Towards Therapeutic Delivery of Extracellular Vesicles: Strategies for In Vivo Tracking and Biodistribution Analysis

Giuliana Di Rocco, Silvia Baldari, Gabriele Toietta, Giuliana Di Rocco, Silvia Baldari, Gabriele Toietta

Abstract

Extracellular vesicles (EVs), such as microvesicles and exosomes, are membranous structures containing bioactive material released by several cells types, including mesenchymal stem/stromal cells (MSCs). Increasing lines of evidences point to EVs as paracrine mediators of the beneficial effects on tissue remodeling associated with cell therapy. Administration of MSCs-derived EVs has therefore the potential to open new and safer therapeutic avenues, alternative to cell-based approaches, for degenerative diseases. However, an enhanced knowledge about in vivo EVs trafficking upon delivery is required before effective clinical translation. Only a few studies have focused on the biodistribution analysis of exogenously administered MSCs-derived EVs. Nevertheless, current strategies for in vivo tracking in animal models have provided valuable insights on the biodistribution upon systemic delivery of EVs isolated from several cellular sources, indicating in liver, spleen, and lungs the preferential target organs. Different strategies for targeting EVs to specific tissues to enhance their therapeutic efficacy and reduce possible off-target effects have been investigated. Here, in the context of a possible clinical application of MSC-derived EVs for tissue regeneration, we review the existing strategies for in vivo tracking and targeting of EVs isolated from different cellular sources and the studies elucidating the biodistribution of exogenously administered EVs.

Conflict of interest statement

The authors declare that there is no conflict of interests regarding the publication of this paper.

Figures

Figure 1
Figure 1
Main areas of potential therapeutic use of mesenchymal stem/stromal cells-derived extracellular vesicles.
Figure 2
Figure 2
Schematic representation of different methods to promote tissue- or cell-type-specific targeting of extracellular vesicles (EVs). EVs can be targeted to particular cellular receptor either by modifications of EVs-producing cells (red squares) or modification of EVs after secretion (yellow squares). In the first case, EVs-producing cells can be modified: expressing ligands, peptides, or viral-derived envelop proteins in the outer portion of a transmembrane protein; loading cells with iron oxide particles to allow for magnetic targeting. Alternatively, secreted EVs can be modified linking cell-specific peptides to the EVs surface via association with polyethylene glycol (PEG) polymer chains or by EVs-liposome fusion. Click chemistry can be used to modify both EVs-producing cells and purified EVs.

References

    1. da Silva Meirelles L., Chagastelles P. C., Nardi N. B. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. Journal of Cell Science. 2006;119(11):2204–2213. doi: 10.1242/jcs.02932.
    1. Caplan A. I. Mesenchymal stem cells. Journal of Orthopaedic Research. 1991;9(5):641–650. doi: 10.1002/jor.1100090504.
    1. Dominici M., Le Blanc K., Mueller I., et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–317. doi: 10.1080/14653240600855905.
    1. Horwitz E. M., Le Blanc K., Dominici M., et al. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy. 2005;7(5):393–395. doi: 10.1080/14653240500319234.
    1. Keating A. Mesenchymal stromal cells: new directions. Cell Stem Cell. 2012;10(6):709–716. doi: 10.1016/j.stem.2012.05.015.
    1. Stoltz J.-F., De Isla N., Li Y. P., et al. Stem cells and regenerative medicine: myth or reality of the 21th century. Stem Cells International. 2015;2015:19. doi: 10.1155/2015/734731.734731
    1. da Silva Meirelles L., Fontes A. M., Covas D. T., Caplan A. I. Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine and Growth Factor Reviews. 2009;20(5-6):419–427. doi: 10.1016/j.cytogfr.2009.10.002.
    1. Semedo P., Burgos-Silva M., Donizetti-Oliveira C., Camara N. O. S. How do mesenchymal stem cells repair? In: Gholamrezanezhad A., editor. Stem Cells in Clinic and Research. chapter 4. Rijeka, Croatia: InTech; 2011. pp. 83–104.
    1. Wu T., Liu Y., Wang B., Li G. The roles of mesenchymal stem cells in tissue repair and disease modification. Current Stem Cell Research and Therapy. 2014;9(5):424–431. doi: 10.2174/1574888X09666140616125446.
