Zebrafish use surprising strategy to replicate the spinal cord – Washington University School of Medicine in St. Louis

Zebrafish are part of a special group of vertebrates that can completely heal a severed spinal cord. A clear understanding of how this regeneration occurs could provide clues to strategies for healing spinal cord injuries in humans. Such injuries can be devastating, leading to permanent loss of sensation and movement.

A new study from Washington University School of Medicine in St. Louis draws up a detailed atlas of all the cells involved – and how they work together – in zebrafish spinal cord regeneration. In an unexpected discovery, the researchers showed that the survival and adaptability of the severed neurons themselves are necessary for complete spinal cord regeneration. Surprisingly, the study showed that stem cells, which can form new neurons – and are usually considered central to regeneration – play a complementary role but do not direct the process.

The study was published in the journal Nature Communications on Thursday, August 15.

Unlike spinal cord injuries in humans and other mammals, where damaged neurons always die, the zebrafish's damaged neurons dramatically change their cellular functions in response to the injury, first to survive and then to take on new and central roles in orchestrating the precise events that control healing, the researchers found. Scientists knew that zebrafish neurons survive spinal cord injuries, and this new study shows how they do it.

“We found that most, if not all, aspects of neuronal repair that we want to achieve in humans occur naturally in zebrafish,” said senior author Mayssa Mokalled, PhD, associate professor of developmental biology. “The surprising observation we made is that powerful neuronal protection and repair mechanisms emerge right after injury. We believe these protection mechanisms allow neurons to survive the injury and then adopt a type of spontaneous plasticity – or flexibility in their functions – that gives the fish time to regenerate new neurons to achieve full recovery. Our study has identified genetic targets that will help us promote this type of plasticity in the cells of humans and other mammals.”

By studying the evolving roles of different cell types involved in regeneration, Mokalled and her colleagues found that the flexibility of surviving injured neurons and their ability to immediately reprogram themselves after injury drive the chain of events required for spinal cord regeneration. When these injury-surviving neurons are deactivated, zebrafish do not regain their normal swimming ability, even if regenerative stem cells remain present.

When the long wires of the spinal cord are crushed or severed in humans and other mammals, it sets off a chain of toxic events that kill neurons and make the spinal cord environment inaccessible to repair mechanisms. This neuronal toxicity may provide an explanation for the failure of attempts to use stem cells to treat spinal cord injuries in humans. Rather than focusing on regeneration with stem cells, the new study suggests that any successful method of healing spinal cord injuries in humans must start with preventing the injured neurons from dying.

“Neurons alone, without connections to other cells, do not survive,” said Mokalled. “We believe that in zebrafish, severed neurons can overcome the stress of injury because their flexibility helps them to form new local connections immediately after injury. Our research suggests that this is a temporary mechanism that buys time, protects neurons from dying, and allows the system to maintain neural circuits while the main spinal cord is being built and regenerated.”

There is some evidence that this ability is present but inactive in mammalian nerve cells, so the researchers say this could be a path to new therapies.

“We hope that identifying the genes that orchestrate this protective process in zebrafish – versions of which are also present in the human genome – will help us find ways to protect neurons in humans from the waves of cell death we see after spinal cord injury,” she said.

While this study focuses on neurons, Mokalled said that spinal cord regeneration is extremely complex, and that in future work her team will examine a new cell atlas to understand the contribution of other cell types to spinal cord regeneration, including non-neuronal cells called glial cells in the central nervous system, as well as cells of the immune system and blood vessels. They also have ongoing studies comparing the results in zebrafish with what happens in mammalian cells, including neural tissue from mice and humans.