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.

Public Health Relevance

The auditory and vestibular components of the inner ear arise from a common area called the otic vesicle. The sonic hedgehog signaling pathway has been shown to play a direct role in development of the cochlea, the structure containing the sensory receptors for hearing, from this otic vesicle. This study will investigate Sonic hedgehog signaling modulation as a potential strategy to generate cochlear cell types in a stem cell model of inner ear development.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31DC015968-03
Application #
9544924
Study Section
Special Emphasis Panel (ZDC1)
Program Officer
Rivera-Rentas, Alberto L
Project Start
2016-09-01
Project End
2019-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Koehler, Karl R; Nie, Jing; Longworth-Mills, Emma et al. (2017) Generation of inner ear organoids containing functional hair cells from human pluripotent stem cells. Nat Biotechnol 35:583-589