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.
View: Text | PDF
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

×

Figure 1

Ex vivo drug treatment enhances HC regeneration in DT-ablated Pou4f3DTR/+ mouse utricle.

Options: View larger image (or click on image) Download as PowerPoint
Ex vivo drug treatment enhances HC regeneration in DT-ablated Pou4f3DTR/...
(A) Schematic of DT in vivo damage. Four-week-old WT and Pou4f3DTR/+ mice received 2 intramuscular injections of diphtheria toxin (DT). Utricles were analyzed 4 and 7 days after damage. (B) MYO7A immunolabeling of undamaged WT and Pou4f3DTR/+ ablated utricles. (C) MYO7A+ cell counts of WT and DT-ablated utricles. (D) Schematic of in vitro drug treatment. At 7 days after damage, utricles were harvested from WT and Pou4f3DTR/+ mice and cultured in medium without drug (–CHV) or supplemented with CHIR, VPA, or CHIR plus VPA (CHV). Utricles were analyzed 10 days after drug treatment. (E) DT-ablated Pou4f3DTR/+utricles without drug treatment and with drug treatment (+CHIR, +VPA, and +CHV). (F) Quantification of MYO7A+ cells from in vitro untreated and drug-treated utricles. HC numbers were significantly increased after CHV treatment compared with treatments with CHIR or VPA alone. All data represent the mean ± SEM. **P < 0.01, ****P < 0.0001 by 1-tailed Student’s t tests (C) and 1-way ANOVA with Tukey’s multiple comparison test (F). Scale bar: 50 μm. A, anterior; L, lateral; M, medial; P, posterior.