Glial Scarring Enhances Nerve-cell Regrowth

	Previously injured nerve fibers (red) regrow through a dense astrocyte scar (green) and around the edges of a biomaterial depot (blue). The growth occurred after the release of growth factors by the biomaterial depot. Image: Courtesy of Dr. Michael Sofroniew

Neuroscientists have long believed that scar tissue formed by glial cells — the cells that surround neurons in the central nervous system — impedes damaged nerve cells from regrowing following an injury to the brain or spinal cord. So it’s no wonder that researchers have assumed that if they could find a way to remove or counteract that scar tissue, injured neurons might spontaneously repair themselves. But a new study by UCLA scientists shows that this assumption might have been impeding research on repairing spinal-cord injuries.

In a study using mice, Michael V. Sofroniew, MD, PhD, professor of neurobiology, and colleagues found that the glial scar tissue that forms after spinal-cord damage actually might favor nerve-cell regeneration. The research could ultimately lead to new approaches to repair catastrophic spinal-cord injury.

“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,” Dr. Sofroniew says. “Now we find that disrupting glial scars actually harms nerve-fiber regeneration that can be stimulated by specific growth factors.”

The spinal cord is a thick cable of nerve projections called axons that course from the brain to activate muscles and from sensory organs back to the brain to provide feedback. Unlike peripheral nerves, which re-sprout axons when they’re damaged, mature spinal neurons don’t regrow axons in the part of the body where the injury has occurred, which results in paralysis below the injury.

So, wondering whether or not preventing or removing scars would encourage the nerves to regenerate, researchers evaluated two types of mice — one in which specific genes could be switched on to prevent the formation of scars and another engineered with genes that could dissolve scars after they formed. Using fluorescent imaging, the researchers then traced individual axons to see if they would approach or cross an injury site if the scarring was blocked or obliterated. In both cases, the axons showed no sign of regrowing through the lesion.

The research also revealed glial scars’ beneficial role in an experiment in which the scientists softly flog injured neurons into regenerating — a strategy Dr. Sofroniew likens to a “carrot-and-a-stick” approach. In either normal or genetically modified mice, neurotrophic growth factors (the carrot) are infused at the spinal-injury site at the same time that additional lesions known to stimulate nerve regrowth (the stick) are applied.

In the normal mice, the approach stimulated robust regrowth of the stalled spinal axons past glial scars and through the injury site. And in the mice that were engineered to eliminate scars, there was a pronounced reduction in this stimulated nerve regeneration — and in some cases, none at all.

The team also performed a biochemical screen to identify molecules expressed in scar tissue and discovered a relatively high level of factors that support axon growth. This shows that scars are capable of producing chemical signals, albeit faint ones, that permit axons to grow over them. Thus, future strategies for repairing the central nervous system might involve concocting even more potent mixtures of growth factors, like Dr. Sofroniew’s “carrot,” that could be continuously infused or implanted near a patient’s injury.

“Astrocyte Scar Formation Aids Central Nervous System Axon Regeneration,” Nature, April 14, 2016