ZHANG Li-Min,BAO Xiu-Li.Potential effect of epithelial mesenchymal transition in pathogenesis of proliferative vitreoretinopathy[J].Recent Advances in Ophthalmology,2018,38(7):692-695.[doi:10.13389/j.cnki.rao.2018.0163]





Potential effect of epithelial mesenchymal transition in pathogenesis of proliferative vitreoretinopathy
010100 内蒙古呼和浩特市,内蒙古医科大学(张利民);010100 内蒙古呼和浩特市,内蒙古医科大学附属医院眼科(包秀丽)
Inner Mongolia Medical University(ZHANG Li-Min),Hohhot,010100,the Inner Mongolia Autonomous Region,China;Ophthalmology,the Affiliated Hospital of Inner Mongolia Medical University(BAO Xiu-Li),Hohhot 010100,Inner Mongolia Autonomous Region,China
proliferative vitreoretinopathyepithelial mesenchymal transitionfibroblastsmyofibroblastscell-cell adhesionscadherintransforming growth factor-β
增生性玻璃体视网膜病变(proliferative vitreoretinopathy,PVR)是一种以纤维化为特点具有潜在致盲性的眼科并发症,其病理改变是产生视网膜前膜(epiretinal membranes,ERMs)。ERMs是一种纤维增殖膜,在视网膜前后表面及玻璃体内形成,当其收缩后导致PVR的发生,最终形成视网膜皱褶和牵引视网膜脱离(tractional retinal detachment,TRD)。多种细胞类型在ERMs中已被确定,视网膜色素上皮(retinal pigment epithelium,RPE)在PVR的病理生理学中至关重要。大量的临床和实验证据研究表明,RPE细胞采用了成纤维细胞表型发生了上皮间充质转化(epithelial-mesenchymal transition,EMT),并且还涉及大量的细胞因子、转录因子。EMT的特点是细胞间黏附和顶面-底侧细胞极性的缺失,这增加了细胞的移行性。由此产生的细胞能够通过细胞外基质迁移和转移。细胞间黏附由连接复合体维系着,它们在维护RPE细胞表型方面起重要作用,其通过激活一些信号通路及转录因子破坏这些连接复合体并导致EMT的发生。经过EMT过程后,转化生长因子-β使RPE细胞进一步分化为肌成纤维细胞。源自RPE细胞的成纤维细胞和肌成纤维细胞可以通过细胞迁移、增殖,导致ERMs的形成,这在PVR的病程发展中起着关键性作用。
Proliferative vitreoretinopathy(PVR) is an ocular complication characterized by fibrosis and potentially blinding.The pathological changes are the production of the epiretinal membranes (ERMs).ERMs is a kind of fibrous membrane,which is formed in the front and back of the retina and in the vitreous body.When it contractions,it causes the occurrence of PVR and eventually forms retinal folds and traction retinal detachments (TRD).Multiple cell types have been identified in ERMs.Retinal pigment epithelium is very important in the pathophysiology of PVR.A large number of clinical and experimental evidence studies have shown that RPE cells have undergone epithelial mesenchymal transition (EMT) to adopt fibroblast phenotype,and also involve a large number of cytokines and transcription factors.EMT is characterized by loss of cell-cell adhesion and apical-basal cell polarit,which enhances cell migration.The resulting cells can migrate through extracellular matrix.Cell-cell adhesions is maintained by the junction complex,which plays an important role in maintaining the phenotype of RPE cells.Furthermore,disruption of these junctional complexes results in EMT via activation of signaling pathways as well as transcription factors.Upon EMT,TGF-β further differentiated RPE cells into myofibroblasts.Fibroblasts and myofibroblasts derived from RPE cells can lead to the formation of ERMs through cell migration and proliferation,which plays a critical role in the development of PVR.