    1. Gnecchi M., Danieli P., Malpasso G., Ciuffreda M. C. Paracrine mechanisms of mesenchymal stem cells in tissue repair. In: Gnecchi M., editor. Mesenchymal Stem Cells: Methods and Protocols. Vol. 1416. Berlin, Germany: Springer; 2016. pp. 123–146. (Methods in Molecular Biology).
    1. Liang X., Ding Y., Zhang Y., Tse H.-F., Lian Q. Paracrine mechanisms of mesenchymal stem cell-based therapy: current status and perspectives. Cell Transplantation. 2014;23(9):1045–1059. doi: 10.3727/096368913x667709.
    1. Hodgkinson C. P., Bareja A., Gomez J. A., Dzau V. J. Emerging concepts in paracrine mechanisms in regenerative cardiovascular medicine and biology. Circulation Research. 2016;118(1):95–107. doi: 10.1161/circresaha.115.305373.
    1. Burdon T. J., Paul A., Noiseux N., Prakash S., Shum-Tim D. Bone marrow stem cell derived paracrine factors for regenerative medicine: current perspectives and therapeutic potential. Bone Marrow Research. 2011;2011:14. doi: 10.1155/2011/207326.207326
    1. Konala V. B. R., Mamidi M. K., Bhonde R., Das A. K., Pochampally R., Pal R. The current landscape of the mesenchymal stromal cell secretome: a new paradigm for cell-free regeneration. Cytotherapy. 2016;18(1):13–24. doi: 10.1016/j.jcyt.2015.10.008.
    1. Katsuda T., Ochiya T. Molecular signatures of mesenchymal stem cell-derived extracellular vesicle-mediated tissue repair. Stem Cell Research and Therapy. 2015;6(1, article 214) doi: 10.1186/s13287-015-0214-y.
    1. Tran C., Damaser M. S. Stem cells as drug delivery methods: application of stem cell secretome for regeneration. Advanced Drug Delivery Reviews. 2015;82-83:1–11. doi: 10.1016/j.addr.2014.10.007.
    1. Kupcova Skalnikova H. Proteomic techniques for characterisation of mesenchymal stem cell secretome. Biochimie. 2013;95(12):2196–2211. doi: 10.1016/j.biochi.2013.07.015.
    1. Makridakis M., Roubelakis M. G., Vlahou A. Stem cells: insights into the secretome. Biochimica et Biophysica Acta. 2013;1834(11):2380–2384. doi: 10.1016/j.bbapap.2013.01.032.
    1. Lavoie J. R., Rosu-Myles M. Uncovering the secretes of mesenchymal stem cells. Biochimie. 2013;95(12):2212–2221. doi: 10.1016/j.biochi.2013.06.017.
    1. Raposo G., Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. Journal of Cell Biology. 2013;200(4):373–383. doi: 10.1083/jcb.201211138.
    1. Yáñez-Mó M., Siljander P. R., Andreu Z., et al. Biological properties of extracellular vesicles and their physiological functions. Journal of Extracellular Vesicles. 2015;4 doi: 10.3402/jev.v4.27066.27066
    1. Kalra H., Drummen G. P. C., Mathivanan S. Focus on extracellular vesicles: introducing the next small big thing. International Journal of Molecular Sciences. 2016;17(2, article 170) doi: 10.3390/ijms17020170.
    1. van der Pol E., Böing A. N., Harrison P., Sturk A., Nieuwland R. Classification, functions, and clinical relevance of extracellular vesicles. Pharmacological Reviews. 2012;64(3):676–705. doi: 10.1124/pr.112.005983.
    1. Xu R., Greening D. W., Zhu H.-J., Takahashi N., Simpson R. J. Extracellular vesicle isolation and characterization: toward clinical application. The Journal of Clinical Investigation. 2016;126:1152–1162. doi: 10.1172/jci81129.
    1. van der Pol E., Hoekstra A. G., Sturk A., Otto C., van Leeuwen T. G., Nieuwland R. Optical and non-optical methods for detection and characterization of microparticles and exosomes. Journal of Thrombosis and Haemostasis. 2010;8(12):2596–2607. doi: 10.1111/j.1538-7836.2010.04074.x.
