Cotransfection of Pax2 and Math1 promote in situ cochlear hair cell regeneration after neomycin insult

Abstract

The ideal strategy for hair cell regeneration is promoting residual supporting cell proliferation followed by induction of hair cell differentiation. In this study, cultured neonatal mouse organs of Corti were treated with neomycin to eliminate hair cells followed by incubation with recombined adenovirus expressing Pax2 and/or Math1. Results showed that overexpression of Pax2 significantly promoted proliferation of supporting cells. The number of BrdU+/myosin VIIA+ cells increased significantly in hair cell pre-existing region two weeks after adenovirus infection in Ad-Pax2-IRES-Math1 group compared to Ad-Pax2 and Ad-Math1 groups. This indicated that cotransfection of Pax2 and Math1 induced supporting cells to proliferate and differentiate into hair cells in situ. Most new hair cells were labeled by FM1-43 suggesting they acquired certain function. The results also suggest that inducing proliferating cells rather than quiescent cells to differentiate into hair cells by forced expression of Math1 is feasible for mammalian hair cell regeneration.

Regeneration of Cochlear Hair Cells with Atoh1 Gene Therapy after Noise-Induced Hearing Loss

“…Nevertheless, the overall higher numbers of HCs in the Atoh1 group, in particular the number of GFP + HCs, strongly indicate that Atoh1 was contributing to HC trans-differentiation and the possibility of additional HC protection or repair of residual HCs by Atoh1 transgene expression cannot be ruled out. There is strong evidence for the conversion of supporting cells to HCs in many studies [28,50,51]. In our study, evidence for conversion was especially prominent in one animal in the Atoh1 group in which GFP + HCs were detected in the OHC location within the noise lesion.…”

Citicoline Protects Auditory Hair Cells Against Neomycin-Induced Damage

“…Cochleae were dissected from postnatal day (P)3 mice and cultured as previously reported ( Chen et al, 2013 ), The explant cultured tissue was pretreated with 10 μM citicoline for 12 h, then 0.5 mM neomycin was added for 12 h to damage the HCs. After removal of the neomycin, the tissues were recovered in serum-free medium for an additional 12 h together with 10 μM citicoline.…”

In Vivo Interplay between p27Kip1, GATA3, ATOH1, and POU4F3 Converts Non-sensory Cells to Hair Cells in Adult Mice

“…The vast majority of SNHL results from the loss of sensory hair cells (HCs), which, in mature mammalian cochleae, do not regenerate (McGill and Schuknecht, 1976; Soucek et al, 1986). Recently, research aimed at regenerating HCs has focused on ATOH1, a basic helix-loop-helix (bHLH) transcription factor that represents a therapeutic target for converting nonsensory supporting cells (SCs) into sensory HCs (Atkinson et al, 2014; Chen et al, 2013; Izumikawa et al, 2008; Izumikawa et al, 2005; Kawamoto et al, 2003; Kelly et al, 2012; Kraft et al, 2013; Kuo et al, 2015; Liu et al, 2012; Liu et al, 2014; Ouji et al, 2013; Pan et al, 2013; Parker et al, 2014; Wu et al, 2013; Yang et al, 2012; Yang et al, 2013; Zhao et al, 2011; Zheng and Gao, 2000). Indeed, clinical trials are being conducted to test whether an ATOH1 gene therapy can rehabilitate hearing in SNHL patients (Novartis-Pharmaceuticals).…”