A fresh research study presents a comprehensive map that details all the cell types involved in the regeneration of the zebrafish spinal cord. Intriguingly, the study found that for the spinal cord to regenerate fully, the survival and adaptability of the cut neurons are essential. Interestingly, while stem cells that can create new neurons were previously considered key players in this process, this research shows they actually have a supportive role rather than being the primary drivers.
Zebrafish belong to a unique category of vertebrates that have the extraordinary ability to fully heal a severed spinal cord. Gaining insight into this regeneration process could pave the way for potential treatments for spinal cord injuries in humans, which can lead to long-lasting loss of sensation and mobility.
Recently, researchers from Washington University School of Medicine in St. Louis developed a detailed atlas illustrating how various cells operate together to facilitate spinal cord regeneration in zebrafish. Remarkably, the study highlighted that the injured neurons’ ability to survive and adapt is vital for complete spinal cord recovery. Contrary to the long-held assumption that stem cells are central to this process, the study revealed they play a supplementary role instead of leading the regeneration.
The findings were published on Thursday, August 15, in the journal Nature Communications.
Unlike spinal cord injuries in humans and other mammals—where damaged neurons generally perish—the injured neurons in zebrafish significantly modify their functions post-injury to first ensure their survival. Subsequently, they assume crucial roles in coordinating the healing process, as demonstrated by the researchers. Although scientists were aware that zebrafish neurons could survive spinal cord damage, this study uncovered the mechanisms behind that survival.
“Our research shows that nearly every aspect of neural repair we hope to achieve in humans naturally occurs in zebrafish,” commented senior author Mayssa Mokalled, PhD, an associate professor of developmental biology. “We were surprised to discover that protective and reparative mechanisms are activated immediately following an injury. These protective mechanisms seem to enable neurons to withstand injury and exhibit a type of spontaneous plasticity—that is, flexibility in their functions—allowing for the regeneration of new neurons for complete recovery. Our findings have identified genetic targets that could help enhance this capacity for plasticity in human and other mammalian cells.”
By examining the changing roles of different cell types in regeneration, Mokalled and her team found that the ability of surviving injured neurons to adapt and reprogram themselves right after an injury is crucial for initiating spinal cord regeneration. If these surviving neurons are disrupted, zebrafish lose their ability to swim normally, even though regenerative stem cells are still present.
When the spinal cord is compressed or severed in humans and other mammals, it triggers detrimental processes that lead to neuronal death and create an unfriendly environment for repair mechanisms. This neuronal toxicity could explain the challenges faced in utilizing stem cells to treat spinal cord injuries in humans. Instead of prioritizing stem cell-based regeneration, this study proposes that successful treatments for spinal cord injuries should concentrate on preserving the injured neurons.
“Neurons on their own cannot survive without connections to other cells,” Mokalled explained. “In zebrafish, it appears that severed neurons can navigate the stress of injury because their adaptability enables them to forge new local connections right after the injury. We believe this is a temporary strategy that helps protect neurons from dying and maintains the neuronal network while the primary spinal cord rebuilds.”
Some evidence suggests that this adaptive ability might exist, albeit inactive, in mammalian neurons, offering a potential path for new therapies, according to researchers.
“We are optimistic that by pinpointing the genes responsible for this protective mechanism in zebrafish—similar versions of which are found in the human genome—we could discover ways to shield human neurons from the extensive cell death observed after spinal cord injuries,” she stated.
While this research focused primarily on neurons, Mokalled noted that spinal cord regeneration is highly complex. Future work will explore a new cell atlas to further comprehend the roles of other cell types involved in spinal cord regeneration, including non-neuronal glial cells in the central nervous system and various immune system and vascular cells. Ongoing studies will also compare the findings in zebrafish with those occurring in mammalian nerve tissues, including those of mice and humans.