    1. Rupert D. L., Claudio V., Lässer C., Bally M. Methods for the physical characterization and quantification of extracellular vesicles in biological samples. Biochimica et Biophysica Acta (BBA)—General Subjects. 2016 doi: 10.1016/j.bbagen.2016.07.028.
    1. Momen-Heravi F., Balaj L., Alian S., et al. Current methods for the isolation of extracellular vesicles. Biological Chemistry. 2013;394(10):1253–1262. doi: 10.1515/hsz-2013-0141.
    1. Théry C., Amigorena S., Raposo G., Clayton A. Current Protocols in Cell Biology. chapter 3, unit 3.22. New York, NY, USA: John Wiley & Sons; 2006. Isolation and characterization of exosomes from cell culture supernatants and biological fluids.
    1. Szatanek R., Baran J., Siedlar M., Baj-Krzyworzeka M. Isolation of extracellular vesicles: determining the correct approach. International Journal of Molecular Medicine. 2015;36(1):11–17. doi: 10.3892/ijmm.2015.2194.
    1. Lötvall J., Hill A. F., Hochberg F., et al. Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. Journal of Extracellular Vesicles. 2014;3 doi: 10.3402/jev.v3.26913.26913
    1. Willms E., Johansson H. J., Mäger I., et al. Cells release subpopulations of exosomes with distinct molecular and biological properties. Scientific Reports. 2016;6 doi: 10.1038/srep22519.22519
    1. Colombo M., Raposo G., Théry C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annual Review of Cell and Developmental Biology. 2014;30:255–289. doi: 10.1146/annurev-cellbio-101512-122326.
    1. El Andaloussi S., Mäger I., Breakefield X. O., Wood M. J. A. Extracellular vesicles: biology and emerging therapeutic opportunities. Nature Reviews Drug Discovery. 2013;12(5):347–357. doi: 10.1038/nrd3978.
    1. Gould S. J., Raposo G. As we wait: coping with an imperfect nomenclature for extracellular vesicles. Journal of Extracellular Vesicles. 2013;2 doi: 10.3402/jev.v2i0.20389.20389
    1. Edgar J. R. Q&A: what are exosomes, exactly? BMC Biology. 2016;14, article 46 doi: 10.1186/s12915-016-0268-z.
    1. Lin J., Li J., Huang B., et al. Exosomes: novel biomarkers for clinical diagnosis. Scientific World Journal. 2015;2015:8. doi: 10.1155/2015/657086.657086
    1. Ferguson S. W., Nguyen J. Exosomes as therapeutics: the implications of molecular composition and exosomal heterogeneity. Journal of Controlled Release. 2016;228:179–190. doi: 10.1016/j.jconrel.2016.02.037.
    1. Valadi H., Ekström K., Bossios A., Sjöstrand M., Lee J. J., Lötvall J. O. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nature Cell Biology. 2007;9(6):654–659. doi: 10.1038/ncb1596.
    1. Ratajczak M. Z., Ratajczak J. Horizontal transfer of RNA and proteins between cells by extracellular microvesicles: 14 years later. Clinical and Translational Medicine. 2016;5, article 7 doi: 10.1186/s40169-016-0087-4.
    1. Eldh M., Ekström K., Valadi H., et al. Exosomes communicate protective messages during oxidative stress; possible role of exosomal shuttle RNA. PLoS ONE. 2010;5(12)e15353
    1. Ohno S.-I., Drummen G. P. C., Kuroda M. Focus on extracellular vesicles: development of extracellular vesicle-based therapeutic systems. International Journal of Molecular Sciences. 2016;17(2):p. 172. doi: 10.3390/ijms17020172.
    1. György B., Hung M. E., Breakefield X. O., Leonard J. N. Therapeutic applications of extracellular vesicles: clinical promise and open questions. Annual Review of Pharmacology and Toxicology. 2015;55:439–464. doi: 10.1146/annurev-pharmtox-010814-124630.
    1. Tominaga N., Yoshioka Y., Ochiya T. A novel platform for cancer therapy using extracellular vesicles. Advanced Drug Delivery Reviews. 2015;95:50–55. doi: 10.1016/j.addr.2015.10.002.
    1. Jarmalavičiūtė A., Pivoriūnas A. Exosomes as a potential novel therapeutic tools against neurodegenerative diseases. Pharmacological Research. 2016 doi: 10.1016/j.phrs.2016.02.002.
