Characterization of mRNA and microRNA in human mast cell‐derived exosomes and their transfer to other mast cells and blood CD34 progenitor cells

Background Exosomes are nanosized vesicles of endocytic origin that are released into the extracellular environment by many different cells. It has been shown that exosomes from various cellular origins contain a substantial amount of RNA (mainly mRNA and microRNA). More importantly, exosomes are capable of delivering their RNA content to target cells, which is a novel way of cell‐to‐cell communication. The aim of this study was to evaluate whether exosomal shuttle RNA could play a role in the communication between human mast cells and between human mast cells and human CD34 + progenitor cells. Methods The mRNA and microRNA content of exosomes from a human mast cell line, HMC‐1, was analysed by using microarray technology. Co‐culture experiments followed by flow cytometry analysis and confocal microscopy as well as radioactive labeling experiments were performed to examine the uptake of these exosomes and the shuttle of the RNA to other mast cells and CD34 + progenitor cells. Results In this study, we show that human mast cells release RNA‐containing exosomes, with the capacity to shuttle RNA between cells. Interestingly, by using microRNA microarray analysis, 116 microRNAs could be identified in the exosomes and 134 microRNAs in the donor mast cells. Furthermore, DNA microarray experiments revealed the presence of approximately 1800 mRNAs in the exosomes, which represent 15% of the donor cell mRNA content. In addition, transfer experiments revealed that exosomes can shuttle RNA between human mast cells and to CD34 + hematopoietic progenitor cells. Conclusion These findings suggest that exosomal shuttle RNA (esRNA) can play a role in the communication between cells, including mast cells and CD34 + progenitor cells, implying a role in cells maturation process.

1. 1.

   Van Niel G, Porto-Carreiro I, Simoes S, Raposo G. Exosomes: a common pathway for a specialized function. J Biochem (Tokyo). 2006;140:13-21.

   Not in our library10.1093/jb/mvj128 (opens in a new tab)

2. 2.

   Raposo G, Tenza D, Mecheri S, Peronet R, Bonnerot C, Desaymard C. Accumulation of major histocompatibility complex class II molecules in mast cell secretory granules and their release upon degranulation. Mol Biol Cell. 1997;8:2631-45.

   Not in our library10.1091/mbc.8.12.2631 (opens in a new tab)

3. 3.

   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;147:599-610.

   Not in our library10.1083/jcb.147.3.599 (opens in a new tab)

4. 4.

   Mears R, Craven RA, Hanrahan S, Totty N, Upton C, Young SL, et al. Proteomic analysis of melanoma-derived exosomes by two-dimensional polyacrylamide gel electrophoresis and mass spectrometry. Proteomics. 2004;4:4019-31.

   Not in our library10.1002/pmic.200400876 (opens in a new tab)

5. 5.

   Pan B-T, Johnstone RM. Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell. 1983;33:967-78.

   Not in our library10.1016/0092-8674(83)90040-5 (opens in a new tab)

6. 6.

   Van Niel G, Raposo G, Candalh C, Boussac M, Hershberg R, Cerf-Bensussan N, et al. Intestinal epithelial cells secrete exosome-like vesicles. Gastroenterology. 2001;121:337-49.

   Not in our library10.1053/gast.2001.26263 (opens in a new tab)

7. 7.

   Raposo G, Nijman H, Stoorvogel W, Liejendekker R, Harding C, Melief C, et al. B lymphocytes secrete antigen-presenting vesicles. J Exp Med. 1996;183:1161-72.

   Not in our library10.1084/jem.183.3.1161 (opens in a new tab)

8. 8.

   Caby M-P, Lankar D, Vincendeau-Scherrer C, Raposo G, Bonnerot C. Exosomal-like vesicles are present in human blood plasma. Int Immunol. 2005;17:879-87.

   Not in our library10.1093/intimm/dxh267 (opens in a new tab)

9. 9.

   Pisitkun T, Shen R-F, Knepper MA. Identification and proteomic profiling of exosomes in human urine. PNAS. 2004;101:13368-73.

   Not in our library10.1073/pnas.0403453101 (opens in a new tab)

10. 10.

