Cell cycle re-entry and arrest in G2/M phase induces senescence and fibrosis in Fuchs Endothelial Corneal Dystrophy

White, Tomas; Deshpande, Neha; Kumar, Varun; Gauthier, Alex; Jurkūnas, Ūla V.

doi:10.1016/j.freeradbiomed.2020.12.445

Cited by 17 publications

(19 citation statements)

References 41 publications

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“…Based on the susceptibility of the corneal endothelium to oxidative stress, we established a non-genetic FECD mouse model whose corneal exposure to UVA recapitulated the symptoms of FECD. 22,44 Targeted irradiation of mouse corneas with UVA light induced the characteristic of lateonset FECD (Figure S6A), which was a readily achieved FECD model. 22,44 Consistent with clinical samples, we detected significantly downregulated Neat1 in mouse corneal endothelium 4 weeks post-irradiation with varying doses (500, 750, and 1,000 J/cm 2 ) (Figure S6B).…”

Section: Silencing Neat1-exacerbated Fecd By Impairing the Oxidantantioxidant Balance In Cencsmentioning

confidence: 99%

“…22,44 Targeted irradiation of mouse corneas with UVA light induced the characteristic of lateonset FECD (Figure S6A), which was a readily achieved FECD model. 22,44 Consistent with clinical samples, we detected significantly downregulated Neat1 in mouse corneal endothelium 4 weeks post-irradiation with varying doses (500, 750, and 1,000 J/cm 2 ) (Figure S6B). To examine the impact of NEAT1 expression on FECD progression, we KD Neat1 expression in the mouse corneal endothelium by directly injecting Neat1-targeting short hairpin RNAs (shRNAs) into anterior chambers before UVA irradiation (Neat1 KD group) (Figures S7A and S7B), and then established a periodic experimental setup, as shown in Figure 5A.…”

Section: Silencing Neat1-exacerbated Fecd By Impairing the Oxidantantioxidant Balance In Cencsmentioning

confidence: 99%

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Heterogeneity of human corneal endothelium implicates lncRNA NEAT1 in Fuchs endothelial corneal dystrophy

Wang

Dou

Zhang

et al. 2022

Molecular Therapy - Nucleic Acids

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Section: Silencing Neat1-exacerbated Fecd By Impairing the Oxidantantioxidant Balance In Cencsmentioning

confidence: 99%

Section: Silencing Neat1-exacerbated Fecd By Impairing the Oxidantantioxidant Balance In Cencsmentioning

confidence: 99%

Heterogeneity of human corneal endothelium implicates lncRNA NEAT1 in Fuchs endothelial corneal dystrophy

Wang

Dou

Zhang

et al. 2022

Molecular Therapy - Nucleic Acids

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“…The copyright holder for this preprint this version posted June 28, 2022. ; https://doi.org/10.1101/2022.06. 27.497862 doi: bioRxiv preprint sensitivity to known exogenous stressors that drive disease progression including ultraviolet light (UV) (9)(10)(11)(12). The cornea is particularly susceptible to damage by ultraviolet A light (UVA, 320 to 400 nm), which comprises the vast majority of incident solar radiation absorbed by CECs (9,10,13).…”

Section: Introductionmentioning

confidence: 99%

“…In all cases, FECD is diagnosed by detecting the loss of corneal endothelial cells (CECs) and formation of degenerative extracellular matrix deposits (guttae) on the corneal endothelium that lines the inner cornea, and results in failure to maintain appropriate corneal hydration through active ion pumping to counter the passive leakage of aqueous humor (8). On the molecular level in FECD, affected CECs have an increased steady-state level of reactive oxygen species (ROS), impaired antioxidant response to oxidative stress, and increased sensitivity to known exogenous stressors that drive disease progression including ultraviolet light (UV) (9)(10)(11)(12). The cornea is particularly susceptible to damage by ultraviolet A light (UVA, 320 to 400 nm), which comprises the vast majority of incident solar radiation absorbed by CECs (9,10,13).…”

Section: Introductionmentioning

confidence: 99%

TCF4trinucleotide repeat expansions and UV irradiation increase susceptibility to ferroptosis in Fuchs endothelial corneal dystrophy

