A Short-Term In Vivo Experimental Model for Fuchs Endothelial Corneal Dystrophy

Haydari, M. Nour; Perron, Marie Claude; Laprise, Simon; Roy, Olivier; Cameron, J. Douglas; Proulx, Stéphanie; Brunette, Isabelle

doi:10.1167/iovs.12-9708

Cited by 21 publications

(18 citation statements)

References 37 publications

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“…This could explain previous results showing that an endothelium tissue-engineered using cultured corneal endothelial cells from patients with end-stage FECD cells retains some functionality. 24 Currently, the only treatment for FECD is transplantation of an allogeneic corneal endothelium, using donor tissue. This work opens the door to a new therapeutic concept, where rehabilitation of a diseased FECD endothelium could potentially be achieved through reimplantation of a new corneal endothelium tissue engineered from cultured autologous endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…We also demonstrated that the diseased endothelial cells of clinically decompensated FECD corneas, when cultured and seeded on a devitalized stromal carrier and transplanted into the living animal eye, can recover active pump function and restore corneal transparency for at least 7 days after transplantation. 24 The partial recovery in culture of these end-stage FECD endothelial cells harvested from the central and most diseased part of the cornea has opened the door to a new perspective, which is herein analyzed from an ''oxidation standpoint.' ' The goal of this study was to investigate the effect of cell culture on the oxidative imbalance documented in FECD corneal endothelial cells.…”

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confidence: 99%

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Restoration of Mitochondrial Integrity, Telomere Length, and Sensitivity to Oxidation by In Vitro Culture of Fuchs' Endothelial Corneal Dystrophy Cells

Gendron

Thériault

Proulx

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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Citation: Gendron SP, Thériault M, Proulx S, Brunette I, Rochette PJ. Restoration of mitochondrial integrity, telomere length, and sensitivity to oxidation by in vitro culture of Fuchs' endothelial corneal dystrophy cells. Invest Ophthalmol Vis Sci. 2016;57:5926-5934. DOI:10.1167/ iovs.16-20551 PURPOSE. Fuchs' endothelial corneal dystrophy (FECD), a degenerative disease of the corneal endothelium that leads to vision loss, is a leading cause of corneal transplantation. The cause of this disease is still unknown, but the implication of oxidative stress is strongly suggested. In this study, we analyzed the impact of FECD on mitochondrial DNA (mtDNA) integrity and telomere length, both of which are affected by the oxidative status of the cell. METHODS.We compared the levels of total mtDNA, mtDNA common deletion (4977 bp), and relative telomere length in the corneal endothelial cells of fresh Descemet's membraneendothelium explants and cultured cells from healthy and late stage FECD subjects. Oxidantantioxidant gene expression and sensitivity to ultraviolet A (UVA)-and H 2 O 2 -induced cell death were assessed in cultured cells. RESULTS.Our results revealed increased mtDNA levels and telomere shortening in FECD explants. We also found that cell culture restores a normal phenotype in terms of mtDNA levels, telomere length, oxidant-antioxidant gene expression balance, and sensitivity to oxidative stress-induced cell death in the FECD cells compared with the healthy cells.CONCLUSIONS. Taken together, these results bring new evidence of the implication of oxidative stress in FECD. They also show that FECD does not evenly affect the integrity of corneal endothelial cells and that cell culture can rehabilitate the molecular phenotypes related to oxidative stress by selecting the more functional FECD cells.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Restoration of Mitochondrial Integrity, Telomere Length, and Sensitivity to Oxidation by In Vitro Culture of Fuchs' Endothelial Corneal Dystrophy Cells

Gendron

Thériault

Proulx

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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“…The barrier function depends on the ability of endothelial cells to fully cover the stromal surface and to maintain cell to cell tight junctions, and both appear to be intact until end stage disease. A study suggests that FECD endothelial cells are capable of migration and division to fully populate a stromal surface despite a reduced ability to control stromal water content (Haydari et al, 2012). In this study, endothelial cells from human FECD patients were grown on devitalized stroma in vitro.…”

Section: Hernandezmentioning

confidence: 98%

“…In this study, endothelial cells from human FECD patients were grown on devitalized stroma in vitro. It was demonstrated that the corneal stroma fully covered by FECD endothelial cells had a thickness of 770 mm compared to stroma covered by normal endothelium (520 mm), and both were thinner than stromal carrier only (1190 mm) (Haydari et al, 2012). Overall integrity of the cellecell tight junctions was found even at low human or bovine endothelial cell density in an in vitro endothelial cell culture model, suggesting that the endothelium may employ compensatory mechanisms to maintain barrier integrity at low density (Singh et al, 2013).…”