    1. de Jong O. G., van Balkom B. W. M., Schiffelers R. M., Bouten C. V. C., Verhaar M. C. Extracellular vesicles: potential roles in regenerative medicine. Frontiers in Immunology. 2014;5, article 608 doi: 10.3389/fimmu.2014.00608.
    1. Natasha G., Gundogan B., Tan A., et al. Exosomes as immunotheranostic nanoparticles. Clinical Therapeutics. 2014;36(6):820–829. doi: 10.1016/j.c11nthera.2014.04.019.
    1. Biancone L., Bruno S., Deregibus M. C., Tetta C., Camussi G. Therapeutic potential of mesenchymal stem cell-derived microvesicles. Nephrology Dialysis Transplantation. 2012;27(8):3037–3042. doi: 10.1093/ndt/gfs168.
    1. Yao K., Ricardo S. D. Mesenchymal stem cells as novel micro-ribonucleic acid delivery vehicles in kidney disease. Nephrology. 2016;21(5):363–371. doi: 10.1111/nep.12643.
    1. Gallina C., Turinetto V., Giachino C. A new paradigm in cardiac regeneration: the mesenchymal stem cell secretome. Stem Cells International. 2015;2015:10. doi: 10.1155/2015/765846.765846
    1. Lener T., Gimona M., Aigner L., et al. Applying extracellular vesicles based therapeutics in clinical trials—an ISEV position paper. Journal of Extracellular Vesicles. 2015;4 doi: 10.3402/jev.v4.30087.30087
    1. Fuster-Matanzo A., Gessler F., Leonardi T., Iraci N., Pluchino S. Acellular approaches for regenerative medicine: On the verge of clinical trials with extracellular membrane vesicles? Extracellular vesicles and regenerative medicine. Stem Cell Research and Therapy. 2015;6(1, article 227) doi: 10.1186/s13287-015-0232-9.
    1. Jung K. O., Youn H., Kim M. J., et al. In vivo PET imaging of radiolabeled exosomes from breast cancer cells. Journal of Nuclear Medicine. 2015;56:p. 11.
    1. Varga Z., Gyurkó I., Pálóczi K., et al. Radiolabeling of extracellular vesicles with (99m)Tc for quantitative in vivo imaging studies. Cancer Biother Radiopharm. 2016;31(5):168–173. doi: 10.1089/cbr.2016.2009.
    1. Hwang D. W., Choi H., Jang S. C., et al. Noninvasive imaging of radiolabeled exosome-mimetic nanovesicle using 99m Tc-HMPAO. Scientific Reports. 2015;5, article 15636 doi: 10.1038/srep15636.
    1. Morishita M., Takahashi Y., Nishikawa M., et al. Quantitative analysis of tissue distribution of the B16BL6-derived exosomes using a streptavidin-lactadherin fusion protein and Iodine-125-labeled biotin derivative after intravenous injection in mice. Journal of Pharmaceutical Sciences. 2015;104(2):705–713. doi: 10.1002/jps.24251.
    1. Hu L., Wickline S. A., Hood J. L. Magnetic resonance imaging of melanoma exosomes in lymph nodes. Magnetic Resonance in Medicine. 2015;74(1):266–271. doi: 10.1002/mrm.25376.
    1. Sun D., Zhuang X., Xiang X., et al. A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Molecular Therapy. 2010;18(9):1606–1614. doi: 10.1038/mt.2010.105.
    1. Wiklander O. P., Nordin J. Z., O'Loughlin A., et al. Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. Journal of Extracellular Vesicles. 2015;4 doi: 10.3402/jev.v4.26316.26316
    1. Grange C., Tapparo M., Bruno S., et al. Biodistribution of mesenchymal stem cell-derived extracellular vesicles in a model of acute kidney injury monitored by optical imaging. International Journal of Molecular Medicine. 2014;33(5):1055–1063. doi: 10.3892/ijmm.2014.1663.
    1. Ohno S.-I., Takanashi M., Sudo K., et al. Systemically injected exosomes targeted to EGFR deliver antitumor microrna to breast cancer cells. Molecular Therapy. 2013;21(1):185–191. doi: 10.1038/mt.2012.180.