Saha

Skeie

Schmidt

et al. 2022

Preprint

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Fuchs endothelial corneal dystrophy (FECD), a progressive polygenic disease that causes degeneration of the corneal endothelium, is the leading indication for corneal transplantation in the U.S. Characteristically, loss of corneal endothelial cells and formation of degenerative extracellular guttae result in failure to maintain appropriate corneal hydration through active ion pumping to counter the passive leakage of aqueous humor. FECD pathogenesis is linked to oxidative stress and environmental exposure to ultraviolet A (UVA), and impaired endogenous response to oxidative stress is common to the disease across multiple genotypes. UV irradiation is also known to cause cellular damage by ferroptosis, a nonapoptotic oxidative cell death resulting from iron-mediated lipid peroxidation. Although a possible role for ferroptosis in FECD has been postulated to account for the increased susceptibility to oxidative damage and lipid peroxidation, this has not been explored systematically. In this study, we investigated the roles of genetic background and UVA exposure in causing lipid membrane damage and endothelial cell degeneration in FECD. We first sought clinical evidence of iron-mediated lipid peroxidation in surgical samples obtained from FECD patients undergoing endothelial keratoplasty, and found increased levels of cytosolic ferrous iron (Fe2+) and evidence of lipid peroxidation were present in end-stage diseased tissues compared with healthy human donor corneas. Next, using immortalized (F35T) and primary cell cultures modeling the TCF4 intronic trinucleotide repeat expansion genotype, we found that alterations in gene and protein expression involved in ferroptosis were conserved in both cell culture and tissue models of FECD disease compared to controls, including elevated levels of the ferroptosis-specific marker transferrin receptor 1. F35T immortalized cells showed significantly higher basal lipid peroxidation than control HCEC-B4G12 cells, indicating higher susceptibility to ferroptosis attributable to genetic background. Then, we tested the impact of physiologically relevant doses of UVA irradiation on F35T cell cultures and found increased cytosolic Fe2+ iron levels indicating a role for ferroptosis in FECD disease progression. Finally, we tested the effects of inhibitory ferroptosis molecules. We found that F35T cells were more prone to RSL3 induced ferroptosis than healthy controls with deferoxamine chelation which indicated increased susceptibility in FECD cells, and cell death could be prevented after experimentally-induced ferroptosis using solubilized antioxidant ubiquinol indicating a role for anti-ferroptosis therapies. This investigation demonstrates that FECD genetic background and UVA exposure contribute to basal and incidental iron-mediated lipid peroxidation and cell death in FECD, and provides the basis for future investigations of ferroptosis-mediated oxidative damage and disease progression in FECD.

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“…In the current study, we presented that AQR, upregulated in different tissues across species by aging and high glucose concentrations, promotes endothelial cell senescence, providing a plausible explanation on why aging increases the susceptibility to diabetes. Cellular senescence, as a state of permanent cell cycle arrest, can occur in both G1 and G2 phase of the cell cycle, terminating the G0/G1 and G2/M progressions, respectively [ 30 ]. Two types of cell cycle arrests have distinct but partially overlapped signaling molecules [ 31 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

Hyperglycemia Promotes Endothelial Cell Senescence through AQR/PLAU Signaling Axis

Wan

Liu

et al. 2022

IJMS

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Hyperglycemia is reported to accelerate endothelial cell senescence that contributes to diabetic complications. The underlying mechanism, however, remains elusive. We previously demonstrated AQR as a susceptibility gene for type 2 diabetes mellitus (T2DM) and showed that it was increased in multiple tissues in models with T2DM or metabolic syndrome. This study aimed to investigate the role of AQR in hyperglycemia-induced senescence and its underlying mechanism. Here, we retrieved several datasets of the aging models and found the expression of AQR was increased by high glucose and by aging across species, including C. elegans (whole-body), rat (cardiac tissues), and monkey (blood). we validated the increased AQR expression in senescent human umbilical vein endothelial cells (HUVECs). When overexpressed, AQR promoted the endothelial cell senescence, confirmed by an increased number of cells stained with senescence-associated beta-galactosidase and upregulation of CDKN1A (P21) as well as the prohibited cellular colony formation and G2/M phase arrest. To explore the mechanism by which AQR regulated the cellular senescence, transcriptomic analyses of HUVECs with the overexpression and knockdown of the AQR were performed. We identified 52 co-expressed genes that were enriched, in the terms of plasminogen activation, innate immunity, immunity, and antiviral defense. Among co-expressed genes, PLAU was selected to evaluate its contribution to senescence for its highest strength in the enrichment of the biological process. We demonstrated that the knockdown of PLAU rescued senescence-related phenotypes, endothelial cell activation, and inflammation in models induced by AQR or TNF-α. These findings, for the first time, indicate that AQR/PLAU is a critical signaling axis in the modulation of endothelial cell senescence, revealing a novel link between hyperglycemia and vascular dysfunction. The study may have implications in the prevention of premature vascular aging associated with T2DM.

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Cell cycle re-entry and arrest in G2/M phase induces senescence and fibrosis in Fuchs Endothelial Corneal Dystrophy

Cited by 17 publications

References 41 publications

Heterogeneity of human corneal endothelium implicates lncRNA NEAT1 in Fuchs endothelial corneal dystrophy

Heterogeneity of human corneal endothelium implicates lncRNA NEAT1 in Fuchs endothelial corneal dystrophy

TCF4trinucleotide repeat expansions and UV irradiation increase susceptibility to ferroptosis in Fuchs endothelial corneal dystrophy

Hyperglycemia Promotes Endothelial Cell Senescence through AQR/PLAU Signaling Axis

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