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subretinal fibrosis secondary to neovascular age-related macular degeneration:mechanisms and potential therapeutic targets

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Neural Regeneration Research 2025年第2期20卷 378-393页

作者： Jingxiang Zhang Xia Sheng Quanju Ding Yujun Wang Jiwei Zhao Jingfa Zhang Department of Ophthalmology People’s Hospital of Huangdao DistrictQingdaoShandong ProvinceChina Department of Urology People’s Hospital of Huangdao DistrictQingdaoShandong ProvinceChina Department of Ophthalmology Shanghai General Hospital(Shanghai First People’s Hospital)Shanghai Jiao Tong University School of MedicineShanghaiChina National Clinical Research Center for Eye Diseases Shanghai Key Laboratory of Ocular Fundus DiseasesShanghai Engineering Center for Visual Science and PhotomedicineShanghai Engineering Center for Precise Diagnosis and Treatment of Eye DiseasesShanghaiChina

subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular degeneration.The pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely unknown.Therefore,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments.The current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10.This review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.

关键词： choroidal neovascularization epithelial-mesenchymal transition mesenchymal transition myofibroblast neovascular age-related macular degeneration submacular fibrosis subretinal fibrosis therapeutic targets transforming growth factor-β vascular endothelial growth factor

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Inhibitory effect on subretinal fibrosis by anti-placental growth factor treatment in a laser-induced choroidal neovascularization model in mice

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International Journal of Ophthalmology(English edition) 2022年第2期15卷 189-196页

作者： Yi Zhang Ding-Ying Liao Jian-Ming Wang Li-Jun Wang Xi-Ting Yang Ai-Yi Zhou Department of Ophthalmology the Second Affiliated Hospital of Xi’an Jiaotong University

AIM:To investigate whether anti-placental growth factor(PGF) can inhibit subretinal fibrosis and whether this effect is mediated by the inhibitory effect of PGF on epithelial-mesenchymal transition(EMT) of retinal pigment epithelial(RPE) cells.METHODS:subretinal fibrosis model was established in laser induced choroidal neovascularization(CNV) mice on day 21 after laser photocoagulation.Immunofluorescence staining(IFS) of cryosections and enzyme-linked immunosorbent assay(ELISA) were used to detect the expression of PGF.IFS of whole choroidal flat-mounts was used to detect the degree of subretinal fibrosis.IFS of cryosections and ELISA were used to detect the expression of EMT related indicators in subretinal fibrosis lesions.RESULTS:The expression of PGF protein in subretinal fibrosis lesions was significantly up-regulated(Psubretinal fibrosis and the ratio of fibrotic/angiogenic area significantly at the concentrations of 0.25,0.5,1.0,and 2.0 μg/μL(all Psubretinal fibrosis lesions,and the application of anti-PGF neutralizing antibody could reverse these changes(Psubretinal fibrosis and mainly expressed in RPE cells.Intravitreal injection of anti-PGF neutralizing antibody can significantly inhibit the degree of subretinal fibrosis in CNV mice,and this effect may be mediated by the inhibition of PGF on EMT of RPE cells.

关键词： placental growth factor subretinal fibrosis epithelial mesenchymal transformation choroidal neovascularization

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METTL3-mediated m^(6)A modification of HMGA2 mRNA promotes subretinal fibrosis and epithelial-mesenchymal transition

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Journal of Molecular Cell Biology 2023年第3期15卷 1-17页

