title: Endogenous RNAs modulate microRNA sorting to exosomes and transfer to acceptor cells.
abstract: MicroRNA (miRNA) transfer via exosomes may mediate cell-to-cell communication. Interestingly, specific miRNAs are enriched in exosomes in a cell-type-dependent fashion. However, the mechanisms whereby miRNAs are sorted to exosomes and the significance of miRNA transfer to acceptor cells are unclear. We used macrophages and endothelial cells (ECs) as a model of heterotypic cell communication in order to investigate both processes. RNA profiling of macrophages and their exosomes shows that miRNA sorting to exosomes is modulated by cell-activation-dependent changes of miRNA target levels in the producer cells. Genetically perturbing the expression of individual miRNAs or their targeted transcripts promotes bidirectional miRNA relocation from the cell cytoplasm/P bodies (sites of miRNA activity) to multivesicular bodies (sites of exosome biogenesis) and controls miRNA sorting to exosomes. Furthermore, the use of Dicer-deficient cells and reporter lentiviral vectors (LVs) for miRNA activity shows that exosomal miRNAs are transferred from macrophages to ECs to detectably repress targeted sequences.
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Mario Leonardo
authors.initials: ML
authors.lastname: Squadrito
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Caroline
authors.initials: C
authors.lastname: Baer
authors.affiliation: Vital-IT, Swiss Institute of Bioinformatics (SIB), 1015 Lausanne, Switzerland.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Burdet
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Claudio
authors.initials: C
authors.lastname: Maderna
authors.affiliation: Department of Medical Genetics and Norwegian High-Throughput Sequencing Centre (NSC), Oslo University Hospital, Kirkeveien 166, 0407 Oslo, Norway.
authors.forename: Gregor D
authors.initials: GD
authors.lastname: Gilfillan
authors.affiliation: Department of Medical Genetics and Norwegian High-Throughput Sequencing Centre (NSC), Oslo University Hospital, Kirkeveien 166, 0407 Oslo, Norway.
authors.forename: Robert
authors.initials: R
authors.lastname: Lyle
authors.affiliation: Vital-IT, Swiss Institute of Bioinformatics (SIB), 1015 Lausanne, Switzerland.
authors.forename: Mark
authors.initials: M
authors.lastname: Ibberson
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland. Electronic address: michele.depalma@epfl.ch.
authors.forename: Michele
authors.initials: M
authors.lastname: De Palma
mesh_terms: D000818:Animals; D001483:Base Sequence; D002450:Cell Communication; D002478:Cells, Cultured; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D055354:Exosomes / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D008969:Molecular Sequence Data; D057146:Multivesicular Bodies / Q000378:metabolism; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism
chemical_list: D035683:MicroRNAs; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases