Abstract
BackgroundFollowing the loss of hair cells from the mammalian cochlea, the sensory epithelium repairs to close the lesions but no new hair cells arise and hearing impairment ensues. For any cell replacement strategy to be successful, the cellular environment of the injured tissue has to be able to nurture new hair cells. This study defines characteristics of the auditory sensory epithelium after hair cell loss.Methodology/Principal FindingsStudies were conducted in C57BL/6 and CBA/Ca mice. Treatment with an aminoglycoside-diuretic combination produced loss of all outer hair cells within 48 hours in both strains. The subsequent progressive tissue re-organisation was examined using immunohistochemistry and electron microscopy. There was no evidence of significant de-differentiation of the specialised columnar supporting cells. Kir4.1 was down regulated but KCC4, GLAST, microtubule bundles, connexin expression patterns and pathways of intercellular communication were retained. The columnar supporting cells became covered with non-specialised cells migrating from the outermost region of the organ of Corti. Eventually non-specialised, flat cells replaced the columnar epithelium. Flat epithelium developed in distributed patches interrupting regions of columnar epithelium formed of differentiated supporting cells. Formation of the flat epithelium was initiated within a few weeks post-treatment in C57BL/6 mice but not for several months in CBA/Ca's, suggesting genetic background influences the rate of re-organisation.Conclusions/SignificanceThe lack of dedifferentiation amongst supporting cells and their replacement by cells from the outer side of the organ of Corti are factors that may need to be considered in any attempt to promote endogenous hair cell regeneration. The variability of the cellular environment along an individual cochlea arising from patch-like generation of flat epithelium, and the possible variability between individuals resulting from genetic influences on the rate at which remodelling occurs may pose challenges to devising the appropriate regenerative therapy for a deaf patient.
Highlights
Death of the sensory ‘‘hair’’ cells from the organ of Corti – the auditory sensory epithelium of the cochlea – is the major cause of sensorineural hearing loss
There is a limited capacity for hair cell regeneration in the vestibular system of the inner ear [8,9,10,11] which has been suggested to occur exclusively by phenotypic conversion [12], but there is no regeneration of hair cells in the mammalian cochlea
The sensory strip within the organ of Corti consists of a single row of inner hair cells (IHC) and, usually, three rows of outer hair cells (OHC), each hair cell separated from its neighbours by intervening supporting cells (Fig. 1A,B)
Summary
Death of the sensory ‘‘hair’’ cells from the organ of Corti – the auditory sensory epithelium of the cochlea – is the major cause of sensorineural hearing loss. In non-mammalian vertebrates, lost hair cells are replaced by new ones. These new hair cells arise from the supporting cells, which are generally unaffected by those agents which kill hair cells. Two means of generating new hair cells have been identified in non-mammalian vertebrates: direct phenotypic conversion (nonmitotic transdifferentiation) of supporting cells into hair cells [1,2,3,4]; and initiation of cell division amongst the supporting cell population with daughter cells subsequently differentiating into hair and/or supporting cells to restore the sensory epithelium [3,5,6,7]. Following the loss of hair cells from the mammalian cochlea, the sensory epithelium repairs to close the lesions but no new hair cells arise and hearing impairment ensues. This study defines characteristics of the auditory sensory epithelium after hair cell loss
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