Sensory hair cell death and regeneration: two halves of the same equation.

Abstract

Sensory hair cells are susceptible to ototoxic damage from a variety of sources, including antibiotic treatment. Unfortunately, this often results in permanent hearing and/or balance problems in humans. By understanding how sensory hair cells die in response to aminoglycoside treatment, preventive strategies may be developed. This review will discuss some of the key recent findings in sensory hair cell death and regeneration. Aminoglycosides induce hair cell death through the initiation of apoptosis. Early and late stages of hair cell apoptosis have been defined, and several of the key molecules involved in the cascade have been identified. Moreover, specific inhibitors of apoptosis rescue hair cells from death and preserve function. Hair cell death has been shown to induce regeneration through supporting cell transdifferentiation, proliferation, and new hair cell differentiation in birds and lower vertebrates. Regeneration in the mammalian cochlea does not occur spontaneously, but genetic manipulation of cell cycle genes, induction of new hair cells through gene therapy, and introduction of stem cells into damaged cochleas suggest that repair and replacement of lost hair cells in the organ of Corti may be possible. Finally, continuing investigations of the mouse, zebrafish, and human genomes may one day enable manipulation of the cochlea so that functional regeneration is readily available as a therapeutic intervention. The discovery that hair cells can regenerate in birds and other nonmammalian vertebrates has fueled a wide range of studies to find ways to restore hearing and balance in mammals. The demonstration that apoptosis and proliferation are coupled as controlling factors in regeneration and the advent of new approaches such as gene therapy, stem cell transplantation, and genomics may lead to methods for inducing hair cell regeneration and repair in the mammalian cochlear and vestibular systems.