Hair cell regeneration in the avian auditory epithelium

Abstract

Regeneration of sensory hair cells in the mature avian inner ear was first described just over 20 years ago. Since then, it has been shown that many other non-mammalian species either continually produce new hair cells or regenerate them in response to trauma. However, mammals exhibit limited hair cell regeneration, particularly in the auditory epithelium. In birds and other non-mammals, regenerated hair cells arise from adjacent non-sensory (supporting) cells. Hair cell regeneration was initially described as a proliferative response whereby supporting cells re-enter the mitotic cycle, forming daughter cells that differentiate into either hair cells or supporting cells and thereby restore cytoarchitecture and function in the sensory epithelium. However, further analyses of the avian auditory epithelium (and amphibian vestibular epithelium) revealed a second regenerative mechanism, direct transdifferentiation, during which supporting cells change their gene expression and convert into hair cells without dividing. In the chicken auditory epithelium, these two distinct mechanisms show unique spatial and temporal patterns, suggesting they are differentially regulated. Current efforts are aimed at identifying signals that maintain supporting cells in a quiescent state or direct them to undergo direct transdifferentiation or cell division. Here, we review current knowledge about supporting cell properties and discuss candidate signaling molecules for regulating supporting cell behavior, in quiescence and after damage. While significant advances have been made in understanding regeneration in nonmammals over the last 20 years, we have yet to determine why the mammalian auditory epithelium lacks the ability to regenerate hair cells spontaneously and whether it is even capable of significant regeneration under additional circumstances. The continued study of mechanisms controlling regeneration in the avian auditory epithelium may lead to strategies for inducing significant and functional regeneration in mammals.

Spontaneous regeneration of cochlear supporting cells after neonatal ablation ensures hearing in the adult mouse

“…This regenerative process is different from the spontaneous regeneration of HCs and SCs seen in nonmammalian vertebrates after damage, which happens via both proliferation and transdifferentiation of SCs (21)(22)(23). It also differs from the limited HC regeneration that occurs in the neonatal organ of Corti after DTA-mediated HC ablation, which also involves proliferation (42).…”

“…Furthermore, SCs are considered a potential source of cells for HC replacement in mammals, because SCs are a documented source of new HCs in cultured neonatal cochlea (19) and in adult utricles (20). Additionally, nonmammalian vertebrates regenerate HCs and SCs after damage and recover hearing, with the SCs being the source of the regenerative response (21)(22)(23). Indeed, if SCs are damaged by insults, the regenerative response is severely compromised (1,24).…”

Vocally correlated seasonal auditory variation in the house sparrow (Passer domesticus)

“…In the midshipman, injection of females with testosterone or 17-estradiol induces the enhanced auditory phenotype outside of the breeding season (Sisneros et al, 2004) whereas in mammals, supplemental estrogen reduces the severity of hearing loss associated with Turner's syndrome in humans and mice (chromosomal abnormalities involving estrogen deficiency), menopause in humans and ovariectomy in rats (Hultcrantz et al, 2006). The morphological differences underlying changes in auditory performance are not clear in these species, but hair cell turnover on the basilar papilla is one possibility in house sparrows based on observations of hair cell regeneration in a wide variety of avian and other non-mammalian vertebrates (Stone and Cotanche, 2007). Natural cycles of hair cell turnover have been found in the vestibular organ of adult birds but generally not on the basilar papilla of the cochlea, where regeneration occurs in response to acoustic trauma or ototoxic drugs.…”

Supporting Cell Division Is Not Required for Regeneration of Auditory Hair Cells After Ototoxic Injury In Vitro

“…Upon HC loss, SCs divide and progeny differentiate into HCs or SCs. Normal numbers of HCs return within 2-3 weeks (reviewed in Stone and Cotanche 2007). Restoration of normal structure and function, including cellular maturation and reinnervation, takes several weeks (reviewed in Bermingham-McDonogh and Rubel 2003).…”

“…Several observations suggest that some HCs in the chicken BP may be regenerated by a process called direct transdifferentiation, which is the phenotypic con-version of SCs into HCs without cell division (reviewed in Morest and Cotanche 2004;Stone and Cotanche 2007). This process contributes to HC regeneration in cultured saccules of frogs and salamanders after aminoglycoside-induced injury (Baird et al 1996(Baird et al , 2000Taylor and Forge 2005).…”