Glia Scar Not The Villain In Spinal Cord Regeneration - Blog - Reeve Foundation

Would you buy it if all of a sudden Cruella de Vil started a shelter for homeless dogs and said she had undergone a change of heart? What about if Lord Voldemort forsook his evil nature to open a summer camp for inner-city muggles? I wouldn’t go for either story. How about this one: the glial scar, the villain of spinal cord injury, is actually one of the good guys?

Take it or leave it, though I’d suggest you take it, this came out this week in the top science journal Nature, from the Michael Sofroniew lab at UCLA: “Astrocyte scar formation aids central nervous system axon regeneration.” It’s a paper that may shake up the way people understand SCI repair or lack thereof.

We have all heard it said that scar lines the lesion area of an injured spinal cord and forms an impenetrable deadzone; nerve cells try to grow but can’t bust through the scar. Strategies to deal with the barrier and thus to encourage nerve repair include removing the scar, dissolving it with enzymes, or bypassing it with a bridge or detour. None of that may be needed. The UCLA group reports new evidence that the scar is not the problem; it’s actually part of the solution. It may be the case that scar-related dogma has indeed impeded research on repairing spinal cord injuries.

Sofroniew has actually been saying for almost 20 years that the scar-is-evil story in spinal cord repair is mostly myth. He’s not saying there is no scar; indeed, reactive astrogliosis is a very real hallmark of central nervous system injury. What he is saying is that gliosis has many gradations. From a 2009 paper:

...reactive astrogliosis is not an all-or-none response, nor is it a single uniform process, nor is it ubiquitously synonymous with scar formation. Instead, reactive astrogliosis is a finely gradated continuum of progressive changes in gene expression and cellular changes that are subtly regulated by complex inter- and intra-cellular signaling.

Understanding the signaling is the key to the research, and perhaps to development of therapies.

Here’s a quote from an interview I had with Sofroniew four years ago:

In one of our early projects on spinal cord injury, we found that if you prevent scar formation (using transgenic animals to completely prevent scar formation) the outcome is devastating, not beneficial. At that time there were still lots of people who thought that the main thing you needed to do after spinal cord injury is prevent the scar from forming. It turns out that the scar forms for a reason. It is essential for wound healing and without it, the wound is much bigger and tissue destruction is much worse; there is more dysfunction. You can’t remove the scar completely. It makes things worse. I prefer to think about bridging across the scar, rather than bulldozing through it. The trick is to find ways around it that are not harmful.

The Nature paper adds further evidence to the notion that the scar isn’t the major problem. From a UCLA press release this week:

"For 20 years, we have been applying technologies to prevent glial scarring in hopes of promoting nerve fiber regeneration, repair and recovery, but never observed a positive effect," said Sofroniew, a professor of neurobiology at the David Geffen School of Medicine at UCLA. "Now we find that disrupting glial scars actually harms nerve fiber regeneration that can be stimulated by specific growth factors."

The UCLA group, including first co-authors Mark Anderson (now at École Polytechnique Fédéral de Lausanne, in Switzerland) and Joshua Burda, a postdoc in Sofroniew's lab, asked a simple question. What if there is no scar, will there be robust regeneration? To answer that question, they used a mouse model in which certain genes were switched on to prevent any scars from forming. They also used another model of mouse that had been engineered so scars could form and then be chemically dissolved. Using fluorescent imaging, the researchers tracked single nerve axons. Did they cross the injury site if the scarring was blocked or zapped away?

No. Counterintuitively, at least by conventional thinking, the axons showed no sign of regrowing through the scar-free lesion in either case.

"This clearly refuted the assumption that getting rid of scars would permit spontaneous regeneration of injured axons," Sofroniew said. "In fact, it hinted that scars might play some sort of positive role."

The research also revealed the beneficial role of glial scars. Applying axon-specific growth factors not present in SCI lesions, plus “priming injuries,” they were able to stimulate “robust, laminin-dependent sensory axon regrowth past scar-forming astrocytes and inhibitory molecules in SCI lesions. Preventing astrocytic scar formation significantly reduced this stimulated axon regrowth.”

Burda suggests the finding could reset thinking in the field. "This paper may encourage some to shift their focus away from trying to decrease astrocyte activity, in particular in scar formation, and toward how to exploit it as a way to promote regeneration," he said.

From the paper:

Our findings show that contrary to the prevailing dogma, astrocyte scar formation aids rather than prevents central nervous system axon regeneration.

In a letter that accompanied the Sofroniew paper, Stanford neurobiologist Ben Barres, who runs one of the seven labs in the Reeve-funded International Research Consortium on Spinal Cord Injury, and his post-doc Shane Liddelow, added to the discussion.

Going forward, it will be important to define the signaling mechanisms that induce activation of the different types of reactive astrocyte. Studies of each cell type should then define their functions, whether they can inhibit axon growth and the molecular mechanisms that underlie their roles. This knowledge could enable the selective manipulation of certain astrocytes by specific molecules, which is preferable to deleting an entire cell popula­tion that may well both promote and inhibit axon regrowth. In any case, Anderson and colleagues have shown that, in spite of long-held beliefs to the contrary, reactive astrocytes may not be the villains of spinal-cord recov­ery, but instead might provide new hope for the regeneration of damaged axons.