A recent study has uncovered important gene regulators that allow some deaf animals, like fish and lizards, to regenerate their hearing naturally. These insights might lead to new ways to encourage the regeneration of sensory hearing cells in individuals experiencing hearing loss and balance issues. The research zeroes in on two inner ear cell types: the sensory cells responsible for sound detection and the supporting cells that help create a conducive environment for these sensory cells. Unlike humans, mice, and other mammals, certain regenerative species, such as fish and lizards, can convert supporting cells into new sensory cells after sustaining an injury.
A recent study from USC Stem Cell, published in the Proceedings of the National Academy of Sciences (PNAS), has pinpointed crucial gene regulators enabling some deaf animals—like fish and lizards—to naturally regenerate their hearing. This research may help in developing methods to stimulate the repair of sensory hearing cells in patients with hearing impairments and balance problems.
The study, spearheaded by first author Tuo Shi and co-corresponding authors Ksenia Gnedeva and Gage Crump from the Keck School of Medicine at USC, investigates two types of cells in the inner ear: the sensory cells that pick up sounds and the supporting cells that foster a suitable environment for sensory cells to function. In species with significant regenerative capabilities, such as fish and lizards, supporting cells can change into new sensory cells after an injury—something that does not occur in humans or other mammals.
To unravel this exceptional regenerative process, researchers focused on how genes specific to sensory cells can be reactivated in the supporting cells of these regenerative animals. They examined the genomic structure in the sensory and supporting cells of the inner ears in zebrafish and green anole lizards, two highly regenerative species. Their comparison also included DNA control elements for sensory genes found in zebrafish and lizards against those in mice, which cannot regenerate sensory hearing cells post-injury.
“By comparing zebrafish and lizards—both capable of regeneration—to non-regenerative mice, we uncovered fundamental insights into how sensory cells are replaced, enabling hearing restoration in certain species,” stated Crump, who is a professor in the Department of Stem Cell Biology and Regenerative Medicine at USC.
The experiments identified a category of DNA control elements known as “enhancers.” Post-injury, these enhancers boost the production of a protein called ATOH1, which triggers a range of genes necessary for forming inner ear sensory cells.
Utilizing the gene editing tool CRISPR, the researchers deleted five of these enhancers in zebrafish. This deletion hindered the development of sensory hearing cells during the growth phase and their regeneration after injury.
“Typically, the removal of single enhancers does not significantly impact development,” Crump explained. “However, by targeting all five enhancers in zebrafish, we revealed their essential role in both development and regeneration.”
Interestingly, while zebrafish have similar sensory cells located in a specialized aquatic organ known as the lateral line, which detects water movement and pressure, the genetic deletions only affected the cells in their inner ears.
The researchers discovered that mice have analogous enhancers that are active during embryonic stages in progenitor cells, which lead to the formation of the inner ear’s sensory and supporting cells. Yet, it is only in regenerative species like fish and lizards that these enhancers remain in an accessible configuration within supporting cells in adulthood, retaining their ability to replace damaged sensory cells.
“We have established that associated cell types in regenerative vertebrates retain open enhancers from their developmental stages into adulthood, allowing these related cells to replenish each other after damage,” Crump noted. “In the future, directed approaches to unlock these enhancers in the human inner ear may enhance our natural regenerative capabilities and potentially reverse hearing loss.”