Pharmacological regeneration of sensory hair cells restores afferent innervation and vestibular function
Hanae Lahlou, Hong Zhu, Wu Zhou, Albert S.B. Edge
Hanae Lahlou, Hong Zhu, Wu Zhou, Albert S.B. Edge
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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 2

Ex vivo CHV treatment increased SC proliferation and differentiation into type I and type II HCs in DT-ablated Pou4f3DTR/+ mouse utricle.

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Ex vivo CHV treatment increased SC proliferation and differentiation int...
(A) Schematic of in vitro drug treatment. At 7 days after damage, utricles were harvested from WT and Pou4f3DTR/+ mice and cultured for 10 days in the absence (–CHV) or presence (+CHV) of drug. (B) WT and DT-ablated utricles with or without CHV treatment immunolabeled for MYO7A (green), SOX2 (red), and nuclei stained with DAPI (blue). High-magnification images show the presence of SCs (gray arrow), type I HCs (cyan arrows) and type II HCs (white arrows. (C) Ki67 immunostaining (gray) in DT-ablated, untreated, and drug-treated utricles. (D) Diagram showing identification strategy for type I HCs, type II HCs, SCs, and newly-divided SCs. (E) Quantification of type I and type II HCs, SCs, and Ki67. An increase in SCs and Ki67 counts was accompanied by an increase in type I and type II HC numbers. All data represent the mean ± SEM. *P < 0.05, ***P < 0.001, ****P < 0.0001, by 2-tailed Student’s t tests and 1-way ANOVA with Tukey’s multiple comparison test (E). Scale bar: 50 μm (B and C, images showing the whole utricle); 100 μm (B and C, high magnification images). A, anterior; L, lateral; M, medial; P, posterior.