Prosensory signals: from discovery to application using inner ear organoids

我们的听觉和平衡感依赖于位于内耳感觉器官中的特殊“毛”细胞。毛细胞只在内耳的胚胎发育过程中产生，它们在成年后的消失是听力损失的主要原因，特别是在老龄化人口中。听力损失的治疗仅限于助听器或人工耳蜗植入物，并且相当需要新的和更有效的疗法。细胞疗法方面最有前途的途径依赖于i）重新激活发育信号以诱导毛细胞再生，以及ii）使用干细胞系统如3D内耳“类器官”来模拟疾病和测试新的治疗方法。在我们以前的MRC资助的研究中，我们已经发现了新的基因和信号通路，这些基因和信号通路对“前感觉特化”至关重要，这是导致毛细胞祖细胞形成的发育过程。在这个项目中，我们将通过人工改变它们在鸡胚内耳中的活性来测试这些候选物的功能。我们还将使用单细胞DNA测序技术来获得哺乳动物前感觉细胞基因表达谱的新见解，从而帮助我们确定控制前感觉细胞规格的最关键信号。最后，我们将使用来自小鼠胚胎干细胞的内耳类器官来研究体外前感觉特化的机制。该项目的结果将有助于揭示发育基因和细胞间通讯途径，这些基因和途径可以被操纵以触发受损内耳的毛细胞再生。它们还将有助于改善目前从胚胎干细胞产生毛细胞的方法，这从基础和临床研究的角度来看是必不可少的。在未来，这项工作可以为人类听力损失的更有效治疗开辟新的途径。

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.