Summary: Study reveals hydrogen peroxide reacts to EGFR in the skin, assisting in wound healing and nerve cell regeneration.
Source: University of Miami
Widely used for modern biomedical research, zebrafish share more than 70 percent of the human genome and possess the impressive power of regeneration. Dr. Sandra Rieger’s research on appendage regeneration and nerve damage at the University of Miami has utilized zebrafish for years.
Now, in a recent study published in the Proceedings of the National Academy of Science (PNAS), Rieger uses these natural marvels with innate healing capacity once more to expand her research on the regenerative potential of hydrogen peroxide in wound repair and nerve regeneration.
As a postdoctoral researcher at the University of California, Los Angeles, Rieger made the groundbreaking discovery that hydrogen peroxide is produced in the epidermis and is responsible for promoting nerve regeneration following injury.
Rieger, who is currently an associate professor of biology in the College of Arts & Sciences, stated, “It was a great discovery, but at the time we did not know the exact molecular mechanisms that drove nerve regeneration after injury.”
In her latest study, Rieger and her colleagues investigated how hydrogen peroxide stimulates nerve regeneration. With the help of fluorescent labeling of proteins in zebrafish and mutant analysis, they used time-lapse imaging to study this process.
“Time-lapse imaging provides a detailed view of the biological processes and relationships between nerves and skin, as well as how these interactions lead to regeneration,” explained Rieger. “The findings we sought will answer the question of how the skin affects regeneration, as the skin is so important in producing factors that are essential to the regeneration process.”
The study essentially found that hydrogen peroxide reacts to the Epidermal Growth Factor Receptor (EGFR) in the skin, which is essential for skin remodeling and aids nerve regrowth into the wound.
“This is vital for the restoration of the skin,” said Rieger.
“However, we discovered that if hydrogen peroxide is not present in neurons, nerve endings also cannot regenerate,” Rieger explained. “It appears that both neurons and skin require hydrogen peroxide to coordinate the regeneration of their nerve endings.”
In 2011, Rieger published her first study as a postdoctoral researcher; now, nearly a decade later, she has advanced this work and shed more light on the molecular functions of hydrogen peroxide in stimulating nerve regeneration. This research will hopefully pave the way for future studies that lead to improved therapies for restoring skin and nervous system functions.
The study, “Coordinated NADPH oxidase/hydrogen peroxide functions regulate cutaneous sensory axon de- and regeneration,” is now available online at PNAS.
Tissue wounding induces cutaneous sensory axon regeneration via hydrogen peroxide (H2O2) that is produced by the epithelial NADPH oxidase, Duox1. Sciatic nerve injury instead induces axon regeneration through neuronal uptake of the NADPH oxidase, Nox2, from macrophages. We therefore reasoned that the tissue environment in which axons are damaged stimulates distinct regenerative mechanisms.
Here, we show that cutaneous axon regeneration induced by tissue wounding depends on both neuronal and keratinocyte-specific mechanisms involving H2O2 signaling.
Genetic depletion of H2O2 in sensory neurons abolishes axon regeneration, whereas keratinocyte-specific H2O2 depletion promotes axonal repulsion, a phenotype mirrored in duox1 mutants. Intriguingly, cyba mutants, deficient in the essential Nox subunit, p22Phox, retain limited axon regenerative capacity but display delayed Wallerian degeneration and axonal fusion, observed so far only in invertebrates.
We further show that keratinocyte-specific oxidation of the epidermal growth factor receptor (EGFR) at a conserved cysteine thiol (C797) serves as an attractive cue for regenerating axons, leading to EGFR-dependent localized epidermal matrix remodeling via the matrix-metalloproteinase, MMP-13.
Therefore, wound-induced cutaneous axon de- and regeneration depend on the coordinated functions of NADPH oxidases mediating distinct processes following injury.