Cedars-Sinai researchers have identified a new mechanism in the central nervous system that could inform future treatments for spinal cord injuries, stroke, and neurological conditions such as multiple sclerosis. The study, published in Nature, focuses on astrocytes—cells known to support nerve function and respond to injury.
Neuroscientist Joshua Burda, PhD, assistant professor of Biomedical Sciences and Neurology at Cedars-Sinai and senior author of the study, explained the findings: "Astrocytes are critical responders to disease and disorders of the central nervous system—the brain and spinal cord. We discovered that astrocytes far from the site of an injury actually help drive spinal cord repair. Our research also uncovered a mechanism used by these unique astrocytes to signal the immune system to clean up debris resulting from the injury, which is a critical step in the tissue-healing process."
The team named these cells "lesion-remote astrocytes" (LRAs) and identified several subtypes. The study details how one LRA subtype can sense and respond to tissue injury from a distance.
The spinal cord consists of gray matter at its center—containing nerve cell bodies and astrocytes—and white matter on the outside, made up of long nerve fibers and more astrocytes. When injury occurs, nerve fibers are damaged or destroyed, leading to paralysis or loss of sensation. Unlike other tissues where inflammation is localized, damage in the spinal cord causes inflammation that spreads beyond the initial site due to the length of nerve fibers.
In experiments with laboratory mice suffering from spinal cord injuries, researchers found that LRAs play a significant role in supporting repair processes. Similar mechanisms were observed in human tissue samples from patients with spinal cord injuries.
One subtype of LRA was found to release a protein called CCN1 that communicates with microglia—immune cells responsible for clearing debris in the central nervous system. Burda stated: "One function of microglia is to serve as chief garbage collectors in the central nervous system. After tissue damage, they eat up pieces of nerve fiber debris—which are very fatty and can cause them to get a kind of indigestion. Our experiments showed that astrocyte CCN1 signals the microglia to change their metabolism so they can better digest all that fat."
According to Burda, this process may contribute to spontaneous recovery seen in some patients after spinal cord injury. When CCN1 was absent, recovery was significantly impaired: "If we remove astrocyte CCN1, the microglia eat, but they don't digest. They call in more microglia, which also eat but don't digest," he said. "Big clusters of debris-filled microglia form, heightening inflammation up and down the spinal cord. And when that happens, the tissue doesn't repair as well."
Researchers also found evidence for this mechanism in tissue from patients with multiple sclerosis. Burda suggested these principles might apply broadly across brain or spinal injuries.
David Underhill, PhD, chair of Cedars-Sinai's Department of Biomedical Sciences commented: "The role of astrocytes in central nervous system healing is remarkably understudied. This work strongly suggests that lesion-remote astrocytes offer a viable path for limiting chronic inflammation, enhancing functionally meaningful regeneration, and promoting neurological recovery after brain and spinal cord injury and in disease."
Burda’s team plans further research into harnessing this mechanism for healing spinal cords as well as exploring its role in neurodegenerative diseases and aging.
