Pharmacological regeneration of sensory hair cells restores afferent innervation and vestibular function
Hanae Lahlou, … , Wu Zhou, Albert S.B. Edge
Hanae Lahlou, … , Wu Zhou, Albert S.B. Edge
Published September 24, 2024
Citation Information: J Clin Invest. 2024;134(22):e181201. https://doi.org/10.1172/JCI181201.
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Research Article Otology

Pharmacological regeneration of sensory hair cells restores afferent innervation and vestibular function

Abstract

The sensory cells that transduce the signals for hearing and balance are highly specialized mechanoreceptors called hair cells that together with supporting cells comprise the sensory epithelia of the inner ear. Loss of hair cells from toxin exposure and age can cause balance disorders and is essentially irreversible due to the inability of mammalian vestibular organs to regenerate physiologically active hair cells. Here, we show substantial regeneration of hair cells in a mouse model of vestibular damage by treatment with a combination of glycogen synthase kinase 3β and histone deacetylase inhibitors. The drugs stimulated supporting cell proliferation and differentiation into hair cells. The new hair cells were reinnervated by vestibular afferent neurons, rescuing otolith function by restoring head translation–evoked otolith afferent responses and vestibuloocular reflexes. Drugs that regenerate hair cells thus represent a potential therapeutic approach to the treatment of balance disorders.

Authors

Hanae Lahlou, Hong Zhu, Wu Zhou, Albert S.B. Edge

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Figure 5

CHV treatment restores vestibular afferent activity in DT-ablated mice.

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CHV treatment restores vestibular afferent activity in DT-ablated mice. ...
(A) Schematic depicting the experimental approach. Four-week-old WT and Pou4f3DTR/+ mice were injected with DT at day 0 and day 2, followed by a local injection of CHV via the semicircular canal at day 7. Single unit recordings of the vestibular nerve were performed 2 months after drug treatment. (B) Schematic showing response dynamics of vestibular afferents from sensory epithelia. Afferents receive inputs from HCs through regular and irregular channels. Each canal afferent encodes information about angular head motion while otolith afferents encode information about translational acceleration in response to gravity. (C) Vestibular afferents recorded from the vestibular nerves of 9 WT mice (n = 279 afferents), 6 DT-ablated mice (n = 140 afferents), 5 DT-ablated mice without CHV (–CHV, n = 104 afferents), and 5 DT-ablated mice with CHV (+CHV, n = 125 afferents) mice. (D) Comparative analysis of afferent distribution. The histograms in the x axis represent rotation distortion, and the y axis represents translation distortion. (E) Vestibular afferent regularity. Normalized coefficient of variation (CV*) of interspike intervals from WT mice (black), DT-ablated mice (orange), and DT-ablated mice with (blue) and without (gray) CHV treatment. (F) Averaged spontaneous firing rates from the same groups. All data represent the mean ± SEM. *P < 0.05, ***P < 0.001, by 1-tailed Student’s t tests (F). A, anterior; L, lateral; M, medial; P, posterior.