Hippo-YAP/TAZ信号在内耳发育、损伤与再生中的作用：证据综合与生物力学刹车假说

文献信息

中文摘要

哺乳动物的感音神经性听力损失基本上是不可逆的。成熟耳蜗毛细胞一旦丢失便不再再生。非哺乳类脊椎动物保留这种能力，但在哺乳动物的Corti器中，支持细胞在出生后失去增殖和转分化能力。经典发育通路的重新激活在成年耳蜗中也显示出有限的成功。在这篇综述中，我们首先综合已发表的关于内耳中Hippo-Yes相关蛋白（YAP）/具有PDZ结合基序的转录共激活因子（TAZ）信号传导的证据，包括对内耳祖细胞、Corti器生长、前庭感觉上皮、耳蜗毛细胞损伤、新生耳蜗再生模型以及新出现的成年耳蜗数据的研究。在此基础上，我们随后评估生物力学刹车假说，该假说提出损伤相关的机械重塑可能与Hippo-YAP/TAZ信号传导相互作用，从而限制成熟哺乳动物耳蜗中支持细胞的可塑性。我们不是将该假说作为已确立的机制来呈现，而是将其视为一个按证据分级的框架，必须针对替代解释进行检验，包括保护性上皮修复、细胞周期抑制、表观遗传限制和发育能力丧失。现有文献表明，Hippo-YAP/TAZ信号传导参与多种内耳过程，包括祖细胞扩增、感觉上皮生长、物种依赖性前庭修复、耳保护反应以及在特定实验条件下的支持细胞增殖。然而，关于损伤诱导的机械重塑因果性抑制成年耳蜗中YAP/TAZ依赖性再生的直接证据仍然有限。因此，我们区分发育、新生、前庭、离体和成年体内证据，并指出当前发现在哪里支持、削弱或仍不足以确立生物力学刹车模型。最后，我们概述了应指导未来工作的具体空白：Hippo相关内耳研究的全面制表、成年支持细胞谱系追踪、耳蜗机械特性和Hippo活性的空间映射、YAP/TAZ信号传导的细胞亚型特异性扰动、通过听性脑干反应和畸变产物耳声发射进行的功能评估，以及上皮稳定性的长期评估。这种组织方式旨在阐明Hippo-YAP/TAZ信号传导在内耳中已被证明的作用、仍属推测的内容，以及在机械生物学调控可被视为一种合理的再生策略之前需要进行哪些实验。

英文摘要

Sensorineural hearing loss in mammals is essentially irreversible. Mature cochlear hair cells, once lost, do not regenerate. Non-mammalian vertebrates retain this ability, but in the mammalian organ of Corti, supporting cells lose their proliferative and transdifferentiation competence after birth. Reactivation of classical developmental pathways has also shown limited success in the adult cochlea. In this review, we first synthesize published evidence on Hippo-Yes-associated protein(YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling in the inner ear, including studies of inner-ear progenitors, organ of Corti growth, vestibular sensory epithelia, cochlear hair-cell injury, neonatal cochlear regeneration models, and emerging adult cochlear data. On this basis, we then evaluate the biomechanical brake hypothesis, which proposes that injury-associated mechanical remodeling may interact with Hippo-YAP/TAZ signaling to restrict supporting-cell plasticity in the mature mammalian cochlea. Rather than presenting this hypothesis as an established mechanism, we treat it as an evidence-graded framework that must be tested against alternative explanations, including protective epithelial repair, cell-cycle inhibition, epigenetic restriction, and loss of developmental competence. The available literature suggests that Hippo-YAP/TAZ signaling participates in several inner-ear processes, including progenitor expansion, sensory epithelial growth, species-dependent vestibular repair, otoprotective responses, and supporting-cell proliferation under defined experimental conditions. However, direct evidence that injury-induced mechanical remodeling causally suppresses YAP/TAZ-dependent regeneration in the adult cochlea remains limited. We therefore distinguish among developmental, neonatal, vestibular, ex vivo, and adult in vivo evidence, and identify where current findings support, weaken, or remain insufficient to establish the biomechanical brake model. Finally, we outline specific gaps that should guide future work: comprehensive tabulation of Hippo-related inner-ear studies, adult supporting-cell lineage tracing, spatial mapping of cochlear mechanical properties and Hippo activity, cell-subtype-specific perturbation of YAP/TAZ signaling, functional assessment by auditory brainstem response and distortion product otoacoustic emission, and long-term evaluation of epithelial stability. This organization is intended to clarify what Hippo-YAP/TAZ signaling has already been shown to do in the inner ear, what remains speculative, and which experiments are required before mechanobiological modulation can be considered a plausible regenerative strategy.