Scarring is nature’s wise way of sealing and healing an open wound. But sometimes Mother Nature outsmarts herself.
One such time, recent research suggests, occurs when trauma inflicts severe injury on the spinal cord. In urgent response, the immune system dispatches fibroblasts and other cells to infiltrate the scene of the lesion, and quickly dam up the damage with impenetrable scar tissue.
“There’s a lot of research going on to eliminate the spinal scar, but perhaps not as a physical barrier,” observed neuroimmunologist Ellen Heber-Katz, a professor at the Wistar Institute in Philadelphia. “A lot of people have been examining the central nervous system in terms of molecules that are inhibitory, and don’t allow axonal growth.”
Heber-Katz is senior author of a paper in tomorrow’s Journal of Neuroscience Research, dated Feb. 1, 2002. It’s titled: “Recovery from spinal cord injury: New transection model in the C57Bl/6 mouse.”
“What we showed,” she told BioWorld Today, “was that if we eliminate scar tissue, there is incredible regenerative capacity in the spinal cord.”
It needs it.
In the U.S. alone, there are a quarter-million chronic spinal-injury patients, many of whom live as long as 40 years with their paraplegic disablement. Each year adds 10,000 to 12,000 new cases, of whom 90 percent survive. Forty percent of these injuries are caused by automobile, motorcycle and bike accidents, followed by violence gunshot and knife wounds falls and sports-related trauma.
In her team’s in vivo experiments, Heber-Katz tested her hypothesis that minimal scar tissue frees up the severed spinal cord to regenerate and recover from its crippling loss of function.
“We had previously been focused on the MRL mouse,” she recounted, ”which has the inbred ability to eliminate scar tissue, or not allow scar tissue to form, and to regenerate function. But more than that, the ability of the spinal cord to make a comeback to the extent that it had in this MRL mouse was quite surprising as we showed some years ago with heart-muscle regeneration.” (See BioWorld Today, Aug. 7, 2001, p. 1.)
To Maximize Healing, Minimize Scarring
“In the present two in vivo experiments cut dura and intact dura we used the common C57Bl/6 mouse,” Heber-Katz related. “We began by making very severe injuries in their spinal cords, cutting widely through the dura mater the tough membrane wrapped around the spinal cord and finding interesting differences. But when we made those severe lesions, we got scarifying infiltrates, over a wide area, allowing fibroblasts to migrate into the wound site. And the two severed stumps of the spinal cord weren’t very close to one another. So we decided to try keeping the injury to a minimum. We wanted to avoid infiltrates, and also keep the two sides of the cord in close apposition.
“So we changed to making a simple, more delicate, transection that minimized scar formation. One way of doing that was cutting a very small incision in the dura mater and keeping those two sides together. However, we did make a complete, severing transection. And what happened was that in the intact dura experiment, the mice regenerated and recovered incredibly.
“In this study we used C57Bl/6 mice for both experiments. The cut dura model was a transection that completely cut the spinal cord and the dura mater. So it resulted in a large separation between the two cut ends of the spinal cord. In the second model, the intact dura, to avoid that we made a very small cut in the dura with a microscopically precise surgical knife, and cut the cord. But because the dura was left relatively intact, we did not get a lot of fibroblast infiltration.
“The functional results,” Heber-Katz continued, “showed that the intact-dura animals were able to walk. With the cut-dura injuries, the mice couldn’t walk, or move their hind limbs, or their tails. In three weeks, the intact-dura model mice displayed coordinated movement. They could move their hind limbs and tails. They were not 100 percent normal,” Heber-Katz allowed, “but I would say 80 percent.
“When we autopsied their cord lesions histologically,” she went on, “we could see axonal bridging. Longitudinal sections revealed multiple areas where there were bridges crossing the transection site. Also areas where there was no bridging. So it was clear that a cut had been made. We looked for astrocytes antigenic cells and could see movement of axons through these bridges, whereas the scar acted as an absolute physical barrier. Astrocytes are cells probably responsible for the glial scars. So the spinal cord scarring seen by others in other models are produced by astrocytes of one cell type. In our case, the astrocytes cannot go through these scars.
“What we’re doing now,” Heber-Katz observed, “is trying to look at the effects of various proteases enzymes that can break down that scar tissue. Alternatively, seeking a mechanical way of opening areas where one can get through the scar. That is, defeating the scar tissue as a physical barrier, which is what we’re worried about. Not the inhibitory molecules in the spinal cord, but that barrier. So if we can eliminate that scar tissue, or find ways of punching holes in it, we should be able to get axonal growth and regeneration. Those are things we would like to test.”
On Drawing Board: Clinical Applications
She made the added point, “More clinically relevant, perhaps, as our research also suggests, is that drugs able to biochemically block scar-tissue formation immediately following such an injury might have a similarly beneficial effect. Most tantalizing,” she went on, “is the possibility raised by the study of therapies designed to eliminate existing scar tissue at the site of past injuries. We would like to work with someone who has something that can break down scar tissue. It’s not been a focus of what we’ve been doing, but it’s clear that’s the direction we have to go in.
“On the other hand,” Heber-Katz said, “we have no information about what happens a year after an injury occurs. Can we take an animal that has a cut dura, so they have a scar and can’t walk, and at later time points eliminate that scar surgically? What would we see? Those experiments,” she concluded, “are ongoing in my lab as well.”