Hyperactive PDGFR signaling induces cataractogenesis via TGF and STAT5-IGF1

Introduction: Cataracts are the worlds leading cause of reversible blindness. Although cataract formation is commonly initiated by lens fiber cell defects, cataractogenesis can be characterized by aberrant proliferation and migration of lens epithelial cells, particularly in posterior capsule opacification. Subsequent overproduction of extracellular matrix components such as fibronectin and collagen by epithelial cells is associated with fibrosis of the lens. Little is known about the role of platelet-derived growth factor receptor (PDGFR) in lens fibrosis. Here, we investigated mice with a conditional knock-in driving mesenchymal-specific PDGFR hyperactivation (Fsp1-cre;Pdgfrb+/D849V), which consistently develop cataracts at a young age. Methods: Lenses from Fsp1-cre;Pdgfrb+/D849V mice and age-matched controls were dissected and visualized via microscopy from 9-15 weeks. Early transcriptional changes were investigated between 10-12 day old Fsp1-cre;Pdgfrb+/D849V and control mice via RNA sequencing followed by gene set enrichment analysis. Confirmation of RNA sequencing results and mechanistic investigation of PDGFR-induced cataractogenesis were determined in lenses isolated from 15-week-old Fsp1-cre;Pdgfrb+/D849V and control mice. Results: Gross examination of cataractous lenses from Fsp1-cre;Pdgfrb+/D849V mice revealed complete opacification by 15 weeks of age compared to no opacification in age-matched controls. Structural changes in the anterior, equatorial, and posterior lens were observed in histology. RNA sequencing revealed significant enrichment of gene sets related to extracellular matrix deposition and reorganization. Mechanistic investigation revealed major roles for TGF, SOCS2, and STAT5-IGF1 signaling axes in PDGFR-induced cataract formation. Conclusion: PDGFR promoted cataractogenesis by modulating pro-fibrotic extracellular matrix changes, likely through TGF, SOCS2, and the STAT5-IGF1 pathways. Future experiments will delineate the precise role of the STAT5-IGF1 signaling pathway in PDGFR-mediated fibrosis and the interplay between PDGFR and TGF in the lens and whether this signaling is targetable to modulate cataractogenesis.