Kelvin Y. Kwan, Ph.D.
Molecular basis of hair cell regeneration, hearing loss
Hearing loss is a common sensory disorder affecting approximately 17% of American adults. The origins of deafness range from inherited genetic defects to noise-induced trauma, but a major cause of hearing loss is hair cell degeneration. Hair cells are the sensory cells of the inner ear that detect sound and convert information into neural signal that is relayed to the brain. Although mammals cannot regenerate hair cells, birds and fish can. During avian and piscine hair cell regeneration, supporting cells that reside adjacent to hair cells undergo a coordinated process of cell division and differentiation to repopulate damaged hair cells.
To understand what promotes regeneration in lower vertebrates and what limits it in mammals, we wanted to recapitulate the processes required for hair cell regeneration in a cellular system. Starting with primary prosensory cells from embryonic cochlea, we generated cell lines that maintain their prosensory cell identity, retain their commitment to become hair cells, supporting cells, and auditory neuron, while possessing the ability to continually divide. These auditory progenitor cells serve as a platform for studying mammalian regeneration of the inner ear.
Two genes that are upregulated during avian hair cell regeneration and present in auditory progenitor cells are c-Myc and Sox2. These two transcription factors are better known as two of the four Yamanaka factors used to generate induced pluripotent stem cells. Deep sequencing of the progenitor cell transcriptome shows transcriptional signatures of self-renewal involving proliferation and maintenance of cell identity similar to stem cells. Analysis of genome-wide binding sites of c-Myc and Sox2 also reveals candidate genes involved in cell division and differentiation. We are currently evaluating the role of these candidate genes in regeneration using mouse models.