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YAP/TAZ Mediate TGFβ2-Induced Schlemm's Canal Cell Dysfunction.

Publication ,  Journal Article
Li, H; Singh, A; Perkumas, KM; Stamer, WD; Ganapathy, PS; Herberg, S
Published in: Invest Ophthalmol Vis Sci
November 1, 2022

PURPOSE: Elevated transforming growth factor beta2 (TGFβ2) levels in the aqueous humor have been linked to glaucomatous outflow tissue dysfunction. Potential mediators of dysfunction are the transcriptional coactivators, Yes-associated protein (YAP) and transcriptional coactivator with PDZ binding motif (TAZ). However, the molecular underpinnings of YAP/TAZ modulation in Schlemm's canal (SC) cells under glaucomatous conditions are not well understood. Here, we investigate how TGFβ2 regulates YAP/TAZ activity in human SC (HSC) cells using biomimetic extracellular matrix hydrogels, and examine whether pharmacological YAP/TAZ inhibition would attenuate TGFβ2-induced HSC cell dysfunction. METHODS: Primary HSC cells were seeded atop photo-cross-linked extracellular matrix hydrogels, made of collagen type I, elastin-like polypeptide and hyaluronic acid, or encapsulated within the hydrogels. HSC cells were induced with TGFβ2 in the absence or presence of concurrent actin destabilization or pharmacological YAP/TAZ inhibition. Changes in actin cytoskeletal organization, YAP/TAZ activity, extracellular matrix production, phospho-myosin light chain levels, and hydrogel contraction were assessed. RESULTS: TGFβ2 significantly increased YAP/TAZ nuclear localization in HSC cells, which was prevented by either filamentous-actin relaxation or depolymerization. Pharmacological YAP/TAZ inhibition using verteporfin without light stimulation decreased fibronectin expression and actomyosin cytoskeletal rearrangement in HSC cells induced by TGFβ2. Similarly, verteporfin significantly attenuated TGFβ2-induced HSC cell-encapsulated hydrogel contraction. CONCLUSIONS: Our data provide evidence for a pathologic role of aberrant YAP/TAZ signaling in HSC cells under simulated glaucomatous conditions and suggest that pharmacological YAP/TAZ inhibition has promising potential to improve outflow tissue dysfunction.

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Published In

Invest Ophthalmol Vis Sci

DOI

EISSN

1552-5783

Publication Date

November 1, 2022

Volume

63

Issue

12

Start / End Page

15

Location

United States

Related Subject Headings

  • YAP-Signaling Proteins
  • Verteporfin
  • Transforming Growth Factor beta2
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • Transcription Factors
  • Trans-Activators
  • Phosphoproteins
  • Ophthalmology & Optometry
  • Intracellular Signaling Peptides and Proteins
  • Hydrogels
 

Citation

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Li, H., Singh, A., Perkumas, K. M., Stamer, W. D., Ganapathy, P. S., & Herberg, S. (2022). YAP/TAZ Mediate TGFβ2-Induced Schlemm's Canal Cell Dysfunction. Invest Ophthalmol Vis Sci, 63(12), 15. https://doi.org/10.1167/iovs.63.12.15
Li, Haiyan, Ayushi Singh, Kristin M. Perkumas, W Daniel Stamer, Preethi S. Ganapathy, and Samuel Herberg. “YAP/TAZ Mediate TGFβ2-Induced Schlemm's Canal Cell Dysfunction.Invest Ophthalmol Vis Sci 63, no. 12 (November 1, 2022): 15. https://doi.org/10.1167/iovs.63.12.15.
Li H, Singh A, Perkumas KM, Stamer WD, Ganapathy PS, Herberg S. YAP/TAZ Mediate TGFβ2-Induced Schlemm's Canal Cell Dysfunction. Invest Ophthalmol Vis Sci. 2022 Nov 1;63(12):15.
Li, Haiyan, et al. “YAP/TAZ Mediate TGFβ2-Induced Schlemm's Canal Cell Dysfunction.Invest Ophthalmol Vis Sci, vol. 63, no. 12, Nov. 2022, p. 15. Pubmed, doi:10.1167/iovs.63.12.15.
Li H, Singh A, Perkumas KM, Stamer WD, Ganapathy PS, Herberg S. YAP/TAZ Mediate TGFβ2-Induced Schlemm's Canal Cell Dysfunction. Invest Ophthalmol Vis Sci. 2022 Nov 1;63(12):15.

Published In

Invest Ophthalmol Vis Sci

DOI

EISSN

1552-5783

Publication Date

November 1, 2022

Volume

63

Issue

12

Start / End Page

15

Location

United States

Related Subject Headings

  • YAP-Signaling Proteins
  • Verteporfin
  • Transforming Growth Factor beta2
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • Transcription Factors
  • Trans-Activators
  • Phosphoproteins
  • Ophthalmology & Optometry
  • Intracellular Signaling Peptides and Proteins
  • Hydrogels