad Sci U S A (2010) 107(14):6328–33.10.1073/pnas.0914843107
    1. De Jong OG, Verhaar MC, Chen Y, Vader P, Gremmels H, Posthuma G, et al. Cellular stress conditions are reflected in the protein and RNA content of endothelial cell-derived exosomes. J Extracell Vesicles (2012) 1:18396.10.3402/jev.v1i0.18396
    1. Huu AL, Paul A, Prakash S, Shum-Tim D. Route of delivery, cell retention, and efficiency of polymeric microcapsules in cellular cardiomyoplasty. Methods Mol Biol (2013) 1036:121–35.10.1007/978-1-62703-511-8_11
    1. Gruber HE, Somayaji S, Riley F, Hoelscher GL, Norton HJ, Ingram J, et al. Human adipose-derived mesenchymal stem cells: serial passaging, doubling time and cell senescence. Biotech Histochem (2012) 87(4):303–11.10.3109/10520295.2011.649785
    1. Stolzing A, Jones E, McGonagle D, Scutt A. Age-related changes in human bone marrow-derived mesenchymal stem cells: consequences for cell therapies. Mech Ageing Dev (2008) 129(3):163–73.10.1016/j.mad.2007.12.002
    1. Adijiang A, Higuchi Y, Nishijima F, Shimizu H, Niwa T. Indoxyl sulfate, a uremic toxin, promotes cell senescence in aorta of hypertensive rats. Biochem Biophys Res Commun (2010) 399(4):637–41.10.1016/j.bbrc.2010.07.130
    1. Bonab MM, Alimoghaddam K, Talebian F, Ghaffari SH, Ghavamzadeh A, Nikbin B. Aging of mesenchymal stem cell in vitro. BMC Cell Biol (2006) 7:14.10.1186/1471-2121-7-14
    1. Vacanti V, Kong E, Suzuki G, Sato K, Canty JM, Lee T. Phenotypic changes of adult porcine mesenchymal stem cells induced by prolonged passaging in culture. J Cell Physiol (2005) 205(2):194–201.10.1002/jcp.20376
    1. Zhou Y, Xu H, Xu W, Wang B, Wu H, Tao Y, et al. Exosomes released by human umbilical cord mesenchymal stem cells protect against cisplatin-induced renal oxidative stress and apoptosis in vivo and in vitro. Stem Cell Res Ther (2013) 4(2):34.10.1186/scrt194
    1. Barile L, Lionetti V, Cervio E, Matteucci M, Gherghiceanu M, Popescu LM, et al. Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction. Cardiovasc Res (2014) 103(4):530–41.10.1093/cvr/cvu167
    1. Reis LA, Borges FT, Simoes MJ, Borges AA, Sinigaglia-Coimbra R, Schor N. Bone marrow-derived mesenchymal stem cells repaired but did not prevent gentamicin-induced acute kidney injury through paracrine effects in rats. PLoS One (2012) 7(9):e44092.10.1371/journal.pone.0044092
    1. Bruno S, Grange C, Collino F, Deregibus MC, Cantaluppi V, Biancone L, et al. Microvesicles derived from mesenchymal stem cells enhance survival in a lethal model of acute kidney injury. PLoS One (2012) 7(3):e33115.10.1371/journal.pone.0033115
    1. Yu B, Gong M, Wang Y, Millard RW, Pasha Z, Yang Y, et al. Cardiomyocyte protection by GATA-4 gene engineered mesenchymal stem cells is partially mediated by translocation of miR-221 in microvesicles. PLoS One (2013) 8(8):e73304.10.1371/journal.pone.0073304
    1. Inder KL, Ruelcke JE, Petelin L, Moon H, Choi E, Rae J, et al. Cavin-1/PTRF alters prostate cancer cell-derived extracellular vesicle content and internalization to attenuate extracellular vesicle-mediated osteoclastogenesis and osteoblast proliferation. J Extracell Vesicles (2014) 3:23784.10.3402/jev.v3.23784
    1. Xu Y, Luo F, Liu Y, Shi L, Lu X, Xu W, et al. Exosomal miR-21 derived from arsenite-transformed human bronchial epithelial cells promotes cell proliferation associated with arsenite carcinogenesis. Arch Toxicol (2014).10.1007/s00204-014-1291-x
    1. Yang L, Wu XH, Wang D, Luo CL, Chen LX. Bladder cancer cell-derived exosomes inhibit tumor cell apoptosis and induce cell proliferation in vitro. Mol Med Rep (2013) 8(4):1272–8.10.3892/mmr.2013.1634
    1. Tomasoni S, Longaretti L, Rota C, Morigi M, Conti S, Gotti E, et al. Transfer of growth factor receptor mRNA via exosomes unravels the regenerative effect of mesenchymal stem cells. Stem Cells Dev (2013) 22(5):772–80.10.1089/scd.2012.0266