[1] UMAZUME K,TSUKAHARA R,LIU L,JUAN P,FERNANDEZ DE C,KEVIN M.Role of retinal pigment epithelial cell β-catenin signaling in experimental proliferative vitreoretinopathy[J].Am J Pathol,2014,184(5):1419-1428.
[2] OBERSTEIN S Y,BYUN J,HERRERA D,CHAPIN E A,FISHER S K.Cell proliferation in human epiretinal membranes:characterization of cell types and correlation with disease condition and duration[J].Mol Vis,2011,17:1794-1805.
[3] CHEN X,YE S,XIAO W,L LUO L,LIU Y.Differentially expressed microRNAs in TGFβ2-induced epithelial-mesenchymal transition in retinal pigment epithelium cells[J].Int J Mol Med.2014,33(5):1195-1200.
[4] YANG S,LI H,LI M,WANG F.Mechanisms of epithelial-mesenchymal transition in proliferative vitreoretinopathy[J].Discov Med,2015,20(110):207-217.
[5] SPEIGHT P,NAKANO H,KELLEY T J,HINZ B,KAPUSA.Differential topical susceptibility to TGFβ in intact and injured regions of the epithelium:key role in myofibroblast transition[J].Mol Biol Cell,2013,24(21):3326-3336.
[6] LIN T,PONN A,HU X,LU J.Requirement of the histone demethylase LSD1 in Snai1-mediated transcriptional repression during epithelial-mesenchymal transition[J].Oncogene,2010,29(35):4896-904.
[7] CHEN Z,SHAO Y,LI X.The roles of signaling pathways in epithelial-to-mesenchymal transition of PVR[J].Mol Vis,2015,21:706-710.
[8] TAMIYA S,LIU L,KAPLAN H J.Epithelial-mesenchymal transition and proliferation of retinal pigment epithelial cells initiated upon loss of cell-cell contact[J].Invest Ophthalmol Vis Sci,2010,51(5):2755-2763.
[9] WANG Z,LI Y,KONG D,FH SARKARFH.The role of notch signaling pathway in epithelial-mesenchymal transition(EMT) during development and tumor aggressiveness[J].Curr Drug Targets,2010,11(6):745-751.
[10] PALMA-NICOLS J P,LPEZ-COLOM A M.Thrombin induces slug-mediated E-cadherin transcriptional repression and the parallel up-regulation of N-cadherin by a transcription-independent mechanism in RPE cells[J].J Cell Physiol,2013,228(3):581-589.
[11] CHIBA C.The retinal pigment epithelium:An important player of retinal disorders and regeneration[J].Exp Eye Res,2014,123:107-114.
[12] KLEIN D,MENDES-MADEIRA A,SCHLEGEL P,ROLLING F,BIRGIT LORENZ B,HAVERKAMP S,et al.Immuno-histochemical analysis of rod and cone reaction to RPE 65 deficiency in the inferior and superior canine retina[J].PLoS One,2014,9(1):e86304.
[13] WALLEZ Y,HUBER P.Endothelial adherens and tight junctions in vascular homeostasis,inflammation and angiogenesis[J].Biochim Biophys Acta,2008,1778(3):794-809.
[14] RIZZOLO L J,PENG S,LUO Y,XIAO W.Integration of tight junctions and claudins with the barrier functions of the retinal pigment epithelium[J].Prog Retin Eye Res,2011,30(5):296-323.
[15] BONILHA V L.Retinal pigment epithelium(RPE) cytoskeleton in vivo and in vitro Vera L.Bonilha[J].Exp Eye Res,2014,126:38-45.
[16] ABU EL-ASRAR A M,DE HERTOGH G,VAN DEN EYNDE K,ALAM K,VAN RAEMDONCK K,OPDENAKKER G,et al.Myofibroblasts in proliferative diabetic retinopathy can originate from infiltrating fibrocytes and through endothelial-to-mesenchymal transition(EndoMT)[J].Exp Eye Res,2015,132:179-189.
[17] MATTER K,BALDA M S.SnapShot:Epithelial tight junctions[J].Cell,2014,157(4):992-992.
