姚曉倩 方媛 陳君毅

·綜述·

調(diào)控Müller 細(xì)胞增殖分化的因子及信號通路的研究

姚曉倩 方媛 陳君毅

Müller 細(xì)胞是視網(wǎng)膜內(nèi)最主要的膠質(zhì)細(xì)胞。斑馬魚和鳥類等低等脊椎動物的視網(wǎng)膜Müller細(xì)胞具有視網(wǎng)膜前體細(xì)胞的特性，當(dāng)視網(wǎng)膜損傷后，Müller細(xì)胞進入細(xì)胞周期增殖并分化產(chǎn)生新的視網(wǎng)膜神經(jīng)細(xì)胞。但是哺乳動物視網(wǎng)膜損傷后，Müller細(xì)胞活化肥大，幾乎不能進入細(xì)胞周期，其增殖分化能力大大降低。目前，許多研究機構(gòu)致力于研究如何促使哺乳動物視網(wǎng)膜Müller細(xì)胞增殖并分化為視網(wǎng)膜神經(jīng)細(xì)胞，如光感受器細(xì)胞和視網(wǎng)膜神經(jīng)節(jié)細(xì)胞 (RGC)等，以期可以挽救年齡相關(guān)性黃斑變性、青光眼及糖尿病性視網(wǎng)膜病變等患者的視覺損害。以往研究表明，生長因子(EGF，F(xiàn)GF2等)、轉(zhuǎn)錄因子(Ascl1a,Atoh)等可通過一些重要的信號通路，如Notch, Wnt, MAPK, Jak/Stat等調(diào)控視網(wǎng)膜Müller細(xì)胞的增殖及分化。本綜述將目前已知的促使Müller細(xì)胞增殖和分化的因子及信號通路進行分類闡述，為治療視網(wǎng)膜神經(jīng)元損傷致盲疾病的研究提供思路。(中國眼耳鼻喉科雜志，2017，17：431-435)

Müller細(xì)胞;增殖;分化;生長因子;信號通路

Müller細(xì)胞是脊椎動物視網(wǎng)膜最主要的膠質(zhì)細(xì)胞，它幾乎貫穿整個視網(wǎng)膜，在解剖結(jié)構(gòu)和功能上，與視網(wǎng)膜各層神經(jīng)元的胞體和突起間有著廣泛的聯(lián)系[1-2]。在斑馬魚等實驗中發(fā)現(xiàn)，Müller細(xì)胞是視網(wǎng)膜受損后視網(wǎng)膜神經(jīng)細(xì)胞再生的主要來源，其可以迅速進入細(xì)胞周期，去分化為多潛能的視網(wǎng)膜前體細(xì)胞，并進一步分化為各種視網(wǎng)膜神經(jīng)細(xì)胞以替代受損的細(xì)胞[3-4]；在鳥類動物中，Müller細(xì)胞的增殖能力明顯降低，且只能分化為部分視網(wǎng)膜神經(jīng)細(xì)胞[5]；在哺乳動物的受損視網(wǎng)膜中，Müller細(xì)胞活化肥大，幾乎不能進入細(xì)胞周期，但在某些特定條件下Müller細(xì)胞可以增殖并分化為視網(wǎng)膜神經(jīng)細(xì)胞[6-7]。因此，Müller細(xì)胞被認(rèn)為是成年哺乳動物眼內(nèi)的一種潛在視網(wǎng)膜干細(xì)胞。目前，年齡相關(guān)性黃斑變性、青光眼及糖尿病性視網(wǎng)膜病變等主要的不可逆致盲性眼病最終都會導(dǎo)致視網(wǎng)膜神經(jīng)細(xì)胞的丟失。所以如何激活視網(wǎng)膜內(nèi)源性干細(xì)胞，使其增殖并分化為有視功能的神經(jīng)細(xì)胞，如光感受器細(xì)胞和視網(wǎng)膜神經(jīng)節(jié)細(xì)胞 (retinal ganglion cell, RGC)，已成為目前眼科領(lǐng)域以及干細(xì)胞研究領(lǐng)域的研究熱點。本文就調(diào)控Müller細(xì)胞增殖和分化的因子及通路機制做一綜述。

