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      Myofibroblasts in macular fibrosis secondary to neovascular age-related macular degeneration - the potential sources and molecular cues for their recruitment and activation

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          Abstract

          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.

          Graphical abstract

          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.

          Highlights

          • 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

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          Most cited references73

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          TGF-beta-induced EMT: mechanisms and implications for fibrotic lung disease.

          Epithelial-mesenchymal transition (EMT), a process whereby fully differentiated epithelial cells undergo transition to a mesenchymal phenotype giving rise to fibroblasts and myofibroblasts, is increasingly recognized as playing an important role in repair and scar formation following epithelial injury. The extent to which this process contributes to fibrosis following injury in the lung is a subject of active investigation. Recently, it was demonstrated that transforming growth factor (TGF)-beta induces EMT in alveolar epithelial cells (AEC) in vitro and in vivo, and epithelial and mesenchymal markers have been colocalized to hyperplastic type II (AT2) cells in lung tissue from patients with idiopathic pulmonary fibrosis (IPF), suggesting that AEC may exhibit extreme plasticity and serve as a source of fibroblasts and/or myofibroblasts in lung fibrosis. In this review, we describe the characteristic features of EMT and its mechanistic underpinnings. We further describe the contribution of EMT to fibrosis in adult tissues following injury, focusing especially on the critical role of TGF-beta and its downstream mediators in this process. Finally, we highlight recent descriptions of EMT in the lung and the potential implications of this process for the treatment of fibrotic lung disease. Treatment for fibrosis of the lung in diseases such as IPF has heretofore focused largely on amelioration of potential inciting processes such as inflammation. It is hoped that this review will stimulate further consideration of the cellular mechanisms of fibrogenesis in the lung and especially the role of the epithelium in this process, potentially leading to innovative avenues of investigation and treatment.
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            The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited.

            During the past ten years, dramatic advances have been made in unraveling the biological bases of age-related macular degeneration (AMD), the most common cause of irreversible blindness in western populations. In that timeframe, two distinct lines of evidence emerged which implicated chronic local inflammation and activation of the complement cascade in AMD pathogenesis. First, a number of complement system proteins, complement activators, and complement regulatory proteins were identified as molecular constituents of drusen, the hallmark extracellular deposits associated with early AMD. Subsequently, genetic studies revealed highly significant statistical associations between AMD and variants of several complement pathway-associated genes including: Complement factor H (CFH), complement factor H-related 1 and 3 (CFHR1 and CFHR3), complement factor B (CFB), complement component 2 (C2), and complement component 3 (C3). In this article, we revisit our original hypothesis that chronic local inflammatory and immune-mediated events at the level of Bruch's membrane play critical roles in drusen biogenesis and, by extension, in the pathobiology of AMD. Secondly, we report the results of a new screening for additional AMD-associated polymorphisms in a battery of 63 complement-related genes. Third, we identify and characterize the local complement system in the RPE-choroid complex - thus adding a new dimension of biological complexity to the role of the complement system in ocular aging and AMD. Finally, we evaluate the most salient, recent evidence that bears directly on the role of complement in AMD pathogenesis and progression. Collectively, these recent findings strongly re-affirm the importance of the complement system in AMD. They lay the groundwork for further studies that may lead to the identification of a transcriptional disease signature of AMD, and hasten the development of new therapeutic approaches that will restore the complement-modulating activity that appears to be compromised in genetically susceptible individuals. Copyright 2009 Elsevier Ltd. All rights reserved.
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              CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair.

              Monocytes/macrophages are critical in orchestrating the tissue-repair response. However, the mechanisms that govern macrophage regenerative activities during the sequential phases of repair are largely unknown. In the present study, we examined the dynamics and functions of diverse monocyte/macrophage phenotypes during the sequential stages of skin repair. By combining the analysis of a new CCR2-eGFP reporter mouse model with conditional mouse mutants defective in myeloid cell-restricted CCR2 signaling or VEGF-A synthesis, we show herein that among the large number of inflammatory CCR2(+)Ly6C(+) macrophages that dominate the early stage of repair, only a small fraction strongly expresses VEGF-A that has nonredundant functions for the induction of vascular sprouts. The switch of macrophage-derived VEGF-A during the early stage of tissue growth toward epidermal-derived VEGF-A during the late stage of tissue maturation was critical to achieving physiologic tissue vascularization and healing progression. The results of the present study provide new mechanistic insights into CCR2-mediated recruitment of blood monocyte subsets into damaged tissue, the dynamics and functional consequences of macrophage plasticity during the sequential repair phases, and the complementary role of macrophage-derived VEGF-A in coordinating effective tissue growth and vascularization in the context of tissue-resident wound cells. Our findings may be relevant for novel monocyte-based therapies to promote tissue vascularization.
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                Author and article information

                Contributors
                Journal
                EBioMedicine
                EBioMedicine
                EBioMedicine
                Elsevier
                2352-3964
                22 November 2018
                December 2018
                22 November 2018
                : 38
                : 283-291
                Affiliations
                [a ]The Welcomme-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Sciences, Queen's University Belfast, UK
                [b ]Aier Eye Institute, Aier School of Ophthalmology, Central South University, Changsha, Hunan, China
                [c ]Guangzhou Aier Eye Hospital, Guangzhou, Guangdong, China
                Author notes
                [* ]Corresponding author at: The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK. heping.xu@ 123456qub.ac.uk
                [1]

                The authors contributed equally.

                Article
                S2352-3964(18)30533-4
                10.1016/j.ebiom.2018.11.029
                6306402
                30473378
                e612a323-8c24-46af-8a33-51f9aaf09780
                © 2018 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 28 September 2018
                : 14 November 2018
                : 14 November 2018
                Categories
                Review

                age-related macular degeneration,macular fibrosis,myofibroblast,risk factors,inflammation

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