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Exosomes are extracellular vesicles (EVs) that are produced in the endosomal compartment of most eukaryotic cells.[1][2][3] The multivesicular body (MVB) is an endosome defined by intraluminal vesicles (ILVs) that bud inward into the endosomal lumen. If the MVB fuses with the cell surface (the plasma membrane), these ILVs are released as exosomes. In multicellular organisms, exosomes and other EVs are present in tissues and can also be found in biological fluids including blood, urine, and cerebrospinal fluid. They are also released in vitro by cultured cells into the culture-conditioned medium.[4][5][6] Since the size of exosomes is limited by that of the parent MVB, exosomes are generally thought to be smaller than most other EVs, from about 30 to several hundred nm in diameter: around the same size as many lipoproteins but much smaller than cells.[4] EVs including exosomes carry markers of cells of origin and have specialized functions in physiological processes, from coagulation and intercellular signalling to waste management.[4] Consequently, there is a growing interest in clinical applications as biomarkers and therapies alike.[7] Compared with EVs in general, it is unclear whether exosomes have unique characteristics or functions or can be distinguished effectively from other vesicles.[1]

Contents

BackgroundEdit

First discovered in the maturing mammalian reticulocyte (immature red blood cell),[8] exosomes were shown to participate in selective removal of many plasma membrane proteins[9] as the reticulocyte becomes a mature red blood cell (erythrocyte). In the reticulocyte, as in most mammalian cells, portions of the plasma membrane are regularly internalized as endosomes, with 50 to 180% of the plasma membrane being recycled every hour.[10] In turn, parts of the membranes of some endosomes are subsequently internalized as smaller vesicles. Such endosomes are called multivesicular bodies because of their appearance, with many small vesicles, (ILVs or "intralumenal endosomal vesicles"), inside the larger body. The ILVs become exosomes if the MVB merges with the cell membrane, releasing the internal vesicles into the extracellular space.[11]

Exosomes contain various molecular constituents of their cell of origin, including proteins and RNA. Although the exosomal protein composition varies with the cell and tissue of origin, most exosomes contain an evolutionarily-conserved common set of protein molecules. The protein content of a single exosome, given certain assumptions of protein size and configuration, and packing parameters, can be about 20,000 molecules.[12] The cargo of mRNA and miRNA in exosomes was first discovered at the University of Gothenburg in Sweden.[13] In that study, the differences in cellular and exosomal mRNA and miRNA content was described, as well as the functionality of the exosomal mRNA cargo. Exosomes have also been shown to carry double-stranded DNA.[14]

Exosomes can transfer molecules from one cell to another via membrane vesicle trafficking, thereby influencing the immune system, such as dendritic cells and B cells, and may play a functional role in mediating adaptive immune responses to pathogens and tumors.[15][16] Therefore, scientists that are actively researching the role that exosomes may play in cell-to-cell signaling, often hypothesize that delivery of their cargo RNA molecules can explain biological effects. For example, mRNA in exosomes has been suggested to affect protein production in the recipient cell.[13][17][18] However, another study has suggested that miRNAs in exosomes secreted by mesenchymal stem cells (MSC) are predominantly pre- and not mature miRNAs.[19] Because the authors of this study did not find RNA-induced silencing complex-associated proteins in these exosomes, they suggested that only the pre-miRNAs but not the mature miRNAs in MSC exosomes have the potential to be biologically active in the recipient cells. Multiple mechanisms have been reported to be involved in loading miRNAs into exosomes, including specific motifs in the miRNA sequences, interactions with lncRNAs localized to the exosomes, interactions with RBPs, and post-translational modifications of Ago[20].

Conversely, exosome production and content may be influenced by molecular signals received by the cell of origin. As evidence for this hypothesis, tumor cells exposed to hypoxia secrete exosomes with enhanced angiogenic and metastatic potential, suggesting that tumor cells adapt to a hypoxic microenvironment by secreting exosomes to stimulate angiogenesis or facilitate metastasis to more favorable environment.[21]

TerminologyEdit

Evolving consensus in the field is that the term "exosome" should be strictly applied to an EV of endosomal origin. Since it can be difficult to prove such an origin after an EV has left the cell, variations on the term "extracellular vesicle" are often appropriate instead.[1]

