The Role of Apoptosis in the Pathogenesis of Fuchs Endothelial Dystrophy of the Cornea

Abstract

To investigate the potential role of apoptosis in the pathogenesis of Fuchs endothelial dystrophy of the cornea.Methods: Twenty-one corneal buttons from patients with Fuchs dystrophy and 15 control corneas were studied. Apoptosis was assessed by the in situ end-labeling of double-stranded DNA breaks, and by immunohistochemical characterization of cellular markers associated with apoptosis (Fas, FasL, Bcl-2, and Bax). Expression of Bcl-2 and Bax mRNA in the corneal stroma and endothelium was separately analyzed by a semiquantitative reverse transcriptase polymerase chain reaction. Furthermore, cultivated keratocytes generated from diseased corneal buttons and donor rims were exposed to camptothecin, an apoptotic inducer, for 6 and 24 hours. They were then examined for protein and messenger RNA (mRNA) expression of apoptotic regulatory molecules.Results: DNA fragmentation was seen in the epithelium, stroma, and endothelium in 6 of 7 corneas with Fuchs dystrophy. A statistically significant difference was identified in the expression of Bax and its mRNA in the stroma, but not in the endothelium of Fuchs dystrophy corneas. Following exposure to camptothecin, keratocytes from patients with Fuchs dystrophy responded with an increased level of Bax and a low level of Bcl-2. This trend was distinctively different from the response of normal keratocytes. Conclusions:The evidence in this study points to a disease-related disturbance in the regulation of apoptosis in Fuchs dystrophy. Our findings suggest that excessive apoptosis may be an important mechanism in the pathogenesis of Fuchs dystrophy.

Extracellular Vesicles Derived From Human Corneal Endothelial Cells Inhibit Proliferation of Human Corneal Endothelial Cells

“…This means that p53 plays a critical role in complex mechanisms regulating oxidative-stress-induced apoptosis in FECD [34]. Studies have also reported that excessive apoptosis may be an important mechanism in the pathogenesis of Fuchs' dystrophy [35]. The cargo analysis in our study using NGS showed that hsa-miR-196b-5p is involved in p53 pathway.…”

Extracellular Vesicles Derived From Human Corneal Endothelial Cells Inhibit Proliferation of Human Corneal Endothelial Cells

“…This means that p53 plays a critical role in complex mechanisms regulating oxidative-stress-induced apoptosis in FECD [34]. Studies have also reported that excessive apoptosis may be an important mechanism in the pathogenesis of Fuchs' dystrophy [35]. The cargo analysis in our study using NGS showed that hsa-miR-196b-5p is involved in p53 pathway.…”

Extracellular Vesicles Derived From Human Corneal Endothelial Cells Inhibit Proliferation of Human Corneal Endothelial Cells

“…This means that p53 plays a critical role in complex mechanisms regulating oxidative-stress-induced apoptosis in FECD (46). Studies have also reported that excessive apoptosis may be an important mechanism in the pathogenesis of FECD (47). The cargo analysis in our study using NGS showed that hsa-miR-196b-5p is involved in p53 pathway.…”

A cellular model for the investigation of Fuchs' Endothelial Corneal Dystrophy

“…Chronic intracellular accumulation of collagen VIII is likely to be injurious to the fragile corneal endothelium and the unfolded protein stress response and increased endothelial cell apoptosis have previously been noted in patients with FECD (Borderie et al, 2000; Engler et al, 2010; Joyce, 2003; Li et al, 2001). Collagen VIII turnover in the cornea is very limited, so retained intracellular collagen VIII remaining after endothelial apoptosis would likely result in collagen VIII accumulation within Descemet’s membrane as noted histologically in FECD (Kabsova et al, 2007)…”

Extracellular Vesicles Derived From Human Corneal Endothelial Cells Inhibit Proliferation of Human Corneal Endothelial Cells

“…This means that p53 plays a critical role in complex mechanisms regulating oxidative-stress-induced apoptosis in FECD [34]. Studies have also reported that excessive apoptosis may be an important mechanism in the pathogenesis of Fuchs' dystrophy [35]. The cargo analysis in our study using NGS showed that hsa-miR-196b-5p is involved in p53 pathway.…”

Extracellular Vesicles Derived From Human Corneal Endothelial Cells Inhibit Proliferation of Human Corneal Endothelial Cells

“…This means that p53 plays a critical role in complex mechanisms regulating oxidative-stress-induced apoptosis in FECD (46). Studies have also reported that excessive apoptosis may be an important mechanism in the pathogenesis of FECD (47). The cargo analysis in our study using NGS showed that hsa-miR-196b-5p is involved in p53 pathway.…”

A cellular model for the investigation of Fuchs' Endothelial Corneal Dystrophy

“…Chronic intracellular accumulation of collagen VIII is likely to be injurious to the fragile corneal endothelium and the unfolded protein stress response and increased endothelial cell apoptosis have previously been noted in patients with FECD (Borderie et al, 2000; Engler et al, 2010; Joyce, 2003; Li et al, 2001). Collagen VIII turnover in the cornea is very limited, so retained intracellular collagen VIII remaining after endothelial apoptosis would likely result in collagen VIII accumulation within Descemet’s membrane as noted histologically in FECD (Kabsova et al, 2007)…”

Extracellular Vesicles Derived From Human Corneal Endothelial Cells Inhibit Proliferation of Human Corneal Endothelial Cells

“…This means that p53 plays a critical role in complex mechanisms regulating oxidative-stress-induced apoptosis in FECD [34]. Studies have also reported that excessive apoptosis may be an important mechanism in the pathogenesis of Fuchs' dystrophy [35]. The cargo analysis in our study using NGS showed that hsa-miR-196b-5p is involved in p53 pathway.…”

Extracellular Vesicles Derived From Human Corneal Endothelial Cells Inhibit Proliferation of Human Corneal Endothelial Cells

“…This means that p53 plays a critical role in complex mechanisms regulating oxidative-stress-induced apoptosis in FECD (46). Studies have also reported that excessive apoptosis may be an important mechanism in the pathogenesis of FECD (47). The cargo analysis in our study using NGS showed that hsa-miR-196b-5p is involved in p53 pathway.…”

A cellular model for the investigation of Fuchs' Endothelial Corneal Dystrophy

“…Chronic intracellular accumulation of collagen VIII is likely to be injurious to the fragile corneal endothelium and the unfolded protein stress response and increased endothelial cell apoptosis have previously been noted in patients with FECD (Borderie et al, 2000; Engler et al, 2010; Joyce, 2003; Li et al, 2001). Collagen VIII turnover in the cornea is very limited, so retained intracellular collagen VIII remaining after endothelial apoptosis would likely result in collagen VIII accumulation within Descemet’s membrane as noted histologically in FECD (Kabsova et al, 2007)…”