Breaking the sound barrier: Ksenia Gnedeva’s transformative research on growth and regeneration in the inner ear sensory organs

Ksenia Gnedeva (Photo by Chris Shinn)
Ksenia Gnedeva (Photo by Chris Shinn)

Some children dream of growing up to be a ballerina or an astronaut, but Ksenia Gnedeva always knew she wanted to be a biologist. “I remember receiving a microscope for my sixth birthday,” Gnedeva said, smiling. “I was interested in how things were built, how things worked.” Flash forward three decades and Gnedeva now has her own laboratory at USC, where she is one of the preeminent researchers on molecular signaling and tissue regeneration in the inner ear. This year, her lab received a highly-competitive and prestigious R01 research grant from the National Institutes of Health for its innovative approach to Hippo-mediated control of growth and regeneration in the inner ear sensory organs.

Gnedeva received her PhD in Developmental and Cell Biology from the Sanford Burnham Prebys Medical Discovery Institute and Koltsov Institute of Developmental Biology, where she worked with the Terskikh Laboratory.  The group worked on central and peripheral neurogenesis and used an “in the dish” model of neural crest cells, a temporary group of cells in embryos that gives rise to dorsal root ganglia of the spinal nerves (neurons carrying sensory information, such as feeling pain and touch, from the body to our brain). Because during normal development neural crest cells also transform into all sorts of other cell types like melanocytes (cells that produce skin pigmentation) and the cells that make up craniofacial cartilage and bones, Gnedeva was interested in whether these cells could be directed to differentiate as dermal papillae – a population of cells in our skin that can induce new hair follicle formation. Her project succeeded at differentiating dermal papillae cells in the dish, which could eventually allow for scientists to regenerate human hair growth in, say, tissues that have been extensively damaged by burns and/or scarring.

After working as the only skin biologist in the neuroscience lab, Gnedeva’s research shifted to sensory neuroscience. For her postdoctoral work, she focused on hair cells, which, in fact, have nothing to do with hair and instead refer to the specialized cells in the inner ear that are responsible for the transduction of sound-evoked mechanical vibrations into electrical signals that are sent to the brain. Hair cells play a key role in our body’s vestibular system (responsible for balance) and auditory system. Gnedeva noted: “Even though it may seem like a big jump to go from studying skin to the inner ear, in terms of developmental biology, both are epithelial organs and have a lot in common when it comes to the signals that direct their development. What’s fascinating is that skin retains remarkable potential for regeneration while the inner ear sensory organs cannot be restored after damage.” Gnedeva completed four years of postdoctoral research at the Rockefeller University in New York, working in the Laboratory of Sensory Neuroscience under A. James Hudspeth, whose research focuses on the normal hearing process, the causes of sensorineural hearing loss, and possible means to regenerate hair cells. Through the use of biophysical modeling, Hudspeth’s lab was able to show that the negative feedback mechanism that controls growth in the inner ear was likely due to a molecular cascade (or chain reaction of particular protein interactions) triggered by a mechanical force. Ultimately, Gnedeva worked in conjunction with Adrian Jacobo (then a postdoctoral associate at Rockefeller University’s Hudspeth Lab and now a principal investigator at CZ Biohub) to determine that tissue growth in the inner ear was mediated by the Hippo signaling pathway, which controls organ size in animals through the regulation of cell proliferation. The pathway takes its name from the protein kinase Hippo (Hpo), since mutations in this gene can lead to tissue overgrowth, or hippopotamus-like phenotypes.

Gnedeva then showed that while in other tissues, like skin, Hippo is inactivated after damage to allow for regeneration, the cascade stays ON in the inner ear to repress regeneration. This discovery was of great significance because if researchers can find ways to interrupt this negative feedback mechanism, they are hopeful that they may be able to find ways to restore the tissue growth necessary for the inner ear to regenerate. Humans are only born with around 15,000 auditory hair cells per ear (formed during gestation) and these cells do not regrow, so once a person’s hair cells are damaged, it can lead to permanent hearing loss. Right now, the only way to mitigate severe hearing loss is through the use of cochlear implants, but this option has several issues in terms of accessibility and cost as well as sound quality and distortion, so if we were able to find a way to enable hair cell regrowth, it would be a potential game-changer.

When Gnedeva’s husband received a residency placement at the University of Southern California after finishing medical school at New York University, Gnedeva was thrilled to finish her postdoctoral research with Neil Segil’s laboratory at USC. Segil had a joint appointment in USC’s Department of Stem Cell Biology and Regenerative Medicine as well as the USC Caruso Department of Otolaryngology–Head and Neck Surgery, and his lab focused on sensory regeneration and inner ear biology. Segil was generous enough to give Gnedeva the time and space to carry on with the postdoctoral research she had begun at Rockefeller University, which was enriched by new techniques to which she was introduced in Segil’s lab. Gnedeva had the privilege of working with Segil for three and a half years, and even after his pancreatic cancer diagnosis, which unfortunately led to his death in July 2022, Segil’s primary concern was for the welfare of the other researchers in his lab. He continued to hold regular lab meetings and scientific discussions and published numerous papers in his last few years, and Gnedeva credits Segil with encouraging her to apply for her own laboratory at USC. In Gnedeva’s words: “I knew I wanted to stay in academia but initially didn’t think I was ready or good enough to apply for my own lab. But Neil pushed me…he was an incredible mentor who always figured out exactly what he needed to do to gently nudge people in the right direction.”

Gnedeva interviewed and had offers from three universities to start her own lab, but she knew that USC was the right fit for her. She was sure that the Department of Otolaryngology–Head and Neck Surgery would give her the tools and resources she needed to conduct cutting-edge research on the inner ear. In addition, with the joint appointment at USC’s Department of Stem Cell Biology and Regenerative Medicine, she receives ample support for basic and clinical research.

The Gnedeva Laboratory investigates how molecular signaling and tissue mechanics control embryonic sensory organ growth and how specialized cell differentiation and growth may be re-initiated in the inner ear after damage. Gnedeva was honored to receive an R01 research grant from the National Institutes of Health in 2023. Among a pool of highly-qualified candidates, only about 10-15% of applicants receive R01 research grants each year, and to receive this grant, Gnedeva had to demonstrate that her research and techniques would prove very important to advancing the field of hearing and communication neuroscience and that the work her laboratory was doing was unique enough that no other lab could do it better. With this grant, Gnedeva will have five years of funding, giving her lab the financial and material resources to push the boundaries of medicine as we know it.

Mentioned in this article: Ksenia Gnedeva, PhD