Abstract
The hallmark of mechanosensory hair cells is the stereocilia, where mechanical stimuli are converted into electrical signals. These delicate stereocilia are susceptible to acoustic trauma and ototoxic drugs. While hair cells in lower vertebrates and the mammalian vestibular system can spontaneously regenerate lost stereocilia, mammalian cochlear hair cells no longer retain this capability. We explored the possibility of regenerating stereocilia in the noise-deafened guinea pig cochlea by cochlear inoculation of a viral vector carrying Atoh1, a gene critical for hair cell differentiation. Exposure to simulated gunfire resulted in a 60–70 dB hearing loss and extensive damage and loss of stereocilia bundles of both inner and outer hair cells along the entire cochlear length. However, most injured hair cells remained in the organ of Corti for up to 10 days after the trauma. A viral vector carrying an EGFP-labeled Atoh1 gene was inoculated into the cochlea through the round window on the seventh day after noise exposure. Auditory brainstem response measured one month after inoculation showed that hearing thresholds were substantially improved. Scanning electron microscopy revealed that the damaged/lost stereocilia bundles were repaired or regenerated after Atoh1 treatment, suggesting that Atoh1 was able to induce repair/regeneration of the damaged or lost stereocilia. Therefore, our studies revealed a new role of Atoh1 as a gene critical for promoting repair/regeneration of stereocilia and maintaining injured hair cells in the adult mammal cochlea. Atoh1-based gene therapy, therefore, has the potential to treat noise-induced hearing loss if the treatment is carried out before hair cells die.
Highlights
Noise-induced hearing loss (NIHL) is a major health problem
The cochlear microphonic (CM), an electrical potential generated in the cochlear hair cells in response to acoustic stimulation, primarily reflects mechanotransduction in the stereocilia of outer hair cells [23]
The reduction represents a significant disruption of outer hair cell (OHC) mechanotransduction after noise exposure
Summary
Noise-induced hearing loss (NIHL) is a major health problem. Acoustic trauma causes NIHL when permanent cochlear damage results from exposure to high-intensity sounds, such as explosions, gunfire, and firecrackers. NIHL is usually due to destruction of cochlear hair cells and/or damage to their hair bundles [1]. The delicate hair bundle is susceptile to both acoustic trauma and ototoxic drugs. The inability of stereocilia to self-repair can subsequently lead to hair cell death and permanent hearing loss. If adult cochlear hair cells can likewise survive for a number of days after loss of stereocilia due to exposure to impulsive noise or ototoxic drugs, this window of opportunity could be crucial for potentially rescuing and repairing hair cells using therapeutic genetic or chemical interventions
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