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A research team from the University of Cologne has shown how zebrafish can rebuild their nerve pathways and restore their locomotor function after a spinal cord injury. Specialized connective tissue cells regulate inflammation and prevent the formation of scar tissue, enabling nerve fibers to regrow. The findings could offer a long-term approach for developing therapies in humans as well.

People who suffer severe spinal cord injuries are usually permanently paralyzed. The severed nerve fibers do not grow back because scar tissue and persistent inflammation prevent regeneration. Zebrafish, on the other hand, can completely heal from even the most severe spinal cord injuries.

In humans, scar tissue that forms around a wound in the spinal cord represents a significant barrier to the regeneration of nerve cells. In addition, persistent activation of the immune system leads to chronic inflammation, which inhibits regeneration even further. Scarring and inflammatory reactions interact closely: The infiltration of immune cells triggered by the injury promotes scar formation, which in turn strengthens and prolongs the immune response and prevents the inflammation from subsiding.

In a new study, titled "Biphasic inflammation control by fibroblasts enables spinal cord regeneration in zebrafish," in Cell Reports, researchers at the University of Cologne analyzed the injured spinal cord of the zebrafish at the single-cell level and discovered that specialized cells of the connective tissue, known as fibroblasts, play a dual role.

The cells first trigger the inflammatory reaction that sets the healing process in motion—and then stop it again so that the tissue can regenerate. At the same time, the fibroblasts in the zebrafish suppress the synthesis of scar components that inhibit regeneration in mammals and humans. This prevents the formation of regeneration-limiting scar tissue.

"The zebrafish controls inflammation and healing with great precision when the spinal cord is injured," explains Professor Dr. Daniel Wehner from the Institute of Zoology at the University of Cologne. "Our long-term goal is to utilize this knowledge to develop therapeutic approaches that promote regeneration in humans. If we understand which signals enable the control of regeneration, we may find ways to promote therapies that restore functions lost after spinal cord injury in humans."

As a basis for research into the healing mechanism, the scientists carried out the first comprehensive high-resolution single-cell analysis of all RNA molecules in the entire wound environment in the zebrafish. The researchers succeeded in systematically mapping all the cells of the nervous system as well as cells invading the wound environment.

"The data set is the first resource of its kind in terms of its scope and allows for the analysis of complex interactions between different cell types," says Professor Wehner. The findings provide valuable starting points for further analyses of the regeneration mechanisms in zebrafish as well as in other animals and humans.