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Hair Cells Regenerated, Hearing Restored in Mice

01/09/2013
Sarah C.P. Williams

Inhibiting a single signaling pathway prompted growth of new cochlear hair cells in mice, which partially restored hearing. Which pathway? Find out...


A drug applied to the inner ears of adult mice can spur the regeneration of hair cells, according to researchers at Harvard Medical School and the Massachusetts Eye and Ear Infirmary in the United States and the Keio University School of Medicine in Japan. The drug works by activating a transcription factor involved in hair cell development. The finding is a first in the field—while fish and birds can regenerate hair cells after damage, scientists have never before shown that this is possible in mammals.

A drug applied to the inner ears of adult mice can spur the regeneration of hair cells. Credit: Neuron, Mizutari et al.





Cochlear hair cells are vital for converting sound waves into electrical signals that inform the brain of noises. They can become damaged or die suddenly through an acoustic injury—the sound of a loud explosion, for example—leading to permanent loss of hearing. Currently, such damage is treated with cochlear implants, surgically implanted devices that convert sounds to electrical signals.

“Cochlear implants are very successful and have helped a lot of people, but there’s a general feeling among clinicians, scientists, and patients that a biological repair would be preferable,” said Albert Edge, an otologist at Harvard University and the Massachusetts Eye and Ear Infirmary and lead author of the Neuron paper that reports these findings (1).

Previously, Edge and his colleagues had shown that inhibiting Notch signaling was important for hair cells to form properly during fetal development (2). In their new work, the group tested whether such inhibition of the Notch pathway could also spur hair cell regeneration in adult mammals. First, they tested different inhibitors to determine their effects on isolated ear tissues; this allowed them to pinpoint one, the ɣ-secretase LY411575, that led to increased expression of a number of molecular markers found in hair cells.

“It was quite a surprise,” said Edge. “We were very excited when we saw that a secretase inhibitor would have any effect at all in an adult animal.”

Then the scientists tested the inhibitor in mice with hearing damage and reduced hair cell populations caused by exposure to a loud noise. They tagged cells in the inner ear to follow their fate and discovered that the drug, when applied to the inner ears of the mice, caused supporting cells to differentiate into replacement hair cells.

The researchers found that these replacement hair cells partially restored hearing at low frequencies of sound, although not at higher frequencies. The effect lasted for at least three months, the longest time period tested.

The study focused on the effect of the drug given one day after noise damage, a time period where Notch signaling is naturally increased, so it is possible that a small window of time exists after an acoustic injury in which the drug must be given to be effective.

“The improvement we saw is modest,” said Edge. “So we’re now looking at variations of the approach and whether we can use the same drug to treat other types of hearing loss.”

References

  1. Mizutari K, Fujioka M, Hosoya M, Bramhall N, et al. Notch Inhibition Induces Cochlear Hair Cell Regeneration and Recovery of Hearing after Acoustic Trauma (2013). Neuron 77, 58-69.
  2. Jeon, S.J., Fujioka, M., Kim, S.C., and Edge, A.S.B. (2011). Notch signaling alters sensory or neuronal cell fate specification of inner ear stem cells. J. Neurosci. 31, 8351–8358.