NEWS - Zebrafish are members of a rare 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 treating injuries that cause permanent loss of sensation and movement.
The researchers mapped out a detailed atlas of all the cells involved in regenerating the zebrafish spinal cord. Stem cells capable of forming new neurons are typically thought of as central to regeneration, playing a complementary role but not leading the process.
Damaged neurons always die after spinal cord injury in humans and other mammals, but damaged neurons in zebrafish drastically change their cellular functions in response to injury to survive and then take on new roles to orchestrate healing.
“We found that most of the aspects of neural repair that we are trying to achieve in humans occur naturally in zebrafish,” says Mayssa Mokalled of Washington University School of Medicine in St. Louis.
Unlike organ regeneration mechanisms in several animals, robust neural repair and protection mechanisms occur immediately after injury in zebrafish. These protective mechanisms allow neurons to survive the injury and then adopt spontaneous plasticity.
Zebrafish get time to regenerate new neurons to achieve full recovery. Researchers have identified genetic targets that could help enhance this type of plasticity in cells from humans and other mammals.
The flexibility of injured neurons that survive injury and their ability to quickly reprogram after injury are a necessary sequence of events for spinal cord regeneration. If these neurons that survive injury are disabled, zebrafish do not regain their normal swimming capacity, even though regenerative stem cells remain.
When the long cord of the spinal cord is compressed or severed in humans and other mammals, a cascade of toxic events sets off neurons that kill and render the spinal cord environment hostile to repair mechanisms.
This neuronal toxicity has frustrated efforts to use stem cells to treat spinal cord injury. Mokalled suggests that any approach to treating spinal cord injury in humans must begin by saving injured neurons from death.
“Neurons without connections to other cells cannot survive. In zebrafish, severed neurons can cope with the stress of injury because their flexibility helps them quickly establish new local connections,” Mokalled says.
This temporary mechanism buys time, protecting neurons from death and allowing the system to preserve neuronal circuits while the primary spinal cord rebuilds and regenerates. There is some evidence that this capacity exists in mammals but is dormant.
"We hope that identifying the gene that regulates this protective process in zebrafish with a version that is also present in the human genome will help find a way to protect neurons in humans from the wave of cell death that we see after spinal cord injury," Mokalled said.
Spinal cord regeneration is complex, and future work will include investigating new cell atlases to understand the contribution of other cell types to spinal cord regeneration, including non-neuronal cells called glia in the central nervous system, immune system cells and blood vessels.
Original research
Saraswathy, V.M., Zhou, L. & Mokalled, M.H. Single-cell analysis of innate spinal cord regeneration identifies intersecting modes of neuronal repair. Nature communications 15, 6808 (2024). DOI:10.1038/s41467-024-50628-y
The researchers mapped out a detailed atlas of all the cells involved in regenerating the zebrafish spinal cord. Stem cells capable of forming new neurons are typically thought of as central to regeneration, playing a complementary role but not leading the process.
Damaged neurons always die after spinal cord injury in humans and other mammals, but damaged neurons in zebrafish drastically change their cellular functions in response to injury to survive and then take on new roles to orchestrate healing.
“We found that most of the aspects of neural repair that we are trying to achieve in humans occur naturally in zebrafish,” says Mayssa Mokalled of Washington University School of Medicine in St. Louis.
Unlike organ regeneration mechanisms in several animals, robust neural repair and protection mechanisms occur immediately after injury in zebrafish. These protective mechanisms allow neurons to survive the injury and then adopt spontaneous plasticity.
Zebrafish get time to regenerate new neurons to achieve full recovery. Researchers have identified genetic targets that could help enhance this type of plasticity in cells from humans and other mammals.
The flexibility of injured neurons that survive injury and their ability to quickly reprogram after injury are a necessary sequence of events for spinal cord regeneration. If these neurons that survive injury are disabled, zebrafish do not regain their normal swimming capacity, even though regenerative stem cells remain.
When the long cord of the spinal cord is compressed or severed in humans and other mammals, a cascade of toxic events sets off neurons that kill and render the spinal cord environment hostile to repair mechanisms.
This neuronal toxicity has frustrated efforts to use stem cells to treat spinal cord injury. Mokalled suggests that any approach to treating spinal cord injury in humans must begin by saving injured neurons from death.
“Neurons without connections to other cells cannot survive. In zebrafish, severed neurons can cope with the stress of injury because their flexibility helps them quickly establish new local connections,” Mokalled says.
This temporary mechanism buys time, protecting neurons from death and allowing the system to preserve neuronal circuits while the primary spinal cord rebuilds and regenerates. There is some evidence that this capacity exists in mammals but is dormant.
"We hope that identifying the gene that regulates this protective process in zebrafish with a version that is also present in the human genome will help find a way to protect neurons in humans from the wave of cell death that we see after spinal cord injury," Mokalled said.
Spinal cord regeneration is complex, and future work will include investigating new cell atlases to understand the contribution of other cell types to spinal cord regeneration, including non-neuronal cells called glia in the central nervous system, immune system cells and blood vessels.
Original research
Saraswathy, V.M., Zhou, L. & Mokalled, M.H. Single-cell analysis of innate spinal cord regeneration identifies intersecting modes of neuronal repair. Nature communications 15, 6808 (2024). DOI:10.1038/s41467-024-50628-y