Feb 2017 Chemical Engineering News, Medical Xpress and MIT News Office

The snail-shell-shaped cochlea of the inner ear contains some 15,000 hair cells that are needed for humans to hear speech, music, and other everyday sounds. Damage to these cells is one of the leading causes of hearing loss, and once damaged, established dogma is that these cells cannot regrow. 'Amazingly, birds and amphibians are capable of regenerating hair cells throughout their life, suggesting that the biology exists and should be possible for humans. Intrigued, we decided to explore whether these hair cells could be regenerated,' said Dr Jeff Karp, a biomedical engineer at Brigham and Women's Hospital. The new study suggests that hair cell death may not be as immutable as it seems. Albert Edge and colleagues from Harvard, MIT, Brigham, and Massachusetts Eye & Ear Infirmary tested mixtures of small molecules on mouse cochlea cells growing in a dish until they found combinations that coaxed the supporting cells to both proliferate and turn into bona fide hair cells. Once they had a large pool of immature progenitor cells (about 2,000-fold greater than any previously reported), the researchers added another set of molecules that provoked the cells to differentiate into mature hair cells. This procedure generated about 60 times more mature hair cells than the technique that had previously worked the best. The team showed that the technique worked with cells from mice, primates and humans.

 Stem CellsLarge clonal colonies of cochlear progenitor cells formed from single cells and converted into high purity colonies hair cells (magenta) with intricate hair bundles (cyan).

Regenerated Hair Cells

Regenerated cochlear hair cells (green, 10 to 15 µm wide) form wispy stereocilia (pink), necessary for sensing sound.

The researchers also found that their new approach also worked in an intact mouse cochlea removed from the body. In that experiment, the researchers did not need to add the second set of drugs because once the progenitor cells were formed, they were naturally exposed to signals that stimulated them to become mature hair cells. “We only need to promote the proliferation of these supporting cells, and then the natural signaling cascade that exists in the body will drive a portion of those cells to become hair cells,” Karp said. Because this treatment involves a simple drug exposure, the researchers believe it could be easy to administer it to human patients. They envision that the drugs could be injected into the middle ear, from which they would diffuse across a membrane into the inner ear. This type of injection is commonly performed to treat ear infections.

"With this knowledge, we can make better shots on goal, which is critical for repairing damaged ears," said Dr. Edge. "We have identified the cells of interest and have identified the pathways and drugs to target to improve on previous results. These clues may lead us closer to finding drugs that could treat hearing loss in adults." Edge cautions that the cocktail used in this study is likely too complex for use in humans, but he thinks it will enable researchers to manipulate large numbers of cochlear cells to boost hair cell populations with a single molecule. Jeffrey Holt, a professor of otolaryngology and neurology at Boston Children’s Hospital and Harvard Medical School, said this approach holds potential for treating hearing loss, if its safety and effectiveness can be demonstrated. 

Dr Karp and colleagues have established a start-up, Frequency Therapeutics, with the aim of developing a treatment for hearing loss, and they hope to begin human clinical trials within 18 months. 'Frequency's development of a disease-modifying therapeutic that can be administered with a simple injection could have a profound effect on chronic noise-induced hearing loss,' said Dr Chris Loose, the company's co-founder.