[18] BARDAG-GORCE F,HOFT R H,WOOD A,OLIVA J,NIIHARA H,MAKALINAO A,et al.The role of E-cadherin in maintaining the barrier function of corneal epithelium after treatment with cultured autologous oral mucosa epithelial cell sheet grafts for limbal stem deficiency[J].J Ophthalmol,2016,2016:4805986.
[19] VAN ROY F,BERX G.The cell-cell adhesion molecule E-cadherin[J].Cell Mol Life Sci,2008,65(23):3756-3788.
[20] LECARPENTIER Y,CLAES V,VALLE A,HBERT J L,et al.Interactions between PPAR gamma and the canonical Wnt/beta-catenin pathway in type 2 diabetes and colon cancer[J].PPAR Res,2017,2017:5879090.
[21] MAHER M T,MO R,FLOZAK A S,PELED O N,GOTTARDI C J.Beta-catenin phosphorylated at serine 45 is spatially uncoupled from beta-cateninphosphorylated in the GSK3 domain:implications for signaling[J].PLoS One,2010,5(4):e10184.
[22] ZHOU J Z,JIANG J,WANG S H,XIA X B.DKK1 inhibits proliferation and migration in human retinal pigment epithelial cells via the Wnt/ β-catenin signaling pathway[J].Exp Ther Med,2016,12(2):859-863.
[23] LIAN I,KIM J,OKAZAWA H,ZHAO J,ZHAO B,YU J,et al.The role of YAP transcription coactivator inregulating stem cell self-renewal and differentiation[J].Genes Dev,2010,24(11):1106-1118.
[24] NEAL C L,HENDERSON V,SMITH B N,MCKEITHEN D,GRAHAM T,VO B T,et al.Snail transcription factor negatively regulates maspin tumor suppressor in human prostatecancer cells[J].BMC Cancer,2012,12:336.
[25] GEORGIADIS A,TSCHERNUTTER M,BAINBRIDGE J W,BALAGGAN K S,MOWAT F,WEST E L,et al.The tight junction associated signalling proteins ZO-1 and ZONAB regulate retinal pigment epithelium homeostasis in mice[J].PLoS One,2010,5(12):e15730.
[26] ZHANG Y,WANG J,LI H YUAN L,WANG L,WU B,et al.Hydrogen sulfide suppresses transforming growth factor-β1-induced differentiation of human cardiac fibroblasts into myofibroblasts[J].Sci China Life Sci,2015,58(11):1126-1134.
[27] KUTTY R K,SAMUEL W,BOYCE K,CHERUKURI A,DUNCAN T,JAWORSKI C,et al.Proinflammatory cytokines decrease the expression of genes critical for RPE function[J].Mol Vis,2016,22:1156-1168.
[28] WANG X,CHU J,WEN C J,FU S B,QIAN Y L,WO Y,et al.Functional characterization of TRAP1-like protein involved in modulating fibrotic processes mediated by TGF-β / Smad signaling in hypertrophic scar fibroblasts[J].Exp Cell Res,2015,332(2):202-211.
[29] AGAJANIAN M,RUNA F,KELBER J A.Identification of a PEAK1/ZEB1 signaling axis during TGFβ / fibronectin-induced EMT in breast cancer[J].Biochem Biophys Res Commun,2015,465(3):606-612.
[30] GAMULESCU M A,CHEN Y,HE S,SPEE C,JIN M,RYAN S J,et al.Transforming growth factor beta2-induced myofibroblastic differentiation of human retinal pigment epithelial cells:regulation by extracellular matrix proteins and hepatocyte growth factor[J].Exp Eye Res,2006,83(1):212-222.
[31] CHIBA C.The retinal pigment epithelium:An important player of retinal disorders and regeneration[J].Exp Eye Res,2014,123:107-114.
