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J Extracell Vesicles. 2017 Mar 7;6(1):1286095. doi: 10.1080/20013078.2017.1286095. eCollection 2017.

Obstacles and opportunities in the functional analysis of extracellular vesicle RNA - an ISEV position paper.

Author information

1
Department of Biology, Swiss Federal Institute of Technology Zurich (ETH Zürich) , Zurich , Switzerland.
2
Department of Biology, Massachusetts Institute of Technology , Cambridge , MA , USA.
3
Department of Nephrology and Hypertension, UMC Utrecht , Utrecht , the Netherlands.
4
Experimental Asthma Research, Priority Area Asthma & Allergy, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL) , Borstel , Germany.
5
Department of Science and Technology, CSIR-Indian Institute of Chemical Biology , Kolkata , India.
6
Department of Genetics, Cell- and Immunobiology, Semmelweis University , Budapest , Hungary.
7
Institute of Immunology and Infection Research, Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh , Edinburgh , UK.
8
IRCCS MultiMedica , Milan , Italy.
9
Cardiovascular Research Institute, Massachusetts General Hospital , Boston , MA , USA.
10
Department of Biochemistry & Cell Biology, Faculty of Veterinary Medicine, Utrecht University , Utrecht , the Netherlands.
11
Immunology Service, Hospital La Princesa , Madrid , Spain.
12
Department of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Medicine, Helen Diller Family Comprehensive Cancer Center, UC San Francisco, San Francisco, CA, USA.
13
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University , Bundoora , Australia.
14
Molecular Immunogenetics & Vaccine Research Section, Vaccine Branch, CCR, NCI , Bethesda , MD , USA.
15
Neurogenomics Division, TGen , Phoenix , AZ , USA.
16
Institute of Biomedical Engineering, National Tsing Hua University , Hsinchu , Taiwan.
17
Department of Neurology and Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital and NeuroDiscovery Center, Harvard Medical School, Boston, MA, USA; Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
18
Department of Experimental Biomedicine and Clinical Neurosciences (BIONEC), University of Palermo , Palermo , Italy.
19
Center for Molecular Medicine, University Medical Center Utrecht & Regenerative Medicine Center , Utrecht , the Netherlands.
20
Department of Neurology and Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital and NeuroDiscovery Center, Harvard Medical School , Boston , MA , USA.
21
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK; Institute of Technology, University of Tartu, Tartu, Estonia.
22
Instituto de Investigación del Hospital 12 de Octubre , Madrid , Spain.
23
Institute of Neurology (Edinger Institute), Frankfurt University Medical School , Frankfurt am Main , Germany.
24
Department of Pathology and Forensic Medicine, Ribeirão Preto School of Medicine, University of Sao Paulo , Sao Paulo , Brazil.
25
Department of Pathology, Exosomes Research Group, VU University Medical Center , Amsterdam , the Netherlands.
26
Animal Physiology and Immunology, School of Life Sciences, Technical University of Munich (TUM) Weihenstephan , Freising , Germany.
27
Laboratory Clinical Chemistry & Haematology, University Medical Center Utrecht , Utrecht , the Netherlands.
28
Department of Cellular and Molecular Biology, Institute of Biomedical & Health Sciences, Hiroshima University , Hiroshima , Japan.
29
Institut Curie, PSL Research University, INSERM U932 , Paris , France.
30
Functional Genomics Unit, Institut Pasteur de Montevideo, Nuclear Research Center, Faculty of Science, Universidad de la República , Montevideo , Uruguay.
31
Department of Molecular and Comparative Pathobiology and Department of Neurology, The Johns Hopkins University School of Medicine , Baltimore , MD , USA.

Abstract

The release of RNA-containing extracellular vesicles (EV) into the extracellular milieu has been demonstrated in a multitude of different in vitro cell systems and in a variety of body fluids. RNA-containing EV are in the limelight for their capacity to communicate genetically encoded messages to other cells, their suitability as candidate biomarkers for diseases, and their use as therapeutic agents. Although EV-RNA has attracted enormous interest from basic researchers, clinicians, and industry, we currently have limited knowledge on which mechanisms drive and regulate RNA incorporation into EV and on how RNA-encoded messages affect signalling processes in EV-targeted cells. Moreover, EV-RNA research faces various technical challenges, such as standardisation of EV isolation methods, optimisation of methodologies to isolate and characterise minute quantities of RNA found in EV, and development of approaches to demonstrate functional transfer of EV-RNA in vivo. These topics were discussed at the 2015 EV-RNA workshop of the International Society for Extracellular Vesicles. This position paper was written by the participants of the workshop not only to give an overview of the current state of knowledge in the field, but also to clarify that our incomplete knowledge - of the nature of EV(-RNA)s and of how to effectively and reliably study them - currently prohibits the implementation of gold standards in EV-RNA research. In addition, this paper creates awareness of possibilities and limitations of currently used strategies to investigate EV-RNA and calls for caution in interpretation of the obtained data.

KEYWORDS:

Extracellular vesicles; RNA binding proteins; exosomes; function; mRNA; non-coding RNA; quantification; sorting

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