Age-related deafness is thought to result from either loss or incapacity of sensory hair cells in the inner ear. One possibly approach to treatment is to stimulate the creation of new hair cells, and their integration with the appropriate nerve pathways to the brain. A number of groups have examined ways to use Wnt and Notch pathways to achieve this end, with an eye to developing drugs that can cause hair cell regeneration, and the work noted here is a recent example.
Despite its prevalence, there remains no available pharmacological therapies to treat hearing loss. Loss of hair cells (HCs), the inner ear sensory cells that detect sound and sense balance, is a major cause of hearing loss and vestibular dysfunction in humans. In lower vertebrates such as birds, fish, and amphibians, HC loss triggers supporting cells (SCs) to re-enter the cell cycle. Proliferating SCs then transdifferentiate into new HCs, resulting in the recovery of hearing and vestibular functions. In contrast, the mature mammalian cochlea completely lacks the capacity to spontaneously proliferate or regenerate HCs, and has very limited regeneration potential in the vestibular system.
In the young mammalian inner ear, SC-to-HC transdifferentiation can be induced by overexpression of HC fate-determining transcription factor, Atoh1. An early study provided evidence that Atoh1 overexpression had limited but similar effects in the adult mammalian cochlea, however, subsequent studies failed to reproduce the essential findings. It is therefore suggested that, in the adult inner ear, overexpression of Atoh1 in SCs alone is inefficient in promoting HC regeneration. To recapture the capacity to respond to HC induction signals, it is likely that mature SCs need to first regain the properties of their younger biological selves.
To identify potential reprogramming factors in the adult mammalian inner ear, we began by studying chick and zebrafish HC regeneration models and uncovered that reactivation of Myc is a major event that leads to cell cycle re-entry. Additional studies have shown that overexpression of Notch1, a receptor important in mammalian inner ear early development and patterning, is sufficient to induce formation of the prosensory domain of the developing mouse otocyst. We hypothesize that the combined action of MYC and NOTCH1 may be sufficient to reprogram adult mouse inner ear cells for cell cycle re-entry and the reprogrammed SCs may regain the properties enabling them to transdifferentiate into HCs in the presence of induction signals.
In this study, by adenovirus-mediated delivery and inducible transgenic mouse models, we demonstrate the proliferation of both HCs and SCs by combined Notch1 and Myc activation in in vitro and in vivo inner ear adult mouse models. These proliferating mature SCs and HCs maintain their respective identities. Moreover, when presented with HC induction signals, reprogrammed adult SCs transdifferentiate into HC-like cells both in vitro and in vivo. Finally, our data suggest that regenerated HC-like cells likely possess functional transduction channels and are able to form connections with adult auditory neurons.