Sonic Hedgehog Signaling in Inner Ear Organoid Development

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ABSTRACT Loss of the finite cochlear hair cells in the inner ear results in sensorineural deafness. Human cochlear hair cells do not regenerate, and there is no cure for deafness. Our lab has recently established a novel three-dimensional culture system for deriving functional sensory hair cells from mouse and human pluripotent stem cells. A major limitation of this approach, however, is that derived hair cells exhibit structural, biochemical and electrophysiological properties of gravity-sensing vestibular hair cells. The processes underlying the commitment to cochlear versus vestibular fate in inner ear sensory hair cell development are poorly understood. Previous studies have shown that establishment of a dorsal-ventral (DV) axis in the developing otic vesicle is necessary for proper morphogenesis of both auditory and vestibular inner ear structures. Sonic hedgehog signaling has been shown to play a key role in precise DV patterning of the otic vesicle. In Specific Aim 1, I will characterize the nature of DV patterning in otic vesicles derived using our three-dimensional inner ear culture model, and determine whether commitment to a vestibular fate is due to a lack of ventralizing signals. In Specific Aim 2, I will assess whether modulation of Sonic hedgehog signaling via small molecule application in our culture model is able to induce differentiation of cochlear cell types. Stem cell-derived cochlear hair cells may serve as a potent human model system to study pathophysiology of various forms of hereditary deafness. Such an advance could profoundly impact our understanding of disease processes that normally occur in utero. Furthermore, an in vitro system recapitulating both cochlear and vestibular sensory cell development is amenable to high-throughput drug screening to identify compounds that either enhance inner ear differentiation, promote the survival of inner ear sensory cells, or have ototoxic effects.