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RNA sequencing analysis for comparing gene expression of the corneal endothelium of Slc4a11-/- vs Slc4a11+/+ mice

ABSTRACT: Purpose: Slc4a11 KO mice show significant edema and altered corneal endothelial morphology at an early age with concomitant increased mitochondrial ROS and oxidative damage relative to wild type. Here we used RNA-Seq with the goal of finding pathways related to corneal endothelial metabolic, pump and barrier function alterations. Methods: Corneal endothelium-Descemet’s membrane (CEDM) samples were from WT and Slc4a11 KO mice at 12 weeks of age. RNA sequencing data was subjected to Ingenuity Pathway Analysis and QPCR for validation. Results: The RNA sequencing IPA analysis predicted activation, inhibition or differential regulation of several pathways. We validated downregulation of Glycolytic enzymes, Mitochondrial complex components and Ion transporters. We observed upregulation of genes of cholesterol biosynthesis, GSH metabolism and tight and adherens junctions. Conclusions: Slc4a11 KO induces a coordinated decrease in glycolysis, glutaminolysis, oxygen consumption, lactate transporters and Na-K-ATPase. These changes together with the altered barrier function cause an accumulation of stromal lactate in Slc4a11 KO mice leading to chronic corneal edema.

ORGANISM(S): Mus musculus

PROVIDER: GSE174586 | GEO | 2022/02/02

REPOSITORIES: GEO

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Pluripotent stem cell-derived corneal endothelial cells as an alternative to donor corneal endothelium in keratoplasty

Project description:Here, we evaluate the efficacy of cryopreserved human embryonic stem cell (hESC)-derived corneal endothelial cells (CECs) to form a functional monolayer of corneal endothelium (CE) in mammals (rabbits) and non-human primates (monkeys). We injected cryopreserved hESC-derived CECs in rabbits and monkeys either immediately after removing 8 mm of the central portion of the CE or a few days later when corneal edema developed. All clinical models developed deturgesced and clear corneas 2-3 weeks following the CEC injection and remained comparable to the CE of the untreated eye. Confocal scanning microscopy confirmed an intact structure of hexagonal/polygonal cells and immunohistochemical analysis illustrated a monolayer expressing barrier and pump function proteins in the regenerated CE. The necropsy examination confirmed no remarkable change in multiple tissues examined for teratoma formation. In conclusion, our data demonstrate the efficacy of cryopreserved hESC-derived CECs to form a functional CE on the denuded Descemet’s membrane.

2021-09-29 | GSE173692 | GEO

High throughput gene expression analysis identifies reliable expression markers of human corneal endothelial cells.

Project description:Considerable interest has been generated for the development through cell-tissue engineering of suitable corneal endothelial graft alternatives, which can potentially alleviate the shortage of corneal transplant material. The advent of less invasive suture-less key-hole surgery options such as Descemet’s Stripping Endothelial Keratoplasty (DSEK) and Descemet’s Membrane Endothelial Keratoplasty (DMEK), which involve transplantation of solely the endothelial layer instead of full thickness cornea, provide further impetus for the development of alternative endothelial grafts for clinical applications. A major challenge for this endeavor is the lack of specific markers for this cell type. To identify genes that reliably mark corneal endothelial cells (CECs) in vivo and in vitro, we performed RNA-sequencing on freshly isolated human CECs (from both young and old donors), CEC cultures, and corneal stroma. Gene expression of these corneal cell types were also compared to that of other human tissue types. Based on high throughput comparative gene expression analysis, we identified a panel of markers that are: i) highly expressed in CECs from both young donors and old donors; ii) expressed in CECs in vivo and in vitro; and iii) not expressed in corneal stroma keratocytes and the activated corneal stroma fibroblasts. These were SLC4A11, COL8A2 and CYYR1. The use of this panel of genes in combination reliably ascertains the identity of the CEC cell type.

2013-05-23 | GSE44064 | GEO

Transcriptome of Immortalized Mouse Corneal Endothelial Cells with SLC4A11 deficiency

Project description:Mutations in the solute-linked carrier family 4 member 11 (SLC4A11) gene are associated with several corneal endothelial dystrophies, in all of which visually significant cornea edema may require corneal transplantation. To elucidate the pathogenesis of SLC4A11 associated corneal endothelial dystrophies, we analyzed the transcriptome of immortalized mouse corneal endothelial cells (Slc4a11-/- MCEnC) and Slc4a11+/+ MCEnC as controls.

2020-08-13 | GSE142635 | GEO

Transcriptome of Human Primary Corneal Endothelial Cells with SLC4A11 deficiency

Project description:Mutations in the solute-linked carrier family 4 member 11 (SLC4A11) gene are associated with several corneal endothelial dystrophies, in all of which visually significant cornea edema may require corneal transplantation. To elucidate the pathogenesis of SLC4A11 associated corneal endothelial dystrophies, we analyzed the transcriptome of SLC4A11 knock-down primary human corneal endothelium (SLC4A11 KD pHCEnC) and scrambled RNA treated pHCEnC as controls.

2020-08-13 | GSE142636 | GEO

Proteomic analysis of Descemet's membrane with corneal endothelial cells derived from patients with Fuchs endothelial corneal dystrophy and healthy control subjects

Project description:This dataset contains proteomic profiles of Descemet's membrane (DM) with corneal endothelial cells derived from patients with Fuchs endothelial corneal dystrophy (FECD) and non-FECD subjects by shotgun proteomics. FECD is the most common inherited corneal disease. Fibrillar focal excrescences, called guttae, and corneal edema due to corneal endothelial cell death result in progressive vision loss. Our dataset indicated that 32 distinctive molecules were expressed only in the FECD-DM but not in the DM of the control subject, possibly having important roles in the pathophysiology of FECD.

2023-01-17 | MSV000091078 | MassIVE

A Genome-Wide Association Study of Fuchs' Endothelial Corneal Dystrophy (FECD)

Project description:<p>Fuchs' Endothelial Corneal Dystrophy (FECD) is a common disease that results in loss of vision associated with progressive corneal edema and loss of corneal transparency. In the initial stages of the disease, excrescences on Descemet's membrane with the appearance of an abnormal posterior collagenous layer, result in the clinical and pathologic appearance of guttae. Corneal edema ensues as endothelial function is compromised that may result in stromal edema, epithelial edema, and painful bullous keratopathy. Penetrating or endothelial keratoplasty is the only definitive treatment, with palliative care the only option prior to surgery. The pathophysiology underlying FECD, particularly in the common cases that affect older individuals, remains unknown, with a genetic predisposition being reported as the single best predictor of disease.</p> <p>Three independent groups funded by the National Eye Institute (NEI), with well-established programs in the genetics of FECD, conducted a genome-wide association study of FECD. The collaboration comprised investigators from Case Western University (CWRU), Duke University (DUEC), and Johns Hopkins University (JHU). CWRU and DUEC contributed samples that were genotyped at CIDR for the GWAS. Johns Hopkins University (JHU) provided samples for the replication phase of the study, where their data are not listed in dbGaP. Cohorts of FECD cases and controls were assembled. Synchronization of clinical and coded data was performed to unify the information across centers. The family history, clinical, demographic information, and genome-wide genotype data for samples from CWRU and DUEC were deposited in dbGaP.</p>

| phs000421 | dbGaP

Proteomics of Fuchs Endothelial Corneal Dystrophy support that the extracellular matrix of Descemet¹s membrane is Disordered

