Fig. 1

Origin of the different populations of extracellular miRNAs in biofluids. (1) In the nucleus, miRNA genes are transcribed by the RNA polymerase II into primary miRNAs (pri-miRNAs) from DNA and processed by the Drosha complex (pre-miRNAs). pre-miRNAs are exported to the cytoplasm and cleaved by Dicer to produce a double-stranded miRNA duplex. The duplex is separated, and a mature miRNA is incorporated into the RNA-induced silencing complex (RISC). Within the RISC complex, miRNAs bind to their target messenger RNAs (mRNAs) to repress their translation or induce their degradation. In the cytoplasm, pre-miRNAs and mature miRNAs can also be incorporated into small vesicles called exosomes, which are released from cells when multivesicular bodies (MVB) fuse with the plasma membrane (2). Pre-miRNA or mature miRNA can also be released through blebbing of the plasma membrane (microparticles) (3) or during cell apoptosis in apoptotic bodies (4). miRNAs are also found in circulation in vesicle-free form. These miRNAs can be associated with high-density lipoproteins (HDL) (5) or bound to RNA-binding proteins (RNP) (6). In addition, miRNAs may be released actively, in an miRNA-specific manner, through interaction with specific membrane channels or proteins (7)