Development and regeneration of vestibular hair cells in mammals

Abstract

Vestibular sensation is essential for gaze stabilization, balance, and perception of gravity. The vestibular receptors in mammals, Type I and Type II hair cells, are located in five small organs in the inner ear. Damage to hair cells and their innervating neurons can cause crippling symptoms such as vertigo, visual field oscillation, and imbalance. In adult rodents, some Type II hair cells are regenerated and become re-innervated after damage, presenting opportunities for restoring vestibular function after hair cell damage. This article reviews features of vestibular sensory cells in mammals, including their basic properties, how they develop, and how they are replaced after damage. We discuss molecules that control vestibular hair cell regeneration and highlight areas in which our understanding of development and regeneration needs to be deepened.

Keywords: Development; Hair cell; Regeneration; Supporting cell; Vestibular.

Figure 1. The sensory organs of the mouse inner ear

The structure of the inner ear sensory organs is shown (left column), as well as the development of the utricular macula in surface (middle column) and cross-sectional (right column) views. The most mature epithelia are shown at the bottom. Left column, Detection of sound or acceleration occurs in the sensory epithelia (green), which are ordered patches comprised of mechanosensitive hair cells and supporting cells. The lateral, posterior, and anterior cristae detect rotational acceleration, the utricle and saccule detect linear acceleration, and the cochlea detects sound. In mammals, each sensory epithelium (green) contains a specialized set of hair cells (tan) that enhance range or sensitivity. In the vestibular organs, these specialized cells are located centrally within the epithelium. Middle and right columns, Surface views and cross-sections depicting development of the mouse utricular macula. By E12.5, a pseudostratified layer of neuroepithelial cells within the otocyst differentiates to form a prosensory domain (green), the precursor to the utricular macula. Neuroepithelial cells surrounding the prosensory domain form the non-sensory transitional epithelium (TE, blue). Prosensory cells exit the cell cycle and begin to differentiate into the first hair cells at E13.5. By birth (P1), progenitors are completing final rounds of cell division. The crescent-shaped striola (tan) has distinguished itself from the surrounding extrastriolar zones (green). Many hair cells display the morphological and electrophysiological characteristics of Type I and II hair cells and have formed connections with vestibular nerve endings. By P12, maturation of the sensory epithelium is nearly complete.

Figure 2. The capacity for mitotic regeneration in the utricle becomes limited during the first postnatal week in mice

Confocal images of utricles from newborn (P0) or adult (P80) mice that were explanted and cultured for 24 h with or without 3mM Neomycin. After Neomycin treatment, utricles were cultured in the presence of BrdU for an additional 72 h, at which point the organs were fixed an immunolabeled for BrdU and the hair cell marker Myo7a. A significant number of supporting cells in P0 mice reentered the cell cycle in response to damage, whereas few if any supporting cells incorporated BrdU in adults. Note that equivalent Neomycin treatment kills many more hair cells in adults than in neonates. One hypothesis for this difference is that many hair cells in the neonatal epithelium are immature and lack mechanotransduction, the route by which aminoglycosides preferentially enter hair cells [195]. Neonatal mouse images reproduced from [123].

Figure 3. A subpopulation of vestibular hair cells is regenerated after near-complete ablation

a. Schematic showing the utricular macula under normal conditions, after damage, and after regeneration. b. Confocal images of the mid-apical region of the organ of Corti in the cochlea (top) and the extrastriolar region of the utricle (bottom) in normal conditions, at 2 weeks post-damage (induced by diphtheria toxin in Pou4f3^DTR mice, see [133], and at 4–6 weeks post-damage. In both sensory organs, hair cells (green) were killed by diphtheria toxin, and replacement hair cells were detected in the utricle but not the cochlea.