    1. Zhang B, Wang M, Gong A, Zhang X, Wu X, Zhu Y, et al. HucMSC-exosome mediated-Wnt4 signaling is required for cutaneous wound healing. Stem Cells (2014).10.1002/stem.1771
    1. Borges FT, Melo SA, Ozdemir BC, Kato N, Revuelta I, Miller CA, et al. TGF-beta1-containing exosomes from injured epithelial cells activate fibroblasts to initiate tissue regenerative responses and fibrosis. J Am Soc Nephrol (2013) 24(3):385–92.10.1681/ASN.2012101031
    1. Yu X, Huang C, Song B, Xiao Y, Fang M, Feng J, et al. CD4+CD25+ regulatory T cells-derived exosomes prolonged kidney allograft survival in a rat model. Cell Immunol (2013) 285(1–2):62–8.10.1016/j.cellimm.2013.06.010
    1. Jain RK, Au P, Tam J, Duda DG, Fukumura D. Engineering vascularized tissue. Nat Biotechnol (2005) 23(7):821–310.1038/nbt0705-821
    1. Du C, Narayanan K, Leong MF, Wan AC. Induced pluripotent stem cell-derived hepatocytes and endothelial cells in multi-component hydrogel fibers for liver tissue engineering. Biomaterials (2014) 35(23):6006–14.10.1016/j.biomaterials.2014.04.011
    1. Glynn JJ, Hinds MT. Endothelial outgrowth cells: function and performance in vascular grafts. Tissue Eng Part B Rev (2013) 20(4):294–30310.1089/ten.teb.2013.0285
    1. Ekstrom EJ, Bergenfelz C, von Bulow V, Serifler F, Carlemalm E, Jonsson G, et al. WNT5A induces release of exosomes containing pro-angiogenic and immunosuppressive factors from malignant melanoma cells. Mol Cancer (2014) 13:88.10.1186/1476-4598-13-88
    1. Hong BS, Cho JH, Kim H, Choi EJ, Rho S, Kim J, et al. Colorectal cancer cell-derived microvesicles are enriched in cell cycle-related mRNAs that promote proliferation of endothelial cells. BMC Genomics (2009) 10:556.10.1186/1471-2164-10-556
    1. Kucharzewska P, Christianson HC, Welch JE, Svensson KJ, Fredlund E, Ringner M, et al. Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development. Proc Natl Acad Sci U S A (2013) 110(18):7312–7.10.1073/pnas.1220998110
    1. Skog J, Wurdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol (2008) 10(12):1470–6.10.1038/ncb1800
    1. Tadokoro H, Umezu T, Ohyashiki K, Hirano T, Ohyashiki JH. Exosomes derived from hypoxic leukemia cells enhance tube formation in endothelial cells. J Biol Chem (2013) 288(48):34343–51.10.1074/jbc.M113.480822
    1. Sheldon H, Heikamp E, Turley H, Dragovic R, Thomas P, Oon CE, et al. New mechanism for Notch signaling to endothelium at a distance by Delta-like 4 incorporation into exosomes. Blood (2010) 116(13):2385–94.10.1182/blood-2009-08-239228
    1. Lopatina T, Bruno S, Tetta C, Kalinina N, Porta M, Camussi G. Platelet-derived growth factor regulates the secretion of extracellular vesicles by adipose mesenchymal stem cells and enhances their angiogenic potential. Cell Commun Signal (2014) 12:26.10.1186/1478-811X-12-26
    1. 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(4):387–97.10.1007/s00109-013-1110-5
    1. Zhang HC, Liu XB, Huang S, Bi XY, Wang HX, Xie LX, et al. Microvesicles derived from human umbilical cord mesenchymal stem cells stimulated by hypoxia promote angiogenesis both in vitro and in vivo. Stem Cells Dev (2012) 21(18):3289–97.10.1089/scd.2012.0095
    1. Cantaluppi V, Biancone L, Figliolini F, Beltramo S, Medica D, Deregibus MC, et al. Microvesicles derived from endothelial progenitor cells enhance neoangiogenesis of human pancreatic islets. Cell Transplant (2012) 21(6):1305–20.10.3727/096368911X627534
    1. Ranghino A, Cantaluppi V, Grange C, Vitillo L, Fop F, Biancone L, et al. Endothelial progenitor cell-derived microvesicles improve neovascularization in a murine model of hindlimb ischemia. Int J Immunopathol Pharmacol (2012) 25(1):75–85.
