Tenascin-C secreted by transdifferentiated retinal pigment epithelial cells promotes choroidal neovascularization via integrin αV.
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 αVin 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 αVinhibitor. 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 αVin a paracrine manner. Therefore, tenascin-C could be a potential therapeutic target for the inhibition of CNV development associated with AMD.
Department of Ophthalmology, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Yoshiyuki
Y
Kobayashi
Department of Ophthalmology, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Shigeo
S
Yoshida
Department of Ophthalmology, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Yedi
Y
Zhou
Department of Ophthalmology, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Takahito
0000-0001-8999-3667
T
Nakama
Department of Ophthalmology, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Keijiro
K
Ishikawa
Department of Ophthalmology, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Yuki
Y
Kubo
Department of Ophthalmology, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Mitsuru
M
Arima
Department of Ophthalmology, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Shintaro
S
Nakao
Department of Ophthalmology, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Toshio
T
Hisatomi
Department of Ophthalmology, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Yasuhiro
Y
Ikeda
Department of Ophthalmology, Juntendo University, Tokyo, Japan.
Akira
A
Matsuda
Department of Ophthalmology, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Koh-Hei
KH
Sonoda
Department of Ophthalmology, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Tatsuro
T
Ishibashi
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002468:Cell Physiological Phenomena; D054338:Cell Transdifferentiation; D020256:Choroidal Neovascularization / Q000378:metabolism*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D039564:Integrin alphaV / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D058628:Myofibroblasts / Q000378:metabolism; D009389:Neovascularization, Pathologic; D055213:Retinal Pigment Epithelium / Q000378:metabolism*; D019063:Tenascin / Q000378:metabolism*; D053781:Transforming Growth Factor beta2
D039564:Integrin alphaV; D019063:Tenascin; D053781:Transforming Growth Factor beta2
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