    1. Smyth T., Kullberg M., Malik N., Smith-Jones P., Graner M. W., Anchordoquy T. J. Biodistribution and delivery efficiency of unmodified tumor-derived exosomes. Journal of Controlled Release. 2015;199:145–155. doi: 10.1016/j.jconrel.2014.12.013.
    1. Takahashi Y., Nishikawa M., Shinotsuka H., et al. Visualization and in vivo tracking of the exosomes of murine melanoma B16-BL6 cells in mice after intravenous injection. Journal of Biotechnology. 2013;165(2):77–84. doi: 10.1016/j.jbiotec.2013.03.013.
    1. Imai T., Takahashi Y., Nishikawa M., et al. Macrophage-dependent clearance of systemically administered B16BL6-derived exosomes from the blood circulation in mice. Journal of Extracellular Vesicles. 2015;4, article 26238 doi: 10.3402/jev.v4.26238.
    1. Lai C. P., Mardini O., Ericsson M., et al. Dynamic biodistribution of extracellular vesicles in vivo using a multimodal imaging reporter. ACS Nano. 2014;8(1):483–494. doi: 10.1021/nn404945r.
    1. Suetsugu A., Honma K., Saji S., Moriwaki H., Ochiya T., Hoffman R. M. Imaging exosome transfer from breast cancer cells to stroma at metastatic sites in orthotopic nude-mouse models. Advanced Drug Delivery Reviews. 2013;65(3):383–390. doi: 10.1016/j.addr.2012.08.007.
    1. Zomer A., Maynard C., Verweij F. J., et al. In vivo imaging reveals extracellular vesicle-mediated phenocopying of metastatic behavior. Cell. 2015;161(5):1046–1057. doi: 10.1016/j.cell.2015.04.042.
    1. Lai C. P., Kim E. Y., Badr C. E., et al. Visualization and tracking of tumour extracellular vesicle delivery and RNA translation using multiplexed reporters. Nature Communications. 2015;6, article 7029 doi: 10.1038/ncomms8029.
    1. Zeelenberg I. S., Ostrowski M., Krumeich S., et al. Targeting tumor antigens to secreted membrane vesicles in vivo induces efficient antitumor immune responses. Cancer Research. 2008;68(4):1228–1235. doi: 10.1158/0008-5472.CAN-07-3163.
    1. Hartman Z. C., Wei J., Glass O. K., et al. Increasing vaccine potency through exosome antigen targeting. Vaccine. 2011;29(50):9361–9367. doi: 10.1016/j.vaccine.2011.09.133.
    1. Alvarez-Erviti L., Seow Y., Yin H., Betts C., Lakhal S., Wood M. J. A. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nature Biotechnology. 2011;29(4):341–345. doi: 10.1038/nbt.1807.
    1. Liu Y., Li D., Liu Z., et al. Targeted exosome-mediated delivery of opioid receptor Mu siRNA for the treatment of morphine relapse. Scientific Reports. 2015;5 doi: 10.1038/srep17543.17543
    1. Cooper J. M., Wiklander P. B. O., Nordin J. Z., et al. Systemic exosomal siRNA delivery reduced alpha-synuclein aggregates in brains of transgenic mice. Movement Disorders. 2014;29(12):1476–1485. doi: 10.1002/mds.25978.
    1. Ruiss R., Jochum S., Mocikat R., Hammerschmidt W., Zeidler R. EBV-gp350 confers B-cell tropism to tailored exosomes and is a neo-antigen in normal and malignant B cells—a new option for the treatment of B-CLL. PLoS ONE. 2011;6(10) doi: 10.1371/journal.pone.0025294.e25294
    1. Tian Y., Li S., Song J., et al. A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. Biomaterials. 2014;35(7):2383–2390. doi: 10.1016/j.biomaterials.2013.11.083.
    1. Silva A. K. A., Luciani N., Gazeau F., et al. Combining magnetic nanoparticles with cell derived microvesicles for drug loading and targeting. Nanomedicine: Nanotechnology, Biology, and Medicine. 2015;11(3):645–655. doi: 10.1016/j.nano.2014.11.009.
