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Q. Zhou, L. Yang, M. Qu, Y. Wang, H. Zhang, Y. Wang; Regulating Effects of Senescent Fibroblasts on Alkali-Induced Corneal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2035.
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This study explored corneal fibroblasts senescence during alkali-induced corneal neovascularization (CNV) and related mechanisms in vitro and in vivo.
Mouse model of corneal neovascularization was produced by alkali burn to the corneas. Corneal sections and isolated stromal cells were stained with senescence-associated β-galactosidase (SA-β-gal), cellular senescence-associated markers (P16, P21) and Vimentin, NG2, CD31 to identify the origin and characteristics of senescent cells. Normal corneal fibroblasts were incubated with hydrogen peroxide to induce premature senescence in vitro. Gene microarray, real time PCR, western blot, gelatin zymography and ELISA were used to examine the changes of gene expression profiles, synthesis and secretion of VEGF and matrix metalloproteases (MMPs) after stress treatment. The regulating effects of senescent corneal fibroblasts on CNV were examined in the absence or presence of MMP inhibitors in vitro and in vivo.
SA-β-gal+ senescent cells accumulated in corneal stromal layer from 7 days to 27 days after alkali burn, which coincided with the development of CNV. In vitro and in vivo assays confirmed that the senescent cells were derived primarily from localized corneal fibroblasts. Furthermore, senescent corneal fibroblasts exhibited enhanced synthesis and secretion of extracellular matrix-degrading enzymes (MMP2, MMP3), angiogenesis-associated factors (VEGF) and decreased expression of anti-angiogenic factors (PEDF, TSPs). Intrastromal injection of premature senescent fibroblasts induced CNV earlier than normal cells, while MMP inhibitors blocked early onset of senescent cells-induced CNV.
Senescent corneal fibroblasts were involved in the alkali-induced CNV, partially via the enhanced secretions of matrix metalloproteases.
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