Secreted monocytic miR-150 enhances targeted endothelial cell migration.

MicroRNAs (miRNAs) are a class of noncoding RNAs that regulate target gene expression at the posttranscriptional level. Here, we report that secreted miRNAs can serve as signaling molecules mediating intercellular communication. In human blood cells and cultured THP-1 cells, miR-150 was selectively packaged into microvesicles (MVs) and actively secreted. THP-1-derived MVs can enter and deliver miR-150 into human HMEC-1 cells, and elevated exogenous miR-150 effectively reduced c-Myb expression and enhanced cell migration in HMEC-1 cells. In vivo studies confirmed that intravenous injection of THP-1 MVs significantly increased the level of miR-150 in mouse blood vessels. MVs isolated from the plasma of patients with atherosclerosis contained higher levels of miR-150, and they more effectively promoted HMEC-1 cell migration than MVs from healthy donors. These results demonstrate that cells can secrete miRNAs and deliver them into recipient cells where the exogenous miRNAs can regulate target gene expression and recipient cell function.

[1]  Laurence Zitvogel,et al.  Exosomes: composition, biogenesis and function , 2002, Nature Reviews Immunology.

[2]  Daniel B. Martin,et al.  Circulating microRNAs as stable blood-based markers for cancer detection , 2008, Proceedings of the National Academy of Sciences.

[3]  K. Kodys,et al.  The Opposite Effects of Acute and Chronic Alcohol on Lipopolysaccharide-Induced Inflammation Are Linked to IRAK-M in Human Monocytes1 , 2009, The Journal of Immunology.

[4]  V. Ambros.  The functions of animal microRNAs , 2004, Nature.

[5]  B. Osterud,et al.  Role of monocytes in atherogenesis. , 2003, Physiological reviews.

[6]  Jacopo Meldolesi,et al.  Shedding microvesicles: artefacts no more. , 2009, Trends in cell biology.

[7]  Yariv Yogev,et al.  Serum MicroRNAs Are Promising Novel Biomarkers , 2008, PloS one.

[8]  F. Saggioro,et al.  MicroRNAs differentially expressed in ACTH-secreting pituitary tumors. , 2009, The Journal of clinical endocrinology and metabolism.

[9]  J. Lötvall,et al.  Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells , 2007, Nature Cell Biology.

[10]  Hansjuerg Alder,et al.  The detection of differentially expressed microRNAs from the serum of ovarian cancer patients using a novel real-time PCR platform. , 2009, Gynecologic oncology.

[11]  A. Gabrielli,et al.  Collagen loss and impaired wound healing is associated with c‐Myb deficiency , 2007, The Journal of pathology.

[12]  M. Lindsay,et al.  microRNAs and the immune response. , 2008, Trends in immunology.

[13]  S. Kashyap,et al.  Lipid‐induced Insulin Resistance Is Associated With Increased Monocyte Expression of Scavenger Receptor CD36 and Internalization of Oxidized LDL , 2009, Obesity.

[14]  Aled Clayton,et al.  Isolation and Characterization of Exosomes from Cell Culture Supernatants and Biological Fluids , 2006, Current protocols in cell biology.

[15]  D. Bartel.  MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[16]  J. Prchal,et al.  Aberrant expression of microRNA in polycythemia vera , 2008, Haematologica.

[17]  J. Hsieh,et al.  Caveolin‐1 secreting LNCaP cells induce tumor growth of caveolin‐1 negative LNCaP cells in vivo , 2008, International journal of cancer.

[18]  C. Print,et al.  MicroRNA-regulated pathways associated with endometriosis. , 2009, Molecular endocrinology.

[19]  Graça Raposo,et al.  Exosomes--vesicular carriers for intercellular communication. , 2009, Current opinion in cell biology.

[20]  Qinxi Li,et al.  Axin determines cell fate by controlling the p53 activation threshold after DNA damage , 2009, Nature Cell Biology.

[21]  N. Rajewsky,et al.  MiR-150 Controls B Cell Differentiation by Targeting the Transcription Factor c-Myb , 2007, Cell.

[22]  J. Meldolesi,et al.  The regulated exocytosis of enlargeosomes is mediated by a SNARE machinery that includes VAMP4 , 2008, Journal of Cell Science.

[23]  H. Kuo,et al.  c-Myb is an evolutionary conserved miR-150 target and miR-150/c-Myb interaction is important for embryonic development. , 2008, Molecular biology and evolution.

[24]  X. Chen,et al.  Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases , 2008, Cell Research.

[25]  C. Croce,et al.  MicroRNAs in normal and malignant hematopoiesis , 2008, Current opinion in hematology.

[26]  R. Johnstone,et al.  Exosomes biological significance: A concise review. , 2006, Blood cells, molecules & diseases.

[27]  W. Liles,et al.  The phagocytes: neutrophils and monocytes. , 2008, Blood.

[28]  T. Yoshino,et al.  Advanced Glycation End Products Subspecies-Selectively Induce Adhesion Molecule Expression and Cytokine Production in Human Peripheral Blood Mononuclear Cells , 2009, Journal of Pharmacology and Experimental Therapeutics.

[29]  Alan M Gewirtz,et al.  The c-myb proto-oncogene and microRNA-15a comprise an active autoregulatory feedback loop in human hematopoietic cells. , 2009, Blood.

[30]  Hamid Cheshmi.  Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers , 2011 .

[31]  E. Ng,et al.  Differential expression of microRNAs in plasma of patients with colorectal cancer: a potential marker for colorectal cancer screening , 2009, Gut.

[32]  G. Escolar,et al.  Induction of microparticle- and cell-associated intravascular tissue factor in human endotoxemia. , 2004, Blood.

[33]  L. Hood,et al.  Circulating microRNAs, potential biomarkers for drug-induced liver injury , 2009, Proceedings of the National Academy of Sciences.