The Differentiation Status of Hair Cells That Regenerate Naturally in the Vestibular Inner Ear of the Adult Mouse

Abstract

Aging, disease, and trauma can lead to loss of vestibular hair cells and permanent vestibular dysfunction. Previous work showed that, following acute destruction of ;95% of vestibular hair cells in adult mice, ;20% regenerate naturally (without exogenous factors) through supporting cell transdifferentiation. There is, however, no evidence for the recovery of vestibular function. To gain insight into the lack of functional recovery, we assessed functional differentiation in regenerated hair cells for up to 15 months, focusing on key stages in stimulus transduction and transmission: hair bundles, voltage-gated conductances, and synaptic contacts. Regenerated hair cells had many features of mature type II vestibular hair cells, including polarized mechanosensitive hair bundles with zone-appropriate stereocilia heights, large voltage-gated potassium currents, basolateral processes, and afferent and efferent synapses. Regeneration failed, however, to recapture the full range of properties of normal populations, and many regenerated hair cells had some properties of immature hair cells, including small transduction currents, voltage-gated sodium currents, and small or absent HCN (hyperpolarizationactivated cyclic nucleotide-gated) currents. Furthermore, although mouse vestibular epithelia normally have slightly more type I hair cells than type II hair cells, regenerated hair cells acquired neither the low-voltage-activated potassium channels nor the afferent synaptic calyces that distinguish mature type I hair cells from type II hair cells and confer distinctive physiology. Thus, natural regeneration of vestibular hair cells in adult mice is limited in total cell number, cell type diversity, and extent of cellular differentiation, suggesting that manipulations are needed to promote full regeneration with the potential for recovery of vestibular function.

Evidence for Vestibular Sensory Reweighting and Improvement in Dynamic Posturography after Computerized Vestibular Retraining for Stable Unilateral Vestibular Deficit

“…[9] Another potential mechanism for restoration comes from experiments in mice that showed the regeneration of hair cells after ablation with diphtheria toxin. [50,51] These data suggest that substitution to contralateral vestibular organs or restoration of ipsilateral function could contribute to compensation in our subjects; however, it is less well understood how common restoration is for patients with unilateral de cits and how important it is for compensation.…”

Contributions of mirror-image hair cell orientation to mouse otolith organ and zebrafish neuromast function

“…We followed procedures described in (Gonzalez-Garrido et al, 2021) to prepare and record from HCs and calyceal afferent terminals in semi-intact utricles comprising the sensory epithelium and attached distal vestibular nerve including the vestibular ganglion. Recordings were analyzed for 83 cells from 57 Gpr156 heterozygotes and 93 cells from 73 Gpr156 -null animals.…”

Regeneration of Hair Cells in the Human Vestibular System

“…Loss of vestibular HCs, whether induced by aminoglycoside antibiotics ( Kawamoto et al, 2009 ), IDPN ( Zeng et al, 2020 ) or other injury methods ( Golub et al, 2012 ; González-Garrido et al, 2021 ), significantly enhances spontaneous regenerative proliferation. However, compared to the complete recovery of vestibular function in most non-mammalian vertebrates ( Jones and Nelson, 1992 ; Carey et al, 1996 ), both the number and the function of the newborn HCs are limited in the mammalian vestibular epithelium ( Forge et al, 1993 ; Kawamoto et al, 2009 ; Golub et al, 2012 ; Zeng et al, 2020 ; González-Garrido et al, 2021 ). As a result, techniques to boost the regeneration of mammalian vestibular HCs are needed.…”