Nintedanib Induces Mesenchymal-to-Epithelial Transition and Reduces Subretinal Fibrosis Through Metabolic...

Area of Science:

• Ophthalmology
• Cell Biology
• Pharmacology

Background:

• Retinal pigment epithelial (RPE) cells undergo epithelial-mesenchymal transition (EMT) contributing to fibrotic diseases.
• Transforming growth factor beta 2 (TGF-β2) is a key inducer of EMT in RPE cells.
• EMT involves significant metabolic reprogramming, including increased glycolysis.

Purpose of the Study:

• To investigate Nintedanib's role in reversing TGF-β2-induced EMT in RPE cells.
• To evaluate Nintedanib's therapeutic potential in a mouse model of subretinal fibrosis.
• To explore Nintedanib's effect on metabolic pathways associated with EMT.

Main Methods:

• In vitro studies using primary human RPE cells and ARPE-19 cell line treated with TGF-β2 and Nintedanib.
• Assessment of EMT markers via qPCR, immunocytochemistry, and morphological analysis.
• Metabolic assays (Seahorse XF) and gene expression analysis of metabolic pathways.
• In vivo studies using a laser-induced subretinal fibrosis mouse model to assess Nintedanib's therapeutic efficacy.

Main Results:

• TGF-β2 induced EMT in RPE cells, characterized by altered gene/protein expression and increased glycolysis.
• Nintedanib treatment reversed TGF-β2-induced EMT markers and normalized cellular metabolism.
• In vivo, Nintedanib intravitreal injection significantly reduced fibrotic lesion size, neovascularization, and vascular leakage in the mouse model.

Conclusions:

• Nintedanib effectively reverses EMT in RPE cells and reduces subretinal fibrosis.
• Nintedanib's therapeutic effect involves metabolic reprogramming and induction of Mesenchymal-to-Epithelial Transition (MET).
• Nintedanib shows potential for repurposing in treating retinal fibrotic conditions.