Johns Hopkins Medicine researchers report new evidence that some animals have the natural ability to regress neuronal damage, but it is inactive.
Specifically, the researchers found that some genetic pathways that allow many fish to repair their eye neurons after injury remain in mammals, but are stopped, blocking regeneration and healing.
“Our research indicates that the potential for regeneration exists in mammals, including humans, but some evolutionary pressure has stopped it,” says Seth Blackshaw, a professor of neuroscience at Johns Hopkins University School of Medicine.
“In fact, regeneration seems to be the default state, and the loss of that ability happened at several points in the evolutionary tree,” he says.
The study had three modules
For study, Blackshaw’s team focused on the support cells found in the back of the eye.
In zebrafish, a standard laboratory model whose genome has been well defined, these cells, known as Müller glia, respond to and repair the light-sensitive retina by growing new cells in the central nervous system.
In addition to increasing eye tissue, the regenerative abilities of zebrafish extend to other parts of the body, including the fins, tails and some internal organs.
The retina is a good test site for mapping genetic activity, Blackshaw explains, because it contains structures common to other cells in the nervous system.
Moreover, in previous studies, scientists have found that retinal genetic networks are well preserved between species, so comparisons between fish, birds, mice and even humans are possible.
For the new experiments, the researchers created retinal lesions in zebrafish, chickens and mice.
They then used high-powered microscopes and a previously developed gene mapping tool to observe how Müller glia support cells responded.
The team was surprised to find, immediately after the injury, that the cells of each of the three species behaved the same: they entered an “active state” characterized by the activation of specific genes, some of which control inflammation.
This active state, says Blackshaw, primarily helps stabilize the lesions and send signals to the cells of the immune system to fight foreign invaders, such as bacteria, or to clean damaged tissue.
Subsequent responses of the species remained divergent
In zebrafish, Müller glia cells have begun to activate a network of transcription factors that control which genes are “on” and which are “off”.
Instead, the research team saw that in the case of chickens with damaged retinas, the birds activated only a part of the “gene switch” transcription factor that is activated in the case of zebrafish. Thus, hens have a much lower ability to create new neurons after injury.
The case studied in mice was very interesting. Mice share the vast majority of their DNA with humans, and their eyes are similar to human eyes.
The researchers found that Müller glia cells remained in the first “active” state for several days, much longer than the eight to 12 hours in which zebrafish are in this state. However, mice have never acquired the ability to produce new neurons.
The scientists found that the same genes that allowed cells to regenerate zebrafish were “ready and ready for action” in the eyes of mice, but that the “on” transcription factor was never activated. Instead, transcription factors actively block the regenerative potential of cells.
Blackshaw suspects that animals with a higher potential to develop disease in the brain and other neurological tissues may have lost this ability over time to protect and stabilize brain cells.
“For example, we know that certain viruses, bacteria and even parasites can infect the brain. It could be disastrous if infected brain cells were allowed to grow and spread the infection through the nervous system, ”says Blackshaw.
Now equipped with a more detailed map of the cellular response to neuronal damage and regeneration, scientists could find a way to activate the regenerative capacities hidden in human DNA.