    1. Kooijmans S. A., Aleza C. G., Roffler S. R., van Solinge W. W., Vader P., Schiffelers R. M. Display of GPI-anchored anti-EGFR nanobodies on extracellular vesicles promotes tumour cell targeting. Journal of Extracellular Vesicles. 2016;5(0) doi: 10.3402/jev.v5.31053.
    1. Kooijmans S. A. A., Fliervoet L. A. L., Van Der Meel R., et al. PEGylated and targeted extracellular vesicles display enhanced cell specificity and circulation time. Journal of Controlled Release. 2016;224:77–85. doi: 10.1016/j.jconrel.2016.01.009.
    1. Koppers-Lalic D., Hogenboom M. M., Middeldorp J. M., Pegtel D. M. Virus-modified exosomes for targeted RNA delivery; A new approach in nanomedicine. Advanced Drug Delivery Reviews. 2013;65(3):348–356. doi: 10.1016/j.addr.2012.07.006.
    1. Sato Y. T., Umezaki K., Sawada S., et al. Engineering hybrid exosomes by membrane fusion with liposomes. Scientific Reports. 2016;6, article 21933 doi: 10.1038/srep21933.
    1. Lee J., Lee H., Goh U., et al. Cellular engineering with membrane fusogenic liposomes to produce functionalized extracellular vesicles. ACS Applied Materials & Interfaces. 2016;8(11):6790–6795. doi: 10.1021/acsami.6b01315.
    1. Wang M., Altinoglu S., Takeda Y. S., Xu Q. Integrating protein engineering and bioorthogonal click conjugation for extracellular vesicle modulation and intracellular delivery. PLoS ONE. 2015;10(11, article e0141860) doi: 10.1371/journal.pone.0141860.
    1. Smyth T., Petrova K., Payton N. M., et al. Surface functionalization of exosomes using click chemistry. Bioconjugate Chemistry. 2014;25(10):1777–1784. doi: 10.1021/bc500291r.
    1. Jiang Y., Jahagirdar B. N., Reinhardt R. L., et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature. 2002;418(6893):41–49. doi: 10.1038/nature00870.
    1. Trivisonno A., Abecassis M., Monti M., Toietta G., Bachir A. Adipose tissue: from energy reservoir to a source of cells for epithelial tissue engineering. In: Shiffman M. A., Di Giuseppe A., Bassetto F., editors. Stem Cells in Aesthetic Procedures. Berlin, Germany: Springer; 2014. pp. 303–326.
    1. Haynesworth S. E., Baber M. A., Caplan A. I. Cytokine expression by human marrow-derived mesenchymal progenitor cells in vitro: effects of dexamethasone and IL-1α . Journal of Cellular Physiology. 1996;166(3):585–592. doi: 10.1002/(sici)1097-4652(199603)166:338;lt;585::aid-jcp13>;2-6.
    1. Camussi G., Deregibus M. C., Cantaluppi V. Role of stem-cell-derived microvesicles in the paracrine action of stem cells. Biochemical Society Transactions. 2013;41(1):283–287. doi: 10.1042/BST20120192.
    1. Johnstone R. M., Adam M., Hammond J. R., Orr L., Turbide C. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes) Journal of Biological Chemistry. 1987;262(19):9412–9420.
    1. Bruno S., Grange C., Deregibus M. C., et al. Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. Journal of the American Society of Nephrology. 2009;20(5):1053–1067. doi: 10.1681/asn.2008070798.
    1. Li T., Yan Y., Wang B., et al. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis. Stem Cells and Development. 2013;22(6):845–854. doi: 10.1089/scd.2012.0395.
    1. Lai R. C., Arslan F., Lee M. M., et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Research. 2010;4(3):214–222. doi: 10.1016/j.scr.2009.12.003.
    1. Marote A., Teixeira F. G., Mendes-Pinheiro B., Salgado A. J. MSCs-derived exosomes: cell-secreted nanovesicles with regenerative potential. Frontiers in Pharmacology. 2016;7, article 231 doi: 10.3389/fphar.2016.00231.
    1. Tetta C., Bruno S., Fonsato V., Deregibus M. C., Camussi G. The role of microvesicles in tissue repair. Organogenesis. 2011;7(2):105–115. doi: 10.4161/org.7.2.15782.