ResearchEdit

Exosomes from red blood cells contain the transferrin receptor which is absent in mature erythrocytes. Dendritic cell-derived exosomes express MHC I, MHC II, and costimulatory molecules and have been proven to be able to induce and enhance antigen-specific T cell responses in vivo. In addition, the first exosome-based cancer vaccination platforms are being explored in early clinical trials.[22] Exosomes can also be released into urine by the kidneys, and their detection might serve as a diagnostic tool.[23][24][25] Urinary exosomes may be useful as treatment response markers in prostate cancer.[26][27] Exosomes secreted from tumour cells can deliver signals to surrounding cells and have been shown to regulate myofibroblast differentiation.[28] In melanoma, tumor-derived vesicles can enter lymphatics and interact with subcapsular sinus macrophages and B cells in lymph nodes.[29] A recent investigation showed that exosome release positively correlates with the invasiveness of ovarian cancer.[30] Exosomes released from tumors into the blood may also have diagnostic potential. Exosomes are remarkably stable in bodily fluids strengthening their utility as reservoirs for disease biomarkers.[31][32] Patient blood samples stored in biorepositories can be used for biomarker analysis as colorectal cancer cell-derived exosomes spiked into blood plasma could be recovered after 90 days of storage at various temperatures.[33]

In malignancies such as cancer, the regulatory circuit which guards exosome homeostasis is co-opted to promote cancer cell survival and metastasis.[34][18]

Urinary exosomes have also proven to be useful in the detection of many pathologies, such as genitourinary cancers and mineralocorticoid hypertension, through their protein and miRNA cargo."[35] [36]

With neurodegenerative disorders, exosomes appear to play a role in the spread of alpha-synuclein, and are being actively investigated as a tool to both monitor disease progression as well as a potential vehicle for delivery of drug and stem cell based therapy.[37]

An online open access database containing genomic information for exosome content has been developed to catalyze research development within the field.[37]

Exosomes and intercellular communicationEdit

Scientists are actively researching the role that exosomes may play in cell-to-cell signaling, hypothesizing that because exosomes can merge with and release their contents into cells that are distant from their cell of origin (see membrane vesicle trafficking), they may influence processes in the recipient cell [38]. For example, RNA that is shuttled from one cell to another, known as "exosomal shuttle RNA," could potentially affect protein production in the recipient cell.[17][39] By transferring molecules from one cell to another, exosomes from certain cells of the immune system, such as dendritic cells and B cells, may play a functional role in mediating adaptive immune responses to pathogens and tumors.[15][29]

Conversely, exosome production and content may be influenced by molecular signals received by the cell of origin. As evidence for this hypothesis, tumor cells exposed to hypoxia secrete exosomes with enhanced angiogenic and metastatic potential, suggesting that tumor cells adapt to a hypoxic microenvironment by secreting exosomes to stimulate angiogenesis or facilitate metastasis to more favorable environment.[21] It has recently been shown that exosomal protein content may change during the progression of chronic lymphocytic leukemia.[40]

A study hypothesized that intercellular communication of tumor exosomes could mediate further regions of metastasis for cancer. Hypothetically, exosomes can plant tumor information, such as tainted RNA, into new cells to prepare for cancer to travel to that organ for metastasis. The study found that tumor exosomal communication has the ability to mediate metastasis to different organs. Furthermore, even when tumor cells have a disadvantage for replicating, the information planted at these new regions, organs, can aid in the expansion of organ specific metastasis.[41]

Exosomes carry cargo, which can augment innate immune responses. For example, exosomes derived from Salmonella enterica-infected macrophages but not exosomes from uninfected cells stimulate naive macrophages and dendritic cells to secrete pro-inflammatory cytokines such as TNF-α, RANTES, IL-1ra, MIP-2, CXCL1, MCP-1, sICAM-1, GM-CSF, and G-CSF. Proinflammatory effects of exosomes are partially attributed to lipopolysaccharide, which is encapsulated within exosomes[42].

IsolationEdit

The isolation and detection of exosomes has proven to be complicated.[4][43] Due to the complexity of body fluids, physical separation of exosomes from cells and similar-sized particles is challenging. Isolation of exosomes using differential ultracentrifugation results in co-isolation of protein and other contaminants and incomplete separation of vesicles from lipoproteins. Combining ultracentrifugation with micro-filtration or a gradient can improve purity.[44][45] Single step isolation of extracellular vesicles by size-exclusion chromatography has been demonstrated to provide greater efficiency for recovering intact vesicles over centrifugation,[46] although a size-based technique alone will not be able to distinguish exosomes from other vesicle types. To isolate a pure population of exosomes a combination of techniques is necessary, based on both physical (e.g. size, density) and biochemical parameters (e.g. presence/absence of certain proteins involved in their biogenesis).

