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 4

In vivo CHV treatment improves vestibular function by promoting HC regeneration.

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In vivo CHV treatment improves vestibular function by promoting HC regen...
(A) Schematic of the in vivo approach for drug delivery in DT-ablated Pou4f3DTR/+ mice. CHIR and VPA were injected in the left ear via the posterior semicircular canal (PSCC) at day 7 after DT ablation; the contralateral ear was used as a control for spontaneous regeneration. Mice were examined at 2 months after drug treatment. (B) MYO7A immunolabeled utricles from 2-month WT, DT-ablated, untreated (–CHV), and treated (+CHV) ears. (C) MYO7A counts from WT utricles (black), DT-ablated utricles (orange), DT-ablated utricles without CHV treatment (gray), and DT-ablated utricles with CHV treatment (blue). (D) Translational vestibuloocular reflexes (tVORs) in response to sinusoidal head translations at 2 Hz for WT (black), DT-ablated (orange), and DT-ablated mice with (blue) and without (gray) CHV treatment. (E) tVOR gains. (F) tVOR phases. (G) Rotational vestibuloocular reflexes (rVORs) to sinusoidal head rotations with representative eye velocity responses to 4 Hz head rotation. (H) rVOR gains. (I) rVOR phases. Numbers of mice tested for each group were 3 for WT (black), 8 for DT ablated (orange), 8 for DT-ablated without CHV treatment (gray), and 5 for DT-ablated with CHV treatment (blue). All data represent the mean ± SEM. ****P < 0.0001 by 1-way ANOVA (C), *P < 0.05, by 2-tailed Student’s t tests (E and H), and *P < 0.05, **P < 0.01 by 2-way ANOVA with Tukey’s multiple comparison test (F and I). Scale bar: 50 μm. A, anterior; L, lateral; M, medial; P, posterior.