    1. Stephen J., Bravo E. L., Colligan D., Fraser A. R., Petrik J., Campbell J. D. M. Mesenchymal stromal cells as multifunctional cellular therapeutics—a potential role for extracellular vesicles. Transfusion and Apheresis Science. 2016;55(1):62–69. doi: 10.1016/j.transci.2016.07.011.
    1. Rani S., Ryan A. E., Griffin M. D., Ritter T. Mesenchymal stem cell-derived extracellular vesicles: toward cell-free therapeutic applications. Molecular Therapy. 2015;23(5):812–823. doi: 10.1038/mt.2015.44.
    1. Chen T. S., Arslan F., Yin Y., et al. Enabling a robust scalable manufacturing process for therapeutic exosomes through oncogenic immortalization of human ESC-derived MSCs. Journal of Translational Medicine. 2011;9, article 47 doi: 10.1186/1479-5876-9-47.
    1. Yeo R. W. Y., Lai R. C., Zhang B., et al. Mesenchymal stem cell: an efficient mass producer of exosomes for drug delivery. Advanced Drug Delivery Reviews. 2013;65(3):336–341. doi: 10.1016/j.addr.2012.07.001.
    1. Rana S., Yue S., Stadel D., Zöller M. Toward tailored exosomes: the exosomal tetraspanin web contributes to target cell selection. International Journal of Biochemistry and Cell Biology. 2012;44(9):1574–1584. doi: 10.1016/j.biocel.2012.06.018.
    1. Sokolova V., Ludwig A.-K., Hornung S., et al. Characterisation of exosomes derived from human cells by nanoparticle tracking analysis and scanning electron microscopy. Colloids and Surfaces B: Biointerfaces. 2011;87(1):146–150. doi: 10.1016/j.colsurfb.2011.05.013.
    1. Akyurekli C., Le Y., Richardson R. B., Fergusson D., Tay J., Allan D. S. A systematic review of preclinical studies on the therapeutic potential of mesenchymal stromal cell-derived microvesicles. Stem Cell Reviews and Reports. 2015;11(1):150–160. doi: 10.1007/s12015-014-9545-9.
    1. Choi H., Lee D. S. Illuminating the physiology of extracellular vesicles. Stem Cell Research & Therapy. 2016;7, article 55 doi: 10.1186/s13287-016-0316-1.
    1. Ullal A. J., Pisetsky D. S., Reich C. F., III Use of SYTO 13, a fluorescent dye binding nucleic acids, for the detection of microparticles in in vitro systems. Cytometry Part A. 2010;77(3):294–301. doi: 10.1002/cyto.a.20833.
    1. Tian T., Wang Y., Wang H., Zhu Z., Xiao Z. Visualizing of the cellular uptake and intracellular trafficking of exosomes by live-cell microscopy. Journal of Cellular Biochemistry. 2010;111(2):488–496. doi: 10.1002/jcb.22733.
    1. Laulagnier K., Vincent-Schneider H., Hamdi S., Subra C., Lankar D., Record M. Characterization of exosome subpopulations from RBL-2H3 cells using fluorescent lipids. Blood Cells, Molecules, and Diseases. 2005;35(2):116–121. doi: 10.1016/j.bcmd.2005.05.010.
    1. van der Vlist E. J., Nolte-'t Hoen E. N. M., Stoorvogel W., Arkesteijn G. J. A., Wauben M. H. M. Fluorescent labeling of nano-sized vesicles released by cells and subsequent quantitative and qualitative analysis by high-resolution flow cytometry. Nature Protocols. 2012;7(7):1311–1326. doi: 10.1038/nprot.2012.065.
    1. Bala S., Csak T., Momen-Heravi F., et al. Biodistribution and function of extracellular miRNA-155 in mice. Scientific Reports. 2015;5, article 10721 doi: 10.1038/srep10721.
    1. Shcherbo D., Merzlyak E. M., Chepurnykh T. V., et al. Bright far-red fluorescent protein for whole-body imaging. Nature Methods. 2007;4(9):741–746. doi: 10.1038/nmeth1083.
    1. Kim J. E., Kalimuthu S., Ahn B.-C. In vivo cell tracking with bioluminescence imaging. Nuclear Medicine and Molecular Imaging. 2015;49(1):3–10. doi: 10.1007/s13139-014-0309-x.
