RRC ID 46789
Author Kobayashi Y, Yoshida S, Zhou Y, Nakama T, Ishikawa K, Kubo Y, Arima M, Nakao S, Hisatomi T, Ikeda Y, Matsuda A, Sonoda KH, Ishibashi T.
Title Tenascin-C secreted by transdifferentiated retinal pigment epithelial cells promotes choroidal neovascularization via integrin αV.
Journal Lab Invest
Abstract Tenascin-C is expressed in choroidal neovascular (CNV) membranes in eyes with age-related macular degeneration (AMD). However, its role in the pathogenesis of CNV remains to be elucidated. Here we investigated the role of tenascin-C in CNV formation. In immunofluorescence analyses, tenascin-C co-stained with α-SMA, pan-cytokeratin, CD31, CD34, and integrin αV in the CNV membranes of patients with AMD and a mouse model of laser-induced CNV. A marked increase in the expression of tenascin-C mRNA and protein was observed 3 days after laser photocoagulation in the mouse CNV model. Tenascin-C was also shown to promote proliferation and inhibit adhesion of human retinal pigment epithelial (hRPE) cells in vitro. Moreover, tenascin-C promoted proliferation, adhesion, migration, and tube formation in human microvascular endothelial cells (HMVECs); these functions were, however, blocked by cilengitide, an integrin αV inhibitor. Exposure to TGF-β2 increased tenascin-C expression in hRPE cells. Conditioned media harvested from TGF-β2-treated hRPE cell cultures enhanced HMVEC proliferation and tube formation, which were inhibited by pretreatment with tenascin-C siRNA. The CNV volume was significantly reduced in tenascin-C knockout mice and tenascin-C siRNA-injected mice. These findings suggest that tenascin-C is secreted by transdifferentiated RPE cells and promotes the development of CNV via integrin αV in a paracrine manner. Therefore, tenascin-C could be a potential therapeutic target for the inhibition of CNV development associated with AMD.
Volume 96(11)
Pages 1178-1188
Published 2016-11-1
DOI 10.1038/labinvest.2016.99
PII labinvest201699
PMID 27668890
MeSH Aged Aged, 80 and over Animals Cell Physiological Phenomena Cell Transdifferentiation Choroidal Neovascularization / metabolism* Disease Models, Animal Endothelial Cells / metabolism Humans Integrin alphaV / metabolism Mice Mice, Inbred C57BL Mice, Knockout Middle Aged Myofibroblasts / metabolism Neovascularization, Pathologic Retinal Pigment Epithelium / metabolism* Tenascin / metabolism* Transforming Growth Factor beta2
IF 4.197
Times Cited 8
Mice RBRC00067