1 調(diào)控視網(wǎng)膜Müller細(xì)胞增殖分化的主要因子及通路

1.1 表皮細(xì)胞生長因子 2012年Wan等[8]研究發(fā)現(xiàn)，在機械損傷的斑馬魚或向正常斑馬魚眼內(nèi)注射肝素結(jié)合的表皮細(xì)胞生長因子(heparin-binding epidermal-like growth factor， HB-EGF),可促進Müller細(xì)胞去分化為視網(wǎng)膜前體細(xì)胞，HB-EGF/表皮生長因子受體(epidermal growth factor receptor， EGFR)/絲裂原活化蛋白激酶(mitogen-activated protein kinases，MAPK)信號通路調(diào)控Müller細(xì)胞去分化進程；同時，發(fā)現(xiàn)損傷后Achaete-scute homolog 1 (Ascl1a) 表達(dá)增加, HB-EGF調(diào)控?fù)p傷后視網(wǎng)膜Müller細(xì)胞去分化的機制還可能有EGFR/MAPK/Ascl1a信號通路的參與。在注射HB-EGF 14 d后，增殖細(xì)胞(BrdU+)可與視錐細(xì)胞標(biāo)記物(Zpr1)、雙極細(xì)胞標(biāo)記物(PKC)、無長突細(xì)胞標(biāo)記物(HuC/D)及RGC標(biāo)記物(Zn5)共染，說明增殖細(xì)胞可以分化為各種視網(wǎng)膜神經(jīng)元。但在2013年，Nelson等[9]報道斑馬魚視網(wǎng)膜光損傷后，HB-EGF不是引起Müller細(xì)胞增殖的因子，因為受損的光感受器細(xì)胞并不產(chǎn)生HB-EGF。說明即使相同物種，但不同的視網(wǎng)膜損傷模型中促使Müller細(xì)胞的增殖機制可能并不相同。

研究發(fā)現(xiàn)，給出生后10 d的大鼠玻璃體腔內(nèi)注射表皮細(xì)胞生長因子(epidermal growth factor， EGF)，發(fā)現(xiàn)促進了Müller細(xì)胞的增殖；但是EGF或者HB-EGF并不能促進成年大鼠正常視網(wǎng)膜中Müller細(xì)胞的增殖及分化。在成年大鼠光損傷模型中或者利用NMDA造成的成年小鼠視網(wǎng)膜損傷后，EGFR表達(dá)增加，玻璃體腔注射EGF或者HB-EGF可以促進Müller細(xì)胞增殖。成年小鼠眼內(nèi)聯(lián)合注入NMDA及EGF 5 d后，發(fā)現(xiàn)增殖細(xì)胞向無長突細(xì)胞及RGC分化[7, 10-11]。HB-EGF對小鼠視網(wǎng)膜Müller細(xì)胞增殖調(diào)控通過MAPK，JAK/ signal transducer and activator of transcription (STAT)信號通路來實現(xiàn)[10]。綜上所述，EGF以及HB-EGF主要通過與受體EGFR受體結(jié)合，然后通過下游MAPK, Janus kinase/signal transducers 3(Jak/stat3)信號通路來調(diào)控視網(wǎng)膜Müller細(xì)胞增殖。

