Anatomical and molecular insights into avian inner ear sensory hair cell regeneration.

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.