Australian scientists at the University of Queensland (UQ) have discovered a new type of lymphatic brain "scavenger" cell in zebrafish, which may provide protection from stroke and dementias such as Alzheimer's disease and have important implications for drug development.
Published in the May 1, 2017, edition of Nature Neuroscience, the study involved researchers from UQ's Institute for Molecular Bioscience (IMB), the University of Melbourne, Monash University, and the National Cerebral and Cardiovascular Centre in Osaka, Japan.
The lymphatic system carries lymphocytes and other immune cells through a network of vessels and tissues, including lymph nodes. It also connects the body's tissues with the bloodstream, performing vital functions such as removal of dead blood cells and other waste. However, the newly discovered cells are not part of that lymphatic network, but are isolated, individual lymphatic scavenger cells.
Lead researcher Ben Hogan, an associate professor and co-head of the Division of Genetic of Development and Disease Research at UQ's IMB said the new discovery would help scientists to understand how the brain forms and functions.
"Our findings suggest that lymphatic cells form in the brain during development, but [subsequently] transition to a cell type not previously appreciated as being lymphatic in nature and found in the meninges of the brain," he told BioWorld Asia.
"It is rare to discover a cell type in the brain that we didn't know about previously, and particularly a cell type that we never expected. The brain is the only organ without a known internal lymphatic system, so these cells being lymphatic in nature and surrounding the inside of the layers around the brain is surprising," Hogan noted.
He acknowledged that previous work has described a lymphatic network in mouse brains. However, "that was outside the brain on the dural membrane surrounding the brain. These dural lymphatic vessels develop outside of the brain in mammals and we have also seen these lymphatic vessels in zebrafish.
"The cells we describe are on the inside of the layer around the brain and develop from within the brain. Importantly, these cells are not part of the lymphatic vessels, even though they have the molecular signature of lymphatic endothelial cells they are individual isolated mural cells that sit on top of blood vessels. This cell type has not been described previously."
Those newly discovered cells appear to be the zebrafish version of those described in humans as lipid-rich fluorescent granular perithelial (FPG) or "mato" cells, which remove fats and lipids from the system, but were not previously known to be lymphatic in nature.
"While these cells have been described in mammals as mato cells or meningeal macrophages, our findings suggest they have lymphatic vascular origins, although they do not form vascular tubes, which adds to our understanding of the different cell types comprising the brain vasculature," said Hogan.
"When wastes such as excess fats leak out of the bloodstream, it is the job of the lymphatic system to clean them out to avoid damaging our organs," he explained. "The presence of this system to scavenge wastes in the brain suggests it is needed, and we are interested in further understanding the functional importance of these cells in cleaning the brain."
He said that while the study focused on the presence and development of such scavenger cells in zebrafish, there was good reason to believe that equivalent cells surround and protect the brain from a buildup of cellular waste in humans.
Small tropical relatives of the minnow, zebrafish are used increasingly in studies of human diseases. Zebrafish are easy to care for and cost-effective, but also offer other biological advantages. In particular, "Zebrafish are naturally transparent, so we can use advanced light microscopes to see directly into the zebrafish brain," Hogan said. "Examining the zebrafish brain up close allowed us to find these cells and see how they form and function in detail.
"Normally, lymphatic endothelial cells group together to form lymphatic vessels to carry fluid, but . . . in the adult zebrafish brain, these cells exist individually, independent of vessels and collect waste that enters the brain from the bloodstream."
Regarding the relevance of zebrafish findings to humans, "zebrafish are now broadly used to model human diseases and have been extremely successful in identifying mechanisms of various diseases, for example of the blood, vasculature, muscle, brain and cancers," Hogan said.
"The zebrafish has led to validation of the functional relevance of many candidate genetic mutations identified in patients, and has also been used successfully to identify new drugs," he added.
"Our focus now is to investigate how these cells function in mammals and even humans and see if we can control them with existing drugs to promote brain health, and improve our understanding of neurological diseases such as stroke and dementia."
While this is an early stage discovery and its long-term implications are unclear, "we hope that a deeper understanding of this biology may serve as a stepping stone to better understand diseases of the neurovasculature and perhaps even neurodegenerative disorders," suggested Hogan.
"Meanwhile, we are working on cell lineages we believe to be equivalent to zebrafish mural lymphatic endothelial cells in mice, to determine their conserved nature and functions. Once we can isolate and manipulate equivalent cells in mice, we can examine mammalian disease paradigms."