Sensory hair cells are required for auditory and vestibular function, and their loss leads to hearing loss and balance dysfunction. In the zebrafish lateral line and chicken auditory and vestibular systems, supporting cells robustly regenerate hair cells through two mechanisms: direct transdifferentiation and mitotic regeneration. While the mammalian cochlea does not regenerate, limited regeneration takes place in the mammalian utricle with direct transdifferentiation being the main mode of regeneration. However, our understanding of the dynamics of the supporting cell-hair cell transition is rather limited. Building on our published and preliminary work that supporting cells can directly transdifferentiate into hair cell-like cells in cultured utricles from mice and human, we hereby propose to characterize the molecular and morphological phenotype of cells transitioning between supporting cells and hair cells in the neonatal, adult mouse and human utricles. By fate-mapping supporting cells in both the striolar and extrastriolar regions, we will analyze transitional cells both via immunohistochemistry and time-lapse imaging. Lastly, with the expectation that inhibition of Notch signaling will enhance the degree of hair cell regeneration, we will treat mouse and human utricles with Notch inhibitors and characterize such a coerced supporting cell-hair cell transition. Overall, this research will systematically characterize the morphologic and molecular phenotypes of early regenerating mouse and human hair cells, including those as a result of potentially translational pharmacologic manipulation.
Sensory hair cells are required for hearing and balance functions and their loss leads to hearing loss and balance dysfunction. Unlike the mammalian cochlea, limited regeneration takes place in the mouse and human utricle. By characterizing the molecular and morphological signatures of regenerating cells in the mouse and human utricles, we aim to reveal the mechanisms of mammalian hair cell regeneration. Completion of the proposed work will gain critical insights into the steps of normative and enhanced mouse and human hair cell regeneration with long-term goal of improving therapeutics for inner ear dysfunction.
