A new USC Stem Cell study published in the Proceedings of the National Academy of Sciences (PNAS), reveals the genetic mechanisms that enable fish and lizards to regenerate their hearing after injury. By identifying key gene regulators and DNA control elements, the research offers valuable insights into sensory cell regeneration, paving the way for potential therapeutic strategies to restore hearing and balance in humans.
Led by first author Tuo Shi and co-corresponding authors Ksenia Gnedeva and Gage Crump from the Keck School of Medicine of USC, the study focuses on two critical cell types in the inner ear: sensory cells, which detect sound, and supporting cells, which sustain their environment. In regenerative species like zebrafish and green anole lizards, supporting cells can transform into replacement sensory cells after injury—an ability absent in humans and other mammals.
This research provides a framework for exploring how such processes might be stimulated in non-regenerative species, including humans.
Unraveling Regenerative Mechanisms
In the zebrafish inner ear, a cell type known as supporting cells (magenta) gives rise to new sensory hearing cells (blue). The study reveals a set of DNA control elements critical for supporting cells to regenerate hair cells after injury in zebrafish, lizards and other regenerative species. Credit: USC (Image by Tuo Shi/Crump and Lozito labs/USC Stem Cell)
To better understand the remarkable regenerative process in certain vertebrates, the researchers investigated how sensory genes are reactivated in the supporting cells of regenerative species. This involved examining the genome’s folding within the inner ear cells of zebrafish and green anole lizards and comparing their DNA control elements with those of non-regenerative mice.
“By comparing two different regenerative vertebrates—zebrafish and lizards—to non-regenerative vertebrates such as mice, we found something that was fundamental to the way sensory cells can be replaced to restore hearing in some vertebrates,” said Crump, professor in the Department of Stem Cell Biology and Regenerative Medicine at USC.
Their analysis identified a class of DNA control elements called “enhancers,” which amplify the production of a protein called ATOH1 following injury. ATOH1 is essential for activating a suite of genes required for the formation of sensory cells. Using CRISPR, the researchers deleted five of these enhancers in zebrafish, which disrupted both the development of sensory hearing cells and their regeneration after injury.
“In the past, deletion of individual enhancers most often does not have much of an effect. But by targeting all five enhancers in zebrafish, we discovered their critical role in both development and regeneration.”
–Gage Crump, PhD, Keck School of Medicine of USC
Interestingly, while zebrafish also possess sensory cells in their lateral line—a specialized aquatic organ for detecting water flow and pressure—the deletions only impacted sensory cells in their inner ears. This specificity highlights the unique role of these enhancers in hearing cell regeneration.
A Step Toward Human Hearing Restoration
The study also revealed that mice possess equivalent enhancers active during embryonic development in the progenitor cells that give rise to sensory and supporting cells in the inner ear. However, in non-regenerative species like mice, these enhancers are closed in adulthood, preventing supporting cells from becoming sensory cells after injury. Regenerative species like fish and lizards, by contrast, maintain these enhancers in an open configuration throughout life, preserving their regenerative potential.
“What we have found is that sister cell types in regenerative vertebrates maintain open enhancers from development into adult stages, thus allowing these related cells to replace each other following damage,” said Crump.
“In the future, targeted strategies to open up these enhancers in the human inner ear could be used to boost our natural regenerative abilities and reverse deafness.”
This groundbreaking discovery provides a roadmap for scientists to explore genetic and molecular techniques to reawaken dormant regenerative capabilities in humans. By targeting enhancers in the human inner ear, researchers may one day enable sensory cell regeneration, offering a transformative approach to treating hearing loss and balance disorders.
Translating Insights into Impact
This study, supported by grants from the National Institutes of Health and the Hearing Restoration Project, underscores the potential of translating findings from regenerative species to human therapies. By revealing how fish and lizards regenerate sensory cells, the USC team has laid the groundwork for new strategies to tackle hearing loss, a condition that affects millions globally.
These findings represent a critical step toward the development of therapies that could one day restore hearing and balance in patients suffering from sensory cell damage.
Citation:
Gnedeva, Ksenia et al., “Long-range Atoh1 enhancers maintain competency for hair cell regeneration in the inner ear,” Proceedings of the National Academy of Sciences (2024). DOI: 10.1073/pnas.2418098121.
Source: USC