1.2 成纖維細(xì)胞生長因子2及胰島素 2002年，F(xiàn)ischer等[12]研究發(fā)現(xiàn)，給出生后7 d的雞眼內(nèi)聯(lián)合注射成纖維細(xì)胞生長因子(fibroblast growth factor， FGF)2和胰島素(insulin)，注射后發(fā)現(xiàn)Müller細(xì)胞來源的前體細(xì)胞(MGPCs)增殖，并且增殖細(xì)胞從視網(wǎng)膜周邊遷徙到中心區(qū)域。2周后發(fā)現(xiàn)一些增殖細(xì)胞分化為Müller細(xì)胞，少量分化為無長突細(xì)胞及雙極細(xì)胞。但當(dāng)FGF2或者胰島素單獨作用時并不促進視網(wǎng)膜前體細(xì)胞的增殖及分化[12]。2016年，Todd 等[13]將NMDA造成雞視網(wǎng)膜損傷或向正常雞玻璃體腔注射FGF2后發(fā)現(xiàn)glycoprotein(gp130)/Jak/Stat3信號通路活化，此通路可促進Müller 細(xì)胞來源的前體細(xì)胞的形成，但是抑制前體細(xì)胞向視網(wǎng)膜神經(jīng)細(xì)胞的分化。這與Fischer 研究結(jié)果有些相悖。

2008年，Karl 等[11]在NMDA造成小鼠視網(wǎng)膜損傷后，連續(xù)眼內(nèi)注射FGF1/胰島素 4 d ，發(fā)現(xiàn)視網(wǎng)膜Müller細(xì)胞的增殖，且少量增殖細(xì)胞分化為無長突細(xì)胞及水平細(xì)胞，但未發(fā)現(xiàn)增殖細(xì)胞向神經(jīng)節(jié)細(xì)胞分化。研究者體外培養(yǎng)人Müller 細(xì)胞(human Müller cell，hMC)，發(fā)現(xiàn)不同培養(yǎng)環(huán)境下可以分化成不同類型的RGC。如在FGF2及DAPT 作用下，其可分化成RGC；在FGF2，retinoic acid，IGF-1，taurine作用下可分化為光感受器細(xì)胞。將這些分化細(xì)胞移植到視網(wǎng)膜受損的大鼠眼內(nèi)，可以和周圍的視網(wǎng)膜神經(jīng)元建立突觸聯(lián)系并釋放一些神經(jīng)保護因子，從而有助于RGCs及光感受器細(xì)胞功能的修復(fù)[14-16]。結(jié)果表明，F(xiàn)GF2及胰島素可以促進雞視網(wǎng)膜Müller細(xì)胞的增殖及分化；在體外研究中，其可促進哺乳動物Müller細(xì)胞向視網(wǎng)膜神經(jīng)細(xì)胞分化。

1.3 Notch信號通路 研究發(fā)現(xiàn)，Notch信號通路可以抑制正常及損傷(機械損傷，光損傷)的斑馬魚視網(wǎng)膜Müller細(xì)胞進入細(xì)胞周期；抑制Notch促進正常斑馬魚Müller細(xì)胞的增殖是通過調(diào)控Ascl1a 及 Stat3 的表達(dá)來實現(xiàn)的。給正常斑馬魚眼內(nèi)注射Notch抑制劑及腫瘤壞死因子α(tumor necrosis factor-α， TNF-α)，可以促進Müller細(xì)胞進入細(xì)胞周期并促進視網(wǎng)膜前體細(xì)胞的增殖；11 d后，發(fā)現(xiàn)增殖細(xì)胞可以與視網(wǎng)膜神經(jīng)細(xì)胞標(biāo)記物zpr-1、PKC及HuC/D等共表達(dá)[8, 17]，說明Notch通路抑制斑馬魚Müller細(xì)胞的增殖及分化進程。