Section: Hernandezmentioning

confidence: 99%

The pathophysiology of Fuchs' endothelial dystrophy – A review of molecular and cellular insights

Zhang

Patel

2015

Experimental Eye Research

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“…18 Most studies, including our own unpublished data, show that FECD CEnCs can be passaged for only one to two passages, unless transduced with Simian virus 40 or E6/E7 oncogenes, because of low proliferative potential and rapid senescence. 19 To date, there is a scarcity of evidence regarding how to generate uniform and functional corneal endothelium from SCs, and corneal tissue remains the only source of normal or FECD HCEnCs.…”

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confidence: 99%

Existence of Neural Crest–Derived Progenitor Cells in Normal and Fuchs Endothelial Dystrophy Corneal Endothelium

Katikireddy

Schmedt

Price

et al. 2016

The American Journal of Pathology

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Human corneal endothelial cells are derived from neural crest and because of postmitotic arrest lack competence to repair cell loss from trauma, aging, and degenerative disorders such as Fuchs endothelial corneal dystrophy (FECD). Herein, we identified a rapidly proliferating subpopulation of cells from the corneal endothelium of adult normal and FECD donors that exhibited features of neural crestederived progenitor (NCDP) cells by showing absence of senescence with passaging, propensity to form spheres, and increased colony forming efficacy compared with the primary cells. The collective expression of stem cellerelated genes SOX2, OCT4, LGR5, TP63 (p63), as well as neural crest marker genes PSIP1 (p75 NTR ), PAX3, SOX9, AP2B1 (AP-2b), and NES, generated a phenotypic footprint of endothelial NCDPs. NCDPs displayed multipotency by differentiating into microtubule-associated protein 2, beIII tubulin, and glial fibrillary acidic protein positive neurons and into p75 NTR -positive human corneal endothelial cells that exhibited transendothelial resistance of functional endothelium. In conclusion, we found that mitotically incompetent ocular tissue cells contain adult NCDPs that exhibit a profile of transcription factors regulating multipotency and neural crest progenitor characteristics. Identification of normal NCDPs in FECD-affected endothelium holds promise for potential autologous cell therapies. Human corneal endothelial cells (HCEnCs) form a monolayer of hexagonal cells on the posterior surface of the cornea and are essential for maintaining appropriate corneal hydration necessary for clear vision. HCEnCs sustain corneal clarity by serving as a barrier between the aqueous humor and the corneal stroma and by active ionic transport that regulates the swelling pressure of the cornea. HCEnCs are arrested in the postmitotic state and have limited proliferative capacity both in vivo and in vitro. The postmitotic arrest has been attributed to contact inhibition, transforming growth factor-b in aqueous fluid, and lack of paracrine stimulation by growth factors of cell-cycle promotion from the G 1 to the S phase.1 In a normal human life span, the endothelial cell density gradually declines.2 Therefore, age-and disease-related HCEnC loss is a major cause of corneal blindness requiring corneal transplantation to restore vision. Specifically, Fuchs endothelial corneal dystrophy (FECD) is the most common cause of endogenous endothelial cell dysfunction; it is associated with progressive cell apoptosis and concurrent extracellular matrix deposition in the form of guttae and is primarily treated by allogeneic endothelial keratoplasty.3,4 The pathogenic mechanism behind FECD is purportedly related to the interplay between genetic mutations and environmental factors. 5Several reports have proposed the existence of endothelial progenitor cells situated in the peripheral cornea, but evidence so far has not been conclusive. 6e8 The description of purported stem cells (SCs) has been based on ex vivo

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A Short-Term In Vivo Experimental Model for Fuchs Endothelial Corneal Dystrophy

Abstract: Restoration of transparency and corneal thickness demonstrated that the TE-FECD grafts were functional in vivo. This novel FECD seven-day living model suggests a potential role for tissue engineering leading to FECD cell rehabilitation.

Cited by 21 publications

References 37 publications

Restoration of Mitochondrial Integrity, Telomere Length, and Sensitivity to Oxidation by In Vitro Culture of Fuchs' Endothelial Corneal Dystrophy Cells

Restoration of Mitochondrial Integrity, Telomere Length, and Sensitivity to Oxidation by In Vitro Culture of Fuchs' Endothelial Corneal Dystrophy Cells

The pathophysiology of Fuchs' endothelial dystrophy – A review of molecular and cellular insights

Existence of Neural Crest–Derived Progenitor Cells in Normal and Fuchs Endothelial Dystrophy Corneal Endothelium

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