Extracellular Matrix Stiffness and TGFβ2 Regulate YAP/TAZ Activity in Human Trabecular Meshwork Cells.
Extracellular Matrix Stiffness and TGFβ2 Regulate YAP/TAZ Activity in Human Trabecular Meshwork Cells.
复制标题
细胞外基质硬度和TGFβ2调节人眼小梁细胞雅普/TAZ活性
DOI：
10.3389/fcell.2022.844342
复制
发表时间：
2022
影响因子：
5.5
通讯作者：
Herberg S
中科院分区：
文献类型：
--
作者：
Li H;Raghunathan V;Stamer WD;Ganapathy PS;Herberg S
原发性开角型青光眼的进展与人小梁网（HTM）刚度增加和房水中转化生长因子β2 （tgf - β2）水平升高有关。yes相关蛋白（YAP）和带pdz结合基元的转录辅激活因子（TAZ）的转录活性增加是机械转导的核心参与者，与青光眼HTM细胞功能障碍有关。然而，HTM细胞中YAP/TAZ调节响应细胞外基质（ECM）刚度和tgf - β2水平变化的详细机制尚不清楚。使用具有可调刚度的仿生ECM水凝胶，我们发现ECM刚度的增加可能通过调节局灶黏附和细胞骨架重排来提高YAP/TAZ核定位。此外，TGFβ2在正常和青光眼HTM细胞中增加细胞核YAP/TAZ，这是通过抑制细胞外信号调节激酶和rho相关激酶信号通路来阻止的。丝状(F)-肌动蛋白解聚逆转tgf - β2诱导的YAP/TAZ核定位。使用siRNA或维替泊芬去除YAP/TAZ可降低局灶粘连、ECM重塑和细胞收缩特性。同样，用维替泊芬灭活YAP/TAZ部分阻断tgf - β2诱导的水凝胶收缩和硬化。总的来说，我们的数据为异常的YAP/TAZ信号在青光眼HTM细胞功能障碍中的病理作用提供了证据，并可能有助于制定新的多因素方法来预防青光眼进行性高眼压。
Primary open-angle glaucoma progression is associated with increased human trabecular meshwork (HTM) stiffness and elevated transforming growth factor beta 2 (TGFβ2) levels in the aqueous humor. Increased transcriptional activity of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), central players in mechanotransduction, are implicated in glaucomatous HTM cell dysfunction. Yet, the detailed mechanisms underlying YAP/TAZ modulation in HTM cells in response to alterations in extracellular matrix (ECM) stiffness and TGFβ2 levels are not well understood. Using biomimetic ECM hydrogels with tunable stiffness, here we show that increased ECM stiffness elevates YAP/TAZ nuclear localization potentially through modulating focal adhesions and cytoskeletal rearrangement. Furthermore, TGFβ2 increased nuclear YAP/TAZ in both normal and glaucomatous HTM cells, which was prevented by inhibiting extracellular-signal-regulated kinase and Rho-associated kinase signaling pathways. Filamentous (F)-actin depolymerization reversed TGFβ2-induced YAP/TAZ nuclear localization. YAP/TAZ depletion using siRNA or verteporfin decreased focal adhesions, ECM remodeling and cell contractile properties. Similarly, YAP/TAZ inactivation with verteporfin partially blocked TGFβ2-induced hydrogel contraction and stiffening. Collectively, our data provide evidence for a pathologic role of aberrant YAP/TAZ signaling in glaucomatous HTM cell dysfunction, and may help inform strategies for the development of novel multifactorial approaches to prevent progressive ocular hypertension in glaucoma.
登录
查看更多内容
影响因子：
4.4
作者：
Dhamodaran, Kamesh;Baidouri, Hasna;Raghunathan, VijayKrishna
通讯作者：
Raghunathan, VijayKrishna
影响因子：
6
作者：
Junglas, Benjamin;Kuespert, Sabrina;Fuchshofer, Rudolf
通讯作者：
Fuchshofer, Rudolf
影响因子：
4.3
作者：
Hensel N;Rademacher S;Claus P
通讯作者：
Claus P
DOI：
10.1007/s004170000241
发表时间：
2001-02-01
影响因子：
2.7
作者：
Inatani, M;Tanihara, H;Honda, Y
通讯作者：
Honda, Y
DOI：
10.1016/j.bbrc.2015.09.012
发表时间：
2015-10-16
影响因子：
3.1
作者：
Chen, Wei-Sheng;Cao, Zhiyi;Panjwani, Noorjahan
通讯作者：
Panjwani, Noorjahan