ABOVE: Mouse meningeal lymphatic vessels are pictured in green and blue, alongside blood vessels in red.

JI HOON AHN

For years, scientists thought the brain lacked a lymphatic system, raising questions about how fluid, macromolecules, and immune cells escape the organ. In 2015, two studies in mice provided evidence that the brain does in fact have a traditional lymphatic system in the outermost layer of the meninges—the coverings that protect the brain and help keep its shape—but scientists hadn’t yet figured out the exact exit route cerebrospinal fluid (CSF) and molecules take.

In a study published today (July 24) in Nature, researchers show that there is a hot spot of meningeal lymphatic vessels at the base of the rodent skull that is specialized to drain CSF and allow proteins and other large molecules to leave the brain.

“What they showed very nicely is that the system of meningeal lymphatics is the drainage system of the CSF of the central nervous system,” says Jonathan Kipnis, a neuroscientist at the University of Virginia who did not participate in the new study, but coauthored the first 2015 study. “We’re just scratching really the surface of understanding what these vessels are doing.”

See “Rethinking Lymphatic Development”

“I’m actually quite relieved because when we published in 2015 . . . we got a lot of contrasting comments and some people were not convinced that the lymphatics really can be involved in cerebrospinal fluid drainage because there was a lot of literature telling otherwise,” Kari Alitalo of the University of Helsinki tells The Scientist. Alitalo coauthored the second 2015 paper describing the brain’s lymphatic system, but was not involved in the current study.

Upon seeing the evidence published by the teams of Kipnis and Alitalo, Gou Young Koh, a researcher at the Korea Advanced Institute of Science and Technology, wanted to clarify exactly how CSF was draining. He and his colleagues used transgenic mice to visualize the anatomy and morphology of the brain’s lymphatic system. They found that, in contrast to dorsal meningeal lymphatic vessels, basal vessels were in close proximity to the fluid-filled space surrounding the brain and had specialized valves and junctions that could allow them to both take up and transport CSF.

When the authors followed CSF drainage with magnetic resonance in rats or a small molecule tracker injected into mice, they saw the tracer was taken up by the basal meningeal vessels and then exited the brain through them. The researchers didn’t see any uptake by dorsal vessels. Finally, they confirmed results that had been shown previously—that aged mice have a reduced turnover and outflow of CSF—and showed that the basal meningeal lymphatic vessels in older mice increased in number, yet were enlarged and dysfunctional, which could explain the animals’ impaired drainage.

“It’s a major piece of data to convince the field that indeed the meningeal lymphatic network is actively participating in the drainage of cerebrospinal fluid,” says Antoine Louveau of the Cleveland Clinic’s Lerner Research Institute. He did not participate in the current work, but, with Kipnis, coauthored the 2015 study, which focused on the dorsal meningeal vessels. He says that the anatomical differences between the dorsal and basal lymphatics and their possible role in neurological disorders are prime targets for future research. “If the [lymphatic vessels] that are in the dorsal part are not made to be draining, then it raises the question, why are they here in the first place? Why would the body make those lymphatics extend so much into a region where they are not functional?"

Others in the field wonder whether this study tells the whole story. “My major misgiving with the paper is that they’re ignoring some of the other outflow routes that we have shown and that many, many others have shown in the past,” says Steven Proulx of the University of Bern. In 2017, his group published a study in which they tracked CSF’s route out of the mouse brain along nerves that exit the skull at the nasal region and along the optic nerve. “It remains an important question what the major outflow route is and how that varies between species. People are dying to see what happens in humans, but it’s been very difficult to try to translate these sorts of studies . . . to people,” he adds.

J.H. Ahn et al., “Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid,” Nature, doi:10.1038/s41586-019-1419-5, 2019.

Abby Olena is a freelance journalist based in North Carolina. Find her on Twitter @abbyolena.