Regenerating hair cells in vestibular sensory epithelia from humans

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Abstract

Human vestibular sensory epithelia in explant culture were incubated in gentamicin to ablate hair cells. Subsequent transduction of supporting cells with ATOH1 using an Ad-2 viral vector resulted in generation of highly significant numbers of cells expressing the hair cell marker protein myosin VIIa. Cells expressing myosin VIIa were also generated after blocking the Notch signalling pathway with TAPI-1 but less efficiently. Transcriptomic analysis following ATOH1 transduction confirmed up-regulation of 335 putative hair cell marker genes, including several downstream targets of ATOH1. Morphological analysis revealed numerous cells bearing dense clusters of microvilli at the apical surfaces which showed some hair cell-like characteristics confirming a degree of conversion of supporting cells. However, no cells bore organised hair bundles and several expected hair cell markers genes were not expressed suggesting incomplete differentiation. Nevertheless, the results show a potential to induce conversion of supporting cells in the vestibular sensory tissues of humans.The inner ear contains our balance system (the vestibular system) and our hearing organ (the cochlea). Their sensing units, the hair cells, detect movement or sound waves. A loss of hair cells is a major cause of inner ear disorders, such as dizziness, imbalance and deafness.When hair cells die, supporting cells that surround them close the ‘wound’ to repair the tissue. In fish, amphibians, reptiles and birds, the supporting cells can replace lost hair cells, but in mammals – including humans – hair cells are unable to regenerate in the cochlea, so hearing loss is permanent. However, previous research has shown that in certain mammals, spontaneous replacement of lost hair cells in the vestibular system can occur, but not enough to lead to a full recovery.Scientists have been able to convert supporting cells in the vestibular system of mice into hair cells by using either certain chemicals, or by introducing a specific gene into the supporting cells. In the mouse embryo, this gene, called Atoh1, switches on a signalling pathway in the inner ear, through which a non-specialised precursor cell becomes a hair cell. Inducing hair cell regeneration could be a therapy for inner ear disorders. Therefore, Taylor et al. wanted to find out if such procedures would work in inner ear tissue from humans.The researchers collected intact tissue samples from the vestibular system of patients who had undergone surgery to have a tumour removed, which would normally destroy the inner ear. All existing hair cells were removed so that mainly supporting cells remained. Then, the tissue was either treated with chemicals that increased the production of hair cells or received the gene ATOH1. The results showed that the cells containing the gene were able to develop many features characteristic of hair cells. And a smaller number of hair cells treated with the chemicals also started to develop hair cell-like features. A gene analysis after the ATOH1 transfer revealed a number of active genes known to be markers of hair cells, but also several inactive ones. This suggests that additional factors are necessary for generating fully functional hair cells.Dizziness and balance disorders present a major health care burden, particularly in the elderly population. Yet, they are often disregarded and overlooked. This study suggests that hair cell regeneration could be a feasible therapy for some forms of balance disorders linked to loss of vestibular hair cells. More research is needed to identify the other factors at play to test if hair cell regeneration in the cochlea could be used to treat hearing impairment.

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Taylor, R. R., Filia, A., Paredes, U., Asai, Y., Holt, J. R., Lovett, M., & Forge, A. (2018). Regenerating hair cells in vestibular sensory epithelia from humans. ELife, 7. https://doi.org/10.7554/eLife.34817

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