The same genes could hold the key to regenerating cells in the ear and eye, according to a new mouse study from the USC Stem Cell laboratory of Ksenia Gnedeva, PhD , published in the Proceedings of the National Academy of Sciences (PNAS).
"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.
In the study, first authors Eva Jahanshir and Juan Llamas from the Gnedeva lab focused on a group of interacting genes called the Hippo pathway, which serve as a "stop growing" signal that the lab has shown to inhibit cell proliferation in the ear during embryonic development. In their experiments, the scientists demonstrated that the Hippo pathway also suppresses the regeneration of damaged sensory receptors in the ear and eye of adult mice.
The scientists used an experimental compound that the lab earlier developed to inhibit a key protein in the Hippo pathway: Lats1/2. When exposed to this drug-like compound in a Petri dish, the progenitor cells known as supporting cells responded by proliferating in the utricle, which is a sensory organ in the inner ear that helps with balance. However, the same cells did not respond in the organ of Corti, which is the hearing sensory organ.
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.
"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."
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).