    1. Sahoo S, Klychko E, Thorne T, Misener S, Schultz KM, Millay M, et al. Exosomes from human CD34(+) stem cells mediate their proangiogenic paracrine activity. Circ Res (2011) 109(7):724–8.10.1161/CIRCRESAHA.111.253286
    1. Clayton A, Turkes A, Dewitt S, Steadman R, Mason MD, Hallett MB. Adhesion and signaling by B cell-derived exosomes: the role of integrins. FASEB J (2004) 18(9):977–9.10.1096/fj.03-1094fje
    1. Segura E, Nicco C, Lombard B, Veron P, Raposo G, Batteux F, et al. ICAM-1 on exosomes from mature dendritic cells is critical for efficient naive T-cell priming. Blood (2005) 106(1):216–23.10.1182/blood-2005-01-0220
    1. Rieu S, Geminard C, Rabesandratana H, Sainte-Marie J, Vidal M. Exosomes released during reticulocyte maturation bind to fibronectin via integrin alpha4beta1. Eur J Biochem (2000) 267(2):583–90.10.1046/j.1432-1327.2000.01036.x
    1. Thery C, Regnault A, Garin J, Wolfers J, Zitvogel L, Ricciardi-Castagnoli P, et al. Molecular characterization of dendritic cell-derived exosomes. Selective accumulation of the heat shock protein hsc73. J Cell Biol (1999) 147(3):599–610.10.1083/jcb.147.3.599
    1. Chen Q, Jin M, Yang F, Zhu J, Xiao Q, Zhang L. Matrix metalloproteinases: inflammatory regulators of cell behaviors in vascular formation and remodeling. Mediators Inflamm (2013) 2013:928315.10.1155/2013/928315
    1. Nissinen L, Kahari VM. Matrix metalloproteinases in inflammation. Biochim Biophys Acta (2014) 1840(8):2571–80.10.1016/j.bbagen.2014.03.007
    1. Hakulinen J, Sankkila L, Sugiyama N, Lehti K, Keski-Oja J. Secretion of active membrane type 1 matrix metalloproteinase (MMP-14) into extracellular space in microvesicular exosomes. J Cell Biochem (2008) 105(5):1211–8.10.1002/jcb.21923
    1. Vrijsen KR, Sluijter JP, Schuchardt MW, van Balkom BW, Noort WA, Chamuleau SA, et al. Cardiomyocyte progenitor cell-derived exosomes stimulate migration of endothelial cells. J Cell Mol Med (2010) 14(5):1064–70.10.1111/j.1582-4934.2010.01081.x
    1. Tauro BJ, Mathias RA, Greening DW, Gopal SK, Ji H, Kapp EA, et al. Oncogenic H-ras reprograms Madin-Darby canine kidney (MDCK) cell-derived exosomal proteins following epithelial-mesenchymal transition. Mol Cell Proteomics (2013) 12(8):2148–59.10.1074/mcp.M112.027086
    1. Medina A, Ghahary A. Transdifferentiated circulating monocytes release exosomes containing 14-3-3 proteins with matrix metalloproteinase-1 stimulating effect for dermal fibroblasts. Wound Repair Regen (2010) 18(2):245–5310.1111/j.1524-475X.2010.00580.x
    1. Athens AA, Makris EA, Hu JC. Induced collagen cross-links enhance cartilage integration. PLoS One (2013) 8(4):e60719.10.1371/journal.pone.0060719
    1. Bignon M, Pichol-Thievend C, Hardouin J, Malbouyres M, Brechot N, Nasciutti L, et al. Lysyl oxidase-like protein-2 regulates sprouting angiogenesis and type IV collagen assembly in the endothelial basement membrane. Blood (2011) 118(14):3979–89.10.1182/blood-2010-10-313296
    1. Hanson S, D’Souza RN, Hematti P. Biomaterial-mesenchymal stem cell constructs for immunomodulation in composite tissue engineering. Tissue Eng Part A (2014) 20(15–16):2162–8.10.1089/ten.tea.2013.0359
    1. Artlett CM. Inflammasomes in wound healing and fibrosis. J Pathol (2012) 229(2):157–6710.1002/path.4116
    1. Galli SJ, Borregaard N, Wynn TA. Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils. Nat Immunol (2011) 12(11):1035–44.10.1038/ni.2109
    1. Brown BN, Ratner BD, Goodman SB, Amar S, Badylak SF. Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine. Biomaterials (2012) 33(15):3792–802.10.1016/j.biomaterials.2012.02.034
    1. Zhang B, Yin Y, Lai RC, Tan SS, Choo AB, Lim SK. Mesenchymal stem cells secrete immunologically active exosomes. Stem Cells Dev (2014) 23(11):1233–44.10.1089/scd.2013.0479
