Fak inhibition attenuates corneal fibroblast differentiation in vitro

Vincent Yeung, Sriniwas Sriram, Jennifer A. Tran, Xiaoqing Guo, Audrey E.K. Hutcheon, James D. Zieske, Dimitrios Karamichos, Joseph B. Ciolino

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Corneal fibrosis (or scarring) occurs in response to ocular trauma or infection, and by reducing corneal transparency, it can lead to visual impairment and blindness. Studies highlight important roles for transforming growth factor (TGF)-β1 and-β3 as modulators in corneal wound healing and fibrosis, leading to increased extracellular matrix (ECM) components and expression of α-smooth muscle actin (αSMA), a myofibroblast marker. In this study, human corneal fibroblasts (hCF) were cultured as a monolayer culture (2D) or on poly-transwell membranes to generate corneal stromal constructs (3D) that were treated with TGF-β1, TGF-β3, or TGF-β1 + FAK inhibitor (FAKi). Results show that hCF 3D constructs treated with TGF-β1 or TGF-β3 impart distinct effects on genes involved in wound healing and fibrosis—ITGAV, ITGB1, SRC and ACTA2. Notably, in the 3D construct model, TGF-β1 enhanced αSMA and focal adhesion kinase (FAK) protein expression, whereas TGF-β3 did not. In addition, in both the hCF 2D cell and 3D construct models, we found that TGF-β1 + FAKi attenuated TGF-β1-mediated myofibroblast differentiation, as shown by abrogated αSMA expression. This study concludes that FAK signaling is important for the onset of TGF-β1-mediated myofibroblast differentiation, and FAK inhibition may provide a novel beneficial therapeutic avenue to reduce corneal scarring.

Original languageEnglish
Article number1682
JournalBiomolecules
Volume11
Issue number11
DOIs
StatePublished - Nov 2021

Keywords

  • 3D cell culture
  • Corneal scarring
  • Extracellular matrix (ECM)
  • Focal adhesion kinase (FAK)
  • α-smooth muscle actin (αSMA)

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