Over the past decade, intensive studies have shown that the brain meningeal lymphatic system acts as the brain's "waste disposal network," maintaining homeostasis by clearing metabolic waste and transporting immune cells. However, the mechanism underlying its development regulation remains unknown—how does this intricate system form, and which cells or signals govern its specific spatial arrangement in the meninges?

A study published in Cell and led by Dr. DU Jiulin's lab at the Institute of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology of the Chinese Academy of Sciences uncovered the core regulatory mechanism of brain meningeal lymphatic system development.

Taking advantage of in vivo long-term imaging in zebrafish, in combination with genetic manipulations and neural activity studies, researchers found that increasing neural activity such as visual stimulation significantly enhances the development of mural lymphatic endothelial cells (muLECs) in the leptomeninges, while inhibiting neural activity such as visual deprivation leads to a significant reduction in the muLEC number. 

Focusing on Vegfc, a key factor necessary for lymphatic system development, researchers identified a specific glial subpopulation—slc6a11b+ RAs—that expresses Vegfc. These cells extended fibers to the brain surface, making them the main source of Vegfc in the brain. Deletion of slc6a11b+ RAs impaired muLEC development, while upregulating these cells' Vegfc signaling enhanced muLEC development. 

Moreover, researchers found that the slc6a11b+ RAs’ activity and their Vegfc expression levels are positively regulated by neural activity. They found that the precursor Vegfc (pro-Vegfc) secreted by slc6a11b+ RAs requires the cooperation of ccbe1+ fibroblasts to be converted into its mature form (mVegfc). This cross-tissue collaboration precisely restricted the distribution of mVegfc to the brain-meningeal interface, ensuring that lymphatic endothelial cells were confined to the brain surface, preventing their invasion into the brain parenchyma, which could cause immune disruptions.

The study shows that the brain acts as a "coordinator" of its microenvironment, and reveals a novel "neural-glia-fibroblast-lymphatic" regulatory axis. This provides a new framework for understanding how the brain adapts its lymphatic network based on functional needs, and explains why the brain meningeal lymphatic system remains confined to the meninges, avoiding invasion into the brain parenchyma. In the future, intervening in this regulatory network may offer new perspectives on the role of the meningeal lymphatic system in neurological diseases and developing treatments.