Notch inhibition induces cochlear hair cell regeneration and recovery of hearing after acoustic trauma.

Summary

Hair cell loss is normally irreversible because mammalian hair cells don't regenerate. This study showed that inhibiting Notch signaling with a gamma-secretase inhibitor after noise trauma raises levels of the transcription factor Atoh1 and drives supporting cells to transdifferentiate into new hair cells, confirmed by genetic lineage tracing. Treated mice showed partial recovery of hearing thresholds compared to untreated noise-damaged controls, the first demonstration that pharmacological Notch inhibition can regenerate hair cells and improve hearing in an adult mammal.

Key findings

• A gamma-secretase inhibitor, selected for potency in stimulating hair cell differentiation from inner ear stem cells in vitro, was delivered to noise-damaged mouse cochleae.
• Notch inhibition increased Atoh1 expression, the transcription factor that drives hair cell fate.
• Cre-lox lineage tracing of Sox2-expressing cells showed the new hair cells came from transdifferentiation of supporting cells, not cell division.
• Treated mice showed partial recovery of hearing after acoustic trauma relative to untreated controls.