ArticleInvestigative ophthalmology & visual science2018
Integrated Stress Response and Decreased ECM in Cultured Stromal Cells From Keratoconus Corneas.
Article in Investigative ophthalmology & visual science, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
29 citing papers in PubMed, 1 synthesis or guideline pooled it, 43 citations in OpenAlex.
- The candidate proteins associated with keratoconus: A meta-analysis and bioinformatic analysis.PloS one · 2024Pooled it
- Oxidative Stress in Keratoconus Is Evident in Tear Fluid and Stromal Cells and Alleviated in Cell Culture by Sulforaphane.Investigative ophthalmology & visual science · 2026Article
- Oxidative-stress related increase in keratoconus tear MDA and GPX3 while NRF2-antioxidant functions decrease in stromal cells.bioRxiv : the preprint server for biology · 2025Article
- Molecular Subtype Identification and Potential Drug Prediction Based on Anoikis-Related Genes Expression in Keratoconus.Investigative ophthalmology & visual science · 2025Article
- Deciphering mitochondrial dysfunction in keratoconus: Insights into ACSL4 from machine learning-based bulk and single-cell transcriptome analyses and experimental validation.Computational and structural biotechnology journal · 2025Article
- Matrix glycosaminoglycans and proteoglycans in human cornea organoids and similarities with fetal corneal stages.The ocular surface · 2025Article
- Investigation of Potential Crucial Genes and Key Pathways in Keratoconus: An Analysis of Gene Expression Omnibus Data.Biochemical genetics · 2023Article
- Animal Models for the Study of Keratoconus.Cells · 2023Review
- Corneal stromal regeneration-keratoconus cell therapy: a review.Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie · 2023Review
- Molecular cues for immune cells from small leucine-rich repeat proteoglycans in their extracellular matrix-associated and free forms.Matrix biology : journal of the International Society for Matrix Biology · 2023Review
- The Impaired Wound Healing Process Is a Major Factor in Remodeling of the Corneal Epithelium in Adult and Adolescent Patients With Keratoconus.Investigative ophthalmology & visual science · 2023Article
- Role of Oxidative Stress in Ocular Diseases: A Balancing Act.Metabolites · 2023Review
- Single cell RNA-seq of human cornea organoids identifies cell fates of a developing immature cornea.PNAS nexus · 2022Article
- Altered Regulation of mRNA and miRNA Expression in Epithelial and Stromal Tissue of Keratoconus Corneas.Investigative ophthalmology & visual science · 2022Article
- Integrated Stress Response Regulation of Corneal Epithelial Cell Motility and Cytokine Production.Investigative ophthalmology & visual science · 2022Article
- Pathogenesis of keratoconus: NRF2-antioxidant, extracellular matrix and cellular dysfunctions.Experimental eye research · 2022Review
- Ehlers-Danlos syndromes and their manifestations in the visual system.Frontiers in medicine · 2022Review
- Induction of the integrated stress response in the rat cornea.Experimental eye research · 2021Article
- Molecular characteristics and spatial distribution of adult human corneal cell subtypes.Scientific reports · 2021Article
- Targeting the integrated stress response in ophthalmology.Current eye research · 2021Review
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
Abstract
Purpose: Keratoconus (KC) is a multifactorial disease where progressive thinning and weakening of the cornea leads to loss of visual acuity. Although the underlying etiology is poorly understood, a major endpoint is a dysfunctional stromal connective tissue matrix. Using multiple individual KC corneas, we determined that matrix production by keratocytes is severely impeded due to an altered stress response program. Methods: KC and donor (DN) stromal keratocytes were cultured in low glucose serum-free medium containing insulin, selenium and transferrin. Fibronectin, collagens and proteins related to their chaperone, processing and export, matrix metalloproteinase, and stress response related proteins were investigated by immunoblotting, immunocytochemistry, hydroxyproline quantification, and gelatin zymography. Multiplexed mass spectrometry was used for global proteomic profiling of 5 individual DN and KC cell culture. Transcription of selected proteins was assayed by qPCR. Results: DN and KC cells showed comparable survival and growth. However, immunoblotting of selected ECM proteins and global proteomics showed decreased fibronectin, collagens, PCOLCE, ADAMTS2, BMP1, HSP47, other structural and cytoskeletal proteins in KC. Phosphorylated (p) eIF2α, a translation regulator and its target, ATF4 were increased in KC cultured cells and corneal sections. Conclusions: The profound decrease in structural proteins in cultured KC cells and increase in the p-eIF2α, and ATF4, suggest a stress related blockade in structural proteins not immediately needed for cell survival. Therefore, this cell culture system reveals an intrinsic aggravated stress response with consequent decrease in ECM proteins as potential pathogenic underpinnings in KC.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.