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

Biochim Biophys Acta Mol Basis Dis. 2022 Apr 1;1868(4):166340. doi: 10.1016/j.bbadis.2022.166340. Epub 2022 Jan 12.


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.

Findings: 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.

Interpretation: 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 Foundation and the Volker Homann Foundation.

Keywords: AMD; CNV; FN14; Human; Laser-induced CNV; Mouse; RNA-Seq; Transcriptomic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bruch Membrane / metabolism
  • Case-Control Studies
  • Choroid / metabolism*
  • Choroid / pathology
  • Choroidal Neovascularization / etiology
  • Choroidal Neovascularization / metabolism*
  • Cytokines / genetics
  • Cytokines / metabolism
  • Disease Models, Animal
  • Female
  • Humans
  • Lasers / adverse effects
  • Ligands
  • Macular Degeneration / metabolism
  • Macular Degeneration / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Phylogeny
  • TWEAK Receptor / antagonists & inhibitors
  • TWEAK Receptor / classification
  • TWEAK Receptor / genetics
  • TWEAK Receptor / metabolism*
  • Transcriptome*
  • Up-Regulation


  • Cytokines
  • Ligands
  • TWEAK Receptor