Often, functional as well as antigenic assays are applied to derive useful information from multiple exosomes. Well-known examples of assays to detect proteins in total populations of exosomes are mass spectrometry and Western blot. However, a limitation of these methods is that contaminants may be present that affect the information obtained from such assays. Preferably, information is derived from single exosomes. Relevant properties of exosomes to detect include size, density, morphology, composition, and zeta potential.[47]

DetectionEdit

Since the diameter of exosomes is typically below 100 nm and because they have a low refractive index, exosomes are below the detection range of many currently used techniques. A number of miniaturized systems, exploiting nanotechnology and microfluidics, have been developed to expedite exosome analyses. These new systems include a microNMR device,[48] a nanoplasmonic chip,[49] and an magneto-electrochemical sensor[50] for protein profiling; and an integrated fluidic cartridge for RNA detection.[51] Flow cytometry is an optical method to detect exosomes in suspension. Nevertheless, the applicability of flow cytometry to detect single exosomes is still inadequate due to limited sensitivity and potential measurement artifacts such as swarm detection.[52] Other methods to detect single exosomes are atomic force microscopy,[53] nanoparticle tracking analysis,[54] Raman microspectroscopy,[55] tunable resistive pulse sensing, and transmission electron microscopy.[52]

Bioinformatics analysisEdit

Exosomes contain RNA, proteins, lipids and metabolites that is reflective of the cell type of origin. As exosomes contain numerous proteins, RNA and lipids, large scale analysis including proteomics and transcriptomics is often performed. Currently, to analyse these data, non-commercial tools such as FunRich[56] can be used to identify over-represented groups of molecules. With the advent of Next generation sequencing technologies, the research on exosomes have been accelerated in not only cancer but various diseases. Recently, bioinformatics based analysis of RNA-Seq data of exosomes extracted from Trypanosoma cruzi has showed the association of these extracellular vesicles with various important gene products that strengthens the probability of finding biomarkers for Chagas disease.[57][58]

Therapeutics and carriers of drugsEdit

Increasingly, exosomes are being recognized as potential therapeutics as they have the ability to elicit potent cellular responses in vitro and in vivo.[59][60][61] Exosomes mediate regenerative outcomes in injury and disease that recapitulate observed bioactivity of stem cell populations.[62] Mesenchymal stem cell exosomes were found to activate several signaling pathways important in wound healing (Akt, ERK, and STAT3) and bone fracture repair.[63][64] They induce the expression of a number of growth factors (hepatocyte growth factor (HGF), insulin-like growth factor-1 (IGF1), nerve growth factor (NGF), and stromal-derived growth factor-1 (SDF1)).[65] Exosomes secreted by human circulating fibrocytes, a population of mesenchymal progenitors involved in normal wound healing via paracrine signaling, exhibited in-vitro proangiogenic properties, activated diabetic dermal fibroblasts, induced the migration and proliferation of diabetic keratinocytes, and accelerated wound closure in diabetic mice in vivo. Important components of the exosomal cargo were heat shock protein-90α, total and activated signal transducer and activator of transcription 3, proangiogenic (miR-126, miR-130a, miR-132) and anti-inflammatory (miR124a, miR-125b) microRNAs, and a microRNA regulating collagen deposition (miR-21).[66] Researchers have also found that exosomes released from oral keratinocytes can accelerate wound healing, even when human exosomes were applied to rat wounds.[67] Exosomes can be considered a promising carrier for effective delivery of small interfering RNA due to their existence in body’s endogenous system and high tolerance.[68][69] Patient-derived exosomes have been employed as a novel cancer immunotherapy in several clinical trials.[70]

Exosomes offer distinct advantages that uniquely position them as highly effective drug carriers. Composed of cellular membranes with multiple adhesive proteins on their surface, exosomes are known to specialize in cell–cell communications and provide an exclusive approach for the delivery of various therapeutic agents to target cells.[71] For example, researchers used exosomes as a vehicle for the delivery of cancer drug paclitaxel. They placed the drug inside exosomes derived from white blood cells, which were then injected into mice with drug-resistant lung cancer. Importantly, incorporation of paclitaxel into exosomes increased cytotoxicity more than 50 times as a result of nearly complete co-localization of airway-delivered exosomes with lung cancer cells.[72]

