Cell Source and Mechanism of Hair Cell Regeneration in the Neonatal Mouse Cochlea

Scientific and Technical Objectives. Specific Aims Aim 1 To determine the cell source of regenerated hair cells in the neonatal mouse cochlea. Aim 2 To determine the mechanism of hair cell regeneration in the neonatal mouse cochlea. Non-mammalian vertebrates such as birds, fish, and amphibians can regenerate hair cells HCs after damage. This occu rs when neighboring supporting cells SCs produce new HCs by either a change in cell fate termed direct transdifferentiation or by cell division termed mitotic regeneration. In contrast, damage to auditory HCs, caused by noise exposure or other factors, is permanent in humans and other mature mammals. However, we have recently developed a novel method to damage HCs in the neonatal mouse cochlea in vivo and observed spontaneous HC regeneration . Regenerated HCs are similar to endogenous HCs expressing espin stereocilia and several HC markers, including prestin, a protein specific to outer HCs that is necessary for the amplification of sound. Our findings demonstrate that, in contrast to common belief, the neonatal mouse coch lea does have the capacity to regenerate HCs after damage and is one step closer to regenerating HCs in humans. This award was focused on further investigation of the cell source, mechanism, and genes involved in the HC regeneration process that occurs in the neonatal mouse cochlea . During the funding period, we completed the original Aim 1 using fatemapping to demonstrate that SCs act as the cell source of regenerated HCs in the neonatal mouse cochlea. However there are seven SC subtypes in the cochlea and little is known about the capacity of individual subtypes to convert into HCs. We thus expanded Aim 1 to investigate which SC subtypes have the ability to act the cell source of regenerated HCs. Aim 2s focus has not changed from the original proposal and is focused on the molecular mechanism which underlies the HC regeneration process in the neonatal mouse cochlea.