Abstract
ABSTRACTLoss of sensory hair cells of the inner ear due to aminoglycoside exposure is a major cause of hearing loss. Using an immortalized multipotent otic progenitor (iMOP) cell line, specific signaling pathways that promote otic cell survival were identified. Of the signaling pathways identified, the PI3K pathway emerged as a strong candidate for promoting hair cell survival. In aging animals, components for active PI3K signaling are present but decrease in hair cells. In this study, we determined whether activated PI3K signaling in hair cells promotes survival. To activate PI3K signaling in hair cells, we used a small molecule inhibitor of PTEN or genetically ablated PTEN using a conditional knockout animal. Hair cell survival was challenged by addition of gentamicin to cochlear cultures. Hair cells with activated PI3K signaling were more resistant to aminoglycoside-induced hair cell death. These results indicate that increased PI3K signaling in hair cells promote survival and the PI3K signaling pathway is a target for preventing aminoglycoside-induced hearing loss.
Highlights
Hair cells in the cochlea are the mechanosensitive sensory cells responsible for converting sounds into auditory neural signal
We showed that PI3K signaling is an important pathway that affects immortalized multipotent otic progenitor (iMOP) cell survival
In addition to the role PI3K signaling plays in proliferation, we showed that activation of PI3K promotes hair cell survival and could play a role in maintaining the viability of hair cells
Summary
Hair cells in the cochlea are the mechanosensitive sensory cells responsible for converting sounds into auditory neural signal. The gradual loss of hair cells contributes to hearing loss. Both environmental and genetic factors contribute to progressive hair cell loss (Jennings and Jones, 2001). Commonly used in treating infections, aminoglycosides have devastating ototoxic effects that lead to hearing loss (Huth et al, 2011). Systemic administration and tracing of fluorescently labeled gentamicin, a class of aminoglycosides, suggests specific accumulation within the sensory hair cells of the inner ear (Wang and Steyger, 2009). These results are consistent with gentamicin accumulation in hair cells across different animal species
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