See alsoEdit

ReferencesEdit

  1. ^ a b c Théry C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, et al. (2018). "Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines". Journal of Extracellular Vesicles. 7 (1): 1535750. doi:10.1080/20013078.2018.1535750. PMC 6322352. PMID 30637094.
  2. ^ Yáñez-Mó M, Siljander PR, Andreu Z, Zavec AB, Borràs FE, Buzas EI, Buzas K, et al. (2015). "Biological properties of extracellular vesicles and their physiological functions". Journal of Extracellular Vesicles. 4: 27066. doi:10.3402/jev.v4.27066. PMC 4433489. PMID 25979354.
  3. ^ van Niel G, D'Angelo G, Raposo G (April 2018). "Shedding light on the cell biology of extracellular vesicles". Nature Reviews. Molecular Cell Biology. 19 (4): 213–228. doi:10.1038/nrm.2017.125. PMID 29339798.
  4. ^ a b c d van der Pol E, Böing AN, Harrison P, Sturk A, Nieuwland R (July 2012). "Classification, functions, and clinical relevance of extracellular vesicles". Pharmacological Reviews. 64 (3): 676–705. doi:10.1124/pr.112.005983. PMID 22722893.
  5. ^ Keller S, Sanderson MP, Stoeck A, Altevogt P (November 2006). "Exosomes: from biogenesis and secretion to biological function". Immunology Letters. 107 (2): 102–8. doi:10.1016/j.imlet.2006.09.005. PMID 17067686.
  6. ^ Spaull R, McPherson B, Gialeli A, Clayton A, Uney J, Heep A, Cordero-Llana Ó (April 2019). "Exosomes populate the cerebrospinal fluid of preterm infants with post-haemorrhagic hydrocephalus". International Journal of Developmental Neuroscience. 73: 59–65. doi:10.1016/j.ijdevneu.2019.01.004. PMID 30639393.
  7. ^ Dhondt B, Van Deun J, Vermaerke S, de Marco A, Lumen N, De Wever O, Hendrix A (June 2018). "Urinary extracellular vesicle biomarkers in urological cancers: From discovery towards clinical implementation". The International Journal of Biochemistry & Cell Biology. 99: 236–256. doi:10.1016/j.biocel.2018.04.009. PMID 29654900.
  8. ^ Johnstone RM, Adam M, Hammond JR, Orr L, Turbide C (July 1987). "Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes)". The Journal of Biological Chemistry. 262 (19): 9412–20. PMID 3597417.
  9. ^ van Niel G, Porto-Carreiro I, Simoes S, Raposo G (July 2006). "Exosomes: a common pathway for a specialized function". Journal of Biochemistry. 140 (1): 13–21. doi:10.1093/jb/mvj128. PMID 16877764.
  10. ^ Huotari J, Helenius A (August 2011). "Endosome maturation". The EMBO Journal. 30 (17): 3481–500. doi:10.1038/emboj.2011.286. PMC 3181477. PMID 21878991.
  11. ^ Gruenberg J, van der Goot FG (July 2006). "Mechanisms of pathogen entry through the endosomal compartments". Nature Reviews. Molecular Cell Biology. 7 (7): 495–504. doi:10.1038/nrm1959. PMID 16773132.
  12. ^ Maguire, Greg (2016) Exosomes: smart nanospheres for drug delivery naturally produced by stem cells. In: Fabrication and Self Assembly of Nanobiomaterials. Elsevier pp. 179-209.
  13. ^ a b Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO (June 2007). "Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells". Nature Cell Biology. 9 (6): 654–9. doi:10.1038/ncb1596. PMID 17486113.
  14. ^ Thakur BK, Zhang H, Becker A, Matei I, Huang Y, Costa-Silva B, Zheng Y, Hoshino A, Brazier H, Xiang J, Williams C, Rodriguez-Barrueco R, Silva JM, Zhang W, Hearn S, Elemento O, Paknejad N, Manova-Todorova K, Welte K, Bromberg J, Peinado H, Lyden D (June 2014). "Double-stranded DNA in exosomes: a novel biomarker in cancer detection". Cell Research. 24 (6): 766–9. doi:10.1038/cr.2014.44. PMC 4042169. PMID 24710597.
  15. ^ a b Li XB, Zhang ZR, Schluesener HJ, Xu SQ (2006). "Role of exosomes in immune regulation". Journal of Cellular and Molecular Medicine. 10 (2): 364–75. doi:10.1111/j.1582-4934.2006.tb00405.x. PMC 3933127. PMID 16796805.
  16. ^ Hough KP, Chanda D, Duncan SR, Thannickal VJ, Deshane JS (April 2017). "Exosomes in immunoregulation of chronic lung diseases". Allergy. 72 (4): 534–544. doi:10.1111/all.13086. PMC 5462600. PMID 27859351.
