Mediating intercellular communication: mechanisms of extracellular vesicle transfer between cells

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Communication between cells is an important process in human health and disease. Generally, communication is mediated by direct cell to cell contact or the secretion of molecules between cells. More recently, it has been shown that cells also secrete vesicles that can mediate various effects in neighbouring cells. These extracellular vesicles are like a 'snap shot' of the original cell from which they are secreted and contain a subset of lipids, proteins, RNAs and DNA specific to that cell. Extracellular vesicles are found in serum, indicating that they are very stable and secreted by many cell types. Additionally, extracellular vesicles are thought to be involved in several disease states including cancer, infection, neurodegeneration and metabolic disorders.There are two main ways that extracellular vesicles mediate communication between cells. The first involves extracellular vesicles binding to receptors on the surface of neighbouring cells to cause activation of signalling pathways within that cell. The second, involves delivery of the contents of the extracellular vesicle into the cytosol (inside) of the neighbouring cell. In order for this to happen the membrane of the extracellular vesicle must fuse with the target cell membrane to release its contents.Exactly how this fusion process occurs is not clear and represents a major gap in our understanding of extracellular vesicle biology. Recently I have shown that there is at least one cytosolic protein on the surface of extracellular vesicles that should (in theory) only be located inside the extracellular vesicles. This raises questions surrounding how these extracellular vesicles are made and what the composition of proteins on the surface of extracellular vesicles is. Building on this observation, I intend to identify other proteins with an unpredicted localisation on the surface of extracellular vesicles. This is important because it will help identify potential candidates involved in the membrane fusion process, which is currently very poorly understood. Identification of proteins involved in the fusion process will allow us to understand intercellular communication better and investigate its role in disease. Additionally, I propose to investigate the fusion process at a scale never observed before with state-of-the-art imaging techniques that will allow images to be captured in extremely high resolution. This will directly demonstrate whether membrane fusion occurs and provide vital information about this process. Finally, there is potential for these extracellular vesicles to be used as therapeutics, this study will help direct the design of extracellular vesicles for the delivery of drugs.