Physiological and patho-physiological roles of lymphatic endothelial cells in the meningeal layer of the zebrafish brain

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The brain is a metabolically extremely active organ, and is in constant demand of supplying neuronal cells with nutrients and oxygen, and likewise to dispose of waste products and possible neurotoxic substances. Strikingly, the brain parenchyma is amply provided with blood vessels, but there are no lymphatic vessels that would be able to control interstitial fluid homeostasis or to take up macromolecules and remove them from the brain. This is counter-intuitive, and it has long been (and still is) a point of scientific contention how the brain disposes of unwanted macromolecular material, in particular protein waste.While absent from the brain, lymphatic vessels do exist in the meningeal layers of the mammalian brain, and recently there has been tremendous excitement in both the neurovascular and the lymphatic vascular field about the physiological role of lymphatic vessels in terms of brain homeostasis and clearance of macromolecules. In the zebrafish meninges, lumenized lymphatic vessels as such do not exist, but in 2017, we and two other independent groups have demonstrated the presence of lymphatic endothelial cells (LECs) in the meningeal layer of the zebrafish brain. Remarkably, these particular LECs do not form an endothelial continuum or are part of a lumenized vessel, but rather persist as individual cells that proliferate, expand in numbers, and ultimately cover, in adult fish, all aspects of the brain. Coined either brain lymphatic endothelial cells (BLECs), mural LECs, or fluorescent granular perithelial (FGP) cells, these cells are characterized by their molecular signature (lymphatic endothelium rather than macrophage), their sprouting from the venous choroid vascular plexus, and their sensitivity to interference with the Vegfc/Ccbe1/Vegfr4 signaling axis. Another defining feature is the presence of large subcellular vesicles.The central objective in the present project is to define the characteristics and function of these cells with an emphasis on the neuro-vascular cross-talk between lymphatic cells in the meninges and neural cells in the brain parenchyma