April 19, 2016

Spinal cord injury repair requires scars

At a Glance

  • A study in mice suggests that scar formation may help, not hinder, nerve regrowth after spinal cord injury.
  • The findings, which contradict previous dogma, could lead to new strategies to encourage nerve fibers to regrow across spinal lesions.
Axon regrowth through an astrocyte scar Previously injured axons (red) can grow through a dense astrocyte scar (green) in the presence of molecules that stimulate growth (blue).Dr. Michael V. Sofroniew, UCLA

Spinal cord injuries can occur after a sudden, traumatic blow to the spine. Most injuries don’t completely sever the spinal cord, but instead fracture or compress the vertebrae. This damage can crush and destroy axons—the nerve cell extensions that carry signals up and down the spinal cord between the brain and the rest of the body. If this communication pathway can’t be repaired, spinal cord damage can cause serious disability, including paralysis.

When the spinal cord is damaged, specialized cells head to the injury site and form a scar. For decades, researchers believed that scar-forming cells called astrocytes prevented neuronal regrowth at sites of spinal cord injury. Therefore, a team led by Dr. Michael V. Sofroniew at the University of California, Los Angeles, investigated whether blocking astrocyte scars from forming or removing them once they’ve formed would allow neurons to regrow. The research was funded in part by NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and National Institute of Mental Health (NIMH). Results were published on April 14, 2016, in Nature.

Using genetically modified mouse models, the researchers removed either astrocyte cells or the chemical signal they release, STAT3. Both are necessary components for astrocyte scar formation. The team then measured the regrowth of 3 different types of neurons—coming from the brain, the periphery, and the brainstem (CST, AST, and 5HT)—8 weeks after a spinal cord lesion.

The scientists found that when astrocyte scar formation was prevented, nerve cells didn’t regenerate. The team also tried removing scars that had formed 5 weeks after a spinal cord injury to see if the nerve cells could spontaneously regrow. The cells, however, didn’t regrow.

A genomic analysis revealed that astrocytes and other cells at the injury site release a diverse mix of chemicals that either block or support axon regrowth. Notably, scar-forming astrocytes and non-astrocyte cells increased levels of certain growth-stimulating molecules. This result suggested that some scar-forming cells may actually encourage axon regrowth.     

The researchers next stimulated axon regeneration by using synthetic hydrogels to deliver growth-inducing molecules to injury sites. They discovered robust AST axon regrowth through astrocyte scars. However, when they used this strategy in the mice that were unable to form scars, regrowth was either significantly reduced or completely absent.

“At first, we were completely surprised when our early studies revealed that blocking scar formation after injury resulted in worse outcomes,” Sofroniew says. “Once we began looking specifically at regrowth, though, we became convinced that scars may actually be beneficial. Our results suggest that scars may be a bridge and not a barrier towards developing better treatments for paralyzing spinal cord injuries.”

The team plans to further investigate the mechanisms by which astrocytic scars support growth and to explore ways to increase that response.

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Reference: Astrocyte scar formation aids central nervous system axon regeneration. Anderson MA, Burda JE, Ren Y, Ao Y, O'Shea TM, Kawaguchi R, Coppola G, Khakh BS, Deming TJ, Sofroniew MV. Nature. 2016 Apr 14;532(7598):195-200. doi: 10.1038/nature17623. Epub 2016 Mar 30. PMID: 27027288.

Funding: NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and National Institute of Mental Health (NIMH); Dr. Miriam and Sheldon G. Adelson Medical Foundation; and Wings for Life.