CLEMSON, South Carolina – A study out of Clemson University’s department of biological sciences has identified tiny particles in the brain that regulate the neuroimmune system, a result that might one day be used in treating traumatic brain injuries or viral infections of the brain.

The particles, called extracellular vesicles, are released from neural stem cells positioned near the center of the brain in a region known as the subventricular zone. The vesicles contain “messages” – in the form of short RNA sequences, or microRNAs – that are selectively received by microglia, the immune cells of the central nervous system that are the first line of defense against infection, damage or inflammation in the brain.

“The surprising finding for us was not only that the extracellular vesicles were being passaged to the microglia, but also that the microglia seemed to read the message and change their physiological state in response,” said David Feliciano, an assistant professor in the department of biological sciences and a corresponding author of the study.

Published on April 3 in Cell Reports, the study suggests that extracellular vesicles could potentially be engineered to direct microglia to diseased or damaged portions of the brain, where they could aid in the immune response.

Feliciano and his colleagues previously demonstrated that extracellular vesicles are found in cerebrospinal fluid (CSF), the colorless, protective liquid of the brain that originates from hollow cavities, known as ventricles. The ventricles themselves are thought to be remnants of embryonic development, and it’s along the outside of these ventricles that neural stem cells reside.

“Historically, cerebrospinal fluid has been seen as this passive liquid that functions as a cushion. One of the questions that we had was whether the CSF is as passive as it has been viewed,” Feliciano said. “Previous studies took a pool of pea soup from the CSF and looked at all the extracellular vesicles in there at one time, but we wanted to know who is contributing what ingredients to this soup.”

Extracellular vesicles are released from neural stem cells, which line the outside of the brain's ventricles.

Extracellular vesicles are released from neural stem cells, which line the subventricular zone in the brain.
Image Credit: Cell Reports, doi: 10.1016/j.celrep.2018.03.037

The team used various techniques to study the release of extracellular vesicles from neural stem cells both in culture – meaning, grown with nutrients in a lab – and in the brain. In one technique, the team genetically modified the neural stem cells to pinpoint where exactly they migrated within the brain. They also isolated the cells from the “pea soup” and grew them in culture, before isolating the extracellular vesicles from within the neural stem cells for more intense study.

“One of the things we’ve done, for example, is sequence the encoded information inside of the extracellular vesicles. This information comes as these small RNA particles – sequences somewhere between 19 and 21 nucleotides in length – and by sequencing those microRNAs, we know what message is inside of the extracellular vesicles,” Feliciano said.

The team also placed the vesicles under a microscope “to see visually with our own two eyes that these extracellular vesicles can actually be released,” he said.

Future studies could potentially generate extracellular vesicles that contain messages which lure microglia to diseased or damaged portions of the brain.

“Microglia can have different types of functions based on the different types of signals they receive,” Feliciano said. “One function could be wound healing, for example, or another function might be to go in and chew up amyloid plaques in a patient that has Alzheimer’s disease. Perhaps another would be in disorders of neuronal hyperconnectivity where seizures are an end result. It’s possible that extracellular vesicles can cause these microglia to change their physiological state to help remove some of these interactions that occur between cells when too many interactions exist.”

Although it’s early on in the discovery, Feliciano said there are definite applications down the road for extracellular vesicles in neurobiology.

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Research reported in this publication was supported by the Whitehall Foundation (2015-08-05). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Whitehall Foundation.