A USC research team discovered that a single genetic signal may be preventing both hearing and vision cells from repairing themselves. By turning off this signal in mice, they triggered cell growth in parts of the ear and eye — a step toward possible future therapies for hearing and vision loss.
A new mouse study from the USC Stem Cell lab of Ksenia Gnedeva, PhD, suggests that the same genes may control the regeneration of sensory cells in both the ear and the eye. The research, published today (March 31) in Proceedings of the National Academy of Sciences (PNAS), offers insight into why these cells fail to regenerate in mammals, and how that barrier might be lifted.
Unlocking Regeneration in Ear and Eye
“The proliferation of progenitor cells in response to injury is a crucial step in the regeneration of sensory receptors, but this process is blocked in the mammalian inner ear and retina. By understanding the genes that enforce this block, we can advance efforts to restore hearing and vision in patients,” said Gnedeva, an assistant professor in the USC Tina and Rick Caruso Department of Otolaryngology – Head and Neck Surgery, and the Department of Stem Cell Biology and Regenerative Medicine at the Keck School of Medicine of USC.
The Hippo Pathway: A Cellular Stop Signal
The team, led by first authors Eva Jahanshir and Juan Llamas, focused on a network of genes known as the Hippo pathway. This pathway acts as a “stop growing” signal, previously shown by the lab to limit cell proliferation in the developing ear. In this study, the researchers found that the same pathway also suppresses the regrowth of damaged sensory cells in the ears and eyes of adult mice.
To test whether they could overcome this barrier, the scientists used a compound developed in their lab that inhibits a key Hippo pathway protein, Lats1/2. When inner ear progenitor cells, known as supporting cells, were exposed to this compound in a Petri dish, they began to multiply in the utricle, a balance-sensing organ. However, the same effect was not observed in the organ of Corti, which is responsible for hearing.
The Role of p27Kip1 in Blocking Regeneration
The scientists next identified what was blocking this important step towards sensory cell regeneration in the organ of Corti — a gene encoding a protein called p27Kip1 — and showed that this inhibitory protein was also high in the retina. They created a transgenic mouse in which the level of p27Kip1 could be reduced in the inner ear and the retina to see how that would impact the proliferation of progenitor cells in response in both organs.
In these mice, inhibiting the Hippo pathway effectively caused supporting cells proliferation in the organ of Corti, an important step towards the regeneration of the ear’s sensory cells. In the retina, inhibiting the Hippo pathway induced the proliferation of progenitor cells known as Müller glia. Surprisingly, the researchers discovered that some of the Müller glia progeny, without further manipulation, converted to sensory photoreceptors and other neuronal cell types in the retina.
A Window of Regenerative Opportunity
“There have been reports that p27Kip1 levels drop following injury, so that might offer a brief window of opportunity for using a drug-like compound to inhibit the Hippo pathway and encourage regeneration in the ear and the eye,” said Gnedeva. “Alternatively, it could be possible to develop another drug-like compound to reduce p27Kip1 levels. So, our discoveries have identified potential new targets for stimulating the regeneration of both hearing and vision.”
Reference: “The Hippo pathway and p27Kip1 cooperate to suppress mitotic regeneration in the organ of Corti and the retina” by Eva Jahanshir, Juan Llamas, Yeeun Kim, Kevin Biju, Sanyukta Oak and Ksenia Gnedeva, 3 April 2025, Proceedings of the National Academy of Sciences.
DOI: 10.1073/pnas.2411313122
Additional co-authors are Yeeun Kim, Kevin Biju, and Sanyukta Oak from the Gnedeva Lab.
This work was supported by federal funding from the National Institutes of Health’s National Institute on Deafness and Other Communication Disorders (grant 1R01DC020268, training grant T32DC009975, and clinician-scientist training grant 5R25DC019700).
Disclosures
Gnedeva is a co-inventor on three patent applications related to this work: 1. Lats kinase inhibitor to treat retinal degeneration (PCT application number PCT/US2024/023146; U.S. Patent and Trademark serial number usc0282prv); 2. Pyrrolopyridine-3- and 4-carboxamide compositions and methods for cellular proliferation (docket number 2877.035P1); and 3. Pyrrolo[2,3-b]pyridine-3-carboxamide compositions and methods for ameliorating hearing loss (application number 62970425).
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