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

Abstract

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 speciesspecific 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 .

Chikungunya patient transcriptional signatures faithfully recapitulated in a C57BL/6J mouse model

“…This model has been used to investigate the virology, immunobiology and immunopathology of CHIKV infections (12,14,(24)(25)(26)(27)(28)(29)(30). Given the considerable debate regarding how faithfully mouse models recapitulate the transcriptional responses seen in humans (10,(31)(32)(33)(34)(35)(36)(37)(38), we recently developed a series of bioinformatic methods for investigating how well the transcriptional responses in a given mouse model mimic those seen in humans (39). For human CHIKV patients, RNA-Seq data is available for peripheral blood from acutely infected adults and children (40,41).…”

Transcriptional Profiling Provides New Insights into Organ Culture-Induced Changes in Human Donor Corneas

“…RNA sequencing was performed by a commercial provider (GenXPro, Frankfurt am Main, Germany) using massive analysis of cDNA ends (MACE), a 3′-RNA sequencing method, as previously described [ 25 ]. We recently demonstrated that MACE allows sequencing of FFPE samples with high accuracy [ 4 ].…”

Liquid Biopsy Proteomics in Ophthalmology

“…In addressing this question, comparing high-resolution human omics data with the molecular profile of the animal model can provide valuable insights when developing novel therapeutic strategies. 100,101 Among the proteomic methods discussed, it is remarkable that liquid biopsies from the vitreous, AH, and even tears can measure proteins originally expressed in the retina. Unexpectedly, these proteins must traverse several anatomic and enzymatic barriers.…”

“…A fundamental question will be which specific molecular aspects of human disease are well reflected by each model. In addressing this question, comparing high-resolution human omics data with the molecular profile of the animal model can provide valuable insights when developing novel therapeutic strategies. , …”

“…In addressing this question, comparing high-resolution human omics data with the molecular profile of the animal model can provide valuable insights when developing novel therapeutic strategies. 100 , 200 …”