Molecular Mechanisms in Cochlear Regeneration
Cross-section of a young mouse cochlea, with hair
cells in pink and supporting cells in green
Why don’t mammals regenerate dying auditory cells? What signals can stimulate cochlear supporting cell proliferation, and what signals stimulate hair cell differentiation? More importantly, if it is possible to stimulate these actions in cochlear cells, why don’t they occur after mammals are deafened? Are the signals not present, or are they blocked somehow?
Ectopic Hair Cell
This is what we know: mammalian supporting cells retain some plasticity to turn on hair cell-specific genes throughout development. Purified supporting cells become hair cells under certain cell culture conditions; there are drugs that induce immature supporting cells to convert to hair cells in organ culture; and forced expression of hair cell specific transcription factors in supporting cells can induce at least part of the hair cell differentiation program. Inducing cell division in supporting cells is a trickier problem. Supporting cells express tumor suppressor proteins, and they can re-enter the cell cycle, at least sporadically, if these proteins are mutated. As supporting cells mature, their ability to re-enter the cell cycle is severely reduced, compared to younger cells in the same assay.
The cochlear regeneration project is divided into two parts. The first investigates signals and mechanisms that might regulate proliferation in immature supporting cells. I am also open to new ideas about how to induce hair cell differentiation in supporting cells. The second part addresses possible age-related differences between mature and immature supporting cells that could alter their intrinsic responses to different signals.
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