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Cell Mol Life Sci. 2018 Oct;75(20):3857-3875. doi: 10.1007/s00018-018-2842-8. Epub 2018 May 28.

Immune stimuli shape the small non-coding transcriptome of extracellular vesicles released by dendritic cells.

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Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Leiden Genome Technology Center, Leiden University Medical Center, Leiden, The Netherlands.
School of Biological Sciences, Centre for Immunity, Infection and Evolution, Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, UK.
Centre for Biomolecular and Molecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands.
Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.


The release and uptake of nano-sized extracellular vesicles (EV) is a highly conserved means of intercellular communication. The molecular composition of EV, and thereby their signaling function to target cells, is regulated by cellular activation and differentiation stimuli. EV are regarded as snapshots of cells and are, therefore, in the limelight as biomarkers for disease. Although research on EV-associated RNA has predominantly focused on microRNAs, the transcriptome of EV consists of multiple classes of small non-coding RNAs with potential gene-regulatory functions. It is not known whether environmental cues imposed on cells induce specific changes in a broad range of EV-associated RNA classes. Here, we investigated whether immune-activating or -suppressing stimuli imposed on primary dendritic cells affected the release of various small non-coding RNAs via EV. The small RNA transcriptomes of highly pure EV populations free from ribonucleoprotein particles were analyzed by RNA sequencing and RT-qPCR. Immune stimulus-specific changes were found in the miRNA, snoRNA, and Y-RNA content of EV from dendritic cells, whereas tRNA and snRNA levels were much less affected. Only part of the changes in EV-RNA content reflected changes in cellular RNA, which urges caution in interpreting EV as snapshots of cells. By comprehensive analysis of RNA obtained from highly purified EV, we demonstrate that multiple RNA classes contribute to genetic messages conveyed via EV. The identification of multiple RNA classes that display cell stimulation-dependent association with EV is the prelude to unraveling the function and biomarker potential of these EV-RNAs.


Biomarker; Extracellular RNA; Immune activation; Immune suppression; Small RNA sequencing

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