Math1Gene Transfer Generates New Cochlear Hair Cells in Mature Guinea PigsIn Vivo

Abstract

Hair cell loss in the mammalian cochlea is irreversible and results in permanent hearing loss. Math1, the basic helix-loop-helix transcription factor homolog of the Drosophila atonal gene, is a positive regulator of hair cell differentiation during cochlear development. Developing hair cells express Math1, and nonsensory cells do not. We set out to determine the outcome of overexpression of Math1 in nonsensory cells of the cochlea on the phenotype of these cells. We demonstrate that in vivo inoculation of adenovirus with the Math1 gene insert into the endolymph of the mature guinea pig cochlea results in Math1 overexpression in nonsensory cochlear cells, as evident from the presence of Math1 protein in supporting cells of the organ of Corti and in adjacent nonsensory epithelial cells. Math1 overexpression leads to the appearance of immature hair cells in the organ of Corti and new hair cells adjacent to the organ of Corti in the interdental cell, inner sulcus, and Hensen cell regions. Axons are extended from the bundle of auditory nerve toward some of the new hair cells, suggesting that the new cells attract auditory neurons. We conclude that nonsensory cells in the mature cochlea retain the competence to generate new hair cells after overexpression of Math1 in vivo and that Math1 is necessary and sufficient to direct hair cell differentiation in these mature nonsensory cells.

Notch-Wnt-Bmp crosstalk regulates radial patterning in the mouse cochlea in a spatiotemporal manner

“…As previously described, the presence of the Atoh1 plasmid induces numerous ectopic HCs (Fig. S3B,B′) (Gubbels et al, 2008;Kawamoto et al, 2003;Liu et al, 2014). This was accompanied by an expansion of the Sox2 domain on the medial side of the OC 4 days later (Fig.…”

Sensory hair cell development and regeneration: similarities and differences

“…In neonatal mice, supporting cells remain competent to form hair cells in response to Atoh1 overexpression, especially in the Kölliker's organ, which is directly medial to the organ of Corti (Kelly et al, 2012;Liu et al, 2012aLiu et al, , 2014Shou et al, 2003;Yang et al, 2013;Zheng and Gao, 2000). However, this competence is significantly diminished in the undamaged, mature cochlea when assessed via either a transgenic approach or direct viral inoculation (Kawamoto et al, 2003;Liu et al, 2012a).…”

Atoh1, an Essential Transcription Factor in Neurogenesis and Intestinal and Inner Ear Development: Function, Regulation, and Context Dependency

“…Attempts to produce ectopic HCs in mature animals and to regenerate HCs in vivo following cochlear injury by either ototoxic drugs or excessive noise have had limited success. One group has shown that adenovirus-mediated expression of Atoh1 in mature guinea pig cochleae results in ectopic hair cells (Kawamoto et al 2003) and infecting newly injured guinea pigs with an adenovirus carrying Atoh1 leads to regeneration of HCs; however, this approach failed to restore HCs in animals with longer-term injuries or more damaged cochleae (Izumikawa et al 2005(Izumikawa et al , 2008. Replication of these results and further investigation into the requirement for SC survival may yield useful information.…”