Department of Speech and Hearing Sciences, University of Washington, Seattle, Washington, United States; Department of Otolaryngology-Head and Neck Surgery and the Virginia Merrill Bloedel Research Center, University of Washington School of Medicine, Seattle, Washington, United States.
University of Montpellier, INM-INSERM Unit 1298, Montpellier, France.
Hear Res. 2022 Dec;426:108642. doi: 10.1016/j.heares.2022.108642. Epub 2022 Oct 27.
Sox2 is a transcription factor that is necessary in the mammalian inner ear for development of sensory hair cells and supporting cells. Sox2 is expressed in supporting cells of adult mammals, but its function in this context is poorly understood. Given its role in the developing inner ear, we hypothesized that Sox2 is required in vestibular supporting cells for regeneration of type II hair cells after damage. Using adult mice, we deleted Sox2 from Sox9-Cre-expressing supporting cells prior to diphtheria toxin-mediated hair cell destruction and used fate-mapping to assess regeneration. In utricles of control mice with normal Sox2 expression, supporting cells regenerated nearly 200 hair cells by 3 weeks post-damage, which doubled by 12 weeks. In contrast, mice with Sox2 deletion from supporting cells had approximately 20 fate-mapped hair cells at 3 weeks post-damage, and this number did not change significantly by 12 weeks, indicating regeneration was dramatically curtailed. We made similar observations for saccules and ampullae. We found no evidence that supporting cells lacking Sox2 had altered cellular density, morphology, or ultrastructure. However, some Sox2-negative supporting cell nuclei appeared to migrate apically but did not turn on hair cell markers, and type I hair cell survival was higher. Sox2 heterozygotes also had reduced regeneration in utricles, but more hair cells were replaced than mice with Sox2 deletion. Our study determined that Sox2 is required in supporting cells for normal levels of vestibular hair cell regeneration but found no other major requirements for Sox2 in adult supporting cells.
Sox2 是一种转录因子，在哺乳动物内耳的发育过程中对于感觉毛细胞和支持细胞的形成是必需的。Sox2 在成年哺乳动物的支持细胞中表达，但它在这个背景下的功能尚不清楚。鉴于其在发育中的内耳中的作用，我们假设 Sox2 在前庭支持细胞中对于毛细胞损伤后的 II 型毛细胞的再生是必需的。我们使用成年小鼠，在白喉毒素介导的毛细胞破坏之前，从 Sox9-Cre 表达的支持细胞中删除 Sox2，并使用命运图谱来评估再生。在具有正常 Sox2 表达的对照组小鼠的椭圆囊中，支持细胞在损伤后 3 周内再生了近 200 个毛细胞，到 12 周时增加了一倍。相比之下，支持细胞中 Sox2 缺失的小鼠在损伤后 3 周时约有 20 个命运图谱毛细胞，到 12 周时这个数量没有明显变化，表明再生明显受到抑制。我们在囊斑和壶腹中也观察到了类似的结果。我们没有发现支持细胞中缺乏 Sox2 的细胞有改变细胞密度、形态或超微结构的证据。然而，一些 Sox2 阴性的支持细胞核似乎向上迁移，但没有开启毛细胞标志物，并且 I 型毛细胞的存活率更高。Sox2 杂合子在椭圆囊中也有减少的再生，但与 Sox2 缺失的小鼠相比，有更多的毛细胞被替代。我们的研究确定 Sox2 在支持细胞中对于正常水平的前庭毛细胞再生是必需的，但没有发现 Sox2 在成年支持细胞中的其他主要需求。
