Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Zurich (USZ), and University of Zurich (UZH), Zurich, Switzerland.
Stem Cells. 2021 Apr;39(4):375-388. doi: 10.1002/stem.3315. Epub 2020 Dec 30.
Hearing loss is the most widely spread sensory disorder in our society. In the majority of cases, it is caused by the loss or malfunctioning of cells in the cochlea: the mechanosensory hair cells, which act as primary sound receptors, and the connecting auditory neurons of the spiral ganglion, which relay the signal to upper brain centers. In contrast to other vertebrates, where damage to the hearing organ can be repaired through the activity of resident cells, acting as tissue progenitors, in mammals, sensory cell damage or loss is irreversible. The understanding of gene and cellular functions, through analysis of different animal models, has helped to identify causes of disease and possible targets for hearing restoration. Translation of these findings to novel therapeutics is, however, hindered by the lack of cellular assays, based on human sensory cells, to evaluate the conservation of molecular pathways across species and the efficacy of novel therapeutic strategies. In the last decade, stem cell technologies enabled to generate human sensory cell types in vitro, providing novel tools to study human inner ear biology, model disease, and validate therapeutics. This review focuses specifically on two technologies: directed differentiation of pluripotent stem cells and direct reprogramming of somatic cell types to sensory hair cells and neurons. Recent development in the field are discussed as well as how these tools could be implemented to become routinely adopted experimental models for hearing research.
听力损失是我们社会中最广泛传播的感觉障碍。在大多数情况下，它是由于耳蜗中的细胞丧失或功能障碍引起的：作为主要声音感受器的机械感觉毛细胞，以及将信号传递到大脑上部中心的螺旋神经节的连接听觉神经元。与其他脊椎动物不同，在其他脊椎动物中，听力器官的损伤可以通过驻留细胞的活动来修复，这些细胞充当组织祖细胞，而在哺乳动物中，感觉细胞的损伤或丧失是不可逆转的。通过对不同动物模型的分析，了解基因和细胞功能有助于确定疾病的原因和可能的听力恢复靶点。然而，由于缺乏基于人感觉细胞的细胞分析，这些发现的转化为新型治疗方法受到了阻碍，无法评估分子途径在不同物种间的保守性和新型治疗策略的疗效。在过去的十年中，干细胞技术使我们能够在体外生成人感觉细胞类型，为研究人类内耳生物学、模拟疾病和验证治疗方法提供了新的工具。本综述特别关注两种技术：多能干细胞的定向分化和体细胞类型向感觉毛细胞和神经元的直接重编程。讨论了该领域的最新进展，以及如何将这些工具应用于成为听力研究的常规实验模型。
