CROSSTALK · Decoding Extracellular Vesicle-mediated organ crosstalk in vivo

To coordinate activities between different tissues, multicellular organisms critically rely on intercellular communication. Whereas homeostatic signalling within organs is studied extensively, inter-organ crosstalk is only starting to be unravelled. In recent years, Extracellular Vesicles (EVs) have emerged as central mediators of this pathway by shuttling specific bioactive cargo including proteins between cells. These nano-sized lipid vesicles are released by virtually every cell type, are transported via the blood and combine the intricacy of cell-cell contact with the long-acting range of cytokines. However, due to their small size and a lack of suitable approaches, to what extent endogenous EVs mediate inter-organ crosstalk and support custom cargo delivery is unclear. I recently developed a unique transparent zebrafish embryo model expressing optical EV-reporters to examine endogenous EV biology at unprecedented detail in vivo. The aim of this proposal is to understand endogenous EV-mediated organ crosstalk by studying EVs secreted by the liver, the central metabolic hub in vertebrates. To this end, I will decode hepatic EV communication routes in vivo in health and liver pathology by exploiting my model system combined with novel tools and high-resolution microscopy. I will pursue three key-objectives: 1) Targets: mapping hepatic EV target organs; 2) Contents: analysing custom cargo delivery by hepatic EVs to specific target organs. 3) Function: determining the function of endogenous hepatic EVs by developing and applying molecular tools to interfere with their release in vivo. This project will provide the first advanced mapping of endogenous EV inter-organ crosstalk in a living model organism. By studying how pathology impacts EV mediated organ crosstalk and gaining precise control over EV release in vivo I will obtain unique insights into EV pathophysiology. In turn, this will open avenues for optimized diagnostics and therapeutic intervention.