In this injured zebrafish spinal cord, green fluorescent protein marks where the ctgfa gene is helping to regenerate and “bridge” the severed ends. | M. Mokalled and K. Poss
Researchers have identified a protein in zebrafish that plays a role in helping heal major spinal cord injuries. The results, published in the 4 November issue of Science, could provide an important clue for researchers looking for ways to facilitate similar tissue repair in humans.
While mammals lack the ability to regenerate nervous system tissue after spinal cord injury, zebrafish can regenerate such tissue. The mechanisms behind this recovery have remained elusive.
"Only six to eight weeks after a paralyzing injury that completely severs their spinal cord, zebrafish form new neurons, regrow axons and recover the ability to swim. Importantly, these regenerative events proceed without massive scarring," explained Mayssa Mokalled of Duke University, a researcher involved in the study.
Scientists have found evidence that glial cells, which support and protect neural cells, may play a key role in the regenerative process. In zebrafish, glial cells help create a bridge across severed spinal cord tissue and facilitate regeneration. In mammals, their role is much less clear, however.
Co-author Ken Poss of Duke University said that, in mammals, glial cells have traditionally been thought of as the scar-causing cells that present a roadblock for spinal cord repair. However, recent evidence shows that disabling glial cells in mammals can hinder recovery. "These findings highlight the need for a deeper understanding of glial cell function after spinal cord injury," he said.
To gain more insights as to why zebrafish are more successful at regenerating spinal tissue, the researchers analyzed the gene expression of fish spinal tissue following injury, identifying seven genes of interest. Of these, connective tissue growth factor a (ctgfa) was expressed in glial cells during a key period of healing, as the cells were actively building bridges across damaged tissue.
Val Altounian/ Science
Zebrafish in which ctgfa was disabled had glial cells that often failed to extend into the lesions, and the fish were unable to recover from spinal injury. In contrast, overexpression of ctgfa resulted in increased bridging, axon regeneration and overall healing. "Together, these experiments indicate that this factor is important for the ability of fish to regenerate spinal cord tissue," said Mokalled.
When the researchers applied a human form of Ctgf protein to lesions in zebrafish, they observed similar recovery of spinal cord function, hinting that other factors within zebrafish spinal tissue may explain the healing differences between mammals and zebrafish.
Poss said there are a lot of possible explanations for these differences in healing. "It is possible that the cells that might express or respond to Ctgf are different in this context. It is also possible that the mammalian form of Ctgf is regulated or processed differently."
"We'll continue to investigate mechanisms by which neural tissue bridges to repair the spinal cord in zebrafish, taking advantage of the power of genome editing to examine other factors," said Poss. "A natural future direction for our [research] is to study potential roles of Ctgf after mammalian spinal cord injury. Together, studies in zebrafish and mammalian models could inform new ways to manipulate glial cells after human spinal cord injury."