Intercellular transport of microRNAs

Abstract

Extracellular microRNAs (miRNA) are present in most biological fluids, relatively stable, and hold great potential for disease biomarkers and novel therapeutics. Circulating miRNAs are transported by membrane-derived vesicles (exosomes and microparticles), lipoproteins, and other ribonucleoprotein complexes. Evidence suggests that miRNAs are selectively exported from cells with distinct signatures that have been found to be altered in many pathophysiologies, including cardiovascular disease. Protected from plasma ribonucleases by their carriers, functional miRNAs are delivered to recipient cells by various routes. Transferred miRNAs use cellular machinery to reduce target gene expression and alter cellular phenotype. Similar to soluble factors, miRNAs mediate cell-to-cell communication linking disparate cell types, diverse biological mechanisms, and homeostatic pathways. Although significant advances have been made, miRNA intercellular communication is full of complexities and many questions remain. This review brings into focus what is currently known and outstanding in a novel field of study with applicability to cardiovascular disease.

Figure 1. Schematic of miRNA intercellular communication

Secreted miRNAs are transported by extracellular carriers and transferred to recipient cells where theyalter gene expression. Membrane-derived exosomes are released from cells as endosomes containing multivesicular bodies (MVB) fuse with the plasma membrane. Microparticles (MP) are released from the plasma membrane through outward budding. Neutral sphingomyelinase 2 (nSMase2) governs the release of extracellular miRNAs. Exosomes and microparticles deliver extracellular microRNAs (miRNA) through endocytosis and membrane fusion. Delivery of high-density lipoproteins (HDL) miRNAs is dependent upon scavenger receptor B1 (SR-BI). Argonaute 2 (AGO2) is the main structure-function protein within the miRNA ribonucleoprotein complex where miRNAs recognize and bind to mRNA targets. LDL, low-density lipoproteins.