Tenascin-C secreted by transdifferentiated retinal pigment epithelial cells promotes choroidal neovascularization via integrin αv

Yoshiyuki Kobayashi, Shigeo Yoshida, Yedi Zhou, Takahito Nakama, Keijiro Ishikawa, Yuki Kubo, Mitsuru Arima, shintaro nakao, Toshio Hisatomi, Yasuhiro Ikeda, Akira Matsuda, Kohei Sonoda, Tatsuro Ishibashi

Research output: Contribution to journalArticle

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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 α V 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 α V 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 α V in a paracrine manner. Therefore, tenascin-C could be a potential therapeutic target for the inhibition of CNV development associated with AMD.

Original languageEnglish
Pages (from-to)1178-1188
Number of pages11
JournalLaboratory Investigation
Volume96
Issue number11
DOIs
Publication statusPublished - Nov 1 2016

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Tenascin
Choroidal Neovascularization
Retinal Pigments
Integrins
Epithelial Cells
Macular Degeneration
Small Interfering RNA
Lasers
Endothelial Cells
Membranes
Light Coagulation
Conditioned Culture Medium
Keratins
Knockout Mice
Fluorescent Antibody Technique

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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Tenascin-C secreted by transdifferentiated retinal pigment epithelial cells promotes choroidal neovascularization via integrin αv. / Kobayashi, Yoshiyuki; Yoshida, Shigeo; Zhou, Yedi; Nakama, Takahito; Ishikawa, Keijiro; Kubo, Yuki; Arima, Mitsuru; nakao, shintaro; Hisatomi, Toshio; Ikeda, Yasuhiro; Matsuda, Akira; Sonoda, Kohei; Ishibashi, Tatsuro.

In: Laboratory Investigation, Vol. 96, No. 11, 01.11.2016, p. 1178-1188.

Research output: Contribution to journalArticle

Kobayashi, Yoshiyuki ; Yoshida, Shigeo ; Zhou, Yedi ; Nakama, Takahito ; Ishikawa, Keijiro ; Kubo, Yuki ; Arima, Mitsuru ; nakao, shintaro ; Hisatomi, Toshio ; Ikeda, Yasuhiro ; Matsuda, Akira ; Sonoda, Kohei ; Ishibashi, Tatsuro. / Tenascin-C secreted by transdifferentiated retinal pigment epithelial cells promotes choroidal neovascularization via integrin αv. In: Laboratory Investigation. 2016 ; Vol. 96, No. 11. pp. 1178-1188.
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AU - Kobayashi, Yoshiyuki

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AU - Ishikawa, Keijiro

AU - Kubo, Yuki

AU - Arima, Mitsuru

AU - nakao, shintaro

AU - Hisatomi, Toshio

AU - Ikeda, Yasuhiro

AU - Matsuda, Akira

AU - Sonoda, Kohei

AU - Ishibashi, Tatsuro

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AB - 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 α V 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 α V 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 α V in a paracrine manner. Therefore, tenascin-C could be a potential therapeutic target for the inhibition of CNV development associated with AMD.

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