Transcriptomic change in human utricles after aminoglycoside-induced hair cell ablation: Dynamic alterations to hair cell and supporting cell genes

Abstract

Losing sensory hair cells from the mammalian inner ear results in deafness and balance disorders. A major cause of acquired hair cell loss is the use of ototoxic drugs, including aminoglycoside antibiotics. Aminoglycosides are commonly prescribed, and are highly effective and cheap, but they specifically kill hair cells. In mammals, the capacity to regenerate hair cells is extremely limited, with only a small fraction being replaced in the vestibular system. Therefore, the functional deficits arising from their loss are permanent. To date there are no therapeutic strategies to prevent hair cell loss or restore them. Whilst most studies in this area have focused on murine or avian models, these may not fully recapitulate the complexity of human disease. Improved understanding of the underlying pathology and of how human tissues respond to ototoxic damage are essential to develop successful therapies. This study aims to fill this gap by describing how human vestibular sensory epithelia respond to aminoglycosides at a transcriptional level, and to identify genes linked to hair cell regeneration. The transcriptomic signature of gentamicin-damaged epithelia was characterised using a publicly-available RNAseq dataset. Particular attention was given to supporting cell-specific genes since these cells are essential for repair of the epithelial lesions resulting from hair cell loss, and for hair cell regeneration. As such they represent targets for therapies aimed towards repopulating damaged inner ear epithelia. The analysis revealed significant changes in adherens junction genes following hair cell loss, and identified genes potentially involved in the spontaneous formation of hair bundles.