Mediating intercellular communication: mechanisms of extracellular vesicle transfer between cells

细胞间的通讯是人类健康和疾病的重要过程。一般来说，通讯是通过细胞间的直接接触或细胞间的分子分泌来介导的。最近，研究表明细胞也会分泌囊泡，这些囊泡可以介导邻近细胞的各种作用。这些细胞外囊泡就像原始细胞的“快照”，它们是从原始细胞分泌出来的，含有细胞特有的脂质、蛋白质、rna和DNA的子集。在血清中发现了细胞外囊泡，表明它们非常稳定，并由许多细胞类型分泌。此外，细胞外囊泡被认为与多种疾病状态有关，包括癌症、感染、神经变性和代谢紊乱。细胞外囊泡介导细胞间通讯主要有两种方式。第一种是细胞外囊泡与邻近细胞表面的受体结合，从而激活细胞内的信号通路。第二种是将细胞外囊泡的内容物运送到邻近细胞的细胞质（内部）。为了发生这种情况，细胞外囊泡的膜必须与靶细胞膜融合以释放其内容物。这种融合过程究竟是如何发生的尚不清楚，这代表了我们对细胞外囊泡生物学理解的一个主要空白。最近我已经证明，在细胞外囊泡表面至少有一种细胞质蛋白（理论上）应该只位于细胞外囊泡内部。这就提出了关于这些细胞外囊泡是如何形成的以及细胞外囊泡表面的蛋白质是什么组成的问题。在此观察的基础上，我打算鉴定在细胞外囊泡表面具有不可预测定位的其他蛋白质。这是很重要的，因为它将有助于确定参与膜融合过程的潜在候选者，这一过程目前知之甚少。鉴定参与融合过程的蛋白质将使我们更好地了解细胞间通讯并研究其在疾病中的作用。此外，我建议以前所未有的规模研究融合过程，使用最先进的成像技术，以极高的分辨率捕获图像。这将直接证明膜融合是否发生，并提供有关这一过程的重要信息。最后，这些细胞外囊泡有可能被用作治疗药物，这项研究将有助于指导细胞外囊泡的设计，以传递药物。

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.