The role of microRNAs in cell:cell communication

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The project investigates a novel form of communication between cells involving the transfer of small regulatory molecules called 'microRNAs' in small sacs or 'microvesicles'. Many cells generate microvesicles from their cell membranes, enclosing contents from inside the cell. The released microvesicles are carried in the blood, for example, until they contact another cell. They can then interact with the surface of the second cell or actually be taken up and release their contents inside. It has been shown that microvesicles convey 'instructions' telling the recipient cell to, for example, divide or form new blood vessels. Whilst microvesicles are ubiquitous in lower organisms, in vertebrates they have been isolated primarily from blood and other body fluids. It may be that routine passage of microvesicles from cell to cell within tissues has simply not been observed due to the difficulties of detection. If this is the case, they are a hugely underestimated form of communication. One of the classes of molecule carried by microvesicles is microRNA. Over the last few years these small RNAs have been shown to play an indispensable role in regulating gene expression and to be essential for normal development. Each of the ~500 microRNAs present in vertebrates targets several hundred messenger RNA molecules (mRNAs). MicroRNAs therefore have the capacity to 'fine tune' global gene expression patterns. The first objective of the project is to demonstrate that microRNAs carried by microvesicles can alter gene expression in their target cells. This has never been reported and would show that it is feasible for cells to communicate between one another using this mechanism. The second objective is to measure the extent and significance of this form of communication in biological systems. We have chosen to concentrate on a critical physiological process called angiogenesis, whereby new blood vessels are formed from pre-existing vessels. Angiogenesis relies on cell-cell communication and can be readily studied in the laboratory setting. A new technique which can simultaneously measure millions of RNA molecules will be used to investigate whether the microRNAs carried in microvesicles are affecting the expression of genes in the endothelial cells as they form new blood vessels. The main expected outcome of this project is knowledge of whether gene expression can be modulated by microRNAs carried by microvesicles and if this is an important mechanism. The several reports of microRNAs in microvesicles appear to represent a general phenomenon because we have replicated this finding in multiple cell types. Given the known and potentially widespread existence of microvesicles, microRNA transfer could be a significant novel form of inter-cellular communication. If this proves to be the case the beneficiaries of the project would be all those who are working in the field of cellular communication, for example during development. This knowledge could lead to better understanding of certain disease processes. This mechanism is amenable to manipulation and could therefore provide a novel approach for intervention in disease and industrial processes.