Prosensory signals: from discovery to application using inner ear organoids

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Our senses of hearing and balance depend on specialized 'hair' cells located in the sensory organs of the inner ear. The hair cells are only produced during the embryonic development of the inner ear, and their disappearance in adult life is the leading cause of hearing loss, in particular in the ageing population. The treatments for hearing loss are limited to hearing aids or cochlear implants, and there is considerable need for new and more efficient therapies. The most promising venues in terms of cellular therapies rely on i) the re-activation of developmental signals to induce hair cell regeneration and ii) the use of stem cell systems such as 3D inner ear "organoids" to model diseases and test new therapeutic approaches. In our previous MRC-funded research, we have uncovered new genes and signalling pathways that are crucial for "prosensory specification", the developmental process leading to the formation of hair cell progenitors. In this project, we will test the function of these candidates by artificially modifying their activity in the embryonic chicken inner ear. We will also use single-cell DNA sequencing technologies to gain new insights into the gene expression profile of mammalian prosensory cells, thereby helping us to pinpoint the most critical signals controlling prosensory specification. Finally, we will use inner ear organoids derived from mouse embryonic stem cells to investigate the mechanisms of prosensory specification in vitro. The results of this project will help to uncover the developmental genes and cell-to-cell communication pathways that could be manipulated to trigger hair cell regeneration in the damaged inner ear. They will also contribute to the improvement of current methods for the generation of hair cells from embryonic stem cells, which are essential from a basic and clinical research perspectives. In the future, this work could open up new venues for more efficient therapies for hearing loss in humans.