Project description:Fuchs’ endothelial corneal dystrophy is major corneal disorder in the western world affecting the innermost part of the cornea, which leads to visual impairment. The morphological changes observed in Fuchs’ endothelial corneal dystrophy is well described, however, much less in known of the pathology at the molecular level. As the morphological changes observed in the cornea is profound in the extracellular matrix we sought to determine in protein profiles and changes herein in the Descement’s membrane and endothelium layer of Fuchs’ endothelial conrneal dystrophy patients when compared to healthy control tissue. Using the extracted ion chromatogram label-free MS based quantification method we quantified approximately the 50 most abundant proteins of the Descemet’s membrane and endothelial layer in in patient and control tissue. In addition, using the isobaric tag for relative and absolute quantification MS method resulted in a total of 22 regulated proteins of which the majority were extracellular proteins known to be involved in proper assembly and modulation of the basement membrane in other tissues. Many of the regulated proteins were furthermore among the most abundant proteins quantified. The two MS methods performed here suggest altered arrangement of the extracellular matrix in Fuchs’ endothelial corneal dystrophy and provide new candidate proteins that may be involved in molecular mechanism of this disease.

2014-05-27 | PXD000746 | Pride

Spatiotemporal determination of metabolite activities in the corneal epithelium on a chip

Project description:The corneal epithelial barrier maintains the metabolic activities of the ocular surface by regulating membrane transporters and metabolic enzymes responsible for the homeostasis of the eye as well as the pharmacokinetic behavior of drugs. Despite its importance, no established biomimetic in vitro methods are available to perform the spatiotemporal investigation of metabolism and determine the transportation of endogenous and exogenous molecules across the corneal epithelium barrier. This study introduces multiple corneal epitheliums on a chip namely, Corneal Epithelium on a Chip (CEpOC), which enables the spatiotemporal collection as well as analysis of micro-scaled extracellular metabolites from both the apical and basolateral sides of the barriers. Longitudinal samples collected during 48 h period were analyzed using untargeted liquid chromatography-mass spectrometry metabolomics method, and 104 metabolites were annotated. We observed the spatiotemporal secretion of biologically relevant metabolites (i.e., antioxidant, glutathione and uric acid) as well as the depletion of essential nutrients such as amino acids and vitamins mimicking the in vivo molecules trafficking across the human corneal epithelium. Through the shifts of extracellular metabolites and quantitative analysis of mRNA associated with transporters, we were able to investigate the secretion and transportation activities across the polarized barrier in a correlation with the expression of corneal transporters. Thus, CEpOC can provide a non-invasive, simple, yet effectively informative method to determine pharmacokinetics and pharmacodynamics as well as to discover novel biomarkers for drug toxicological and safety tests as advanced experimental model of the human corneal epithelium.

2021-07-13 | MTBLS2274 | MetaboLights

A Genome-Wide Association Study of Fuchs' Endothelial Corneal Dystrophy (FECD)

| phs000421.v1.p1 | EGA

The Mitochondrial Protein Mitofusin 2 Stabilizes Adherens Junctions and Suppresses Endothelial Inflammation via Modualtion of β-catenin Signaling

Project description:Endothelial barrier integrity is ensured by the stability of the adherens junction (AJ) complexes comprised of VE-cadherin as well as accessory proteins such as β-catenin and p120-catenin. Disruption of the endothelial barrier due to disassembly of AJs results in tissue edema and the influx of inflammatory cells. Using three-dimensional structured illumination microscopy (3D- SIM), we found that the mitochondrial protein Mitofusin-2 (Mfn2) co-localizes at the plasma membrane with VE-cadherin and β-catenin in endothelial cells during homeostasis. Upon inflammatory stimulation, Mfn2 is sulfenylated, the Mfn2/β-catenin complex disassociates from the AJs and translocates into the nucleus where Mfn2 negatively regulates the transcriptional activity of β-catenin. Endothelial-specific deletion of Mfn2 resulted in inflammatory injury, indicating an anti-inflammatory role of Mfn2 in vivo. Our results suggest that Mfn2 acts in a non- canonical manner to suppress the inflammatory response by stabilizing cell-cell adherens junctions and by binding to the transcriptional activator β-catenin.

2023-04-18 | GSE148987 | GEO

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