Recent findings have shown that the blood vessels of different organs exert an active role in regulating organ function. In detail, the endothelium that aligns the vasculature of most organs is fundamental in maintaining organ homeostasis and in promoting organ recovery following injury. Mechanistically, endothelial cells (EC) of tissues such as the liver, lungs or the bone marrow (BM) have been shown to produce "angiocrine" factors that promote organ recovery and restore normal organ function. Controlled production of angiocrine factors following organ injury is therefore essential to promote organ regeneration and to restore organ function. However, the molecular mechanisms underlying the coordinated production and function of such "angiocrine" factors are largely undisclosed and were the subject of the present study. In detail, we identified for the first time a microRNA (miRNA) expressed by BM EC that regulates the expression of angiocrine genes involved in BM recovery following irradiation. Using a microarray-based approach, we identified several miRNA expressed by irradiated BMEC. After validating the variations in miRNA expression by semi-quantitative PCR, we chose to study further the ones showing consistent variations between experiments, and those predicted to regulate (directly or indirectly) angiogenic and angiocrine factors. Of the mi-RNA that were chosen, miR-363-5p (previously termed miR-363*) was subsequently shown to modulate the expression of numerous EC-specific genes including some angiocrine factors. By luciferase reporter assays, miR-363-5p is shown to regulate the expression of angiocrine factors tissue inhibitor of metalloproteinases-1 (Timp-1) and thrombospondin 3 (THBS3) at post-transcriptional level. Moreover, miR-363-5p reduction using anti-miR is shown to affect EC angiogenic properties (such as the response to angiogenic factors stimulation) and the interaction between EC and hematopoietic precursors (particularly relevant in a BM setting). miR-363-5p reduction resulted in a significant decrease in EC tube formation on matrigel, but increased hematopoietic precursor cells adhesion onto EC, a mechanism that is shown to involve kit ligand-mediated cell adhesion. Taken together, we have identified a miRNA induced by irradiation that regulates angiocrine factors expression on EC and as such modulates EC properties. Further studies on the importance of miR-363-5p on normal BM function and in disease are warranted.
Pubmed ID: 24257019 RIS Download
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Central online repository for microRNA nomenclature, sequence data, annotation and target prediction.Collection of published miRNA sequences and annotation.
View all literature mentionsAn algorithm for the identification of microRNA targets. Details are provided (3' UTR alignments with predicted sites, links to various public databases etc) regarding: # microRNA target predictions in vertebrates (Krek et al, Nature Genetics 37:495-500 (2005)) # microRNA target predictions in seven Drosophila species (Grn et al, PLoS Comp. Biol. 1:e13 (2005)) # microRNA targets in three nematode species (Lall et al, Current Biology 16, 1-12 (2006)) # human microRNA targets that are not conserved but co-expressed (i.e. the microRNA and mRNA are expressed in the same tissue) (Chen and Rajewsky, Nat Genet 38, 1452-1456 (2006)) co-expressed targets
View all literature mentionsWeb tool to predict biological targets of miRNAs by searching for presence of conserved 8mer, 7mer and 6mer sites that match seed region of each miRNA. Nonconserved sites are also predicted and sites with mismatches in seed region that are compensated by conserved 3' pairing. Used to search for predicted microRNA targets in mammals.
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