title: Role of senescent fibroblasts on alkali-induced corneal neovascularization.
abstract: Cellular senescence acts as a potent regulator of tumor suppression and fibrosis limitation; however, its contribution and crosstalk with neovascularization during normal wound healing has not been examined. Here, we explored the role of senescent fibroblasts on neovascularization with a mouse model of alkali-induced corneal wound healing. Senescent cells accumulated in corneal stroma from day 7 to 27 after alkali burn and peaked on day 14, which was consistent with the development of corneal neovascularization (CNV). In vitro and in vivo assays confirmed that the senescent cells were derived primarily from activated corneal fibroblasts. Furthermore, senescent corneal fibroblasts exhibited enhanced synthesis and secretion of extracellular matrix-degrading enzymes (matrix metalloproteinases 2, 3, and 14 and tissue- and urokinase-type plasminogen activators) and angiogenic factors (vascular endothelial growth factor) and decreased expression of anti-angiogenic factors (pigment epithelium-derived factor and thrombospondins), which supported the proliferation, migration, and promotion of tube formation of vascular endothelial cells. Intrastromal injection of premature senescent fibroblasts induced CNV earlier than that of normal fibroblasts, while matrix metalloproteinase inhibitors blocked the early onset of senescent cell-induced CNV. Therefore, senescent fibroblasts promoted the alkali-induced CNV partially via the enhanced secretion of matrix metalloproteases.
authors.affiliation: State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Qingdao, China.
authors.forename: Qingjun
authors.initials: Q
authors.lastname: Zhou
authors.forename: Lingling
authors.initials: L
authors.lastname: Yang
authors.forename: Mingli
authors.initials: M
authors.lastname: Qu
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
authors.forename: Peng
authors.initials: P
authors.lastname: Chen
authors.forename: Yiqiang
authors.initials: Y
authors.lastname: Wang
authors.forename: Weiyun
authors.initials: W
authors.lastname: Shi
mesh_terms: D000468:Alkalies / Q000494:pharmacology*; D000818:Animals; D016922:Cellular Senescence / Q000502:physiology*; D018920:Coculture Techniques; D016510:Corneal Neovascularization / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D004728:Endothelium, Corneal / Q000098:blood supply / Q000166:cytology; D005126:Eye Burns / Q000503:physiopathology*; D005347:Fibroblasts / Q000473:pathology* / Q000502:physiology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D016850:Limbus Corneae / Q000098:blood supply / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL
chemical_list: D000468:Alkalies