Abstract
The mammalian cochlea is a highly specialized organ within the inner ear. Sensory hair cells (HC) in the cochlea detect and transduce sound waves into electrical impulses that are sent to the brain. Studies of the molecular pathways regulating HC formation are hindered by the very sparse nature of HCs, where only ~3300 are found within an entire mouse cochlea. Current cell lines mimic certain aspects of HCs but lack terminal HC marker expression. Here we successfully “pseudo-immortalized” cochlear progenitor cells using the “conditional reprogramming” technique. These cells, termed “Conditionally Reprogrammed Otic Stem Cells” (CR-OSC), are able to bypass the senescence inherent to cochlear progenitor cells without genetic alterations, allowing for the generation of over 15 million cells from a single cochlea. These cells can be differentiated and up-regulate both early and terminal differentiation genes associated with HCs, including the terminal HC differentiation marker prestin. CR-OSCs also respond to known HC cues, including upregulation of HC genes in response to Atoh1 overexpression, and upregulation of prestin expression after thyroid hormone application. Overall, we describe the creation of a HC line capable of regulated expression of HC genes that can easily be recreated in any laboratory from any mouse of interest.
Highlights
The mammalian cochlea is a highly specialized organ within the inner ear
Electromotility of outer hair cells (OHCs) is controlled by the non-traditional motor protein prestin[5], which is coded for by the Slc26a5 gene, and is a unique protein expressed in OHCs
In this study we explored the conditional reprogramming technique, which was designed to allow the unlimited proliferation of breast and prostate progenitor cells without affecting their lineage restricted differentiation potential[26]
Summary
The mammalian cochlea is a highly specialized organ within the inner ear. Sensory hair cells (HC) in the cochlea detect and transduce sound waves into electrical impulses that are sent to the brain. These cells, termed “Conditionally Reprogrammed Otic Stem Cells” (CR-OSC), are able to bypass the senescence inherent to cochlear progenitor cells without genetic alterations, allowing for the generation of over 15 million cells from a single cochlea These cells can be differentiated and up-regulate both early and terminal differentiation genes associated with HCs, including the terminal HC differentiation marker prestin. Most studies to date have been performed in cochlear explants, vastly limiting the material available, the speed at which experiments can be done, and dramatically increasing the cost of the experiment This is true for investigations into the regulation of any genes or proteins expressed in HCs. this is true for investigations into the regulation of any genes or proteins expressed in HCs To bridge this gap, multiple cell lines have been developed to aid in the study of HC development or to be used as screening tools for the prevention of ototoxicity. Studies have shown that some of these cell lines have begun to show significant phenotypic drift and are no longer sensitive to aminoglycoside induced cell death[20,21]
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