Phased bidirectional regulation of Notch signaling drives the proliferative regeneration of hair cells in adult mice

Abstract

Abstract The loss of the vestibular hair cells (HCs) causes balance disorders, and there is little capability to regenerate HCs in adult mammals. Here, we reprogramed adult vestibular sensory cells through bidirectional regulation of Notch signaling in a phase-dependent manner, which recapitulated the dynamic changes in Notch signaling that occur during inner ear development. We observed that the activation of Notch signaling induced the proliferation of supporting cells (SCs) in the damaged adult utricle and primed the proliferating cells with the capacity to regenerate sensory HCs. Further inhibition of Notch signaling could remove the barrier of lateral inhibition and induce the transition from proliferating SCs to HCs. Our results highlight the pivotal roles of Notch signaling in promoting vestibular HC regeneration.