2007年，NMDA造成的雞視網(wǎng)膜損傷后第4天注入Notch 信號通路抑制劑DAPT，4 d后，Hayes等[18]發(fā)現(xiàn)增殖細(xì)胞與視網(wǎng)膜神經(jīng)細(xì)胞標(biāo)記物，Hu，calretinin(無長突細(xì)胞，神經(jīng)節(jié)細(xì)胞，水平細(xì)胞)，islet(神經(jīng)節(jié)細(xì)胞，無長突細(xì)胞，雙極細(xì)胞)及visinin(視錐細(xì)胞)共染，且DAPT組與對照組(DMSO)相比，共染細(xì)胞數(shù)目明顯增多，說明抑制Notch通路可以促進Müller細(xì)胞增殖分化。2010年， Ghai等[19]在正常雞眼內(nèi)注射DAPT后，可抑制FGF2/MAPK調(diào)控下Müller細(xì)胞的增殖。Todd 等[13]證明gp130/Jak/Stat信號通路調(diào)控?fù)p傷后，雞視網(wǎng)膜Müller細(xì)胞的增殖分化。抑制gp130后，他們發(fā)現(xiàn)Notch 信號通路相關(guān)基因notch1與hes5下調(diào)，同時抑制gp130和Notch信號通路將促進Müller 細(xì)胞來源前體細(xì)胞向視網(wǎng)膜神經(jīng)細(xì)胞分化。這些結(jié)果表明，Notch通路對雞視網(wǎng)膜Müller細(xì)胞增殖分化的調(diào)控作用在不同時期有所不同。

在哺乳動物的研究中，2009年，Muto等[20]發(fā)現(xiàn)體外培養(yǎng)的小鼠視網(wǎng)膜細(xì)胞，Notch信號通路可調(diào)控SOX8及SOX9,后兩者對Müller細(xì)胞增殖有重要作用，抑制Notch可減少SOX8及SOX9的表達(dá)。2010年，Del等[21]在體外培養(yǎng)小鼠視網(wǎng)膜組織，加入Notch激動劑Jag1及Wnt3a，3 d后發(fā)現(xiàn)內(nèi)核層的Müller細(xì)胞增殖，1周后發(fā)現(xiàn)增殖細(xì)胞遷徙到外核層并可表達(dá)光感受器標(biāo)記物opsin，說明增殖細(xì)胞分化為感光細(xì)胞。體內(nèi)研究為給出生后10 d S334ter大鼠(視網(wǎng)膜色素大鼠模型)玻璃體腔內(nèi)連續(xù) 2 d 注射Jag1和Wnt2b，接下來3 d分別注射shh，shh+DAPT，DAPT；在第31天，發(fā)現(xiàn)Müller來源的增殖細(xì)胞可以和opsin共表達(dá)，說明通過先激活Notch和Wnt通路刺激增殖，然后通過抑制Notch通路和激活Shh通路誘導(dǎo)分化，可以在體內(nèi)實現(xiàn)Müller細(xì)胞增殖并分化為感光細(xì)胞[21]。2013年，Song等[22]在體外培養(yǎng)出生21 d大鼠視網(wǎng)膜Müller細(xì)胞，發(fā)現(xiàn)Atoh7可促進Müller細(xì)胞來源干細(xì)胞分化為RGC，這種促分化作用是通過抑制Notch信號通路來實現(xiàn)的。2015年，Jian等[23]發(fā)現(xiàn)，對大鼠腹腔注射NaIO3造成其視網(wǎng)膜損傷，Notch1及其配體Delta在損傷早期表達(dá)下調(diào)，從而刺激Müller細(xì)胞進入細(xì)胞周期，促進細(xì)胞增殖；在損傷后第3天開始，發(fā)現(xiàn)一些增殖細(xì)胞可表達(dá)光感受器細(xì)胞標(biāo)記物-crx及rhodopsin；在損傷第28天，仍可觀察到這種分化細(xì)胞存在。以上的研究表明，Notch通路既可以抑制又可促進Müller細(xì)胞的增殖，且對于抑制干細(xì)胞的分化上發(fā)揮了重要作用。

