Scientists have picked apart the role of scarring after spinal cord injury and found that there is at least one component of the glial scar that is helpful for tissue regeneration.

“The role of the scar tissue is complex, but it has mainly been implicated in inhibiting regeneration.” Senior author Jonas Frisen of the Karolinska Institutet explained in a podcast published along with the paper, which appeared in the Nov. 1, 2013, issue of Science. “However, we now show that one distinct component of the scar generated by neural stem cells is necessary for limiting the injury and also for supporting the survival of nerve cells close to the lesion.”

Scarring after spinal cord injury involves several different cell types, but the most-studied aspect of such scarring is the glial scar, which formed by astrocytes. Most of those astrocytes are derived from a reservoir of neural stem cells that appears to be around for this specific purpose.

“In the intact issue, they do not really do anything,” Frisen said. But in response to injury, those stem cells generate most of the astrocytes that form the glial scar.

To understand the contributions of those stem cells, Frisen and his team knocked out the ras gene, which is indispensable for cells to progress through the cell cycle.

“We didn’t actually . . . destroy these cells,” Frisen said. “They just couldn’t generate any progeny that could generate scar tissue.”

Frisen and his team then looked at the effects of spinal cord injury in ras knockouts over 14 weeks. They found that recovery proceeded quite differently in the knockouts than in control animals.

“In intact animals, very dense scar tissue forms after the lesions, which gradually contracts over time,” Frisen said. Knockouts, on the other hand, had “large holes in the lesion.”

Their lesions also grew at a time when the lesions of control animals were contracting after injury. “Starting about three weeks after the lesion, their injuries started to expand,” Frisen said, while the control animals’ injury was decreasing.

The effects were due specifically to the lack of progeny from neural stem cells. When Frisen and his colleagues blocked the injury response of pericytes, which contribute to the fibrosis that stabilizes the scar, that blockade did not lead to changes in the size of the scar compared to controls.

Ras knockouts also produced fewer neurotrophic factors. As a result, the knockouts had thinner spinal cords after 14 weeks. They also had fewer inflammatory cells in the injury site than control animals.

Frisen said that his team’s results means that the role – and the targeting – of scar formation needs in spinal cord injury should be rethought.

“There have been many suggestions that it would be beneficial to block or reduce the formation of scar tissue in the injured spinal cord,” because they produce inhibitory factors that can block neural sprouting. (See BioWorld Today, Nov. 4, 2004, and July 19, 2011.)

“I think our study highlights that this is really rather complex . . . by studying one distinct component of the scar tissue that is generated by the neural stem cells, we can clearly say that this particular component of the scar tissue is not attractive to block or to inhibit its formation.”

On the other hand, the studies provide additional insight into the benefits of stem cell transplantation. Stemcells Inc. is in trials with human neural stem cell-derived cells for the treatment of chronic spinal cord injury, and Geron Corp., whose stem cell assets were acquired by Asterias Biotherapeutics Inc. earlier this year, had launched a Phase I trial of embryonic stem cell-derived oligodendrocyte precursors in spinal cord injury – the first FDA-approved clinical trial of embryonic stem cells. (See BioWorld Today, Aug. 4, 2010, and April 5, 2013.)

“It is attractive to perhaps consider increasing the generation of progeny from the neural stem cells,” Frisen said, though he noted that transplantation is not the only way to achieve those benefits. “An alternative to transplanting cells could be to modulate the response of the endogenous . . . cells which are present in the spinal cord.”