    Admyre C, Johansson SM, Qazi KR, Filen J-J, Lahesmaa R, Norman M, et al. Exosomes with immune modulatory features are present in human breast milk. J Immunol. 2007;179:1969-78.

    Not in our library10.4049/jimmunol.179.3.1969 (opens in a new tab)

11. 11.

    Keller S, Rupp C, Stoeck A, Runz S, Fogel M, Lugert S, et al. CD24 is a marker of exosomes secreted into urine and amniotic fluid. Kidney Int. 2007;72:1095-102.

    Not in our library10.1038/sj.ki.5002486 (opens in a new tab)

12. 12.

    Raposo G, Moore M, Innes D, Leijendekker R, Leigh-Brown A, Benaroch P, et al. Human macrophages accumulate HIV-1 particles in MHC II compartments. Traffic. 2002;3:718-29.

    Not in our library10.1034/j.1600-0854.2002.31004.x (opens in a new tab)

13. 13.

    Admyre C, Grunewald J, Thyberg J, Gripenback S, Tornling G, Eklund A, et al. Exosomes with major histocompatibility complex class II and co-stimulatory molecules are present in human BAL fluid. Eur Respir J. 2003;22:578-83.

    Not in our library10.1183/09031936.03.00041703 (opens in a new tab)

14. 14.

    Sprent J. Direct stimulation of naive T cells by antigen-presenting cell vesicles. Blood Cells Mol. Dis. 2005;35:17-20.

    Not in our library10.1016/j.bcmd.2005.04.004 (opens in a new tab)

15. 15.

    Karlsson M, Lundin S, Dahlgren U, Kahu H, Petterson I, Telemo E. “Tolerosomes” are produced by intestinal epithelial cells. Eur J Immunol. 2001;31:2892-900.

    Not in our library10.1002/1521-4141(2001010)31:10<2892::aid-immu2892>3.0.co;2-i (opens in a new tab)

16. 16.

    Skokos D, Le Panse S, Villa I, Rousselle J-C, Peronet R, David B, et al. Mast cell-dependent B and T lymphocyte activation is mediated by the secretion of immunologically active exosomes. J Immunol. 2001;166:868-76.

    Not in our library10.4049/jimmunol.166.2.868 (opens in a new tab)

17. 17.

    Al-Nedawi K, Szemraj J, Cierniewski CS. Mast cell-derived exosomes activate endothelial cells to secrete plasminogen activator inhibitor type 1. Arterioscler Thromb Vasc Biol. 2005;25:1744-9.

    Not in our library10.1161/01.atv.0000172007.86541.76 (opens in a new tab)

18. 18.

    Skokos D, Botros HG, Demeure C, Morin J, Peronet R, Birkenmeier G, et al. Mast cell-derived exosomes induce phenotypic and functional maturation of dendritic cells and elicit specific immune responses in vivo. J Immunol. 2003;170:3037-45.

    Not in our library10.4049/jimmunol.170.6.3037 (opens in a new tab)

19. 19.

    Hao S, Moyana T, Xiang J. Review: cancer immunotherapy by exosome-based vaccines. Cancer Biother Radiopharm. 2007;22:692-703.

    Not in our library10.1089/cbr.2007.368-r (opens in a new tab)

20. 20.

    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;9:654-9.

    Not in our library10.1038/ncb1596 (opens in a new tab)

21. 21.

    Skog J, Wurdinger T, van Rijn S, Meijer DH, Gainche L, Curry WT, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol. 2008;10:1470-6.

    Not in our library10.1038/ncb1800 (opens in a new tab)

22. 22.

    Nanostructural and Transcriptomic Analyses of Human Saliva Derived Exosomes · 2010

23. 23.

    Pegtel DM, Cosmopoulos K, Thorley-Lawson DA, van Eijndhoven MAJ, Hopmans ES, Lindenberg JL, et al. Functional delivery of viral miRNAs via exosomes. Proc. Natl Acad Sci. 2010;107:6328-33.

    Not in our library10.1073/pnas.0914843107 (opens in a new tab)

24. 24.

    Kosaka N, Izumi H, Yoshioka Y, Takeshita F, Matsuki Y, Ochiya T. Secretory mechanisms and intercellular transfer of microRNAs in living cells. J Biol Chem. 2010;285:17442-52.

