Fibronectin has multifunctional roles in posterior capsular opacification (PCO)

Area of Science:

• Ophthalmology
• Cell Biology
• Biochemistry

Background:

• Posterior capsular opacification (PCO) is a common complication after cataract surgery, involving lens epithelial cells (LCs) transforming and forming scar tissue.
• Fibronectin is highly produced by LCs post-surgery, but its specific role in PCO pathogenesis remains unclear.

Purpose of the Study:

• To investigate the function of fibronectin in the development of fibrotic PCO.
• To determine how fibronectin influences cell signaling pathways during PCO formation.

Main Methods:

• Created fibronectin conditional knock-out (FNcKO) mice lacking the fibronectin gene in the lens.
• Modeled cataract surgery by removing lens fiber cells in FNcKO and wild-type (WT) mice.
• Assessed fibrotic response, cell proliferation, extracellular matrix production, and gene/protein expression (TGFβ, BMP, E-cadherin, αSMA, gremlin-1, SMAD2/3 phosphorylation) post-surgery.
• Utilized RNA sequencing to analyze gene expression changes.

Main Results:

• FNcKO mice showed a significantly reduced fibrotic response, decreased cell proliferation, and less extracellular matrix deposition compared to WT mice after surgery.
• Fibronectin deficiency led to reduced upregulation of Transforming Growth Factor β (TGFβ) and integrin signaling, with sustained Bone Morphogenetic Protein (BMP) signaling and elevated E-cadherin.
• RNA sequencing revealed attenuated upregulation of fibrosis-related genes, including gremlin-1, in FNcKO LCs.
• Exogenous TGFβ1 or gremlin-1 administration rescued the fibrotic response in FNcKO mice.

Conclusions:

• Fibronectin plays essential, multifaceted roles in the pathogenesis of fibrotic PCO.
• Fibronectin influences key signaling pathways, including TGFβ and BMP, which regulate fibrotic responses in LCs post-cataract surgery.
• Targeting fibronectin may offer a therapeutic strategy to prevent or treat PCO.