Adenovirus-mediated co-regulation of Notch, FGF and BMP signaling pathways promotes the regeneration of cochlear hair cells in neonatal mice.

BACKGROUND

Studies on hearing loss indicate that the regulation of signaling pathways (including Notch, Wnt, FGF and BMP) can induce the regeneration of mammalian hair cells. As one of the potential vectors of gene therapy, adenovirus is hoped to resolve non-genetic hearing loss for its high transfection rate to supporting cells. The role of adenovirus-mediated regulation of the Notch, FGF, and BMP signaling pathways in hair cell regeneration warrants further investigation.

METHODS

We employed adenoviruses to selectively inhibit the Notch (Notch1-RNAi-AD) or FGF (FGFR3-RNAi-AD) signaling pathways individually, as well as to simultaneously inhibit both Notch and BMP signaling pathways (Notch1-Noggin-AD).

RESULTS

Show that inhibiting the Notch pathway significantly increased the number of hair cells through transdifferentiation, which occurred at the expense of supporting cell loss. Following the inhibition of FGF signaling pathway, a small amount of cell proliferation was observed in the sensory epithelium in the apex of the cochlea. In contrast, after infection with Notch1-RNAi-AD and FGFR3-RNAi-AD, the number of hair cells increased significantly, and transdifferentiation and supporting cells proliferation also increased simultaneously in the cochlea. Finally, simultaneous infection of Notch1-Noggin-AD and FGFR3-RNAi-AD further increased the number of hair cells from transdifferentiation and proliferation.

CONCLUSION

Here, we used adenoviruses to regulate the activity of signaling pathways to induce the regeneration of cochlear hair cells in neonatal mice explants and achieved some expected results. Our study suggests that regulation of the FGF signaling pathway induces the proliferation of supporting cells, which is different from transdifferentiation by Notch inhibition, and the co-regulation of the Notch, FGF and BMP signaling pathways can promote more significant hair cell regeneration from supporting cell proliferation, followed by transdifferentiation, and avoid the large loss of supporting cells.