Excess Transforming Growth Factor-α Changed the Cell Properties of Corneal Epithelium and Stroma

Abstract

This study is to investigate the corneal anomaly caused by excess transforming growth factor-α (TGF-α) during mouse development. METHODS. Bitransgenic Kera RT /TGF-α mice, generated via cross-mating tetO-TGF-α and Kera RT mice, were induced to overexpress TGF-α by doxycycline commencing at embryonic day 0 or postnatal day 0 to different developmental stages. Bitransgenic mice with doxycycline induction were defined as TGF-α ECK mice (TGF-α excess expression by corneal keratocytes). Mouse eyes were examined by hematoxylin and eosin staining, immunofluorescent staining and transmission electron microscopy. Protein and RNA from mouse cornea were subjected to western blotting and real-time quantitative polymerase chain reaction. RESULTS. In TGF-α ECK mice, TGF-α overexpression resulted in corneal opacity. Excess TGFα initially caused corneal epithelial hyperplasia and subsequent epithelium degeneration as the mouse developed, which was accompanied by gradually diminished K12 expression from the periphery of corneal epithelium and increased K13 expression toward the corneal center. Interestingly, K14 was detected in all layers of corneal epithelium of TGF-α ECK mice, whereas it was limited at basal layer of controls. Transmission electron microscopy showed desmosome loss between corneal epithelial cells of TGF-α ECK mice. In TGF-α ECK mice, keratocan expression was abolished; α-SMA expression was increased while expression of Col1a1, Col1a2, and Col5a1 was diminished. Cell proliferation increased in the corneal epithelium and stroma, but not in the endothelium of TGF-α ECK mice. CONCLUSIONS. Excess TGF-α had detrimental effects on corneal morphogenesis during mouse development in that it changed the cell fate of corneal epithelial cells to assume conjunctival phenotypic expression of K13, and keratocytes to myofibroblast phenotype.

The role of the PI3K/AKT signalling pathway in the corneal epithelium: recent updates

“…Eukaryotic translation initiation factor 5A (eIF5A), a nucleocytoplasmic shuttle protein, is the substrate of the EGF-induced EGFR/Src/PI3K/AKT/mTOR/p70S6K/rpS6 signalling pathway and induces the expression of MMP-9 in the extracellular matrix and proliferating cell nuclear antigen in vitro [ 25 , 26 ]. Furthermore, in mouse CECs in vivo, excess transforming growth factor-α expression promotes the expression of proliferating cell nuclear antigen likely by transactivating the EGFR/PI3K/AKT cascade.…”

“…MMP-9 mediates the ectodomain shedding of EGF and/or HB-EGF, further activating EGFR/Src/PI3K/AKT signalling by increasing local proteolysis. Proliferating cell nuclear antigen facilitates proliferation by inducing DNA duplication through an increase the activity of DNA polymerase and eIF5A [ 25 , 26 ].…”

Elucidating the mechanism of corneal epithelial cell repair: unraveling the impact of growth factors

“…Notably, TGF-α knockout mice exhibit significant ocular abnormalities, characterized by corneal epithelial thinning, inflammation, and edema ( 23 , 24 ). TGF-α also promotes the proliferation of corneal epithelial and stromal cells ( 25 ). Additionally, TGF-α stimulates EGFR, facilitating the internalization and recycling of ligand-receptor complexes ( 22 ).…”

Leptinin Yara İyileşmesi Üzerine In Vitro Etkisinin Büyüme Faktörleri Üzerinden İncelenmesi

“…TGF-α'nın embriyonik gelişim sırıasında ve erişkin çağda homeostazın korunmasında hücrelerin çoğalması, farklılaşması ve göçü gibi çoklu hücresel davranışlarla ilişkili olduğu bilinmektedir. Epitel hücreleri ile TGF-α gibi büyüme faktörlerinin aracılık ettiği stromal mezenkimal hücreler arasındaki çift yönlü etkileşim, doku onarımı sırasında morfogenezde önemli rol oynamaktadır (46). Bununla birlikte, TGF-a'nın yara iyileşmesi sırasında fibroblast hücrelerinde ifade edilip edilmediği belirsizliğini korumaktadır.…”

“…KGF, yara alanındaki dermal dokudan güçlü bir şekilde salgılanarak keratinosit hücrelerindeki reseptörüne bağlanır ve yara bölgesine hücre göçünü teşvik eder (14). Transforme edici büyüme faktörü-alfa (TGF-α); epidermal büyüme faktörü (EGF) ailesi üyelerinden erişkinde homeostazın korunması sırasında epitel gelişimini kontrol eden bir proteindir (15). Transforme edici büyüme faktörü-beta 1 (TGF-β1)'in ise yara iyileşmesi, hücre çoğalması, hücre farklılaşması ve apopitoz süreçlerinin düzenleyicisi olduğu bilinmekte ve hemen hemen her hücre tipinden salgılanmaktadır (16).…”