Activation of PI3K signaling prevents aminoglycoside-induced hair cell death in the murine cochlea

Abstract

Loss 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.

ERBB2 is a Key Mediator in Hearing Restoration in Noise-Deafened Young Adult Mice

“…Under this interpretation, our work extends these findings in several important ways. First, we prove that activation in supporting cells alone is sufficient to promote hair cell survival, as the previous studies used either pharmacological inhibitors, deleted PTEN in both supporting cells and hair cells, or both (57,58). Second, our work indicates that the induction of CA-ERBB2, and/or its potential effector PI3K, can rescue adult hair cells from a noise-induced death.…”

Activation of CHK1 in Supporting Cells Indirectly Promotes Hair Cell Survival

“…We previously showed that activation of PI3K signaling could promote hair cell survival (Jadali and Kwan, 2016). We wanted to extend our findings and determine if activation of the PI3K signaling can promote supporting cell survival in the cochlea when subjected to ototoxic damage.…”

Tuberous sclerosis complex–mediated mTORC1 overactivation promotes age-related hearing loss

“…However, Pten ablation in NSE in the same Atoh1-Cre mice did not cause hearing loss in mice (34). Pten knockout in hair cells was recently reported to prevent gentamicin-induced hair cell death (35). To explain this discrepancy, we determined the expression levels of downstream targets of Pten in Pten-cKO (Pten gene inactivated by Atoh1-Cre) cochleae.…”