The sensory hair cells of the inner ear convert the mechanical deflections caused by sound or head movements into electrical signals that are conveyed to the brain. Hair cells in the mammalian ear are formed during a limited period of embryonic development, and can be lost later in life as a consequence of acoustic trauma, treatment with ototoxic drugs, infections or autoimmune pathologies, or as part of the aging process. In humans, loss of hair cells from the cochlea and vestibular organs can result in permanent deficits in hearing and equilibrium. Most nonmammalian vertebrates (fish, amphibians, and birds) can quickly regenerate hair cells after injury, but the mammalian inner ear has a very limited potential for spontaneous regeneration. The factors that allow sensory regeneration to occur in the ears of nonmammals and inhibit such regeneration in mammals are not known, but are of great biological and clinical interest.
The process of hair cell regeneration has been characterized most completely in the inner ears of birds. Both the avian cochlea and vestibular organs possess a robust capacity to quickly replace lost sensory cells. Although several distinct mechanisms may be responsible for the production of new hair cells hair cell regeneration in the avian ear appears to involve the proliferation of epithelial supporting cells. Although the undamaged cochlea is mitotically quiescent, numerous studies have shown that the loss of hair cells from the avian ear stimulates renewed mitosis of supporting cells, and that the progeny of those divisions go onto differentiate as replacement hair cells and supporting cells. A more limited regenerative response also occurs in the vestibular organs of mammals, but sensory regeneration does not occur in the normal mammalian cochlea.
Many of the cellular events that occur during regeneration in the avian ear have been described, but the precise signaling events that initiate regenerative proliferation are not known.
In addition to regeneration after injury, hair cells in the vestibular organs of birds also display a unique pattern of postnatal survival and replacement. In most vertebrates, hair cells appear to be capable of surviving for the lifetime of the animal. Interestingly, vestibular (but not cochlear) hair cells in mature birds have a relatively short lifetime, estimated at 1-2 months. Dying hair cells are quickly replaced by new sensory cells that are produced by ongoing proliferation of epithelial supporting cells. Significant levels of cell death and cell proliferation are observed in the undamaged chick utricle, suggesting that a sizable fraction of hair cells in that organ are either in an immature state or are near-death. The factors that are responsible for the limited lifetime of these hair cells are not known, but their identification may produce insights in the mechanisms of age related hearing and balance disorders.
The cochlea and vestibular organs of mature birds exhibit very different patterns of hair cell production and survival. Hair cells in the cochlea are produced during a short period in embryonic development. Cell proliferation in the sensory regions of the cochlea terminates on about embryonic day ten as hair cells and supporting cells begin to differentiate. Under normal conditions, cochlear hair cells appear to be capable of surviving for the lifetime of the animal, and the normal (undamaged) cochleae of mature birds contains very few proliferative cells. In contrast, hair cells in the vestibular sensory organs (which are initially produced during a similar period of embryonic development) have a very short normal lifetime. Hair cells in the mature vestibular organs appear to die spontaneously, and are then replaced by new cells that arise from the ongoing proliferation of epithelial supporting cells. Estimates of the lifespan of vestibular hair cells in chickens range from 2-6 weeks.
Few studies to-date have examined the genetic basis for hair cell regeneration. Studies based on differential display of mRNA following acoustic trauma have described 70 cDNA bands that are observed in the avian cochlea after injury. The identities of most of these bands were not determined, although it was shown that genes for parathyroid hormone-related protein, a neuron-specific CaM-kinase, the GTPase Cdc42, and UBE3B (a ubiquitin ligase) were expressed within 48 hours of cochlear injury. Also, as noted above, expression of certain members of the FGF family of growth factors and their receptors are observed after cochlear injury. Finally, a recent study has shown ototoxic insult to the avian utricle results in increased gene expression for certain cytoskeletal proteins.
Another strategy for determining the role of specific genes in the process of hair cell regeneration is to study the regenerative capabilities of mice with identified genetic deficits. Such techniques have demonstrated that disruption of the gene for the cyclin dependent kinase inhibitor p27Kip1 appears to permit the proliferation of cochlear supporting cells in mature mice. These are the first results that have conclusively demonstrated postnatal proliferation in the mammalian cochlea, and suggest that the inability of the normal mammalian cochlea to regenerate hair cells may be due (in part) to the expression of genes that inhibit renewed proliferation. Additional studies have shown an age-related decrease in expression of the CDK inhibitor p57Kip2 in the developing vestibular organs of mice.