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

大脑是一个代谢非常活跃的器官，并且不断需要为神经元细胞提供营养和氧气，并且同样需要处理废物和可能的神经毒性物质。引人注目的是，脑实质中有大量的血管，但没有淋巴管能够控制间质液的稳态或吸收大分子并将其从脑中清除。这是违反直觉的，长期以来，大脑如何处理不需要的大分子物质，特别是蛋白质废物，这是一个科学争论的焦点。虽然大脑中没有淋巴管，但哺乳动物大脑的脑膜层中确实存在淋巴管，最近，在神经血管和淋巴血管领域，关于淋巴管的生理作用，脑内环境稳定和大分子清除的术语。在斑马鱼脑膜中，管腔化淋巴管本身并不存在，但在2017年，我们和另外两个独立的研究小组证明了斑马鱼大脑脑膜层中存在淋巴内皮细胞（LEC）。值得注意的是，这些特定的LEC不形成内皮连续体或管腔化血管的一部分，而是作为增殖的个体细胞持续存在，在数量上扩大，并最终覆盖成鱼大脑的所有方面。这些细胞被称为脑淋巴内皮细胞（BLECs），壁LECs或荧光颗粒周皮细胞（FGP），其特征在于它们的分子特征（淋巴内皮细胞而不是巨噬细胞），它们从静脉脉络膜血管丛发芽，以及它们对干扰Vegfc/Ccbe 1/Vegfr 4信号轴的敏感性。另一个显著特征是存在大的亚细胞囊泡。本项目的中心目标是确定这些细胞的特征和功能，重点是脑膜中淋巴细胞和脑实质中神经细胞之间的神经血管串扰

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