  17. ^ a b Balaj L, Lessard R, Dai L, Cho YJ, Pomeroy SL, Breakefield XO, Skog J (February 2011). "Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences". Nature Communications. 2 (2): 180. Bibcode:2011NatCo...2E.180B. doi:10.1038/ncomms1180. PMC 3040683. PMID 21285958.
  18. ^ a b Oushy S, Hellwinkel JE, Wang M, Nguyen GJ, Gunaydin D, Harland TA, Anchordoquy TJ, Graner MW (January 2018). "Glioblastoma multiforme-derived extracellular vesicles drive normal astrocytes towards a tumour-enhancing phenotype". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 373 (1737): 20160477. doi:10.1098/rstb.2016.0477. PMC 5717433. PMID 29158308.
  19. ^ Chen TS, Lai RC, Lee MM, Choo AB, Lee CN, Lim SK (January 2010). "Mesenchymal stem cell secretes microparticles enriched in pre-microRNAs". Nucleic Acids Research. 38 (1): 215–24. doi:10.1093/nar/gkp857. PMC 2800221. PMID 19850715.
  20. ^ Gebert LF, MacRae IJ (January 2019). "Regulation of microRNA function in animals". Nature Reviews. Molecular Cell Biology. 20 (1): 21–37. doi:10.1038/s41580-018-0045-7. PMID 30108335.
  21. ^ a b Park JE, Tan HS, Datta A, Lai RC, Zhang H, Meng W, Lim SK, Sze SK (June 2010). "Hypoxic tumor cell modulates its microenvironment to enhance angiogenic and metastatic potential by secretion of proteins and exosomes". Molecular & Cellular Proteomics. 9 (6): 1085–99. doi:10.1074/mcp.M900381-MCP200. PMC 2877972. PMID 20124223.
  22. ^ Mignot G, Roux S, Thery C, Ségura E, Zitvogel L (2006). "Prospects for exosomes in immunotherapy of cancer". Journal of Cellular and Molecular Medicine. 10 (2): 376–88. doi:10.1111/j.1582-4934.2006.tb00406.x. PMC 3933128. PMID 16796806.
  23. ^ Pisitkun T, Shen RF, Knepper MA (September 2004). "Identification and proteomic profiling of exosomes in human urine". Proceedings of the National Academy of Sciences of the United States of America. 101 (36): 13368–73. Bibcode:2004PNAS..10113368P. doi:10.1073/pnas.0403453101. PMC 516573. PMID 15326289.
  24. ^ "Urinary Exosome Protein Database". NHLBI. 2009-05-12. Retrieved 2009-10-01.
  25. ^ Nilsson J, Skog J, Nordstrand A, Baranov V, Mincheva-Nilsson L, Breakefield XO, Widmark A (May 2009). "Prostate cancer-derived urine exosomes: a novel approach to biomarkers for prostate cancer". British Journal of Cancer. 100 (10): 1603–7. doi:10.1038/sj.bjc.6605058. PMC 2696767. PMID 19401683.
  26. ^ "Fat capsules carry markers for deadly prostate cancer". The Medical News. 2009-05-13. Retrieved 2009-10-01.
  27. ^ Mitchell PJ, Welton J, Staffurth J, Court J, Mason MD, Tabi Z, Clayton A (January 2009). "Can urinary exosomes act as treatment response markers in prostate cancer?". Journal of Translational Medicine. 7 (1): 4. doi:10.1186/1479-5876-7-4. PMC 2631476. PMID 19138409.
  28. ^ Webber J, Steadman R, Mason MD, Tabi Z, Clayton A (December 2010). "Cancer exosomes trigger fibroblast to myofibroblast differentiation". Cancer Research. 70 (23): 9621–30. doi:10.1158/0008-5472.CAN-10-1722. PMID 21098712.
  29. ^ a b Pucci F, Garris C, Lai CP, Newton A, Pfirschke C, Engblom C, Alvarez D, Sprachman M, Evavold C, Magnuson A, von Andrian UH, Glatz K, Breakefield XO, Mempel TR, Weissleder R, Pittet MJ (April 2016). "SCS macrophages suppress melanoma by restricting tumor-derived vesicle-B cell interactions". Science. 352 (6282): 242–6. Bibcode:2016Sci...352..242P. doi:10.1126/science.aaf1328. PMC 4960636. PMID 26989197.
  30. ^ Kobayashi M, Salomon C, Tapia J, Illanes SE, Mitchell MD, Rice GE (January 2014). "Ovarian cancer cell invasiveness is associated with discordant exosomal sequestration of Let-7 miRNA and miR-200". Journal of Translational Medicine. 12: 4. doi:10.1186/1479-5876-12-4. PMC 3896684. PMID 24393345.
  31. ^ Williams C, Royo F, Aizpurua-Olaizola O, Pazos R, Boons GJ, Reichardt NC, Falcon-Perez JM (2018). "Glycosylation of extracellular vesicles: current knowledge, tools and clinical perspectives". Journal of Extracellular Vesicles. 7 (1): 1442985. doi:10.1080/20013078.2018.1442985. PMC 5844028. PMID 29535851.