[32] BAKIN A V,RINEHART C,TOMLINSON A K,ARTEAGA C L.p38 mitogen-activated protein kinase is required for TGF beta-mediated fibroblastic transdifferentiation and cell migration[J].J Cell Sci,2002,115(Pt 15):3193-206.
[33] YAO H,LI H,YANG S,LI M,LI M,ZHAO C,ZHANG J,et al.Inhibitory effect of bone morphogenetic protein 4 in retinal pigment epithelial-mesenchymal transition[J].Sci Rep,2016,6:32182.
[34] USUI-OUCHI A,OUCHI Y,KIYOKAWA M,SAKUMA T,ITO R,EBIHARA N.Upregulation of mir-21 levels in the vitreous humor is associated with development of proliferative vitreoretinal disease[J].PLoS One,2016,11(6):e0158043.
[35] OKAYAMA K,AZUMA J,DOSAKA N,IEKUSHI K,SANADA F,KUSUNOKI H,et al.Hepatocyte growth factor reduces cardiac fibrosis by inhibiting endothelial-mesenchymaltransition[J].Hypertension,2012,59(5):958-965.
[36] ISHIKAWA K,HE S,TERASAKI H,NAZARI H,ZHANG H,SPEE C,et al.Resveratrol inhibits epithelial-mesenchymal transition of retinal pigment epithelium and development of proliferative vitreoretinopathy[J].Sci Rep,2015,5:16386.
[37] ZHANG J,YUAN G,DONG M,ZHANG T,HUA G,ZHOU Q,et al.Notch signaling modulates proliferative vitreoretinopathy via regulating retinal pigment epithelial-to-mesenchymal transition[J].Histochem Cell Biol,2017,147(3):367-375.
[38] SANDBO N,SMOLYANINOVA L V,ORLOV S N,DULIN N O.Control of myofibroblast differentiation and function by cytoskeletal signaling[J].Biochemistry(Mosc),2016,81(13):1698-1708.
[39] SPARROW J R,HICKS D,HAMEL C P.The retinal pigment epithelium in health and disease[J].Curr Mol Med,2010,10(9):802-823.
[40] EASTLAKE K,BANERJEE P J,ANGBOHANG A,CHARTERIS D G,KHAW P T,LIMB G A.Müller glia as an important source of cytokines and inflammatory factors present in the gliotic retina during proliferative vitreoretinopathy[J].Glia,2016,64(4):495-506.
[41] UMAZUME K,BARAK Y,MCDONALD K,LIU L,KAPLAN H J,TAMIYA S.Proliferative vitreoretinopathy in the swine-a new model[J].Invest Ophthalmol Vis Sci,2012,53(8):4910-4916.


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[2]吴岩 于靖.增生性玻璃体视网膜病变相关蛋白研究进展[J].眼科新进展,2012,32(1):000.
[3]赵红梅 于靖 盛敏杰 陈轶卉.胰岛素样生长因子结合蛋白-6对 RPE 细胞增殖和迁移的影响[J].眼科新进展,2012,32(3):000.
[4]司艳芳 王君 关娟 韩泉洪 惠延年.α-平滑肌肌动蛋白在PVR增生膜中的表达以及PDGF对其在人RPE细胞中表达的影响[J].眼科新进展,2012,32(11):000.
[5]刘巍 邓爱军 刘建伟 刘艳 丁敏.β-葡聚糖对大鼠增生性玻璃体视网膜病变的作用及其机制研究[J].眼科新进展,2013,33(10):000.
[6]李林 徐剑容 王咏针 孙玉莹 李斌. 微小RNA-7对人视网膜色素上皮细胞增生和迁移的影响[J].眼科新进展,2014,34(2):122.
[7]司艳芳 樊旭 关娟 周历 赵娟. 非转移性黑色素瘤糖蛋白B在增生性玻璃体视网膜病变及视网膜色素上皮细胞中的作用[J].眼科新进展,2014,34(2):131.
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更新日期/Last Update: 2018-07-12