Boschian Camilla, Forge Andrew, Lovett Michael, Gale Jonathan E, Jagger Daniel J
UCL Ear Institute, University College London, 332 Grays Inn Road, London, WC1X 8EE, United Kingdom.
National Heart and Lung Institute, Imperial College London, London, SW3 6LY, United Kingdom.
Hear Res. 2025 Jun 20;465:109339. doi: 10.1016/j.heares.2025.109339.
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.
哺乳动物内耳感觉毛细胞的丧失会导致耳聋和平衡障碍。获得性毛细胞丧失的一个主要原因是使用耳毒性药物，包括氨基糖苷类抗生素。氨基糖苷类药物是常用药物，高效且便宜，但它们会特异性杀死毛细胞。在哺乳动物中，毛细胞再生能力极其有限，前庭系统中只有一小部分毛细胞能够被替换。因此，毛细胞丧失导致的功能缺陷是永久性的。迄今为止，尚无预防毛细胞丧失或使其恢复的治疗策略。虽然该领域的大多数研究都集中在小鼠或鸟类模型上，但这些模型可能无法完全概括人类疾病的复杂性。更好地理解潜在病理以及人体组织如何应对耳毒性损伤对于开发成功的治疗方法至关重要。本研究旨在通过描述人类前庭感觉上皮在转录水平上对氨基糖苷类药物的反应，并识别与毛细胞再生相关的基因来填补这一空白。使用公开可用的RNAseq数据集对庆大霉素损伤上皮的转录组特征进行了表征。特别关注支持细胞特异性基因，因为这些细胞对于修复毛细胞丧失导致的上皮损伤以及毛细胞再生至关重要。因此，它们代表了旨在重新填充受损内耳上皮的治疗靶点。分析揭示了毛细胞丧失后黏附连接基因的显著变化，并确定了可能参与毛束自发形成的基因。
