Extracellular Matrix Stiffness and TGFβ2 Regulate YAP/TAZ Activity in Human Trabecular Meshwork Cells

Area of Science:

• Ophthalmology
• Cell Biology
• Biomaterials Science

Background:

• Primary open-angle glaucoma progression correlates with human trabecular meshwork (HTM) stiffness and elevated transforming growth factor beta 2 (TGFβ2).
• Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are key mechanotransduction players implicated in glaucomatous HTM cell dysfunction.

Purpose of the Study:

• To elucidate the mechanisms of YAP/TAZ modulation in HTM cells in response to extracellular matrix (ECM) stiffness and TGFβ2.
• To investigate the role of YAP/TAZ signaling in glaucomatous HTM cell dysfunction and potential therapeutic targets.

Main Methods:

• Utilized biomimetic ECM hydrogels with tunable stiffness to assess YAP/TAZ localization and function.
• Employed small interfering RNA (siRNA) and verteporfin for YAP/TAZ depletion and inactivation.
• Investigated the involvement of extracellular-signal-regulated kinase (ERK) and Rho-associated kinase (ROCK) signaling pathways.

Main Results:

• Increased ECM stiffness promoted YAP/TAZ nuclear localization via focal adhesions and cytoskeletal rearrangement.
• TGFβ2 elevated nuclear YAP/TAZ in HTM cells, an effect mitigated by inhibiting ERK and ROCK pathways.
• YAP/TAZ depletion or inactivation reduced focal adhesions, ECM remodeling, cell contractility, and TGFβ2-induced hydrogel stiffening.

Conclusions:

• Aberrant YAP/TAZ signaling plays a pathological role in glaucomatous HTM cell dysfunction.
• Findings suggest that targeting YAP/TAZ signaling could be a novel therapeutic strategy for progressive ocular hypertension in glaucoma.