Cochlear Sox2+ Glial Cells Are Potent Progenitors for Spiral Ganglion Neuron Reprogramming Induced by Small Molecules

Zhen Chen; Yuhang Huang; Chaorong Yu; Qing Liu; Cui Qiu; Guoqiang Wan

doi:10.3389/fcell.2021.728352

Cochlear Sox2⁺ Glial Cells Are Potent Progenitors for Spiral Ganglion Neuron Reprogramming Induced by Small Molecules

Front Cell Dev Biol. 2021 Sep 21:9:728352. doi: 10.3389/fcell.2021.728352. eCollection 2021.

Authors

Zhen Chen¹, Yuhang Huang¹, Chaorong Yu¹, Qing Liu¹, Cui Qiu¹, Guoqiang Wan^{1

2

3

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Affiliations

¹ MOE Key Laboratory of Model Animal for Disease Study, Department of Otorhinolaryngology Head and Neck Surgery, The Affiliated Drum Tower Hospital of Medical School, Model Animal Research Center of Medical School, Nanjing University, Nanjing, China.
² Research Institute of Otolaryngology, Nanjing, China.
³ Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China.
⁴ Institute for Brain Sciences, Nanjing University, Nanjing, China.

Abstract

In the mammalian cochlea, spiral ganglion neurons (SGNs) relay the acoustic information to the central auditory circuits. Degeneration of SGNs is a major cause of sensorineural hearing loss and severely affects the effectiveness of cochlear implant therapy. Cochlear glial cells are able to form spheres and differentiate into neurons in vitro. However, the identity of these progenitor cells is elusive, and it is unclear how to differentiate these cells toward functional SGNs. In this study, we found that Sox2⁺ subpopulation of cochlear glial cells preserves high potency of neuronal differentiation. Interestingly, Sox2 expression was downregulated during neuronal differentiation and Sox2 overexpression paradoxically inhibited neuronal differentiation. Our data suggest that Sox2⁺ glial cells are potent SGN progenitor cells, a phenotype independent of Sox2 expression. Furthermore, we identified a combination of small molecules that not only promoted neuronal differentiation of Sox2^- glial cells, but also removed glial cell identity and promoted the maturation of the induced neurons (iNs) toward SGN fate. In summary, we identified Sox2⁺ glial subpopulation with high neuronal potency and small molecules inducing neuronal differentiation toward SGNs.

Keywords: SGN regeneration; Sox2+ glial cells; glia-to-neuron conversion; lineage tracing; small molecules reprogramming.