作者： Yuwei Wang Yuhong Chen Jian Liang Mei Jiang Ting Zhang Xiaoling Wan Jiahui Wu Xiaomeng Li Jieqiong Chen Junran Sun Yifan Hu Peirong Huang Jingyang Feng Te Liu Xiaodong Sun Department of Ophthalmology Shanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai 200080China Shanghai Key Laboratory of Ocular Fundus Diseases Shanghai 200080China Shanghai Geriatric Institute of Chinese Medicine Shanghai University of Traditional Chinese MedicineShanghai 200031China National Clinical Research Center for Eye Diseases Shanghai 200080China Shanghai Engineering Center for Visual Science and Photomedicine Shanghai 200080China

subretinal fibrosis is a major cause of the poor visual prognosis for patients with neovascular age-related macular degeneration(nAMD).Myofibroblasts originated from retinal pigment epithelial(RPE)cells through epithelial-mesenchymal transition(EMT)contribute to the fibrosis formation.N^(6)-Methyladenosine(m^(6)A)modification has been implicated in the EMT process and multiple fibrotic diseases.The role of m^(6)A modification in EMT-related subretinal fibrosis has not yet been elucidated.In this study,we found that during subretinal fibrosis in the mouse model of laser-induced choroidal neovascularization,METTL3 was upregulated in RPE cells.Through m^(6)A epitranscriptomic microarray and further verification,high-mobility group AT-hook 2(HMGA2)was identified as thekey downstream target of METTL3,subsequently activating potent EMT-inducing transcription factor SNAIL.Finally,by subretinal injections of adeno-associated virus vectors,we confirmed that METTL3 deficiency in RPE cells could efficiently attenuate subretinal fibrosis in vivo.In conclusion,our present research identified an epigenetic mechanism of METTL3-m^(6)A-HMGA2 in subretinal fibrosis and EMT of RPE cells,providing a novel therapeutic target for subretinal fibrosis secondary to nAMD.

关键词： METTL3 N^(6)-methyladenosine epithelial-mesenchymal transition subretinal fibrosis HMGA2

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Interleukin-6 receptor blockade suppresses subretinal fibrosis in a mouse model

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International Journal of Ophthalmology(English edition) 2014年第2期7卷 194-197页

作者： Wei Cui Han Zhang Zhe-Li Liu Department of Ophthalmology the First Hospital of China Medical University

AIM:To determine the involvement of the interleukin(IL)-6 with the development of experimental subretinal fibrosis in a mouse model.METHODS:subretinal fibrosis was induced by subretinal injection of macrophage-rich peritoneal exudate cells and the local expression of IL-6 was assessed by quantitative real-time reverse transcriptionpolymerase chain reaction(RT-PCR)and enzyme-linked immunosorbent assay(ELISA)at various time points.In addition,we investigated the effect of IL-6 receptor(IL-6R)monoclonal antibody(MR16-1)on subretinal fibrosis development.RESULTS:IL-6 mRNA level was significantly elevated at 1d after subretinal fibrosis induction and increased further to about 12-fold at 2d,reaching the peak.The result of ELISA showed that IL-6 protein was not detected in naive mice.At 2d after subretinal fibrosis induction,IL-6 protein level was upregulated to 67.33±14.96 pg/mg in subretinal fibrosis mice.MR16-1treatment resulted in a reduced subretinal fibrosis area by 48%compared to animals from control group at 7d.CONCLUSION:Our results indicated that IL-6 signaling may contribute to the pathogenesis of subretinal fibrogenesis and IL-6R inhibition may provide an effective,novel treatment of advanced and late-stage neovascular age-related macular degeneration.

关键词： interleukin-6 subretinal fibrosis age-related macular degeneration

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Transforming growth factor -β neutralizing antibodies inhibit subretinal fibrosis in a mouse model

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International Journal of Ophthalmology(English edition) 2012年第3期5卷 307-311页

作者： Han Zhang Zhe-Li Liu Department of Ophthalmology the First Hospital of China Medical University Shenyang 110001 Liaoning Province China