  32. ^ Aizpurua-Olaizola O, Toraño JS, Falcon-Perez JM, Williams C, Reichardt N, Boons GJ (2018). "Mass spectrometry for glycan biomarker discovery". TrAC Trends in Analytical Chemistry. 100: 7–14. doi:10.1016/j.trac.2017.12.015.
  33. ^ Kalra H, Adda CG, Liem M, Ang CS, Mechler A, Simpson RJ, Hulett MD, Mathivanan S (November 2013). "Comparative proteomics evaluation of plasma exosome isolation techniques and assessment of the stability of exosomes in normal human blood plasma". Proteomics. 13 (22): 3354–64. doi:10.1002/pmic.201300282. PMID 24115447.
  34. ^ Syn N, Wang L, Sethi G, Thiery JP, Goh BC (July 2016). "Exosome-Mediated Metastasis: From Epithelial-Mesenchymal Transition to Escape from Immunosurveillance". Trends in Pharmacological Sciences. 37 (7): 606–617. doi:10.1016/j.tips.2016.04.006. PMID 27157716.
  35. ^ Barros ER, Carvajal CA (2017-09-08). "Urinary Exosomes and Their Cargo: Potential Biomarkers for Mineralocorticoid Arterial Hypertension?". Frontiers in Endocrinology. 8: 230. doi:10.3389/fendo.2017.00230. PMC 5599782. PMID 28951728.
  36. ^ Dhondt B, Van Deun J, Vermaerke S, de Marco A, Lumen N, De Wever O, Hendrix A (June 2018). "Urinary extracellular vesicle biomarkers in urological cancers: From discovery towards clinical implementation". The International Journal of Biochemistry & Cell Biology. 99: 236–256. doi:10.1016/j.biocel.2018.04.009. PMID 29654900.
  37. ^ a b Tofaris GK (2017). "A Critical Assessment of Exosomes in the Pathogenesis and Stratification of Parkinson's Disease". Journal of Parkinson's Disease. 7 (4): 569–576. doi:10.3233/JPD-171176. PMC 5676982. PMID 28922170.
  38. ^ Dhondt B, Rousseau Q, De Wever O, Hendrix A (September 2016). "Function of extracellular vesicle-associated miRNAs in metastasis". Cell and Tissue Research. 365 (3): 621–41. doi:10.1007/s00441-016-2430-x. hdl:1854/LU-7250365. PMID 27289232.
  39. ^ Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO (June 2007). "Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells". Nature Cell Biology. 9 (6): 654–9. doi:10.1038/ncb1596. PMID 17486113.
  40. ^ Prieto D, Sotelo N, Seija N, Sernbo S, Abreu C, Durán R, Gil M, Sicco E, Irigoin V, Oliver C, Landoni AI, Gabus R, Dighiero G, Oppezzo P (August 2017). "S100-A9 protein in exosomes from chronic lymphocytic leukemia cells promotes NF-κB activity during disease progression". Blood. 130 (6): 777–788. doi:10.1182/blood-2017-02-769851. PMID 28596424.
  41. ^ Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, Molina H, Kohsaka S, Di Giannatale A, Ceder S, Singh S, Williams C, Soplop N, Uryu K, Pharmer L, King T, Bojmar L, Davies AE, Ararso Y, Zhang T, Zhang H, Hernandez J, Weiss JM, Dumont-Cole VD, Kramer K, Wexler LH, Narendran A, Schwartz GK, Healey JH, Sandstrom P, Labori KJ, Kure EH, Grandgenett PM, Hollingsworth MA, de Sousa M, Kaur S, Jain M, Mallya K, Batra SK, Jarnagin WR, Brady MS, Fodstad O, Muller V, Pantel K, Minn AJ, Bissell MJ, Garcia BA, Kang Y, Rajasekhar VK, Ghajar CM, Matei I, Peinado H, Bromberg J, Lyden D (November 2015). "Tumour exosome integrins determine organotropic metastasis". Nature. 527 (7578): 329–35. Bibcode:2015Natur.527..329H. doi:10.1038/nature15756. PMC 4788391. PMID 26524530.
  42. ^ Hui WW, Hercik K, Belsare S, Alugubelly N, Clapp B, Rinaldi C, Edelmann MJ (February 2018). "Salmonella enterica Serovar Typhimurium Alters the Extracellular Proteome of Macrophages and Leads to the Production of Proinflammatory Exosomes". Infection and Immunity. 86 (2): e00386–17. doi:10.1128/IAI.00386-17. PMC 5778363. PMID 29158431.
  43. ^ Thind A, Wilson C (2016). "Exosomal miRNAs as cancer biomarkers and therapeutic targets". Journal of Extracellular Vesicles. 5: 31292. doi:10.3402/jev.v5.31292. PMC 4954869. PMID 27440105.
