Targeting YAP/TAZ mechanosignaling to ameliorate stiffness-induced Schlemm's canal cell pathobiology.
Targeting YAP/TAZ mechanosignaling to ameliorate stiffness-induced Schlemm's canal cell pathobiology.
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靶向 YAP/TAZ 机械信号传导以改善僵硬诱导的施累姆氏管细胞病理学。
DOI：
10.1152/ajpcell.00438.2023
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Herberg,Samuel
中科院分区：
文献类型：
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作者：
Li,Haiyan;Kuhn,Megan;Kelly,RuthA;Singh,Ayushi;Palanivel,KavipriyaKovai;Salama,Izzy;DeIeso,MichaelL;Stamer,WDaniel;Ganapathy,PreethiS;Herberg,Samuel
施莱姆管（SC）内壁内皮及其邻近区域生物力学特性的病理改变与青光眼患者因流出设施减少而引起的高眼压密切相关。具体来说，青光眼的小梁网比正常眼睛的小梁网硬得多。这提高了机械转导过程在驱动SC细胞功能障碍中的关键参与的可能性。青光眼相关蛋白（YAP）已成为青光眼发病的关键因素。然而，SC细胞通过YAP和带pdz结合基元（TAZ）的转录共激活因子对青光眼细胞外基质（ECM）硬化的机械信号传导的分子基础尚不清楚。使用一种新的生物聚合物水凝胶，促进动态和可逆的刚度调节，我们研究了ECM硬化如何调节原代人SC细胞中的YAP/TAZ活性，以及YAP/TAZ机械信号的破坏是否会减弱SC细胞的病理生物学并增加体外流出设施。我们证明了ECM硬化驱动SC细胞的病理YAP/TAZ激活和细胞骨架重组，这是通过基质软化以一种独特的时间依赖性方式完全可逆的。此外，我们发现YAP/TAZ机械信号的药理学或遗传破坏可消除僵硬诱导的SC细胞功能障碍，包括改变细胞骨架和ECM重塑。最后，我们发现灌注临床使用的小分子YAP/TAZ抑制剂维替波芬（无光激活）可增加正常小鼠眼睛的体外流出设施。总之，我们的数据为异常的YAP/TAZ机械信号在SC细胞功能障碍中的病理作用提供了新的证据，并表明YAP/TAZ抑制对青光眼的高眼压具有治疗价值。最近证实，施莱姆管（SC）内壁微环境病理改变的生物力学特性是高眼压青光眼流出阻力增加的原因。然而，在这些疾病过程中具体的机械转导途径的参与在很大程度上是不清楚的。在这里，我们证明yes相关蛋白(YAP)/带pdz结合基序的转录共激活因子（TAZ）是青光眼样SC细胞功能障碍的中心调节因子，以响应细胞外基质硬化，并且YAP/TAZ机械信号的靶向破坏减弱SC细胞的病理生物学并增强外流功能。
Pathological alterations in the biomechanical properties of the Schlemm’s canal (SC) inner wall endothelium and its immediate vicinity are strongly associated with ocular hypertension in glaucoma due to decreased outflow facility. Specifically, the underlying trabecular meshwork is substantially stiffer in glaucomatous eyes compared with that from normal eyes. This raises the possibility of a critical involvement of mechanotransduction processes in driving SC cell dysfunction. Yes-associated protein (YAP) has emerged as a key contributor to glaucoma pathogenesis. However, the molecular underpinnings of SC cell mechanosignaling via YAP and transcriptional coactivator with PDZ-binding motif (TAZ) in response to glaucomatous extracellular matrix (ECM) stiffening are not well understood. Using a novel biopolymer hydrogel that facilitates dynamic and reversible stiffness tuning, we investigated how ECM stiffening modulates YAP/TAZ activity in primary human SC cells, and whether disruption of YAP/TAZ mechanosignaling attenuates SC cell pathobiology and increases ex vivo outflow facility. We demonstrated that ECM stiffening drives pathologic YAP/TAZ activation and cytoskeletal reorganization in SC cells, which was fully reversible by matrix softening in a distinct time-dependent manner. Furthermore, we showed that pharmacologic or genetic disruption of YAP/TAZ mechanosignaling abrogates stiffness-induced SC cell dysfunction involving altered cytoskeletal and ECM remodeling. Finally, we found that perfusion of the clinically used, small molecule YAP/TAZ inhibitor verteporfin (without light activation) increases ex vivo outflow facility in normal mouse eyes. Collectively, our data provide new evidence for a pathologic role of aberrant YAP/TAZ mechanosignaling in SC cell dysfunction and suggest that YAP/TAZ inhibition has therapeutic value for treating ocular hypertension in glaucoma.NEW & NOTEWORTHYPathologically altered biomechanical properties of the Schlemm’s canal (SC) inner wall microenvironment were recently validated as the cause for increased outflow resistance in ocular hypertensive glaucoma. However, the involvement of specific mechanotransduction pathways in these disease processes is largely unclear. Here, we demonstrate that Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) are central regulators of glaucoma-like SC cell dysfunction in response to extracellular matrix stiffening and that targeted disruption of YAP/TAZ mechanosignaling attenuates SC cell pathobiology and enhances outflow function.