1.4 Wnt信號通路 研究[24-25]發(fā)現(xiàn)在熱/光損傷的斑馬魚模型中，Ascl1a 表達(dá)增加，其不但可以下調(diào)Wnt 信號通路抑制因子Dkk的表達(dá)，而且還可上調(diào)Wnt4a的表達(dá)，Wnt/β-catenin信號通路可促進視網(wǎng)膜前體細(xì)胞的增殖而抑制其分化進程。2016年，Gallina等[26]研究發(fā)現(xiàn)，玻璃體腔內(nèi)注射NMDA造成雞胚視網(wǎng)膜損傷；在損傷后第3天，Müller來源的前體細(xì)胞中β-catenin達(dá)到高峰。抑制Wnt信號通路可抑制MGPCs的形成。給正常雞眼內(nèi)注射FGF2，F(xiàn)GF2/MAPK信號通路促進MGPCs的發(fā)育進程需要通過激活Wnt/β-catenin信號通路來實現(xiàn)。

2006年，Das等[27]發(fā)現(xiàn)在出生后21 d的大鼠玻璃體腔注射NMDA。若同時聯(lián)合注射Wnt2b, Müller細(xì)胞的增殖明顯增多。2007年，Osakata 等[28]發(fā)現(xiàn)，體外培養(yǎng)成年大鼠的視網(wǎng)膜組織，加入Wnt3a后，Müller細(xì)胞來源的增殖細(xì)胞數(shù)目明顯增多。當(dāng)加入Wnt信號通路阻滯劑Dkk-1后，增殖細(xì)胞數(shù)目明顯減少。他們又研究了Wnt/β-catenin在小鼠體內(nèi)的作用，選用Wnt reporter(TOPGAL)小鼠，在視網(wǎng)膜正常小鼠中未發(fā)現(xiàn)細(xì)胞表達(dá)β-galactosidase(β-gal)；但對小鼠玻璃體腔注射NMDA后，發(fā)現(xiàn)β-gal+細(xì)胞，且玻璃體腔注射Wnt3a 后可引起β-gal+細(xì)胞數(shù)目增多，這些增殖細(xì)胞表達(dá)Müller細(xì)胞特性。同樣，對視網(wǎng)膜色素變性模型小鼠玻璃體腔注射Wnt3a 后，增殖細(xì)胞數(shù)目增多[28]。2016年，Yao等[29]在NMDA造成成年小鼠視網(wǎng)膜損傷后，Wnt 信號通路被激活，從而促進Müller細(xì)胞增殖。將含有β-catenin基因的adeno-associated virus (AAV)轉(zhuǎn)染到正常小鼠眼內(nèi)，發(fā)現(xiàn)其可以促進Müller細(xì)胞重新進入細(xì)胞周期，并且增殖細(xì)胞可進一步分化為無長突細(xì)胞。2016年，Angbohang等[30]在體外培養(yǎng)人Müller干細(xì)胞(hMSC)，發(fā)現(xiàn)insulin-like growth factor type1(FTRI)通過促進經(jīng)典Wnt 信號通路配體Wnt2b的表達(dá)來調(diào)控光感受器細(xì)胞的分化進程。轉(zhuǎn)化生長因子(transforming growth factor, TGF)β1可能通過下調(diào)經(jīng)典Wnt通路配體Wnt2b及上調(diào)非經(jīng)典Wnt通路配體Wnt5b抑制FTRI對hMSC的這種調(diào)控作用。同年，Sanges等[31]將造血干細(xì)胞(hematopoietic stem and progenitor cell, HSPC)移植到視網(wǎng)膜色素變性模型小鼠視網(wǎng)膜上，發(fā)現(xiàn)HSPC與Müller細(xì)胞迅速融合，在Wnt信號通路的作用下可促進HSPC-Müller細(xì)胞混合體向光感受器細(xì)胞分化。綜上所述，Wnt信號通路是調(diào)控Müller細(xì)胞增殖分化的重要通路，可以和多種因子間相互作用，其作用機制還有待進一步探究。

