Zebrafish gives hope for spinal cord repair

The zebrafish might hold some hope for scientists looking for ways to repair damaged spinal cords with proteins that build bridges across gaps where injury occurred.

Scientists at Duke University, North Carolina, studied the way the fish repair the injury, something that would be either fatal or life-changing for humans. In a study reported in the journal Science, they found a particular protein that stimulated the regeneration.

In the process of bridge building, supporting cells called glia extend projections into a distance tens of times their own length and connect across a wide gulf of the injury.

Full nerve cells then grow across and, after about 8 weeks, new nerve tissue will have filled the gap meaning that the animals fully reverse their paralysis.

 "This is one of nature's most remarkable feats of regeneration," said the study's senior investigator Kenneth Poss, professor of cell biology and director of the Regeneration Next initiative at Duke. "Given the limited number of successful therapies available today for repairing lost tissues, we need to look to animals like zebrafish for new clues about how to stimulate regeneration."

A prize catch protein

Scientists then went on a "molecular fishing expedition," searching for all of the genes whose activity abruptly changed after spinal cord injury. They found seven proteins that were secreted by cells following injury and honed in on one of them, connective tissue growth factor (CTGF or CTGFA), that increased particularly in the glial cells.

"We thought that these glial cells and this gene must be important,” said lead author Mayssa Mokalled, a postdoctoral fellow in Poss's group. When they tried deleting CTGF genetically, the fish were unable to regenerate, and mutations meant that the process was disrupted. People and zebrafish share most protein-coding genes, and CTGF is also produced by humans. When manufactured doses of human CTGF were delivered at the site of injury, the regeneration process accelerated - the fish were active again within two weeks.

"The fish go from paralyzed to swimming in the tank. The effect of the protein is striking," Mokalled said. Scientists even found that a particular part of the protein, which has more than one function, was needed for the healing to take place. That might make it easier to deliver in a therapeutic setting.

Extra factors at play

However, CTGF is probably not sufficient on its own for people to regenerate their own spinal cords, in part because scar tissue forms around the injury, preventing bridging from taking place. Researchers at Duke University now hope to look at mouse cells.

"Mouse experiments could be key," Mokalled said. "When do they express CTGF, and in what cell types?"

The group also plans to follow up on some of those other proteins secreted after injury, thinking they might provide hints as to why zebrafish are so good at regeneration.

"I don't think CTGF is the complete answer, but it's a great thing to have in hand to inform new ways to think about the real challenge of trying to improve regeneration," said Poss.