A new understanding of how birds regenerate hearing may lead to therapies for people with hearing loss

Professor Stefan Heller, PhD

Dec 20, 2023

By Christopher Vaughan

Millions of people exposed to loud noises at concerts, work or in the general environment may know intellectually that loud noises are harmful, but they often don’t fully realize that once the sensory hair cells in our inner ears are damaged and die, they never regenerate. When hearing goes, it’s gone for good.

Now a team from the Stanford University School of Medicine has unlocked a biological process that could provide clues for developing biological treatments for hearing loss. By studying birds, which unlike mammals can naturally regenerate lost sensory cells in the inner ear, the researchers have identified an essential trigger that controls hair cell regeneration in the cochlea.

Researchers in the laboratory of Professor of otolaryngology Stefan Heller, PhD, used advanced, single-cell analysis to discover the exact chain of event that allow birds to regenerate their sensory cells in the inner ear, or cochlea. Their work was published in the journal Developmental Cell. Nesrine Benkafadar, PhD, PharmD, is the first author on the publication. Heller, who is the Edward C. and Amy H. Sewall Professor, is the senior author. 

Almost half a billion people worldwide are affected by hearing loss as a result of aging, noise exposure or drug side-effects. The World Health Organization estimates that by 2050, one in four people will suffer a hearing disability. There is currently no therapy that prompts the body to regenerate lost sensory hair cells and restore hearing.

But about 30 years ago, said Heller, researchers discovered that birds are able to restore lost cochlear sensory cells and restore their hearing. The question was how birds did this.

“We have been pushing the concept for years that there is an adult stem cell involved and that it gets activated somehow when sensory cells are damaged,” Heller said. “Over the years, we and others showed that the activation of this stem cell was not the direct response to some factor given off by dying sensory cells, nor was there a ‘dead-man’s switch’ where healthy cells would always give off a signal and the lack of that signal would initiate regeneration.”

With their current research, Heller and his colleagues discovered that the key lay in a “completely novel signaling trigger,” he said. Signals from dying sensory cochlear cells prompted changes not in the stem cell, but in cells that surround and support the stem cells. Changes in cell surface receptors on the support cells lead to changes in those cells’ activity. The team carefully documented a series of biochemical changes in the support cells that ultimately led to activation of regenerative stem cells. “This whole concept was not even on the table” before their research, Heller said. 

Now the question, the researchers say, is why mammalian cochlea are different, and whether applying some of what they learned during their research with birds might ultimately be used therapeutically in humans.

“We identified specific transcriptional regulators that are now candidates for further studies,” said Benkafadar.  For example, she said, they might first start simply by testing whether these regulators might on their own prompt sensory cell regeneration in mice and humans.

"Our findings represent a significant leap forward in understanding how auditory hair cells regenerate in birds," said Benkafadar. "It's a promising step towards a future where hearing loss can be effectively treated through regenerative medicine."

The research was supported by the National Institutes of Health (R01-DC019619 and K08-DC019683), the American Hearing Research Foundation, the Hearing Restoration Project Consortium of the Hearing Health Foundation, and the Stanford Initiative to Cure Hearing Loss.