2 其他因子及信號通路對視網(wǎng)膜Müller細(xì)胞增殖分化的影響

2.1 睫狀體神經(jīng)營養(yǎng)因子 2005年，Goureau等[32]發(fā)現(xiàn)睫狀體神經(jīng)營養(yǎng)因子(ciliary neurotrophic factor,CNTF)可以促進體外培養(yǎng)的小鼠Müller細(xì)胞增殖，其是通過細(xì)胞外調(diào)節(jié)蛋白激酶(extracellular regulated protein kinases, ERK)/Stat3信號通路來實現(xiàn)。2009年，在斑馬魚模型中，Kassen等[33]證明CNTF通過Stat3信號通路調(diào)控Müller細(xì)胞的增殖。2016年， Todd 等[13]給正常剛出生雞玻璃體腔內(nèi)聯(lián)合注射CNTF和FGF2，與單獨注射FGF2相比，Müller細(xì)胞增殖細(xì)胞數(shù)目明顯增加，證明FGF2，CNTF 通過調(diào)控Jak/Stat3，MAPK等信號通路調(diào)控Müller細(xì)胞的增殖。

2.2 腦源性神經(jīng)營養(yǎng)因子 2004年，Pinzón-Duarte 等[34]發(fā)現(xiàn)腦源性神經(jīng)營養(yǎng)因子(brain-derived neurotrophic factor，BDNF)可以促進體外培養(yǎng)的大鼠Müller細(xì)胞增殖。2010年，曾琦等[35]將Müller細(xì)胞來源的神經(jīng)球轉(zhuǎn)移到含有BDNF的培養(yǎng)基中培養(yǎng)7～10 d，可以進一步分化為RGC。2011年，Harada等[36]將MNU注射到小鼠腹腔后，給其眼內(nèi)注射BDNF，發(fā)現(xiàn)BDNF通過結(jié)合其受體TrkB來調(diào)控Müller細(xì)胞增殖。

2.3 Sonic hedgehog(Shh) 2015年，Todd 等[13]發(fā)現(xiàn)，將NMDA注射到雞(6～28 d)玻璃體腔后, Shh 調(diào)控其Müller細(xì)胞的去分化和增殖。2007年，Wan等[37]研究發(fā)現(xiàn)Shh可以促進體外培養(yǎng)的大鼠Müller細(xì)胞增殖及去分化進程。給正常大鼠玻璃體腔內(nèi)注射Shh并未發(fā)現(xiàn)增殖細(xì)胞，但當(dāng)MNU造成視網(wǎng)膜受損后再注射Shh則發(fā)現(xiàn)明顯的Müller細(xì)胞增殖，而且增殖細(xì)胞最后分化為表達(dá)rhodopsin的感光細(xì)胞。2016年，Gueta等[38]發(fā)現(xiàn)LIM domain binding (Ldb) 蛋白1/Ldb2-Lhx2復(fù)合體通過Notch及Shh信號通路調(diào)控小鼠視網(wǎng)膜前體細(xì)胞的增殖進程，抑制Shh信號通路，發(fā)現(xiàn)視網(wǎng)膜前體細(xì)胞增殖減弱，且RGC的數(shù)量減少。

2.4 腫瘤壞死因子α 2013年Nelson等[39]發(fā)現(xiàn)斑馬魚光損傷后死亡的感光細(xì)胞會產(chǎn)生腫瘤壞死因子α(tumor necrosis factor-α，TNFα)，隨后TNFα也會在Müller細(xì)胞中表達(dá)。直接加入TNFα蛋白可以促進正常視網(wǎng)膜中Müller細(xì)胞增殖；TNFα調(diào)控Müller細(xì)胞去分化的分子機制可能主要通過ASCL1a通路和Stat3通路來調(diào)控。TNFα作為一種炎癥因子，目前研究也只發(fā)現(xiàn)其對斑馬魚視網(wǎng)膜Müller細(xì)胞增殖有促進作用，在哺乳動物中(豬缺血再灌注模型)只發(fā)現(xiàn)TNFα在Müller細(xì)胞及外叢狀層中表達(dá)上調(diào)[40-41]，其是否對Müller細(xì)胞有促進增殖作用尚不清楚。

