Lee Sungsu, Kurioka Takaomi, Lee Min Young, Beyer Lisa A, Swiderski Donald L, Ritter K Elaine, Raphael Yehoash
Kresge Hearing Research Institute, Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI, USA.
Kresge Hearing Research Institute, Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI, USA; Department of Otorhinolaryngology-Head and Neck Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan.
Neuroscience. 2021 Jan 15;453:57-68. doi: 10.1016/j.neuroscience.2020.11.041. Epub 2020 Dec 5.
The auditory sensory epithelium of the mammalian inner ear is a highly organized structure that contains sensory hair cells (HCs) and non-sensory supporting cells (SCs). Following the partial loss of HCs after cochlear insults such as overstimulation or ototoxic drugs, SCs seal the luminal epithelial surface (reticular lamina) and reorganize its cellular pattern. Here we investigated the changes in the sensory epithelium following a rapid and severe cochlear insult in the diphtheria toxin receptor (DTR) mouse, where diphtheria toxin (DT) injection leads to a HC-specific lesion resulting in a complete HC loss. We found that DT-induced selective HC ablation could lead to a pattern of scar formation and apical cell-cell adherens and tight junction reorganization similar to that occurring after other types of cochlear insult. Prestin, an outer HC-specific protein, was present in amorphous clumps at the sites where SCs had expanded to fill the spaces vacated by the dead HCs for up to 2 months after the DT induced lesion. Many of the prestin clumps appeared to occupy spaces within SCs, suggesting that SCs participate in the removal process of HC corpses in the DTR deafness model. Prestin clumps could be seen in different areas all along the length of the SCs, and appeared to be inside the SCs as well as in the inter-cellular spaces between SCs. The findings suggest that HC elimination in the DTR deafness model follows a mechanism similar to that in overstimulation or ototoxicity models, making the DTR mouse useful for understanding the process underlying HC elimination and the role of SCs in this process.
哺乳动物内耳的听觉感觉上皮是一种高度有序的结构，包含感觉毛细胞（HCs）和非感觉支持细胞（SCs）。在受到如过度刺激或耳毒性药物等耳蜗损伤后，HCs部分丧失，SCs封闭管腔上皮表面（网状板）并重新组织其细胞模式。在此，我们研究了白喉毒素受体（DTR）小鼠快速且严重的耳蜗损伤后感觉上皮的变化，在该模型中，注射白喉毒素（DT）会导致HC特异性损伤，从而使HCs完全丧失。我们发现，DT诱导的选择性HC消融可导致瘢痕形成模式以及顶端细胞间黏附连接和紧密连接的重新组织，这与其他类型的耳蜗损伤后发生的情况相似。Prestin是一种外毛细胞特异性蛋白，在DT诱导损伤后的长达2个月内，在SCs扩展以填充死亡HCs腾出的空间的部位，以无定形团块的形式存在。许多Prestin团块似乎占据了SCs内的空间，这表明SCs参与了DTR耳聋模型中HC尸体的清除过程。沿着SCs的整个长度，在不同区域都可以看到Prestin团块，并且似乎既在SCs内部，也在SCs之间的细胞间隙中。这些发现表明，DTR耳聋模型中HC的清除遵循与过度刺激或耳毒性模型类似的机制，这使得DTR小鼠有助于理解HC清除的潜在过程以及SCs在此过程中的作用。
