Desmin deficiency is not sufficient to prevent corneal fibrosis
| Autor: | Paola Bargagna-Mohan, Christopher Hampton, Royce Mohan, Ling Lei, Sonali Pal-Ghosh, Yassemi Capetanaki, Gauri Tadvalkar, Alexandra Pietraszkiewicz, Sonny Caplash, Mary Ann Stepp |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Pathology Vimentin Desmin Cornea chemistry.chemical_compound Mice 0302 clinical medicine Corneal Opacity Fibrosis Mice Knockout Microscopy Confocal biology Sensory Systems Eye Burns Female Myofibroblast medicine.medical_specialty Stromal cell Blotting Western macromolecular substances Article 03 medical and health sciences Cellular and Molecular Neuroscience Cytokeratin Microscopy Electron Transmission Burns Chemical medicine Animals Sodium Hydroxide Withanolides Cell Proliferation Wound Healing business.industry medicine.disease eye diseases Actins Ophthalmology 030104 developmental biology chemistry Withaferin A 030221 ophthalmology & optometry biology.protein Keratin 8 sense organs business |
| Zdroj: | Experimental eye research. 180 |
| ISSN: | 1096-0007 |
| Popis: | The type III intermediate filament (IF) proteins vimentin and desmin are sequentially overexpressed in stromal myofibroblasts over the period when fibrosis sets in after corneal injury. Prior findings have revealed vimentin-deficient mice are significantly protected from corneal fibrosis after alkali injury, which has implicated this IF protein as an important regulator of corneal fibrosis. It has remained as yet unproven whether desmin contributes in any significant manner to corneal fibrosis. Here we have employed desmin-deficient (Des KO) mice in the corneal alkali injury model and show that injured Des KO mice develop fibrosis and show similar levels of corneal opacity at 14 days post-injury as wild type (WT) mice and retain this phenotype even at 30d post injury. Des KO corneas from injured mice show upregulation of vimentin and alpha-smooth muscle actin expression to equivalent levels as WT corneas, illuminating that desmin deficiency does not interfere with myofibrobast differentiation. Employing the small molecule withaferin A (WFA), an inhibitor of vimentin, we show that WFA treatment causes the decrease in steady state levels of vimentin and serine 38 phosphorylated vimentin, the latter a biomarker associated with corneal fibrosis, and improved corneal clarity through blockade of myofibroblast differentiation. To investigate further the mechanism of fibrosis in desmin deficiency, we examined keratin 8 expression in the epithelium, and found reduced levels of this cytokeratin in injured Des KO corneas compared to WT corneas. This finding also corroborates the decrease of cell proliferation in injured Des KO corneas compared to that in WT corneas. The fibrotic phenotype of Des KO corneas also features abundant vascularization, further exemplifying the magnitude of corneal pathology. Together, these findings illuminate that desmin does not contribute significantly to corneal fibrosis in this injury model. |
| Databáze: | OpenAIRE |
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