AIM:To determine the involvement of the transforming growth factor(TGF)-β with the development of experimental subretinal fibrosis in a mouse model.· METHODS:subretinal fibrosis was induced by subretinal injection of macrophage-rich peritoneal exudate cells(PECs) and the local expression of TGF-β isoforms was assessed by quantitative real-time reverse transcription-polymerase chain reaction(RT-PCR) and enzyme-linked immunosorbent assay(ELISA) at various time points.In addition,we investigated the effect of TFG-β-neutralizing antibodies(TGF-β NAb) on subretinal fibrosis development.· RESULTS:TGF-β1 and TGF-β2 mRNA level was significantly elevated at day 2 after subretinal fibrosis induction and increased further to 5 and 6.5-fold respectively at day 5,reaching the peak.TGF-β3 mRNA was not detected in the present study.The result of ELSIA showed that active TGF-β1 and TGF-β2 levels were upregulated to 10-fold approximately,while total TGF-β1 and TGF-β2 levels were even upregulated more than 10-fold and more than 20-fold respectively in subretinal fibrosis mice in comparison with na?觙ve mice at day 5.TGF-β NAb resulted in a reduced subretinal fibrosis areas by 65% compared to animals from control group at day 7.· CONCLUSION:Our results indicate that TGF-β signaling may contribute to the pathogenesis of subretinal fibrogenesis and TGF-β inhibition may provide an effective,novel treatment of advanced and late-stage neovascular age-related macular degeneration.·

关键词： transforming growth factor-β subretinal fibrosis transforming growth factor-β neutralizing antibody

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LRG1 promotes epithelial-mesenchymal transition of retinal pigment epithelium cells by activating NOX4

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International Journal of Ophthalmology(English edition) 2021年第3期14卷 349-355页

作者： Li Zhou De-Peng Shi Wen-Juan Chu Ling-Ling Yang Hai-Feng Xu Medical Collge Qingdao UniversityQingdao 266071Shandong ProvinceChina State Key Laboratory Cultivation Base Shandong Provincial Key Laboratory of OphthalmologyShandong Eye InstituteShandong First Medical University&Shandong Academyof Medical SciencesQingdao 266071Shandong ProvinceChina Qingdao Eye Hospital Shandong Eye InstituteShandong First Medical University&Shandong Academy of Medical SciencesQingdao 266071Shandong ProvinceChina

AIM:To investigate the effect of leucine-rich-alpha-2-glycoprotein 1(LRG1)on epithelial-mesenchymal transition(EMT)in retinal pigment epithelium(RPE)cells,and to explore the role of NADPH oxidase 4(NOX4).METHODS:RPE cells(ARPE-19 cell line)were treated with transforming growth factor-β1(TGF-β1)to induce EMT.Changes of the m RNA and protein expression levels of LRG1 were tested in the TGF-β1 treated cells.The recombinant human LRG1 protein(r LRG1)and si RNA of LRG1 were used to establish accumulation of exogenous LRG1 model and the down-regulation of LRG1 model in ARPE-19 cells respectively,and to detect EMT-related markers including fibronectin,α-smooth muscle actin(α-SMA)and zonula occludens-1(ZO-1).The m RNA and protein expression level of NOX4 were measured according to the above treatments.VAS2870 was used as a NOX4 inhibitor in r LRG1-treated cells.EMT-related markers were detected to verify the effect of NOX4 in the process of EMT.RESULTS:TGF-β1 promoted the expression of LRG1 at both the m RNA and protein levels during the process of EMT which showed the up-regulation of fibronectin andα-SMA,as well as the down-regulation of ZO-1.Furthermore,the r LRG1 promoted EMT of ARPE-19 cells,which manifested high levels of fibronectin andα-SMA and low level of ZO-1,whereas knockdown of LRG1 prevented EMT by decreasing the expressions of fibronectin andα-SMA and increasing the expression of ZO-1 in ARPE-19 cells.Besides,the r LRG1 activated and LRG1 si RNA suppressed NOX4 expression.EMT was inhibited when VAS2870 was used in the r LRG1-treated cells.CONCLUSION:These results for the first time demonstrate that LRG1 promotes EMT of RPE cells by activating NOX4,which may provide a novel direction to explore the mechanisms of subretinal fibrosis.

关键词： leucine-rich-alpha-2-glycoprotein 1 epithelial-mesenchymal transition NADPH oxidase 4 retinal pigment epithelium cells subretinal fibrosis

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