Abstract
Primary auditory neurons (PANs) play a critical role in hearing by transmitting sound information from the inner ear to the brain. Their progressive degeneration is associated with excessive noise, disease and aging. The loss of PANs leads to permanent hearing impairment since they are incapable of regenerating. Spiral ganglion non-neuronal cells (SGNNCs), comprised mainly of glia, are resident within the modiolus and continue to survive after PAN loss. These attributes make SGNNCs an excellent target for replacing damaged PANs through cellular reprogramming. We used the neurogenic pioneer transcription factor Ascl1 and the auditory neuron differentiation factor NeuroD1 to reprogram SGNNCs into induced neurons (iNs). The overexpression of both Ascl1 and NeuroD1 in vitro generated iNs at high efficiency. Transcriptome analyses revealed that iNs displayed a transcriptome profile resembling that of endogenous PANs, including expression of several key markers of neuronal identity: Tubb3, Map2, Prph, Snap25, and Prox1. Pathway analyses indicated that essential pathways in neuronal growth and maturation were activated in cells upon neuronal induction. Furthermore, iNs extended projections toward cochlear hair cells and cochlear nucleus neurons when cultured with each respective tissue. Taken together, our study demonstrates that PAN-like neurons can be generated from endogenous SGNNCs. This work suggests that gene therapy can be a viable strategy to treat sensorineural hearing loss caused by degeneration of PANs.
Highlights
Primary auditory neurons (PANs), known as spiral ganglion neurons, transmit electrical signals from the inner ear to the central cochlear nucleus in the brainstem (Dabdoub et al, 2015)
Six to ten days post-transfection, 49 and 41% of wild-type Spiral ganglion non-neuronal cells (SGNNCs) transfected with Ascl1 expressed common neuronal markers TuJ1 and microtubule-associated protein 2 (MAP2), respectively, and exhibited a neuronal morphology (Figures 1A,D). induced neurons (iNs) expressed vesicular glutamate transporter 1 (VGLUT1) (Figure 1B), which packages glutamate into synaptic vesicles (Zhou et al, 2007; Yuan et al, 2014), and the transcription factor Prox1 (Figure 1C), which is expressed in developing PANs, mature type I PANs and the support cells of the organ of Corti (Bermingham-McDonogh et al, 2006; Karalay, 2011; Nishimura et al, 2017)
These results indicate that Ascl1 has the ability to induce neuron-like cells from SGNNCs
Summary
Primary auditory neurons (PANs), known as spiral ganglion neurons, transmit electrical signals from the inner ear to the central cochlear nucleus in the brainstem (Dabdoub et al, 2015). Hearing aids and cochlear implants are auditory prosthetics that require the stimulation of PANs, either indirectly or directly, to transmit sound information to the brain, patients lacking a suitable number of healthy PANs cannot benefit from these devices. If PANs could be replaced or regenerated, it might be possible to restore the hearing of patients with severely damaged PANs (Dabdoub and Nishimura, 2017). Regeneration of PANs may benefit individuals with hidden hearing loss, a condition correlated with PAN degeneration. Hidden hearing loss describes when individuals experience difficulty hearing in noisy settings but do not clinically present with auditory disability (see review Liberman and Kujawa, 2017)
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