Zombie Cells Help Develop Crucial Blood-Brain and Cerebrospinal Fluid Barriers

Among the body's most crucial protective features are the brain barrier systems, including the blood-brain and blood-cerebrospinal fluid (CSF) barriers. These barriers are made of highly specialized cells that allow essential nutrients to enter, yet repel dangerous toxins and pathogens that may be circulating in the bloodstream. Scientists have long known what these barriers do, but less about how they are built during development.

A new study led by University of California San Diego researchers and published in Cell has uncovered a key contributor: senescent cells. Often associated with aging and disease, these cells instead appear to help construct and support the brain's protective barriers during development.

Central to their new insights is an evolving understanding of senescent cells, which traditionally have been labelled as "zombie" cells since they no longer are able to divide, yet don't fully die off. Senescent cells accumulate with age and have been linked to tissue dysfunction, chronic inflammation and cognitive decline, making them an attractive target for therapies aimed at slowing age-related decline.

In recent years, however, new studies have shown that senescent cells are not strictly tied to aging and disease. Researchers identified senescent cells that appear temporarily in developing mouse embryos and play roles in limb and kidney development. Other studies found that senescent cells have a transient role in wound healing, suggesting that these cells can be beneficial in some contexts. This led to the idea that senescence can be helpful when it is temporary, but harmful when it persists.

Research from the laboratory of School of Biological Sciences Assistant Professor Hiruy Meharena indicates that senescent cells play previously unrecognized roles in brain development.

Studying the developing brains of mice, Associate Project Scientist Ashley Watson identified senescent cells that emerge at distinct stages during the formation of two critical brain barrier systems: the blood-brain and blood-CSF barriers.

We found that these senescence-associated states appear in very specialized barrier cell types and at precise moments during brain development, suggesting they may play specialized roles in building the brain's protective barriers."

Ashley Watson, Associate Project Scientist, University of California San Diego

The researchers used an array of methods during the study, including single-cell RNA sequencing, imaging and genetic lineage tracing. They found that three cell types enter a senescent state during development: vascular endothelial cells, brain-resident macrophages and choroid plexus epithelial cells. These cells contribute to the formation of the brain's protective barriers in different ways. In endothelial cells and macrophages, senescence appears to help coordinate blood vessel patterning and formation of the blood-brain barrier. In the choroid plexus, which produces CSF and forms the blood-CSF barrier, senescence appears to support barrier development and function.

Senescent vascular endothelial cells and brain-resident macrophages appeared only transiently during growth and remodeling of the embryonic blood vessels that form the blood-brain barrier, they found. Choroid plexus epithelial cells, in contrast, retained features of senescence long after development and remained present into adulthood.

"That was one of the most unexpected findings," said Meharena. "Developmental senescence has generally been viewed as a transient process. Here, we identified a population of cells in the brain that appears to maintain senescence-associated features well into adulthood. This study shows that senescence can take many different forms in the brain, depending on the cell type and stage of development."

To test whether these cells were functionally important, the researchers eliminated senescent cells during embryonic development. Mouse embryos lacking these cells developed abnormalities in brain-barrier formation and fluid balance, indicating that senescence-associated cells contribute to normal brain development.

"What surprised us most was that senescence wasn't a single state. It looked very different across cell types and appeared to serve distinct functions depending on where and when it occurred," said Watson. "Moreover, the cells weren't acting independently. Senescence seemed to help different cell types work together to build, and in some cases sustain, the brain's protective barriers." 

The researchers are now studying how senescence and related processes unfold in brain diseases.