scholarly journals Comparative transcriptome analysis of human and murine choroidal neovascularization identifies fibroblast growth factor inducible-14 as phylogenetically conserved mediator of neovascular age-related macular degeneration

2022 ◽  
pp. 166340
Author(s):  
Julian Wolf ◽  
Anja Schlecht ◽  
Dennis-Dominik Rosmus ◽  
Stefaniya Boneva ◽  
Hansjürgen Agostini ◽  
...  
Keyword(s):  
Growth Factor ◽  
Macular Degeneration ◽  
Fibroblast Growth Factor ◽  
Choroidal Neovascularization ◽  
Transcriptome Analysis ◽  
Age Related Macular Degeneration ◽  
Fibroblast Growth ◽  
Comparative Transcriptome ◽  
Comparative Transcriptome Analysis ◽  
Age Related

scholarly journals Comparative transcriptome analysis of human and murine choroidal neovascularization identifies fibroblast growth factor inducible-14 as phylogenetically conserved mediator of neovascular age-related macular degeneration

2021 ◽  
Author(s):  
Julian Wolf ◽  
Anja Schlecht ◽  
Dennis-Dominik Rosmus ◽  
Stefaniya Boneva ◽  
Hansjuergen Agostini ◽  
...  
Keyword(s):  
Growth Factor ◽  
Macular Degeneration ◽  
Fibroblast Growth Factor ◽  
Choroidal Neovascularization ◽  
Visual Outcome ◽  
Age Related Macular Degeneration ◽  
Fibroblast Growth ◽  
Age Related ◽  
Human And Mouse

Background: Visual outcome of patients with neovascular age-related macular degeneration has significantly improved during the last years following the introduction of anti-vascular endothelial growth factor (VEGF) therapy. However, about one third of patients show persistent exudation and decreasing visual acuity despite recurrent anti-VEGF treatment, which implies a role of other, still unknown proangiogenic mediators. Methods: The present study applied transcriptional profiling of human and mouse (C57BL/6J wildtype) choroidal neovascularization (CNV) membranes each with reference to healthy control tissue to identify yet unrecognized mediators of CNV formation. Key factors were further investigated by immunohistochemistry as well as by intravitreal inhibition experiments and multiplex protein assays in the laser-induced CNV mouse model. Results: Transcriptional profiles of CNV membranes were characterized by enhanced activation of blood vessel development, cytoskeletal organization, and cytokine production, with angiogenesis and wound healing processes predominating in humans and activation of immune processes in mice. Besides several species-specific factors, 95 phylogenetically conserved CNV-associated genes were detected, among which fibroblast growth factor inducible-14 (FN14), a member of the tumor necrosis factor (TNF) receptor family, was identified as a key player of CNV formation. Blocking the pathway by intravitreal injection of a FN14 decoy receptor modulated the cytokine profile - most notably IL-6 - and led to a significant reduction of CNV size in vivo. Conclusions: This study characterizes the transcriptome of human and mouse CNV membranes in an unprejudiced manner and identifies FN14 as a phylogenetically conserved mediator of CNV formation and a promising new therapeutic target for neovascular AMD. Funding: This study was funded by the Helmut-Ecker-Stiftung and the Volker-Homann-Stiftung.

scholarly journals Sorsby Fundus Dystrophy Mutation in Tissue Inhibitor of Metalloproteinase 3 (TIMP3) promotes Choroidal Neovascularization via a Fibroblast Growth Factor-dependent Mechanism

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Jian Hua Qi ◽  
Brent Bell ◽  
Rupesh Singh ◽  
Julia Batoki ◽  
Alyson Wolk ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Choroidal Neovascularization ◽  
Molecular Mechanisms ◽  
Retinal Pigment ◽  
Western Hemisphere ◽  
Age Related Macular Degeneration ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Fibroblast Growth ◽  
Tissue Inhibitor

AbstractChoroidal neovascularization (CNV) leads to loss of vision in patients with Sorsby Fundus Dystrophy (SFD), an inherited, macular degenerative disorder, caused by mutations in the Tissue Inhibitor of Metalloproteinase-3 (TIMP3) gene. SFD closely resembles age-related macular degeneration (AMD), which is the leading cause of blindness in the elderly population of the Western hemisphere. Variants in TIMP3 gene have recently been identified in patients with AMD. A majority of patients with AMD also lose vision as a consequence of choroidal neovascularization (CNV). Thus, understanding the molecular mechanisms that contribute to CNV as a consequence of TIMP-3 mutations will provide insight into the pathophysiology in SFD and likely the neovascular component of the more commonly seen AMD. While the role of VEGF in CNV has been studied extensively, it is becoming increasingly clear that other factors likely play a significant role. The objective of this study was to test the hypothesis that basic Fibroblast Growth Factor (bFGF) regulates SFD-related CNV. In this study we demonstrate that mice expressing mutant TIMP3 (Timp3S179C/S179C) showed reduced MMP inhibitory activity with an increase in MMP2 activity and bFGF levels, as well as accentuated CNV leakage when subjected to laser injury. S179C mutant-TIMP3 in retinal pigment epithelial (RPE) cells showed increased secretion of bFGF and conditioned medium from these cells induced increased angiogenesis in endothelial cells. These studies suggest that S179C-TIMP3 may promote angiogenesis and CNV via a FGFR-1-dependent pathway by increasing bFGF release and activity.

A gradient of basic fibroblast growth factor in rod photoreceptors in the normal human retina

1997 ◽  
Vol 14 (4) ◽  
pp. 671-679 ◽  
Author(s):  
Zong-Yi Li ◽  
Jean H. Chang ◽  
Ann H. Milam
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Basic Fibroblast Growth Factor ◽  
Amacrine Cells ◽  
Age Related Macular Degeneration ◽  
Human Retina ◽  
Fibroblast Growth ◽  
Rod Photoreceptors ◽  
Age Related ◽  
Normal Human

AbstractRetinitis pigmentosa (RP) is an inherited disease that causes primary degeneration of rod photoreceptors in the retina. Although the causal gene (e.g. rhodopsin) is thought to be expressed in all rods across the retina, the degeneration is typically nonuniform, with rods in the far periphery surviving significantly longer than those in the midperiphery and macula. Basic fibroblast growth factor (bFGF) is a putative survival factor for photoreceptors, and the characteristic regional pattern of rod cell survival in RP suggested that bFGF might be distributed nonuniformly in the human retina. We performed double-label immunocytochemistry on 15 normal human retinas, using anti-bFGF and other antibody markers for retinal neurons and glia. Immunoreactivity for bFGF was consistently absent from cones but was present in rods, populations of cone bipolar and amacrine cells, Müller glial cells, and astrocytes. In the macula, the percentage of bFGF-reactive rods was very low (~0.5%) but it increased in a central to peripheral gradient, accounting for up to ~88% of the rods in the far periphery. These findings suggest that a central to peripheral gradient of rod bFGF is present in normal human retina and may influence the pattern of photoreceptor degeneration in RP. The absence of bFGF in cones and the low number of bFGF-positive rods in the macula may correlate with the vulnerability of these cells in RP, age-related macular degeneration, and other retinal diseases.

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