  44. ^ Tauro BJ, Greening DW, Mathias RA, Ji H, Mathivanan S, Scott AM, Simpson RJ (February 2012). "Comparison of ultracentrifugation, density gradient separation, and immunoaffinity capture methods for isolating human colon cancer cell line LIM1863-derived exosomes". Methods. 56 (2): 293–304. doi:10.1016/j.ymeth.2012.01.002. PMID 22285593.
  45. ^ Van Deun J, Mestdagh P, Sormunen R, Cocquyt V, Vermaelen K, Vandesompele J, Bracke M, De Wever O, Hendrix A (2014). "The impact of disparate isolation methods for extracellular vesicles on downstream RNA profiling". Journal of Extracellular Vesicles. 3: 24858. doi:10.3402/jev.v3.24858. PMC 4169610. PMID 25317274.
  46. ^ Böing AN, van der Pol E, Grootemaat AE, Coumans FA, Sturk A, Nieuwland R (2014). "Single-step isolation of extracellular vesicles by size-exclusion chromatography". Journal of Extracellular Vesicles. 3: 23430. doi:10.3402/jev.v3.23430. PMC 4159761. PMID 25279113.
  47. ^ van der Pol E, Hoekstra AG, Sturk A, Otto C, van Leeuwen TG, Nieuwland R (December 2010). "Optical and non-optical methods for detection and characterization of microparticles and exosomes". Journal of Thrombosis and Haemostasis. 8 (12): 2596–607. doi:10.1111/j.1538-7836.2010.04074.x. PMID 20880256.
  48. ^ Shao H, Chung J, Balaj L, Charest A, Bigner DD, Carter BS, Hochberg FH, Breakefield XO, Weissleder R, Lee H (December 2012). "Protein typing of circulating microvesicles allows real-time monitoring of glioblastoma therapy". Nature Medicine. 18 (12): 1835–40. doi:10.1038/nm.2994. PMC 3518564. PMID 23142818.
  49. ^ Im H, Shao H, Park YI, Peterson VM, Castro CM, Weissleder R, Lee H (May 2014). "Label-free detection and molecular profiling of exosomes with a nano-plasmonic sensor". Nature Biotechnology. 32 (5): 490–5. doi:10.1038/nbt.2886. PMC 4356947. PMID 24752081.
  50. ^ Jeong S, Park J, Pathania D, Castro CM, Weissleder R, Lee H (February 2016). "Integrated Magneto-Electrochemical Sensor for Exosome Analysis". ACS Nano. 10 (2): 1802–9. doi:10.1021/acsnano.5b07584. PMC 4802494. PMID 26808216.
  51. ^ Shao H, Chung J, Lee K, Balaj L, Min C, Carter BS, Hochberg FH, Breakefield XO, Lee H, Weissleder R (May 2015). "Chip-based analysis of exosomal mRNA mediating drug resistance in glioblastoma". Nature Communications. 6: 6999. Bibcode:2015NatCo...6E6999S. doi:10.1038/ncomms7999. PMC 4430127. PMID 25959588.
  52. ^ a b van der Pol E, van Gemert MJ, Sturk A, Nieuwland R, van Leeuwen TG (May 2012). "Single vs. swarm detection of microparticles and exosomes by flow cytometry". Journal of Thrombosis and Haemostasis. 10 (5): 919–30. doi:10.1111/j.1538-7836.2012.04683.x. PMID 22394434.
  53. ^ Yuana Y, Oosterkamp TH, Bahatyrova S, Ashcroft B, Garcia Rodriguez P, Bertina RM, Osanto S (February 2010). "Atomic force microscopy: a novel approach to the detection of nanosized blood microparticles". Journal of Thrombosis and Haemostasis. 8 (2): 315–23. doi:10.1111/j.1538-7836.2009.03654.x. PMID 19840362.
  54. ^ Dragovic RA, Gardiner C, Brooks AS, Tannetta DS, Ferguson DJ, Hole P, Carr B, Redman CW, Harris AL, Dobson PJ, Harrison P, Sargent IL (December 2011). "Sizing and phenotyping of cellular vesicles using Nanoparticle Tracking Analysis". Nanomedicine. 7 (6): 780–8. doi:10.1016/j.nano.2011.04.003. PMC 3280380. PMID 21601655.
  55. ^ Tatischeff I, Larquet E, Falcón-Pérez JM, Turpin PY, Kruglik SG (2012). "Fast characterisation of cell-derived extracellular vesicles by nanoparticles tracking analysis, cryo-electron microscopy, and Raman tweezers microspectroscopy". Journal of Extracellular Vesicles. 1: 19179. doi:10.3402/jev.v1i0.19179. PMC 3760651. PMID 24009887.
  56. ^ Pathan M, Keerthikumar S, Ang CS, Gangoda L, Quek CY, Williamson NA, Mouradov D, Sieber OM, Simpson RJ, Salim A, Bacic A, Hill AF, Stroud DA, Ryan MT, Agbinya JI, Mariadason JM, Burgess AW, Mathivanan S (August 2015). "FunRich: An open access standalone functional enrichment and interaction network analysis tool". Proteomics. 15 (15): 2597–601. doi:10.1002/pmic.201400515. PMID 25921073.
