Initiating Cell Regeneration in the Mammalian Cochlea

Exposure to chemotherapy, antibiotics, and loud noise often causes loss of sensory hair cells in the cochlea of the inner ear, leading to permanent hearing loss in humans. While mammals cannot replace damaged sensory hair cells, chickens, fish, and amphibians can by division of neighboring supporting cells which then adopt sensory hair cell characteristics. Is it possible to give a mammal the chicken's ability to regenerate auditory hair cells? We propose a three-step working model for regeneration of mammalian cochlear hair cells in vivo that involves hair cell damage, supporting cell division, and cell fate change (or transdifferentiation) to hair cells. Recent advances in mouse genetics provide an unprecedented avenue to test this model. We first focused on the neonatal mouse cochlea because neonatal tissue is generally more plastic and regenerative than adult tissue. Since it is difficult to damage hair cells in the neonatal mouse cochlea with ototoxic drugs or noise, we have instead adopted a novel genetic method to kill hair cells by expressing a toxin specifically in hair cells beginning at birth. To further induce proliferation of supporting cells, we have deleted one of two key cell cycle regulators specifically in neonatal supporting cells, the retinoblastoma (Rb) protein and p27(Kip1). Finally, to make new hair cells, we are manipulating several transcription factors (i.e., Atoh1) in neonatal supporting cells. Our studies complement other strategies for hair cell regeneration in the mammalian cochlea and provide promising therapeutic avenues to restore hearing.