Project description:Hyperglycemia leads to functional decline of various corneal cells, which induces corneal diseases. However, cellular and molecular mechanisms underlying how hyperglycemia affects the corneal epithelium have not been determined. Here, by undertaking single-cell transcriptomics of corneal epithelial cells obtained from healthy and diabetic non-human primates, we identified cell type-specific transcriptional alterations and shared changes across cell types, such as upregulation of FOXO3. Targeted depletion of FOXO3 in human corneal epithelial cells regulated metabolic remodeling by inhibiting glycolysis and oxidative phosphorylation. Furthermore, FOXO3 can not only sense reactive oxygen species (ROS) in corneal epithelial cells and scavenge ROS, but also mediate the proliferation and migration of corneal epithelial cells, demonstrating FOXO3 as a guardian factor in maintaining primate corneal epithelial homeostasis. Our study provides novel insight into the role of FOXO3 in metabolic remodeling and maintenance of ROS homeostasis in corneal epithelium at single-cell level, laying a foundation for decoding the molecular mechanism of the diagnosis and treatment of diabetic eye disease.

2024-12-19 | GSE197745 | GEO

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

Transcriptional Network Analysis Reveals the Role of miR-223-5p During Diabetic Corneal Epithelial Regeneration [miRNA-seq]

Project description:Diabetes mellitus (DM) is a complex metabolic disorder. Long-term hyperglycemia may induce diabetic keratopathy (DK), which is mainly characterized by delayed corneal epithelial regeneration. MicroRNAs (miRNAs) have been reported to play regulatory roles during tissue regeneration. However, the molecular mechanism by which miRNAs influence epithelial regeneration in DK is largely unknown. In this study, we performed miRNA and mRNA sequencing of regenerative corneal epithelium tissue from streptozotocin-induced type 1 diabetic (T1DM) and wild-type mice to screen for differentially expressed miRNAs and mRNAs. Based on regulatory network analysis, miR-223-5p was selected for subsequent experiments and Hpgds was then identified as a direct target gene. MiR-223-5p downregulation significantly promoted diabetic corneal epithelial wound healing and nerve regeneration. However, the beneficial effects of miR-223-5p inhibition were abolished by an Hpgds inhibitor. Furthermore, mechanistic studies demonstrated that miR-223-5p suppression ameliorated inflammation and enhanced cell proliferation signaling in DK. Taken together, our findings revealed that the regulatory role of miR-223-5p in diabetic corneal epithelial and nerve regeneration by mediating inflammatory processes and cell proliferation signaling. And silencing miR-223-5p may contribute to the development of potential therapeutic strategies for DK.

2021-08-23 | GSE180493 | GEO

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