  57. ^ Gaur P, Chaturvedi A (2016). "Trypanosoma cruzi: a step closer to early diagnosis of neglected Chagas disease". PeerJ. 4: e2693. doi:10.7717/peerj.2693. PMC 5126619. PMID 27904804.
  58. ^ Gaur P, Chaturvedi A (2016-11-24). "Trypanosoma cruzi: a step closer to early diagnosis of neglected Chagas disease". PeerJ. 4: e2693. doi:10.7717/peerj.2693. PMC 5126619. PMID 27904804.
  59. ^ Han C, Sun X, Liu L, Jiang H, Shen Y, Xu X, Li J, Zhang G, Huang J, Lin Z, Xiong N, Wang T (2016). "Exosomes and Their Therapeutic Potentials of Stem Cells". Stem Cells International. 2016: 7653489. doi:10.1155/2016/7653489. PMC 4684885. PMID 26770213.
  60. ^ Yeo, R. W. Y., & Lim, S. K. (2016). Exosomes and their Therapeutic Applications. In ADVANCES IN PHARMACEUTICAL CELL THERAPY: Principles of Cell-Based Biopharmaceuticals (pp. 477-501). ISBN 978-981-4616-80-5
  61. ^ Di Rocco G, Baldari S, Toietta G (2016). "In Vivo Tracking and Biodistribution Analysis". Stem Cells International. 2016: 5029619. doi:10.1155/2016/5029619. PMC 5141304. PMID 27994623.
  62. ^ Basu J, Ludlow JW (2016). "Exosomes for repair, regeneration and rejuvenation". Expert Opinion on Biological Therapy. 16 (4): 489–506. doi:10.1517/14712598.2016.1131976. PMID 26817494.
  63. ^ MSC-derived Exosomes Promote Bone Fracture Repair
  64. ^ Silva, A. M., Teixeira, J. H., Almeida, M. I., Gonçalves, R. M., Barbosa, M. A., & Santos, S. G. (2016). Extracellular vesicles: immunomodulatory messengers in the context of tissue repair/regeneration. European Journal of Pharmaceutical Sciences. doi:10.1016/j.ejps.2016.09.017
  65. ^ Shabbir A, Cox A, Rodriguez-Menocal L, Salgado M, Van Badiavas E (July 2015). "Mesenchymal Stem Cell Exosomes Induce Proliferation and Migration of Normal and Chronic Wound Fibroblasts, and Enhance Angiogenesis In Vitro". Stem Cells and Development. 24 (14): 1635–47. doi:10.1089/scd.2014.0316. PMC 4499790. PMID 25867197.
  66. ^ Geiger A, Walker A, Nissen E (November 2015). "Human fibrocyte-derived exosomes accelerate wound healing in genetically diabetic mice". Biochemical and Biophysical Research Communications. 467 (2): 303–9. doi:10.1016/j.bbrc.2015.09.166. PMID 26454169.
  67. ^ Sjöqvist S, Ishikawa T, Shimura D, Kasai Y, Imafuku A, Bou-Ghannam S, Iwata T, Kanai N (20 January 2019). "Exosomes derived from clinical-grade oral mucosal epithelial cell sheets promote wound healing". Journal of Extracellular Vesicles. 8 (1): 1565264. doi:10.1080/20013078.2019.1565264. PMC 6346716. PMID 30719240.
  68. ^ Wahlgren J, Statello L, Skogberg G, Telemo E, Valadi H (2016). "Delivery of Small Interfering RNAs to Cells via Exosomes". SiRNA Delivery Methods. Methods in Molecular Biology. 1364. pp. 105–25. doi:10.1007/978-1-4939-3112-5_10. ISBN 978-1-4939-3111-8. PMID 26472446.
  69. ^ Kumar L, Verma S, Vaidya B, Gupta V (2015). "Exosomes: Natural Carriers for siRNA Delivery". Current Pharmaceutical Design. 21 (31): 4556–65. doi:10.2174/138161282131151013190112. PMID 26486142.
  70. ^ Bell BM, Kirk ID, Hiltbrunner S, Gabrielsson S, Bultema JJ (January 2016). "Designer exosomes as next-generation cancer immunotherapy". Nanomedicine. 12 (1): 163–9. doi:10.1016/j.nano.2015.09.011. PMID 26500074.
  71. ^ Batrakova EV, Kim MS (December 2015). "Using exosomes, naturally-equipped nanocarriers, for drug delivery". Journal of Controlled Release. 219: 396–405. doi:10.1016/j.jconrel.2015.07.030. PMC 4656109. PMID 26241750.
  72. ^ Kim MS, Haney MJ, Zhao Y, Mahajan V, Deygen I, Klyachko NL, Inskoe E, Piroyan A, Sokolsky M, Okolie O, Hingtgen SD, Kabanov AV, Batrakova EV (April 2016). "Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells". Nanomedicine. 12 (3): 655–664. doi:10.1016/j.nano.2015.10.012. PMC 4809755. PMID 26586551.
  73. ^ Mathivanan S, Simpson RJ (November 2009). "ExoCarta: A compendium of exosomal proteins and RNA". Proteomics. 9 (21): 4997–5000. doi:10.1002/pmic.200900351. PMID 19810033.