Trends in Cell Biology
OpinionSecreted microRNAs: a new form of intercellular communication
Section snippets
Secreted miRNAs as an emerging new form of intercellular communication
The ability of a cell to communicate with neighboring cells and to sense their local microenvironment forms the basis for coordinated cellular activity in multicellular organisms. Classic cell-to-cell communication is mediated by several methods, including cell junctions, adhesion contacts or soluble messengers (Figure 1) 1, 2, 3, 4. Findings over the past several years, however, suggest the existence of an additional form of intercellular communication: horizontal transfer of secreted miRNAs (
Definition of secreted miRNAs
Numerous studies have documented the importance of miRNAs, which are a class of endogenous noncoding RNAs consisting of 19 to 24 nucleotides that regulate the post-transcriptional silencing of protein-coding genes in eukaryotes (Box 1) 5, 6, 7. Once thought to be unstable molecules, miRNAs were recently demonstrated to circulate in a highly stable, cell-free form in various body fluids, including serum 8, 9, 10, plasma [11], saliva [12], urine [13] and milk 14, 15. Furthermore, circulating
Molecular basis for the stability of secreted miRNAs
A crucial question surrounding secreted miRNAs concerns their stability in the circulation despite the presence of ubiquitous ribonucleases (RNases). Two possible mechanisms have been suggested: (i) protection of secreted miRNAs by the membrane structures of microvesicles 26, 27, 28, 30; and (ii) stabilization of secreted miRNAs by their association with RNA-binding proteins, such as AGO2 and NPM1 32, 33, 34. Both of these mechanisms – microvesicle membrane enclosure and protein conjunction –
Molecular mechanism for packaging and secretion of miRNAs
Evidence suggests that miRNA packaging occurs non-randomly and that specific miRNA populations are preferentially sorted into microvesicles. We have found direct evidence that blood cells and cultured THP-1 cells actively and selectively package miRNAs into microvesicles and secrete them into the circulation or culture medium in response to various stimuli [27]. Other studies have demonstrated that certain miRNAs are present dominantly or at higher levels in exosomes than in the donor cells
Uptake of secreted miRNAs by recipient cells
Another important point that requires future study is how secreted miRNAs execute their functions in recipient cells. THP-1 cell-derived microvesicles containing abundant miR-150 can deliver miR-150 into the human microvascular endothelial cell line (HMEC-1), resulting in suppression of c-Myb (a known target gene for miR-150 [39]) in recipient cells and enhanced migration capacity [27]. Secreted miR-146a suppresses expression of its known target gene ROCK1 [40] in recipient prostate cancer PC-3
Role of secreted miRNAs in regulating physiological and pathological processes
miRNAs secreted by immune cells, stem cells, adipocytes and blood cells have recently been identified (Table 1). There is evidence for antigen-driven unidirectional transfer of miRNAs, such as miR-335, from T cells to antigen-presenting cells (APCs) via CD63+ exosomes during T cell–APC cognate immune interactions [29]. Furthermore, upon co-culture of T cells with APCs, a luciferase reporter containing the 3′-UTR of SOX4 (a direct target of miR-335) was significantly reduced, presumably via
Secreted miRNAs as a new tool for fetal–maternal crosstalk
Recent studies have demonstrated that placenta-derived exosomes function as immune regulators in fetal–maternal crosstalk, thus improving maternal adaptation to the ongoing pregnancy and promoting fetal allograft survival [56]. Placenta-specific miRNAs have been observed in exosomes from villous trophoblasts [57]. More investigation is needed to elucidate the role of these miRNAs during pregnancy, however, and to test if they have the capacity to enter and reprogram maternal cells in favor of
Concluding remarks
It has traditionally been thought that ‘classic’ cell-to-cell communication is mediated by cell junctions, adhesion contacts or secreted signals, such as hormones (Figure 1). However, an additional mechanism of intercellular communication mediated by secreted miRNA has recently been uncovered (Figure 1). As a new type of signaling molecule, secreted miRNAs have some important features: (i) they appear to be a common phenomenon affecting many cell types; (ii) they can have biological effects
Acknowledgments
This work was supported by grants from the National Natural Science Foundation of China (nos 90813035, 81101330, 81171661, 30988003, 30890044, 30772484, 30725008, 30890032, 31071232, 31000323, 90608010, and J1103512), the Natural Science Foundation of Jiangsu Province (no. BK2011013), and the Fundamental Research Funds for the Central Universities (no. 1107020839).
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