Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in developed countries. Neovascular AMD (nAMD) accounts for 90% of AMD-related vision loss. Although intravitreal injection of VEGF inhibitors can improve vision in nAMD, approximately 1/3 of patients do not benefit from the therapy due to macular fibrosis. The molecular mechanism underlying the transition of the neovascular lesion to a fibrovascular phenotype remains unknown. Here we discussed the clinical features and risk factors of macular fibrosis secondary to nAMD. Myofibroblasts are key cells in fibrosis development. However, fibroblasts do not exist in the macula. Potential sources of myofibroblast precursors, the molecular cues in the macular microenvironment that recruit them and the pathways that control their differentiation and activation in macular fibrosis were also discussed. Furthermore, we highlighted the challenges in macular fibrosis research and the urgent need for better animal models for mechanistic and therapeutic studies.
Macular fibrosis in neovascular age-related macular degeneration (nAMD) arises from pre-existing neovascular lesions (e.g., CNV). Persistent damage to RPE and the outer layers of the neuronal retina in nAMD increases the risk of macular fibrosis. Myofibroblasts drive the conversion of CNV to fibrovascular membrane, and multiple types of cells may contribute to this process directly or indirectly. Choroidal fibroblasts may be activated by pro-fibrotic growth factors (e.g., TGFβ, PDGF etc.) and migrate to CNV. Circulating fibrocytes may be recruited to CNV by chemokines such as CCL2. RPE cells can undergo Epithelial-Mesenchymal-Transition (EMT). Active vascular endothelial cells in CNV may undergo Endothelial-Mesenchymal-Transition (EndoMT). Macrophages may transdifferentiate into myofibroblasts through Macrophage-Mesenchymal-Transition (MMT). In addition, pericytes and Muller glial cells may also participate in macular fibrosis. Infiltrating macrophages and RPE cells are the major sources of chemokines and growth factors that recruit and activate myofibroblast precursors at the lesion site. BM – Bruch's membrane, CNV – choroidal neovascularization.
Macular fibrosis is the end stage of nAMD
Persistent damages in RPE and neuroretina increase the risks of macular fibrosis in nAMD
Macular fibrosis is the conversion of new blood vessels to fibrovascular lesion
Multiple cell types may contribute to macular fibrosis through activation or trans-differentiation into myofibroblasts
Molecules involved in the recruitment and activation of myofibroblast precursors remains elusive