Genetic Reprogramming Regenerates Lost Hair Cells in the Mature Mouse Inner Ear
By Melissa McGovern, Ph.D.
Sensory hair cells in the cochlea detect sounds in the environment and allow us to hear. These cells are susceptible to loud noises, some medications, and the natural aging process.
When hair cells are damaged by these environmental factors, they are often killed and are not naturally replaced or regenerated. As a result, the accumulation of this damage leads to loss of hearing that is currently irreversible.
Regenerated hair cells were observed throughout the entire length of the cochlea after three key hair cell fate-promoting proteins in supporting cells were activated. Credit: McGovern et al./PNAS Nexus
While hearing aids and cochlear implants can offer relief from hearing loss, the hearing these devices offer do not accurately recapitulate natural hearing. Therefore, the development of therapeutics that convert cells inside the ear, called nonsensory cells or supporting cells, into hair cells is one potential strategy for hearing restoration.
Historically, a significant hurdle to hair cell regeneration has been the age of the organ. Supporting cells in very young animals are more plastic and can convert into hair cells after the hair cells die.
As animals age, cells in the inner ear mature into distinct cell types that can no longer regenerate naturally. One reason that this occurs is that the systems controlling the genes important for cell identity become stronger as the organ matures—the cells become locked into their identities and can no longer change them. As a result, supporting cells can no longer change into hair cells.
However, we recently showed in our PNAS Nexus paper, published in October 2024, that we can overcome this “lock” of supporting cell identity by activating three key hair cell fate-promoting proteins in supporting cells of adult mice after we killed the original hair cells. We found that a significant number of these supporting cells will convert into cells resembling hair cells, offering a potential strategy for hair cell regeneration.
The genes that we expressed in nonsensory cells are transcription factors. Transcription factors are proteins that interact with the DNA in a cell and increase or decrease the activity of other genes.
The three transcription factors that we used are: Atoh1, Gfi1, and Pou4f3. These three factors work in combination with one an ther to turn on genes that are critical for the formation of hair cells during the development of the inner ear, and we found they will also reprogram supporting cells into hair cell-like cells in the adult mouse cochlea.
In addition, we found that supporting cells best respond to our reprogramming when the original hair cells are killed, suggesting that hair cells somehow control the identity of neighboring cells.
The regenerated hair cells were able to attract nerve cells, which will be critical for the recovery of hearing. Therefore, by expressing Atoh1, Gfi1, and Pou4f3 in mature cochlear supporting cells following hair cell death, we can regenerate lost hair cells, offering a potential strategy to recover hearing.
Our results suggest that mature cochlear supporting cells can be reprogrammed into sensory hair cells, providing a possible target for hair cell regeneration. Further work is ongoing in the Groves and McGovern labs to understand how to refine and improve hair cell reprogramming in order to best achieve hearing restoration.
Melissa McGovern, Ph.D., is an assistant professor in the department of otolaryngology at the University of Pittsburgh. She is a 2024–2025 Emerging Research Grants (ERG) scientist and the recipient of the Neil Segil Memorial Award in Hair Cell Regeneration. Coauthors of the PNAS Nexus paper include 1996–1997 and 2012 ERG scientist Andy Groves, Ph.D., a member of HHF’s Hearing Restoration Project, which helped fund this study, who is a professor and the Vivian L. Smith Endowed Chair in Neuroscience in the departments of neuroscience and molecular and human genetics at Baylor College of Medicine; and 2012 and 2013 ERG scientist Bradley Walters, Ph.D., who is an associate professor at the University of Mississippi Medical Center in the department of otolaryngology–head and neck surgery.