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.

Future directions of extracellular vesicle-associated miRNAs in metastasis

“…Besides this mechanism, secretion of miRNAs could additionally be more specific. Makarova et al, 2016 (20) suggested the presence of universal sequencespecific sorting mechanisms for miRNA loading into EVs since miRNA repertoires in EVs derived from different cell types shared a higher similarity than that of EVs and their corresponding parental cells (21), moreover, significant differences in intracellular and extravesicular miRNA profiles reported by several research groups strengthen this hypothesis (22)(23)(24)(25)(26)(27)(28).…”

Cell-secreted vesicles containing microRNAs as regulators of gamete maturation

“…Squadrito and coworkers demonstrated that overexpression (physiologically activated or artificial) of microRNA target sequences leads to depletion of microRNAs from MVBs where exosomes are formed, and instead their enrichment in P-bodies (site of microRNA function) (Squadrito et al 2014). Alternatively, overexpression of microRNAs leads to their increased presence in MVBs and secreted exosomes.…”

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