Cedars-Sinai investigators have discovered a healing mechanism that could one day be harnessed to help treat patients with spinal cord injuries, stroke, and neurological conditions such as multiple sclerosis. Their study, published in Nature , describes a previously unknown function of astrocytes, a type of 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 investigators dubbed these astrocytes "lesion-remote astrocytes," or LRAs, and identified several distinct LRA subtypes. Their study describes for the first time how one LRA subtype remotely senses and responds to tissue injury.
The spinal cord is a bundle of nerve tissue that runs from the brain down the back. At its center is gray matter, which contains the bodies of nerve cells and support cells called astrocytes. Surrounding it is white matter, made up of astrocytes and long nerve fibers that stretch up and down the cord to send signals between the brain and the rest of the body. Astrocytes help keep the nervous system healthy and ensure that these signals flow smoothly.
Spinal cord injuries damage nerve fibers, paralyzing parts of the body and disrupting sensory input such as touch and temperature. The severed fibers die off and become debris. In most other types of tissue in the body, inflammation takes place only at the site of injury. But because of the length of nerve fibers in the spinal cord, damage and inflammation extend far beyond the injury site.
Investigators looked at laboratory mice with spinal cord injury and found that LRAs play an important role in supporting nervous system repair. They saw strong evidence of the same mechanism in tissue samples from human patients with spinal cord injury.
The Burda Lab identified one LRA subtype that sends out a protein called CCN1 to signal to immune cells called 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."
Burda said this efficient debris clearing might have a role in the spontaneous recovery found in many patients with spinal cord injury. In the absence of the astrocyte-derived CCN1 protein, the investigators found that recovery is drastically 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," 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."
When investigators looked at spinal cord tissue from human patients with multiple sclerosis, they found the same mechanism at work, Burda said. He added that these fundamental principles of tissue repair likely apply to any sort of injury of 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 leading efforts to harness this CCN1 mechanism in spinal cord healing and to further investigate the role of astrocyte CCN1 in inflammatory neurodegenerative disease and in 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.
Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.
