Insulin-like growth factor 1 inhibits hair cell apoptosis and promotes the cell cycle of supporting cells by activating different downstream cascades after pharmacological hair cell injury in neonatal mice

Abstract

Sensorineural hearing loss, which is mainly caused by cochlear hair cell damage, is an intractable disease, as cochlear hair cells and supporting cells are unable to proliferate in postnatal mammals. As a novel and potent treatment for sensorineural hearing loss, we have studied IGF-1 and found that it protects cochlear hair cells from the damage caused by noise and ischemic trauma. Through a clinical trial, we have also confirmed that IGF-1 is an effective treatment for idiopathic sudden sensorineural hearing loss. In the current study, we attempted to identify the downstream pathways of the IGF-1 signal and the mechanisms by which IGF-1 protects the neonatal mouse cochlear hair cells that have been damaged by neomycin. IGF-1 activated both the PI3K/Akt and MEK/ERK pathways to maintain the hair cell numbers in the injured cochlea. The PI3K/Akt pathway specifically protected the cochlear inner hair cells through the inhibition of apoptosis. In contrast, the MEK/ERK pathway induced the cell cycle promotion of Hensen's and Claudius' cells, the supporting cells that are located lateral to the outer hair cells of the cochlea. This cell cycle promotion of the supporting cells resulted in the maintenance of the outer hair cell numbers. These results indicate that IGF-1 is a growth factor that efficiently regulates different mechanisms through different downstream cascades, thereby protecting cochlear hair cells.

Keywords: Apoptosis; Cell cycle promotion; Cochlea; ERK; HC; Hair cell; IGF-1; IHC; Insulin-like growth factor 1; MAPK; MAPK/ERK kinase; MEK; OHC; PI3K; SC; extracellular signal-regulated kinases; hair cell; inner hair cell; insulin like growth factor 1; mitogen-activated protein kinases; outer hair cell; phosphatidylinositol 3-kinase; supporting cell.