期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 164, 期 -, 页码 34-43出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2020.12.445
关键词
Fuchs endothelial corneal dystrophy; Senescence; Endothelial-mesenchymal transition; Fibrosis; Cell cycle
资金
- NIH/National Eye Institute [R01EY020581]
- Alcon Young Investigator Grant
- Research to Prevent Blindness
- Alcon Research Institute
- [P30EY003790]
Fuchs endothelial corneal dystrophy is an age-related disease that causes vision loss due to the progressive loss of corneal endothelial cells. The study has shown a causal relationship between senescence and endothelial-mesenchymal transition, with UVA light inducing EMT and senescence in CEnCs. Inhibiting ATR signaling and preventing G2/M arrest attenuated EMT, while selectively eliminating senescent cells using dasatinib and quercetin cocktail reduced UVA-induced fibrosis, suggesting a potential new therapeutic intervention for FECD.
Fuchs endothelial corneal dystrophy (FECD) is an age-related disease whereby progressive loss of corneal endothelial cells (CEnCs) leads to loss of vision. There is currently a lack of therapeutic interventions as the etiology of the disease is complex, with both genetic and environmental factors. In this study, we have provided further insights into the pathogenesis of the disease, showing a causal relationship between senescence and endothelial-mesenchymal transition (EMT) using in vitro and in vivo models. Ultraviolet A (UVA) light induced EMT and senescence in CEnCs. Senescent cells were arrested in G2/M phase of the cell cycle and responsible for the resulting profibrotic phenotype. Inhibiting ATR signaling and subsequently preventing G2/M arrest attenuated EMT. In vivo, UVA irradiation induced cell cycle re-entry in post mitotic CEnCs, resulting in senescence and fibrosis at 1- and 2-weeks post-UVA. Selectively eliminating senescent cells using the senolytic cocktail of dasatinib and quercetin attenuated UVA-induced fibrosis, highlighting the potential for a new therapeutic intervention for FECD.
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