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 6

Identification of the source cells of new SGNs.

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Identification of the source cells of new SGNs. (A) Schematic representa...
(A) Schematic representation of tamoxifen-inducible EGFP expression in Sox10-CreERT2 R26mTmG transgenic mice. mT, membrane-targeted tandem dimer Tomato; mG, membrane-targeted enhanced green fluorescent protein; pA, polyadenylation sequence. (B) Experimental scheme for assessing EGFP expression in Schwann cells in intact mice. Adult Sox10-CreERT2 R26mTmG mice were administered with tamoxifen daily for 4 days and sacrificed 4 days after the last tamoxifen administration. (C) Representative images of EGFP-positive Schwann cells after tamoxifen administration. The area outlined by a white square is enlarged in the panels to the right. The rightmost image is an ortho-view of Z-stack images. (Scale bars, 50 μm.) (D) Experimental scheme for lineage-tracing analysis of the new SGNs in response to combined treatment with GFs and VPA. (E) Representative images of new SGNs transformed from EGFP-positive Schwann cells by GFs and VPA treatment. The area outlined by a white square is enlarged in the panels to the right. EGFP/β-III tubulin–double-positive cells were found (arrowheads). The rightmost image is an ortho-view of Z-stack images. (Scale bars, 50 μm.)