Miranda Portillo Lyn S, Huang Austin P, Hosamani Ishwar V, Sanchez Celeste N, Heller Stefan, Benkafadar Nesrine
Department of Otolaryngology - Head & Neck Surgery, Stanford University School of Medicine, Stanford, CA, 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Dev Biol. 2025 Sep;525:13-25. doi: 10.1016/j.ydbio.2025.05.021. Epub 2025 May 23.
Inner ear sensory hair cells are essential for auditory and vestibular functions. In mammals, loss of these cells leads to permanent hearing loss due to the inability of supporting cells to regenerate hair cells. In contrast, avian species exhibit a remarkable capacity for hair cell regeneration, primarily through the activation and proliferation of supporting cells. This review provides a comprehensive examination of the anatomical and molecular mechanisms underlying sensory hair cell regeneration in two critical avian inner ear structures: the basilar papilla and the utricle. We describe the structural and functional differences between avian and mammalian inner ear epithelia and highlight how these distinctions correlate with regenerative capabilities. Specifically, we discuss two distinct regenerative mechanisms - mitotic regeneration and direct transdifferentiation - employed by avian supporting cells in response to hair cell loss. We also explore how epithelial organization influences regenerative responses, including cellular density, cytoskeletal dynamics such as circumferential filamentous actin bands, and mechanical properties like tissue jamming and unjamming states. Additionally, we examine molecular pathways such as Hippo signaling, which mediates mechanical cues critical for regulating supporting cell proliferation and differentiation during regeneration. Recent advancements in single-cell -omics technologies have further elucidated molecular signatures and signaling pathways involved in these processes, offering novel insights that may inform therapeutic strategies aimed at inducing hair cell regeneration in mammals. This review highlights key anatomical and molecular concepts derived from avian models that hold promise for overcoming regenerative limitations in mammalian inner ears, paving the way for innovative treatments for hearing loss.
内耳感觉毛细胞对听觉和前庭功能至关重要。在哺乳动物中，由于支持细胞无法再生毛细胞，这些细胞的丧失会导致永久性听力损失。相比之下，鸟类具有显著的毛细胞再生能力，主要通过支持细胞的激活和增殖来实现。本综述全面考察了鸟类内耳两个关键结构——基底乳头和椭圆囊——中感觉毛细胞再生的解剖学和分子机制。我们描述了鸟类和哺乳动物内耳上皮的结构和功能差异，并强调了这些差异如何与再生能力相关联。具体而言，我们讨论了鸟类支持细胞在毛细胞损失后采用的两种不同的再生机制——有丝分裂再生和直接转分化。我们还探讨了上皮组织如何影响再生反应，包括细胞密度、细胞骨架动力学（如圆周丝状肌动蛋白带）以及组织堵塞和疏通状态等机械特性。此外，我们研究了诸如Hippo信号通路等分子途径，该通路介导了对调节再生过程中支持细胞增殖和分化至关重要的机械信号。单细胞组学技术的最新进展进一步阐明了这些过程中涉及的分子特征和信号通路，提供了新的见解，可能为旨在诱导哺乳动物毛细胞再生的治疗策略提供信息。本综述强调了从鸟类模型中得出的关键解剖学和分子概念，这些概念有望克服哺乳动物内耳的再生限制，为听力损失的创新治疗铺平道路。
