By contrast, in the inner ear the support cells upregulate

the Notch pathway, but inhibiting the pathway does not prevent support cell transdifferentiation to hair cells. These results suggest that the upregulation of Notch after damage Fludarabine concentration may not be required in the inner ear, but nevertheless the presence (and upregulation) of Notch signaling is a reliable indicator of a regenerating system. This is an important conclusion in light of the fact that the downstream Notch effector Hes5 is not expressed in either the normal adult mouse cochlea, or after damage to the hair cells (Hartman et al., 2009). Unbiased screening for critical factors in the regeneration process, using small molecule libraries, microarray studies, and genetics (Brignull et al., 2009), will certainly lead to a better understanding of the differences between

the successful and non-successful regenerates. A process of ongoing sensory receptor cell replacement characterizes the sensory epithelia that show robust regeneration. This does not appear to be present in the retinas or cochleas of mammals. Therefore, the main options for therapy will likely involve reinitiating the process of regulated reprogramming to a selleck inhibitor proliferative progenitor state in the glia and support cells. Although stimulation of regeneration in mammalian inner ear and retina to the level present nonmammalian vertebrates would be ideal, considerably less effective regeneration could still be useful for below patients. For example, stimulation of proliferation in support cells in the cochlea may not be necessary for some recovery.

In many individuals with age-related hearing loss, the inner hair cells are thought to survive, longer than the outer hair cells. The loss of outer hair cells causes dramatic loss in cochlear function (e.g., Chen et al., 2009). Therefore, the restoration of only 30%–40% of the outer hair cells, by stimulation of transdifferentiation of the remaining Deiters’ cells, could result in a significant hearing improvement. The same may be true for the retina. The degeneration of foveal cones in late stages of macular degeneration leads to significant vision loss, though these cells make up less than 1% of the total retinal cell population. As the molecular pathways are further elucidated, one can imagine a scheme in which these pathways could be targeted by gene therapy to initiate a process of regulated reprogramming; in the mammalian inner ear, viral expression of Atoh1 has already been shown to restore some hair cells to damaged cochlea. Perhaps more promising are small molecule approaches to stimulate this process, since these have proven successful in the more drastic reprogramming that is required to generate iPS cells (Li et al., 2009).