    1. Soki FN, Koh AJ, Jones JD, Kim YW, Dai J, Keller ET, et al. Polarization of prostate cancer-associated macrophages is induced by milk fat globule-EGF factor 8 (MFG-E8)-mediated efferocytosis. J Biol Chem (2008) 289(35):24560–72.10.1074/jbc.M114.571620
    1. Jang JY, Lee JK, Jeon YK, Kim CW. Exosome derived from epigallocatechin gallate treated breast cancer cells suppresses tumor growth by inhibiting tumor-associated macrophage infiltration and M2 polarization. BMC Cancer (2013) 13:421.10.1186/1471-2407-13-421
    1. Li X, Li JJ, Yang JY, Wang DS, Zhao W, Song WJ, et al. Tolerance induction by exosomes from immature dendritic cells and rapamycin in a mouse cardiac allograft model. PLoS One (2013) 7(8):e44045.10.1371/journal.pone.0044045
    1. Yang X, Meng S, Jiang H, Zhu C, Wu W. Exosomes derived from immature bone marrow dendritic cells induce tolerogenicity of intestinal transplantation in rats. J Surg Res (2011) 171(2):826–32.10.1016/j.jss.2010.05.021
    1. Corcione A, Benvenuto F, Ferretti E, Giunti D, Cappiello V, Cazzanti F, et al. Human mesenchymal stem cells modulate B-cell functions. Blood (2006) 107(1):367–7210.1182/blood-2005-07-2657
    1. Shi M, Liu ZW, Wang FS. Immunomodulatory properties and therapeutic application of mesenchymal stem cells. Clin Exp Immunol (2011) 164(1):1–8.10.1111/j.1365-2249.2011.04327.x
    1. Xue Q, Luan XY, Gu YZ, Wu HY, Zhang GB, Yu GH, et al. The negative co-signaling molecule b7-h4 is expressed by human bone marrow-derived mesenchymal stem cells and mediates its T-cell modulatory activity. Stem Cells Dev (2010) 19(1):27–38.10.1089/scd.2009.0076
    1. 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(1–2):47–54.10.1016/j.imlet.2012.06.001
    1. Arslan F, Lai RC, Smeets MB, Akeroyd L, Choo A, Aguor EN, 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 Res (2013) 10(3):301–12.10.1016/j.scr.2013.01.002
    1. Zou X, Zhang G, Cheng Z, Yin D, Du T, Ju G, et al. Microvesicles derived from human Wharton’s Jelly mesenchymal stromal cells ameliorate renal ischemia-reperfusion injury in rats by suppressing CX3CL1. Stem Cell Res Ther (2014) 5(2):40.10.1186/scrt428
    1. Akyurekli C, Le Y, Richardson RB, Fergusson D, Tay J, Allan DS. A systematic review of preclinical studies on the therapeutic potential of mesenchymal stromal cell-derived microvesicles. Stem Cell Rev Rep (2014).10.1007/s12015-014-9545-9
    1. Lamichhane TN, Sokic S, Schardt JS, Raiker RS, Lin JW, Jay SM. Emerging roles for extracellular vesicles in tissue engineering and regenerative medicine. Tissue Eng Part B Rev (2014).10.1089/ten.teb.2014.0300
    1. Witwer KW, Buzas EI, Bemis LT, Bora A, Lasser C, Lotvall J, et al. Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J Extracell Vesicles (2013) 2:20360.10.3402/jev.v2i0.20360
    1. Li W, Mu D, Tian F, Hu Y, Jiang T, Han Y, et al. Exosomes derived from Rab27a-overexpressing tumor cells elicit efficient induction of antitumor immunity. Mol Med Rep (2013) 8(6):1876–82.10.3892/mmr.2013.1738
    1. Squadrito ML, Baer C, Burdet F, Maderna C, Gilfillan GD, Lyle R, et al. Endogenous RNAs modulate microRNA sorting to exosomes and transfer to acceptor cells. Cell Rep (2014) 8(5):1432–46.10.1016/j.celrep.2014.07.035
    1. Daemen T, de Mare A, Bungener L, de Jonge J, Huckriede A, Wilschut J. Virosomes for antigen and DNA delivery. Adv Drug Deliv Rev (2005) 57(3):451–63.10.1016/j.addr.2004.09.005
    1. van der Meel R, Fens MH, Vader P, van Solinge WW, Eniola-Adefeso O, Schiffelers RM. Extracellular vesicles as drug delivery systems: lessons from the liposome field. J Control Release (2014) 195:72–85.10.1016/j.jconrel.2014.07.049
    1. van der Meel R, Vehmeijer LJ, Kok RJ, Storm G, van Gaal EV. Ligand-targeted particulate nanomedicines undergoing clinical evaluation: current status. Adv Drug Deliv Rev (2013) 65(10):1284–98.10.1016/j.addr.2013.08.012

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