Boschian, Camilla; (2023) Systematic bioinformatic analysis of expression profiles of human vestibular sensory epithelia in response to aminoglycoside toxicity. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Deafness and balance dysfunction are commonly caused by a loss of sensory hair cells (HCs) due to a combination of factors including genetics, ageing, noise, drugs, infections, noise. Spontaneous HC regeneration occurs in non-mammals, but in mammals, this capacity is limited to the vestibular sensory epithelium, and this decreases over time. Recently, the induction of the transcription factor ATOH1 has been shown to promote the transdifferentiation of human and mouse vestibular supporting cells (SCs) into immature HCs. However, despite these promising results, additional genes and pathways are required for functional HC maturation. This project aimed to further elucidate the mechanism of aminoglycoside toxicity in the human inner ear and to identify novel biomarkers and candidate genes for HCs regeneration. A new RNAseq dataset of purified human vestibular epithelia treated for 24hr with gentamicin was characterised and compared with published datasets, allowing the identification of novel toxic effects, activated signalling pathways and putative genes promoting HC regeneration. Gene expression of the purified human vestibular epithelia showed a global inhibition of the transcription and translation machineries. GJB2 (coding for connexin 26) and endoplasmic reticulum (ER) stress genes were the most altered during the early phases of the insult. These features were exacerbated after total HCs loss, as observed when compared with the published dataset of the whole human utricle treated with gentamicin for 48hr. The analyses of the whole utricle treated with gentamicin identified genes involved in the spontaneous formation of cilia and in cytoskeletal rearrangement. A cross-species comparison with chick sensory epithelia showed significant differences in inflammatory response upon toxic insults and in genes/pathways important for HCs development and regeneration. A deeper analysis of these differences allowed the identification of MYC and LIF as two new potential candidate genes for the promotion of HC regeneration.

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