Investigating the role of perivascular mesenchymal stem cells in macular fibrosis secondary to neovascular age-related macular degeneration

点击翻译按钮获取中文摘要

Age-related macular degeneration (AMD) is a disease that affects the macula, the central part of the retina at the back of the eye, causing progressive loss of central vision in the elderly. Globally, 200 million people are affected by AMD and this number is expected to increase to 300 million by 2040. In the developed world, AMD is the most common cause of blindness in the elderly. AMD has two advanced forms: wet (also known as neovascular AMD) and dry (also known as geographic atrophy); the former accounts for ~80% of AMD-related visual impairment. Wet AMD occurs when diseased blood vessels grow into the macula, causing fluid leakage and bleeding that impairs vision. It is currently treated with injections of VEGF inhibitor (e.g. Lucentis or Avastin) into the eye, which reduces the growth of blood vessels. Although such treatment can stabilise or even improve visual function, 50% of treated eyes eventually develop fibrosis (scarring) in the macula. Unlike scarring of the skin, which heals the wound, scarring in the macula, instead reduces the efficacy of VEGF inhibitors. The fibrovascular membranes that emerge from diseased blood vessels eventually destroy the entire macula. Currently, there are no medications to prevent or treat this condition due to a poor understanding of the disease mechanism. New blood vessels in wet AMD develop into fibrovascular scar when cells, called myofibroblasts, infiltrate and accumulate in the macula. Myofibroblasts produce excessive amounts of scar-forming extracellular matrix such as collagens and fibronectins. Myofibroblasts are absent from the healthy retina, including the macula, and we do not yet know where they come from and how they are activated in wet AMD. This knowledge is crucial for developing therapeutic interventions to wet AMD and macular fibrosis. Recently, perivascular mesenchymal stem cells (pMSC), a unique type of cell residing around blood vessels were identified as a major source of myofibroblasts in injury-induced scars in multiple organs, including the lung, kidney, heart, and skin. These pMSCs are known to safeguard blood vessels and maintain their integrity. During injury, they detach from blood vessel walls and travel to the site of damage, where they participate in tissue repair and regeneration. When the injury persists or when injury-mediated inflammation does not resolve promptly, these pMSCs expand and become myofibroblasts leading to organ fibrosis. We have found that within the eye, the retina and choroid also contain a network of pMSCs. In an experimental model of wet AMD-mediated retinal fibrosis, over 60% of myofibroblast originated from pMSCs, and genetic deletion of pMSCs reduced retinal fibrosis. Our aim is to understand why pMSCs become myofibroblasts in wet AMD and how we might prevent or reverse this process. We will use advanced genomic techniques to uncover the gene expression profile of individual pMSCs within the diseased tissue at different stages of retinal fibrosis. This will inform us of which pMSC subtypes give rise to myofibroblasts and the pathways that control this process. We will verify these pathways in pMSC cultures derived from the retina, choroid, and retinal scar tissue. We will then target these pathways with pharmacological approaches to prevent or reverse the differentiation of pMSCs into myofibroblasts using in vitro and in vivo models of retinal fibrosis. Our results will inform further research and enhance our understanding of retinal repair and fibrosis in wet AMD and other sight-threatening diseases caused by abnormal tissue repair (e.g. proliferative diabetic retinopathy [PDR] and proliferative vitreoretinopathy [PVR]). Ultimately, our research will aim in developing effective treatments for retinal fibrosis.