Once a human’s inner-ear hair cells are destroyed, they never grow back—and the hearing loss is permanent. This project asks why that is, and whether we can change it. The problem is that mammals, unlike birds or fish, cannot regenerate the sensory hair cells in the cochlea after damage. Some limited regeneration does occur in the vestibular system (which controls balance), but it fades with age. The underlying molecular mechanisms are unknown. This researcher will compare the utricle—a balance organ—in mice (which regenerate poorly) and chicks (which regenerate fully), using single-cell genomics and spatial sequencing to map exactly which genes and cell states block regeneration as the tissue matures. If the work succeeds, it will identify the specific molecular switches that shut off regeneration in adult mammals. That knowledge could eventually lead to therapies that reactivate those pathways in humans—not just for hearing, but potentially for balance disorders caused by hair cell loss. This is fundamental science: it will not produce a treatment tomorrow. But understanding why mammalian sensory cells lose their regenerative capacity is a necessary first step toward ever restoring it.
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In humans, as with all mammals,, the loss of auditory sensory hair cells (HCs) is irreversible. However, different degrees of HC regeneration occur in vestibular sensory epithelia, at early developmental stages, or in non-mammalian species. HC regeneration results from division and/or trans-differentiation of neighbouring supporting cells (SCs). It is generally accepted that poor/absent HC regeneration relates to the differentiation state reached by SCs and HCs, but the mechanisms behind this are unknown. What dictates HC regeneration potential? Taking on a multi-layered approach, combining single-cell multi-omics, in-situ sequencing and transcriptional manipulations, I will study the vestibular utricle to evaluate the connection between maturation and HC regeneration potential. First, I will identify the cell/tissue level factors that interact during maturation to distinguish the mouse (marginally-regenerating) and chick (fully-regenerating) utricle. Second, I will study the regeneration trajectories of postnatal and adult mouse utricle to zoom-in on the factors driving the age-related decrease in regeneration potential. Finally, I will perform simultaneous transcriptional manipulation of identified targets aiming to overturn the poor HC regeneration of the adult mammalian utricle. My research will generate unprecedented cell/tissue-level insight on the maturation and regeneration of sensory epithelia, identifying potential novel therapeutic avenues for recovery from pathological HC loss.
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