Ultraviolet-A light-induced chronic hyperploidization causes fibrosis in post-mitotic cells affected by Fuchs endothelial corneal dystrophy
4 affiliations
- 1Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, MA USA
- 2Department of Ophthalmology, Harvard Medical School, Boston, MA USA
- 3PriceVision Group, Indianapolis, IN USA
- 4Biology Department, Boston College, Chestnut Hill, MA USA
Abstract
Fuchs endothelial corneal dystrophy (FECD) is a progressive disorder characterized by corneal endothelial (CE) cell loss and accumulation of extracellular matrix (ECM) excrescences (guttae) in Descemet’s membrane, leading to corneal edema and visual impairment. We previously demonstrated that ultraviolet-A (UVA) exposure induces oxidative stress and CE cell loss in a non-genetic murine model of FECD. Here, we investigated whether UVA triggers polyploidization, a conserved stress-adaptation mechanism observed in several post-mitotic tissues. Using our UVA-based FECD model, we performed temporal analyses of CE cell ploidy, and molecular markers associated with cell-cycle regulation and ECM deposition seen in FECD. UVA exposure induced oxidative DNA damage and apoptosis, resulting in decreased cell density. Surviving CE cells re-entered the cell cycle and underwent endocycling, generating enlarged polyploid nuclei in about 60% of cells with increased DNA content reaching up to 64 C by day 3, compared to 6 C at day 1 post-UVA. Early polyploidization served a compensatory role preserving tissue integrity following cell loss. However, persistent oxidative stress promoted progression toward endomitosis and multinucleation, accompanied by cellular senescence and fibrosis observed during disease progression. Mechanistically, UVA-induced cell-cycle re-entry and polyploidization were mediated by YAP1 and its downstream effectors, E2F1 and CDK2. Pharmacologic inhibition of YAP1 using the small-molecule CA3 suppressed polyploidization-associated multinucleation and reduced pro-fibrotic changes, ultimately mitigating CE cell loss in vivo. Together, these findings identify distinct early protective and later pathogenic roles of polyploidization in CE cells and highlight YAP1-mediated hyperploidization as a potential therapeutic target for FECD.
Fuchs endothelial corneal dystrophy (FECD) involves progressive corneal endothelial cell loss driven by oxidative stress. Using a UVA-induced mouse model, we show that surviving cells undergo YAP1-mediated polyploidization. While initially compensatory, persistent hyperploidization promotes senescence and disease progression. Inhibiting YAP1 reduces polyploidy and preserves endothelial cell survival, identifying a potential therapeutic target.
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BibTeX
@article{adhikari2026ultravioleta,
title = {{Ultraviolet-A light-induced chronic hyperploidization causes fibrosis in post-mitotic cells affected by Fuchs endothelial corneal dystrophy}},
author = {Yadav Adhikari and Mohit Parekh and Neha Deshpande and Annie Miall and Queenie Cheung and Marianne O. Price and Francis W. Price and Vicki P. Losick and Ula V. Jurkunas},
journal = {Cell Death Discovery},
year = {2026},
month = aug,
doi = {10.1038/s41420-026-03292-8},
url = {https://doi.org/10.1038/s41420-026-03292-8},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Ultraviolet-A light-induced chronic hyperploidization causes fibrosis in post-mitotic cells affected by Fuchs endothelial corneal dystrophy
AU - Yadav Adhikari
AU - Mohit Parekh
AU - Neha Deshpande
AU - Annie Miall
AU - Queenie Cheung
AU - Marianne O. Price
AU - Francis W. Price
AU - Vicki P. Losick
AU - Ula V. Jurkunas
PY - 2026
DA - 2026/08/08
JO - Cell Death Discovery
DO - 10.1038/s41420-026-03292-8
UR - https://doi.org/10.1038/s41420-026-03292-8
AB - Fuchs endothelial corneal dystrophy (FECD) is a progressive disorder characterized by corneal endothelial (CE) cell loss and accumulation of extracellular matrix (ECM) excrescences (guttae) in Descemet’s membrane, leading to corneal edema and visual impairment. We previously demonstrated that ultraviolet-A (UVA) exposure induces oxidative stress and CE cell loss in a non-genetic murine model of FECD. Here, we investigated whether UVA triggers polyploidization, a conserved stress-adaptation mechanism observed in several post-mitotic tissues. Using our UVA-based FECD model, we performed temporal analyses of CE cell ploidy, and molecular markers associated with cell-cycle regulation and ECM deposition seen in FECD. UVA exposure induced oxidative DNA damage and apoptosis, resulting in decreased cell density. Surviving CE cells re-entered the cell cycle and underwent endocycling, generating enlarged polyploid nuclei in about 60% of cells with increased DNA content reaching up to 64 C by day 3, compared to 6 C at day 1 post-UVA. Early polyploidization served a compensatory role preserving tissue integrity following cell loss. However, persistent oxidative stress promoted progression toward endomitosis and multinucleation, accompanied by cellular senescence and fibrosis observed during disease progression. Mechanistically, UVA-induced cell-cycle re-entry and polyploidization were mediated by YAP1 and its downstream effectors, E2F1 and CDK2. Pharmacologic inhibition of YAP1 using the small-molecule CA3 suppressed polyploidization-associated multinucleation and reduced pro-fibrotic changes, ultimately mitigating CE cell loss in vivo. Together, these findings identify distinct early protective and later pathogenic roles of polyploidization in CE cells and highlight YAP1-mediated hyperploidization as a potential therapeutic target for FECD. Fuchs endothelial corneal dystrophy (FECD) involves progressive corneal endothelial cell loss driven by oxidative stress. Using a UVA-induced mouse model, we show that surviving cells undergo YAP1-mediated polyploidization. While initially compensatory, persistent hyperploidization promotes senescence and disease progression. Inhibiting YAP1 reduces polyploidy and preserves endothelial cell survival, identifying a potential therapeutic target.
SN - 2058-7716
ER -