2.5 谷氨酸鹽及其擬似物α-Aminadipate 2004年，Ooto等[42]發(fā)現(xiàn)，谷氨酸受體激動劑NMDA注射到成年大鼠玻璃體腔后，發(fā)現(xiàn)少量的Müller細(xì)胞增殖，并且增殖細(xì)胞可表達(dá)雙極細(xì)胞和視桿細(xì)胞標(biāo)記物，推測增殖細(xì)胞發(fā)生了分化。2008年Takeda等[43]在成年小鼠視網(wǎng)膜下腔注射谷氨酸鹽(l-glutamate)及其擬似物α-Aminadipate (α-AA)，發(fā)現(xiàn)谷氨酸鹽及α-AA組視網(wǎng)膜上可見明顯的增殖細(xì)胞，并且增殖細(xì)胞可表達(dá)Müller細(xì)胞標(biāo)記物，推測來源于Müller細(xì)胞，最終增殖細(xì)胞可分化為感光細(xì)胞。

3 結(jié)語

近年來，對于視網(wǎng)膜Müller細(xì)胞的增殖和分化的調(diào)控機制的研究已經(jīng)取得了很多進展，目前的研究熱點集中在EGF、Wnt及Notch通路的研究。但仍有很多未知：比如新增殖的細(xì)胞無法長期存活，不能做到真正功能的恢復(fù)；在體內(nèi)實驗中視網(wǎng)膜的新增殖細(xì)胞無確切證據(jù)追溯其來源；在哺乳動物的體內(nèi)實驗內(nèi)，新增殖的細(xì)胞還無分化為視網(wǎng)膜神經(jīng)節(jié)細(xì)胞的報道；以及各種因子之間的協(xié)同作用尚不清楚。這些都需要今后的實驗進一步解決，從而為更好地調(diào)控Müller細(xì)胞增殖和分化，實現(xiàn)視網(wǎng)膜神經(jīng)細(xì)胞再生，治療各種神經(jīng)細(xì)胞喪失的眼病提供新的思路和方法。

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2016-10-27)

(本文編輯 諸靜英)

FactorsandsignalingpathwaysregulatingMüllercellstoproliferateanddifferentiate

YAOXiao-qian,FANGYuan,CHENJun-yi.

DepartmentofOphthalmology,EyeEarNoseandThroatHospitalofFudanUniversity,Shanghai200031,China

CHEN Jun-yi, Email: clyde-chen@163.com

Müller cells are the main glial cells in the retina, which display the characteristics of retinal progenitor cells in lower vertebrate, such as zebrafish and birds. When the retina injuries, the Müller cells in lower vertebrate can reenter the cell cycle, proliferate and differentiate into new retinal cells. However, when the retina injuries, the Müller cells in mammals are activated and become hypertrophy, which almost can not reenter the cell cycle and the capacity of proliferation and differentiation is limited. In order to rescue the visual impairment in patients with age-related macular degeneration, glaucoma and diabetic retinopathy, at present many research institutions are dedicated to improve the Müller cells proliferation in mammals and make them differentiate into retinal neuronal cells, like photoreceptor cells, retinal ganglion cells, etc. Previous studies presented that some growth factors (EGF, FGF2), transcription factors (Ascl1a, Atoh7) et al. could regulate the proliferation and differentiation of Müller cells through various signaling pathways, such as Notch, Wnt, MAPK and Jak/Stat et al. This paper reviewed the current known growth factors and signaling pathways that regulate Müller cells proliferation and differentiation and provided new insights in the treatment of retinal blinding diseases. (Chin J Ophthalmol and Otorhinolaryngol,2017,17:431-435)

Müller cells; Proliferation; Differentiation; Growth factors; Signaling pathways

復(fù)旦大學(xué)附屬眼耳鼻喉科醫(yī)院眼科 上海 200031

陳君毅(Email: clyde-chen@163.com)

10.14166/j.issn.1671-2420.2017.06.015