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Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells

Abstract

Exosomes are vesicles of endocytic origin released by many cells. These vesicles can mediate communication between cells, facilitating processes such as antigen presentation. Here, we show that exosomes from a mouse and a human mast cell line (MC/9 and HMC-1, respectively), as well as primary bone marrow-derived mouse mast cells, contain RNA. Microarray assessments revealed the presence of mRNA from approximately 1300 genes, many of which are not present in the cytoplasm of the donor cell. In vitro translation proved that the exosome mRNAs were functional. Quality control RNA analysis of total RNA derived from exosomes also revealed presence of small RNAs, including microRNAs. The RNA from mast cell exosomes is transferable to other mouse and human mast cells. After transfer of mouse exosomal RNA to human mast cells, new mouse proteins were found in the recipient cells, indicating that transferred exosomal mRNA can be translated after entering another cell. In summary, we show that exosomes contain both mRNA and microRNA, which can be delivered to another cell, and can be functional in this new location. We propose that this RNA is called “exosomal shuttle RNA” (esRNA).

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Figure 1: Identification and characterization of exosomes.
Figure 2: Exosomes contain multiple and heterogeneous RNA species.
Figure 3: Characterization and transfer of exosomal RNA.
Figure 4: Identification of exosomal microRNA.

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Acknowledgements

We gratefully acknowledge Swegene Microarray Resource Centre at Lund University for help with the Affymetrix microarray processing and analysis and the Exiqon Company for analysing the microRNA. We thank core facility, Proteomics Resource Centre at Göteborg University (http://www.proteomics.cf.gu.se) for the help with LC-MS/MS and MALDI-TOF. The human mast cell line HMC-1 was kindly provided by G. Nilsson (Uppsala University) and J. Butterfield (Mayo Clinic). We have had exceedingly helpful discussions with E. Telemo and K. McNagny during the progress of the project. We thank B. R. Johansson, U. Nannmark and Y. Josefsson at The Electron Microscopy Unit, Inst Biomedicine, Göteborg University for the help with electron microscopy, and N. Almqvist for taking several of the electron microscopy photographs. We are also grateful to T. Nyström and A. Farwell for providing laboratory resources for some of the experiments at the Cell and Molecular Biology Laboratory at Göteborg University. The current experiments were funded by the Swedish Research Council (K2005-74X-13429-06A), the Swedish Heart and Lung foundation and the Swedish Asthma-Allergy Foundation. J.L. is funded by Herman Krefting's Foundation against Asthma/Allergy.

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H.V. and K.E., with contributions from A.B., performed all experiments. J.L. conceived the study and participated in the overall planning of the study, with support from all authors. All authors participated in the design of specific experiments and in writing the manuscript.

Corresponding author

Correspondence to Jan O Lötvall.

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Competing interests

J.L., H.V., K.E., M.S. and A.B. co-own the commercial development of a US patent application related to utilization of exosomes as a vector for therapy.

Supplementary information

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Supplementary figures S1, S2, S3 and Supplementary methods (PDF 529 kb)

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Supplementary Table S6 (PDF 54 kb)

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Valadi, H., Ekström, K., Bossios, A. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9, 654–659 (2007). https://doi.org/10.1038/ncb1596

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