The mammalian inner ear lacks the capacity to regenerate hair cells. Using functional genomics approach, we identified the retinoblastoma gene (Rb1) as a gene essential in cell cycle exit and postmitotic maintenance of hair cells. We showed that when the Rb1 is deleted in the inner ear, normally postmitotic hair cell progenitor cells undergo proliferation, which then proceed normally with hair cell specification, differentiation and become functional.
We created a hair-cell-specific Rb1 deletion model, and showed that the adult Rb1-null vestibular hair cells continue to proliferate and are functional at both the cellular and the system levels. In postnatal cochlea, Rb1-null hair cells die due to impaired maturation. Thus, pRb is also required for cochlear hair cell maturation and survival. The study is the first to demonstrate that in mammals functional hair cells can be regenerated through cell cycle re-entry of existing hair cells, which has important implication in regeneration of other postmitotic cells including neurons. Using the chick hair cell regeneration model for expression profiling, we identified two pathways: c-Myc and Fgf, in hair cell regeneration. Using the zebrafish model, we demonstrate that spontaneous regeneration of the lateral line neuromast hair cells can be suppressed by blocking c-myc or Fgf pathways pharmacologically or genetically. One of the most important goals is to renew proliferation and hair cell regeneration in adult and aged mammalian inner ear. We have recently identified a mechanism by which adult and aged mammalian inner ear cells can re-enter cell cycle. Further under a proper condition the dividing cells can transdifferentiate to functional hair cells that are connected to ganglion neurons. This exciting work sets a stage to restore hearing in deaf animals and animals with noise-induced and age-related hearing loss.