ReviewDevelopment and regeneration of vestibular hair cells in mammals
Introduction
Vestibular hair cells are sensory receptors in the inner ear that detect head motion and thereby enable animals to orient their bodies and coordinate movements. In mammals, vestibular hair cells and their innervating neurons degenerate with age [1], [2], [3], and they can be destroyed by therapeutic drugs such as aminoglycoside antibiotics [4], [5]. Extensive loss of vestibular sensory cells is highly debilitating and can elicit nauseating bouts of dizziness, imbalance, and incapacitation. Vestibular deficits are prevalent in the human population. They are estimated to affect 35% of the U.S. population >40 years old, and they increase significantly with age [6]. Although mammals compensate after vestibular hair cell loss by invoking visual and proprioceptive senses, functional deficits can persist and affect balance throughout life.
The pathology of vestibular aging and toxicity is complex, affecting various cell types and structures in the sensory organs, neurons of the vestibular ganglion, and the central pathways to which the neurons project [1], [2], [3], [4], [7]. Indeed, the degree to which losses of vestibular hair cells and neurons contribute to vestibular dysfunction in humans is not well understood. Regeneration of vestibular hair cells is one treatment strategy being explored for some forms of vestibular dysfunction. The majority of hair cells in mammalian vestibular organs are formed during embryogenesis. However, adult mammals can regenerate a subpopulation of these cells after damage, increasing the likelihood that cellular repair or replacement could potentially benefit millions of people suffering from vestibular deficits. This review summarizes the current state of knowledge on development, damage, and regeneration of sensory cell types in the mammalian vestibular system and highlights critical information gaps that must be addressed before new therapies for vestibular dysfunction can be defined.
Section snippets
The mammalian vestibular organs contain a diverse array of cell types
The sense of balance is achieved by integrating vestibular, visual, and somatosensory inputs. Five vestibular organs located in the inner ear sense head position and movements in different directions (Fig. 1). Mechanosensitive hair cells are receptor cells located in the sensory epithelium of each vestibular organ. Hair cells and their innervating neurons detect head velocity and acceleration when a specialized bundle of stiff finger-like projections (stereocilia) located at their apical
Development
The sensory epithelia of the vestibular organs derive from the otic placode, a patch of head ectoderm that forms during early development. The placode grows in size and invaginates into the mesoderm, forming a fluid-filled ball called the otocyst.
The first signs of sensorineural cell fate decisions become apparent when neuroblasts delaminate from the ventral region of the otocyst (E9.5 in mouse) and migrate to the ventro-medial location, where they will eventually differentiate into neurons of
Vestibular cell types and subtypes might exhibit differential susceptibility to damage
Age-related degeneration of Type I and Type II hair cells has been observed in surface preparations and sections of human maculae and cristae [1], [2], [13], [81], [82], [83], [84]. Similar declines have been observed in mouse and guinea pig [85], [86]. In several of the aforementioned studies, aged maculae showed less hair cell loss than the cristae, suggesting the utricle and saccule might be less susceptible. Concomitant with loss of sensory hair cells, numbers of vestibular ganglion neurons
Spontaneous regeneration of vestibular hair cells after damage declines with age but persists into adulthood
Remarkably, many adult non-mammalian vertebrates respond to vestibular hair cell death by generating replacements that become innervated and restore sensory function within days or weeks (for a review on cross-species comparisons, see [105]). In birds, which have been most well studied, many replacement hair cells arise as a result of neighboring supporting cells re-entering the cell cycle and dividing [106], [107], [108], [109], [110], [111]. Post-mitotic cells then differentiate into new hair
Lessons from development: molecular level control of proliferation and differentiation in adult vestibular epithelia
A possible explanation for distinct regenerative capacities is that mammalian supporting cells execute a more specialized differentiation program than non-mammalian supporting cells, creating more barriers to de-differentiation after damage. Consistent with this hypothesis, mammalian supporting cells develop extensive cytoskeletal and junctional specializations around the same time their capacity for proliferative regeneration wanes, whereas such specializations are absent in many species of
Future outlook
In contrast to the cochlea, the cellular plasticity that persists into adulthood within mammalian vestibular organs could make restoration of vestibular function more feasible in the near-term than overcoming the many challenges associated with hearing loss. Morphology, patterning, and physiology of vestibular cells also appear to be less complex than their cochlear counterparts. However, the vestibular organs are still relatively intricate structures that contain a diverse array of cell types
Acknowledgments
We would like to thank Mark Warchol (Washington University, St Louis) for critical comments on the manuscript, as well as the efforts of reviewers and editors who helped build this special journal issue. The Stone lab receives research support from National Institutes of Health (DC013358 and DC013771) and the Hearing Health Foundation’s Hearing Restoration Project.
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