Department of Neuroscience, University of Virginia, School of Medicine, Charlottesville, Virginia 22908, and.
Department of Neuroscience, University of Virginia, School of Medicine, Charlottesville, Virginia 22908, and
J Neurosci. 2020 Mar 25;40(13):2618-2632. doi: 10.1523/JNEUROSCI.2630-19.2020. Epub 2020 Feb 20.
Sensory hair cell losses underlie the vast majority of permanent hearing and balance deficits in humans, but many nonmammalian vertebrates can fully recover from hearing impairments and balance dysfunctions because supporting cells (SCs) in their ears retain lifelong regenerative capacities that depend on proliferation and differentiation as replacement hair cells. Most SCs in vertebrate ears stop dividing during embryogenesis; and soon after birth, vestibular SCs in mammals transition to lasting quiescence as they develop massively thickened circumferential F-actin bands at their E-cadherin-rich adherens junctions. Here, we report that treatment with EGF and a GSK3 inhibitor thinned the circumferential F-actin bands throughout the sensory epithelium of cultured utricles that were isolated from adult mice of either sex. That treatment also caused decreases in E-cadherin, β-catenin, and YAP in the striola, and stimulated robust proliferation of mature, normally quiescent striolar SCs. The findings suggest that E-cadherin-rich junctions, which are not present in the SCs of the fish, amphibians, and birds which readily regenerate hair cells, are responsible in part for the mammalian ear's vulnerability to permanent balance and hearing deficits. Millions of people are affected by hearing and balance deficits that arise when loud sounds, ototoxic drugs, infections, and aging cause hair cell losses. Such deficits are permanent for humans and other mammals, but nonmammals can recover hearing and balance after supporting cells regenerate replacement hair cells. Mammalian supporting cells lose the capacity to proliferate around the time they develop unique, exceptionally reinforced, E-cadherin-rich intercellular junctions. Here, we report the discovery of a pharmacological treatment that thins F-actin bands, depletes E-cadherin, and stimulates proliferation in long-quiescent supporting cells within a balance epithelium from adult mice. The findings suggest that high E-cadherin in those supporting cell junctions may be responsible, in part, for the permanence of hair cell loss in mammals.
感觉毛细胞的损失是人类绝大多数永久性听力和平衡缺陷的基础，但许多非哺乳动物脊椎动物可以完全从听力损伤和平衡功能障碍中恢复过来，因为它们耳朵中的支持细胞 (SCs) 具有终生的再生能力，这依赖于增殖和分化以替代毛细胞。脊椎动物耳朵中的大多数 SC 在胚胎发生过程中停止分裂；并且在出生后不久，哺乳动物的前庭 SC 就会过渡到持久的静止状态，因为它们在 E-钙粘蛋白丰富的黏着连接处形成了大量增厚的环形 F-肌动蛋白带。在这里，我们报告说，用 EGF 和 GSK3 抑制剂处理可以使培养的来自成年雌雄小鼠的耳石脱离器的感觉上皮的整个环形 F-肌动蛋白带变薄。该处理还导致条纹中的 E-钙粘蛋白、β-连环蛋白和 YAP 减少，并刺激成熟的、通常静止的条纹 SC 大量增殖。研究结果表明，E-钙粘蛋白丰富的连接，在鱼类、两栖动物和鸟类中不存在，这些动物很容易再生毛细胞，部分原因是哺乳动物耳朵容易受到永久性平衡和听力缺陷的影响。当强音、耳毒性药物、感染和衰老导致毛细胞损失时，数百万人会受到听力和平衡缺陷的影响。这些缺陷对人类和其他哺乳动物来说是永久性的，但非哺乳动物可以在支持细胞再生替代毛细胞后恢复听力和平衡。哺乳动物的支持细胞在发育出独特的、异常强化的 E-钙粘蛋白丰富的细胞间连接时，失去了增殖的能力。在这里，我们报告了一种药理学治疗的发现，该治疗可以使 F-肌动蛋白带变薄，耗尽 E-钙粘蛋白，并刺激成年小鼠的平衡上皮中长时间静止的支持细胞增殖。研究结果表明，这些支持细胞连接中的高 E-钙粘蛋白可能部分导致哺乳动物毛细胞损失的永久性。
