Researchers at Cedars-Sinai have identified a biological repair process that could eventually lead to new treatments for spinal cord injuries, stroke, and neurological diseases such as multiple sclerosis. The findings, published in Nature, reveal an unexpected role for astrocytes, a major support cell in the central nervous system.
“Astrocytes are critical responders to disease and disorders of the central nervous system — the brain and spinal cord,” said neuroscientist Joshua Burda, PhD, assistant professor of Biomedical Sciences and Neurology at Cedars-Sinai and senior author of the study. “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,” or LRAs. They also identified several distinct subtypes. For the first time, the study explains how one subtype can detect damage from a distance and respond in ways that support recovery.
How the Spinal Cord Responds to Injury
The spinal cord is a long bundle of nerve tissue that extends from the brain down the back. Its inner region, called gray matter, contains nerve cell bodies along with astrocytes. Surrounding that is white matter, made up of astrocytes and long nerve fibers that carry signals between the brain and the rest of the body. Astrocytes help maintain a stable environment so these signals can travel properly.
When the spinal cord is injured, nerve fibers are torn apart. This can cause paralysis and disrupt sensations such as touch and temperature. The damaged fibers break down into debris. In most tissues, inflammation remains confined to the injured area. In the spinal cord, however, nerve fibers can span long distances, so damage and inflammation can spread well beyond the original injury site.
Lesion-Remote Astrocytes and Immune Cleanup
In experiments involving mice with spinal cord injuries, researchers found that LRAs play a key role in promoting repair. They also found strong signs that the same process occurs in spinal cord tissue from human patients.
One LRA subtype produces a protein called CCN1. This molecule sends signals to immune cells known as microglia.
“One function of microglia is to serve as chief garbage collectors in the central nervous system,” Burda said. “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 improved debris removal may help explain why some patients experience partial, spontaneous recovery after spinal cord injury. When researchers eliminated astrocyte-derived CCN1, healing was significantly reduced.
“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,” Burda 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.”
Implications for Multiple Sclerosis and Brain Injury
When scientists examined spinal cord samples from people with multiple sclerosis, they observed the same CCN1-related repair process. Burda noted that these basic repair principles may apply broadly to injuries affecting either the brain or spinal cord.
“The role of astrocytes in central nervous system healing is remarkably understudied,” said David Underhill, PhD, chair of the Department of Biomedical Sciences. “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 is now working to develop strategies that harness the CCN1 pathway to improve spinal cord healing. His team is also studying how astrocyte CCN1 may influence inflammatory neurodegenerative diseases and aging.
Additional Cedars-Sinai authors include Sarah McCallum, Keshav B. Suresh, Timothy S. Islam, Manish K. Tripathi, Ann W. Saustad, Oksana Shelest, Aditya Patil, David Lee, Brandon Kwon, Katherine Leitholf, Inga Yenokian, Sophia E. Shaka, Jasmine Plummer, Vinicius F. Calsavara, and Simon R.V. Knott.
Other authors include Connor H. Beveridge, Palak Manchandra, Caitlin E. Randolph, Gordon P. Meares, Ranjan Dutta, Riki Kawaguchi, and Gaurav Chopra.
Funding: This work was supported by: the US National Institutes of Health (NIH) 5R01NS128094, R00NS105915, K99NS105915 (to J.E.B.), F31NS129372 (to K.S.), K99AG084864 (S.M.) R35 NS097303 and R01 NS123532 (RD), R01MH128866, U18TR004146, P30 CA023168 and ASPIRE Challenge and Reduction-to-Practice award (to G.C.); the Paralyzed Veterans Research Foundation of America (to J.E.B.); Wings for Life (to J.E.B.); Cedars-Sinai Center for Neuroscience and Medicine Postdoctoral Fellowship (to S.M.); American Academy of Neurology Neuroscience Research Fellowship (to S.M.); California Institute for Regenerative Medicine Postdoctoral Scholarship (to S.M.); The United States Department of Defense USAMRAA award W81XWH2010665 through the Peer Reviewed Alzheimer’s Research Program (to G.C.); The Arnold O. Beckman Postdoctoral Fellowship (to C.E.R.); The Purdue University Center for Cancer Research funded by NIH grant P30 CA023168 is also acknowledged.