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Characterizing adult cochlear supporting cell transcriptional diversity using single-cell RNA-Seq: Validation in the adult mouse and translational implications for the adult human cochlea

ABSTRACT: Characterizing adult cochlear supporting cell transcriptional diversity using scRNA-Seq Hearing loss is a significant disability that impacts 432 million people worldwide. A significant proportion of these individuals are dissatisfied with or do not have access to available treatment options which include hearing aids and cochlear implants. An alternative approach to restore hearing would be to regenerate lost cells, including hair cells in the adult cochlea. Such therapy would require restoration of the organ of Corti’s complex architecture, necessitating regeneration of both mature hair cells and supporting cells. We characterize the first single-cell adult cochlear supporting cell transcriptomes with the goals of: (1) demonstrating their transcriptional distinctiveness from perinatal cochlear supporting cells, (2) providing a metric for future attempts at regenerating mature cochlear supporting cells by identifying both cell type-specific and regional-specific expression, and (3) identify cell cycle gene expression present in adult supporting cells at the single cell level which may establish a basis for targeting cell cycle regulation pathways to force these cells out of quiescence.

ORGANISM(S): Mus musculus

PROVIDER: GSE135703 | GEO | 2020/02/19

REPOSITORIES: GEO

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Project description:Spiral ganglion neurons (SGNs) and the associated components of the auditory nerve are primary carriers of auditory information from hair cells to the brain. Loss of SGNs occurs with many pathological conditions, resulting in permanent sensorineural hearing loss. Neural stem/progenitors (NSPs) have been well-characterized in several locations of adult brain and retina. However, it is unclear whether NSPs are present in the adult auditory nerve. Here we examined the self-renewal potential of the adult auditory nerve using ouabain application as a well-established mouse model of acute SGN injury. The observed increase in cell proliferation, alteration in enchromatin/heterochromatin ratio and down-regulation of histone deacetylase expression in glial cells suggest that the quiescent glial cells convert to an activated state after SGN degeneration. This was further confirmed by global gene expression analysis of injured auditory nerves, which showed up-regulation of numerous neurogenesis- and/or development-associated genes shortly after ouabain exposure. These genes include molecular markers commonly used for the identification of NSPs. Under a strict culture regimen, auditory nerve-derived cells of adult mouse ears gave rise to neurospheres, suggesting that multipotent NSPs are present in adult cochlear nerve. Neurosphere assays on Sox2 transgenic mice revealed that Sox2+ glial cells are the source for NSPs. Our data also showed that acute injury or hypoxia enhances neurosphere formation. Taken together, our study revealed that glial cells of adult cochlea exhibit several NSP characteristics, and hence these mature non-neuronal cells may be important targets for promoting self-repair of degenerative auditory nerves. Analysis was conducted on auditory nerve samples from stages encompassing maturation and onset of hearing. Cochleas were collected from euthanized mice (CBA/CaJ) at perinatal (P) stages P0, P3, P7, P10, P14 and P21. Cochleas underwent microdissection to remove the outer bony cochlear shell and cochlear lateral wall, thus preserving the modiolus portion of cochlea which contains mainly the auditory nerve. Paired cochleas (i.e., from left and right ears) from each mouse were pooled to make individual samples. All sample types were done in experimental duplicate (n=2).

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Characterizing adult cochlear supporting cell transcriptional diversity using single-cell RNA-Seq: Validation in the adult mouse and translational implications for the adult human cochlea

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