    Not in our library10.1074/jbc.m110.107821 (opens in a new tab)

25. 25.

    Kogure T, Lin W-L, Yan IK, Braconi C, Patel T. Intercellular nanovesicle-mediated microRNA transfer: a mechanism of environmental modulation of hepatocellular cancer cell growth. Hepatology. 2011;54:1237-48.

    Not in our library10.1002/hep.24504 (opens in a new tab)

26. 26.

    Montecalvo A, Larregina AT, Shufesky WJ, Beer Stolz D, Sullivan MLG, Karlsson JM, et al. Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood. 2012;119:756-66.

    Not in our library10.1182/blood-2011-02-338004 (opens in a new tab)

27. 27.

    Exosomes Communicate Protective Messages during Oxidative Stress; Possible Role of Exosomal Shuttle RNA · 2010

28. 28.

    Escola J-M, 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;273:20121-7.

    Not in our library10.1074/jbc.273.32.20121 (opens in a new tab)

29. 29.

    Admyre C, Johansson SM, Staffan P, Gabrielsson S. Direct exosome stimulation of peripheral human T cells detected by ELISPOT. Eur J Immunol. 2006;36:1772-81.

    Not in our library10.1002/eji.200535615 (opens in a new tab)

30. 30.

    Kesimer M, Scull M, Brighton B, DeMaria G, Burns K, O'Neal W, et al. Characterization of exosome-like vesicles released from human tracheobronchial ciliated epithelium: a possible role in innate defense. FASEB J. 2009;23:1858-68.

    Not in our library10.1096/fj.08-119131 (opens in a new tab)

31. 31.

    Luo S-S, Ishibashi O, Ishikawa G, Ishikawa T, Katayama A, Mishima T, et al. Human villous trophoblasts express and secrete placenta-specific microRNAs into maternal circulation via exosomes. Biol Reprod. 2009;81:717-29.

    Not in our library10.1095/biolreprod.108.075481 (opens in a new tab)

32. 32.

    Prostate cancer-derived urine exosomes: a novel approach to biomarkers for prostate cancer · 2009

33. 33.

    Taylor DD, Gercel-Taylor C. MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol. 2008;110:13-21.

    Not in our library10.1016/j.ygyno.2008.04.033 (opens in a new tab)

34. 34.

    Krek A, Grun D, Poy MN, Wolf R, Rosenberg L, Epstein EJ, et al. Combinatorial microRNA target predictions. Nat Genet. 2005;37:495-500.

    Not in our library10.1038/ng1536 (opens in a new tab)

35. 35.

    Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJA. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotech. 2011;29:341-5.

    Not in our library10.1038/nbt.1807 (opens in a new tab)

36. 36.

    Identification of nucleotide patterns enriched in secreted RNAs as putative cis-acting elements targeting them to exosome nano-vesicles · 2011

• Corrected

  Unpacking extracellular vesicles: RNA cargo loading and function · 2022

• Exosome-based immunotherapy: a promising approach for cancer treatment · 2020

• The roles of exosomal miRNAs and lncRNAs in lung diseases · 2019

• Roles of Exosomes Derived From Immune Cells in Cardiovascular Diseases · 2019

• Identification of RNA-binding proteins in exosomes capable of interacting with different types of RNA: RBP-facilitated transport of RNAs into exosomes · 2018

• Large Extracellular Vesicles: Have We Found the Holy Grail of Inflammation? · 2018

• Stem Cell Extracellular Vesicles: Extended Messages of Regeneration · 2017

• Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism · 2016

• Visualization and tracking of tumour extracellular vesicle delivery and RNA translation using multiplexed reporters · 2015

• KRAS-dependent sorting of miRNA to exosomes · 2015

• Mast Cell Mediators: Their Differential Release and the Secretory Pathways Involved · 2014

• Standardization of sample collection, isolation and analysis methods in extracellular vesicle research · 2013

• Monocyte Exosomes Stimulate the Osteogenic Gene Expression of Mesenchymal Stem Cells · 2013

• Distinct RNA profiles in subpopulations of extracellular vesicles: apoptotic bodies, microvesicles and exosomes · 2013

• EVpedia: an integrated database of high‐throughput data for systemic analyses of extracellular vesicles · 2013

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.