Abstract
Chronic inflammation is associated with a variety of pathological conditions in epithelial tissues, including cancer, metaplasia and aberrant wound healing. In relation to this, a significant body of evidence suggests that aberration of epithelial stem and progenitor cell function is a contributing factor in inflammation-related disease, although the underlying cellular and molecular mechanisms remain to be fully elucidated. In this study, we have delineated the effect of chronic inflammation on epithelial stem/progenitor cells using the corneal epithelium as a model tissue. Using a combination of mouse genetics, pharmacological approaches and in vitro assays, we demonstrate that chronic inflammation elicits aberrant mechanotransduction in the regenerating corneal epithelium. As a consequence, a YAP-TAZ/β-catenin cascade is triggered, resulting in the induction of epidermal differentiation on the ocular surface. Collectively, the results of this study demonstrate that chronic inflammation and mechanotransduction are linked and act to elicit pathological responses in regenerating epithelia.
MeSH terms
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Acyltransferases
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Administration, Ophthalmic
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Animals
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Anti-Inflammatory Agents / administration & dosage
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Cell Cycle Proteins
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Cell Differentiation* / drug effects
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Chronic Disease
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Corneal Injuries / genetics
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Corneal Injuries / metabolism*
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Corneal Injuries / pathology
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Disease Models, Animal
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism*
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Epithelial Cells / pathology
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Epithelium, Corneal / drug effects
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Epithelium, Corneal / injuries
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Epithelium, Corneal / metabolism*
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Epithelium, Corneal / pathology
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Extracellular Matrix / metabolism
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HEK293 Cells
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Humans
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Inflammation Mediators / metabolism
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Keratitis / genetics
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Keratitis / metabolism*
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Keratitis / pathology
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Keratitis / prevention & control
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Mechanotransduction, Cellular* / drug effects
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Mice, Inbred C57BL
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Mice, Knockout
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Receptor, Notch1 / deficiency
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Receptor, Notch1 / genetics
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Regeneration* / drug effects
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Stem Cells / drug effects
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Stem Cells / metabolism*
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Stem Cells / pathology
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Swine
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Time Factors
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transfection
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Wnt Signaling Pathway
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YAP-Signaling Proteins
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beta Catenin / genetics
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beta Catenin / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Anti-Inflammatory Agents
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CTNNB1 protein, mouse
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Cell Cycle Proteins
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Inflammation Mediators
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Notch1 protein, mouse
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Phosphoproteins
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Receptor, Notch1
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Transcription Factors
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YAP-Signaling Proteins
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Yap1 protein, mouse
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beta Catenin
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Acyltransferases
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tafazzin protein, mouse