Growth factors with valproic acid restore injury-impaired hearing by promoting neuronal regeneration
Takahiro Wakizono, Hideyuki Nakashima, Tetsuro Yasui, Teppei Noda, Kei Aoyagi, Kanako Okada, Yasuhiro Yamada, Takashi Nakagawa, Kinichi Nakashima
Takahiro Wakizono, Hideyuki Nakashima, Tetsuro Yasui, Teppei Noda, Kei Aoyagi, Kanako Okada, Yasuhiro Yamada, Takashi Nakagawa, Kinichi Nakashima
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Resource and Technical Advance Neuroscience Stem cells

Growth factors with valproic acid restore injury-impaired hearing by promoting neuronal regeneration

Abstract

Spiral ganglion neurons (SGNs) are primary auditory neurons in the spiral ganglion that transmit sound information from the inner ear to the brain and play an important role in hearing. Impairment of SGNs causes sensorineural hearing loss (SNHL), and it has been thought until now that SGNs cannot be regenerated once lost. Furthermore, no fundamental therapeutic strategy for SNHL has been established other than inserting devices such as hearing aids and cochlear implants. Here we show that the mouse spiral ganglion contains cells that are able to proliferate and indeed differentiate into neurons in response to injury. We suggest that SRY-box transcription factor 2/SRY-box transcription factor 10–double-positive (Sox2/Sox10–double-positive) Schwann cells sequentially started to proliferate, lost Sox10 expression, and became neurons, although the number of new neurons generated spontaneously was very small. To increase the abundance of new neurons, we treated mice with 2 growth factors in combination with valproic acid, which is known to promote neuronal differentiation and survival. This treatment resulted in a dramatic increase in the number of SGNs, accompanied by a partial recovery of the hearing loss induced by injury. Taken together, our findings offer a step toward developing strategies for treatment of SNHL.

Authors

Takahiro Wakizono, Hideyuki Nakashima, Tetsuro Yasui, Teppei Noda, Kei Aoyagi, Kanako Okada, Yasuhiro Yamada, Takashi Nakagawa, Kinichi Nakashima

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Figure 5

VPA promotes SGN regeneration.

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VPA promotes SGN regeneration. (A) Experimental scheme to investigate ne...
(A) Experimental scheme to investigate neuronal differentiation of proliferating cells in response to combined treatment with GFs and VPA. BrdU was injected intraperitoneally at 50 mg/kg every day on days 3 to 7. Intact mice did not receive any operation or treatment with reagents. Ctrl is mice without reoperation and sacrificed on day 28 after ouabain administration. (B) Representative staining of cells in intact, Ctrl, and GF+VPA–treated SGs on day 28 after ouabain administration. The area outlined by a white square is enlarged to the right. (Scale bars, 50 μm.) (C) Quantification of the number of BrdU-positive, β-III tubulin–positive, and β-III tubulin/BrdU–double-positive new neurons per hbSG of intact, Ctrl, GF alone–, and GF+VPA–treated mice. In the leftmost graph, the number of BrdU-positive cells in the hbSG of mice administered with GFs and sacrificed on day 7 is also indicated for comparison (n = 3 animals each; error bars are mean ± SEM; ***P ≤ 0.001; 1-way ANOVA and Tukey’s multiple-comparison test). (D) Quantification of the percentage of Sox2-positive and β-III tubulin–positive cells among BrdU-positive cells in the hbSG of mice treated with GFs with or without VPA after ouabain injury (n = 3 animals each; error bars are mean ± SEM; *P ≤ 0.05; 2-tailed Student’s t test).