    1. Di Rocco G., Gentile A., Antonini A., et al. Analysis of biodistribution and engraftment into the liver of genetically modified mesenchymal stromal cells derived from adipose tissue. Cell Transplantation. 2012;21(9):1997–2008. doi: 10.3727/096368911x637452.
    1. Lai R. C., Tan S. S., Yeo R. W., et al. MSC secretes at least 3 EV types each with a unique permutation of membrane lipid, protein and RNA. Journal of Extracellular Vesicles. 2016;5 doi: 10.3402/jev.v5.29828.29828
    1. van der Meel R., Fens M. H. A. M., Vader P., Van Solinge W. W., Eniola-Adefeso O., Schiffelers R. M. Extracellular vesicles as drug delivery systems: lessons from the liposome field. Journal of Controlled Release. 2014;195:72–85. doi: 10.1016/j.jconrel.2014.07.049.
    1. Linares R., Tan S., Gounou C., Arraud N., Brisson A. R. High-speed centrifugation induces aggregation of extracellular vesicles. Journal of Extracellular Vesicles. 2015;4, article 29509 doi: 10.3402/jev.v4.29509.
    1. György B., Módos K., Pállinger É., et al. Detection and isolation of cell-derived microparticles are compromised by protein complexes resulting from shared biophysical parameters. Blood. 2011;117(4):e39–e48. doi: 10.1182/blood-2010-09-307595.
    1. Moreno-Gonzalo O., Villarroya-Beltri C., Sánchez-Madrid F. Post-translational modifications of exosomal proteins. Frontiers in Immunology. 2014;5, article 383 doi: 10.3389/fimmu.2014.00383.
    1. Mulcahy L. A., Pink R. C., Carter D. R. Routes and mechanisms of extracellular vesicle uptake. Journal of Extracellular Vesicles. 2014;3 doi: 10.3402/jev.v3.24641.24641
    1. Feng D., Zhao W.-L., Ye Y.-Y., et al. Cellular internalization of exosomes occurs through phagocytosis. Traffic. 2010;11(5):675–687. doi: 10.1111/j.1600-0854.2010.01041.x.
    1. Ha D., Yang N., Nadithe V. Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: current perspectives and future challenges. Acta Pharmaceutica Sinica B. 2016;6(4):287–296. doi: 10.1016/j.apsb.2016.02.001.
    1. Hajrasouliha A. R., Jiang G., Lu Q., et al. Exosomes from retinal astrocytes contain antiangiogenic components that inhibit laser-induced choroidal neovascularization. Journal of Biological Chemistry. 2013;288(39):28058–28067. doi: 10.1074/jbc.M113.470765.
    1. van Dongen H. M., Masoumi N., Witwer K. W., Pegtel D. M. Extracellular vesicles exploit viral entry routes for cargo delivery. Microbiology and Molecular Biology Reviews. 2016;80(2):369–386. doi: 10.1128/mmbr.00063-15.
    1. Kotmakçı M., Çetintaş V. B. Extracellular vesicles as natural nanosized delivery systems for small-molecule drugs and genetic material: steps towards the future nanomedicines. Journal of Pharmacy and Pharmaceutical Sciences. 2015;18(3):396–413. doi: 10.18433/j36w3x.
    1. EL Andaloussi S., Lakhal S., Mäger I., Wood M. J. A. Exosomes for targeted siRNA delivery across biological barriers. Advanced Drug Delivery Reviews. 2013;65(3):391–397. doi: 10.1016/j.addr.2012.08.008.
    1. Kooijmans S. A., Schiffelers R. M., Zarovni N., Vago R. Modulation of tissue tropism and biological activity of exosomes and other extracellular vesicles: new nanotools for cancer treatment. Pharmacological Research. 2016;111:487–500. doi: 10.1016/j.phrs.2016.07.006.
    1. Hung M. E., Leonard J. N. Stabilization of exosome-targeting peptides via engineered glycosylation. The Journal of Biological Chemistry. 2015;290(13):8166–8172. doi: 10.1074/jbc.m114.621383.
    1. Garay R. P., El-Gewely R., Armstrong J. K., Garratty G., Richette P. Antibodies against polyethylene glycol in healthy subjects and in patients treated with PEG-conjugated agents. Expert Opinion on Drug Delivery. 2012;9(11):1319–1323. doi: 10.1517/17425247.2012.720969.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe