调控Müller细胞增殖分化的因子及信号通路的研究
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摘要
Müller细胞是视网膜内最主要的胶质细胞。斑马鱼和鸟类等低等脊椎动物的视网膜Müller细胞具有视网膜前体细胞的特性,当视网膜损伤后,Müller细胞进入细胞周期增殖并分化产生新的视网膜神经细胞。但是哺乳动物视网膜损伤后,Müller细胞活化肥大,几乎不能进入细胞周期,其增殖分化能力大大降低。目前,许多研究机构致力于研究如何促使哺乳动物视网膜Müller细胞增殖并分化为视网膜神经细胞,如光感受器细胞和视网膜神经节细胞(RGC)等,以期可以挽救年龄相关性黄斑变性、青光眼及糖尿病性视网膜病变等患者的视觉损害。以往研究表明,生长因子(EGF,FGF2等)、转录因子(Ascl1a,Atoh)等可通过一些重要的信号通路,如Notch,Wnt,MAPK,Jak/Stat等调控视网膜Müller细胞的增殖及分化。本综述将目前已知的促使Müller细胞增殖和分化的因子及信号通路进行分类阐述,为治疗视网膜神经元损伤致盲疾病的研究提供思路。
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( Ascl1 a,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.
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( Ascl1 a,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.
引文
[1]高凤,季敏,吴继红,等.视网膜Müller细胞的生理功能及在青光眼病理中的作用[J].生理学报,2013,65(6):654-663.
[2]Bringmann A,Pannicke T,Grosche J et al.Müller cells in the healthy and diseased retina[J].Prog Retin Eye Res,2006,25(4):397-424.
[3]Kassen SC,Ramanan V,Montgomery JE,et al.Time course analysis of gene expression during light-induced photoreceptor cell death and regeneration inalbino zebrafish[J].Dev Neurobiol,2007,67(8):1009-1031.
[4]Thummel R,Kassen SC,Montgomery JE,et al.Inhibition of Müller glial cell division blocks regeneration of the light-damaged zebrafish retina[J].Dev Neurobiol,2008,68(3):392-408.
[5]Fischer AJ,Reh TA.Muller glia are a potential source of neural regeneration in the postnatal chicken retina[J].Nat Neurosci,2001,4(3):247-252.
[6]Chang ML,Wu CH,Jiang-Shieh YF,et al.Reactive changes of retinal astrocytes and Müller glial cells in kainate-induced neuroexcitotoxicity[J].J Anat,2007,210(1):54-65.
[7]Close JL,Liu J,Gumuscu B,et al.Epidermal growth factor receptor expression regulates proliferation in the postnatal rat retina[J].Glia,2006,54(2):94-104.
[8]Wan J,Ramachandran R,Goldman D.HB-EGF is necessary and sufficient for Muller glia dedifferentiation and retina regeneration[J].Dev Cell,2012,22(2):334-347.
[9]Nelson CM,Ackerman KM,O'Hayer P,et al.Tumor necrosis factoralpha is produced by dying retinal meurons and is required for müller glia proliferation during zebrafish retinal regeneration[J].J Neurosci,2013,33(15):6524-6539.
[10]Todd L,Volkov LI,Zelinka C,et al.Heparin-binding EGF-like growth factor(HB-EGF)stimulates the proliferation of Müller gliaderived progenitor cells in avian and murine retinas[J].Mol Cell Neurosci,2015,69:54-64.
[11]Karl MO,Hayes S,Nelson BR,et al.Stimulation of neural regeneration in the mouse retina[J].Proc Natl Acad Sci U S A,2008,105(49):19508-19513.
[12]Fischer AJ,Mc Guire CR,Dierks BD,et al.Insulin and fibroblast growth factor 2 activate a neurogenic program in Muller glia of the chicken retina[J].J Neurosci,2002,22(21):9387-9398.
[13]Todd L,Squires N,Suarez L,et al.Jak/Stat signaling regulates the proliferation and neurogenic potential of Müller glia-derived progenitor cells in the avian retina[J].Sci Rep,2016,6:35703.
[14]Jayaram H,Jones MF,Eastlake K,et al.Transplantation of photoreceptors derived from human Müller glia restore rod function in the P23H rat[J].Stem Cells Transl Med,2014,3(3):323-333.
[15]Giannelli SG,Demontis GC,Pertile G,et al.Adult human müller glia cells are a highly efficient source of rod photoreceptors[J].Stem Cells,2011,29(2):344-356.
[16]Singhal S,Bhatia B,Jayaram H,et al.Human müller glia with stem cell characteristics differentiate into retinal ganglion cell(RGC)precursors in vitro and partially restore RGC function in vivo following transplantation[J].Stem Cells Transl Med,2012,1(3):188-199.
[17]Conner C,Ackerman KM,Lahne M,et al.Repressing Notch Signaling and Expressing TNFα?Are Sufficient to Mimic Retinal Regeneration by Inducing Muller Glial Proliferation to Generate Committed Progenitor Cells[J].J Neurosci,2014,34(43):14403-14419.
[18]Hayes S,Nelson BR,Buckingham B,et al.Notch signaling regulates regeneration in the avian retina[J].Dev Biol,2007,312(1):300-311.
[19]Ghai K,Zelinka C,Fischer AJ.Notch signaling influences neuroprotective and proliferative properties of mature müller glia[J].J Neurosci,2010,30(8):3101-3112.
[20]Muto A,Iida A,Satoh S,et al.The group E Sox genes Sox8 and Sox9 are regulated by Notch signaling and are required for Müller glial cell development in mouse retina[J].Exp Eye Res,2009,89(4):549-558.
[21]Del Debbio CB,Balasubramanian S,Parameswaran S,et al.Notch and Wnt signaling mediated rod photoreceptor regeneration by Muller cells in adult mammalian retina[J].PLo S One,2010,5(8):e12425.
[22]Song WT,Zhang XY,Xia XB.Atoh7 promotes the differentiation of retinal stem cells derived from Müller cells into retinal ganglion cells by inhibiting Notch signaling[J].Stem Cell Res Ther,2013,4(4):94.
[23]Jian Q,Tao Z,Li Y,et al.Acute retinal injury and the relationship between nerve growth factor,Notch1 transcription and short-lived dedifferentiation transient changes of mammalian Müller cells[J].Vision Res,2015,110(Pt A):107-117.
[24]Ramachandran R,Zhao XF,Goldman D.Ascl1a/Dkk/β-catenin signaling pathway is necessary and glycogen synthase kinase-3Beta inhibition is sufficient for zebrafish retina regeneration[J].Proc Natl Acad Sci U S A,2011,108(38):15858-15863.
[25]Meyers JR,Hu L,Moses A,et al.β-catenin/Wnt signaling controls progenitor fate in the developing and regenerating zebrafish retina[J].Neural Dev,2012,7:30.
[26]Gallina D,Palazzo I,Steffenson L,et al.Wnt/β-catenin-signaling and the formation of Müller glia-derived progenitors in the chick retina[J].Dev Neurobiol,2016,76(9):983-1002.
[27]Das AV,Mallya KB,Zhao X,et al.Neural stem cell properties of Müller glia in the mammalian retina:regulation by motch and wnt signaling[J].Dev Biol,2006,299(1):283-302.
[28]Osakada F,Ooto S,Akagi T,et al.Wnt signaling promotes regeneration in the retina of adult mammals[J].J Neurosci,2007,27(15):4210-4219.
[29]Yao K,Qiu S,Tian L,et al.Wnt Regulates proliferation and neurogenic potential of müller glial cells via a lin28/let-7 miRNAdependent pathway in adult mammalian retinas[J].Cell Rep,2016,17(1):165-178.
[30]Angbohang A,Wu N,Charalambous T,et al.Downregulation of the canonical WNT signaling pathway by TGFβ1 inhibits photoreceptor differentiation of adult human müller glia with stem cell characteristics[J].Stem Cells Dev,2016,25(1):1-12.
[31]Sanges D,Simonte G,Di Vicino U,et al.Reprogramming Müller glia via in vivo cell fusion regenerates murine photoreceptors[J].J Clin Invest,2016,126(8):3104-3116.
[32]Goureau O,Rhee KD,Yang XJ.Ciliary neurotrophic factor promotes müller glia differentiation from the postnatal retinal progenitor pool[J].Dev Neurosci,2004,26(5-6):359-370.
[33]Kassen SC,Thummel R,Campochiaro LA,et al.CNTF induces photoreceptor neuroprotection and Müller glial cell proliferation through two different signaling pathways in the adult zebrafish retina[J].Exp Eye Res,2009,88(6):1051-1064.
[34]Pinzón-Duarte G,Arango-González B,Guenther E,et al.Effects of brain-derived neurotrophic factor on cell survival,differentiation and patterning of neuronal connections and Müller glia cells in the developing retina[J].Eur J Neurosci,2004,19(6):1475-1484.
[35]曾琦,夏晓波.体外诱导大鼠视网膜Müller细胞向神经节细胞定向分化的研究[J].中华眼科杂志,2010,46(7):615-620.
[36]Harada C,Guo X,Namekata K,et al.Glia-and neuron-specific functions of Trk B signalling during retinal degeneration and regeneration[J].Nat Commun,2011,2:189.
[37]Wan J,Zheng H,Xiao HL,et al.Sonic hedgehog promotes stemcell potential of Müller glia in the mammalian retina[J].Biochem Biophys Res Commun,2007,363(2):347-354.
[38]Gueta K,David A,Cohen T,et al.The stage-dependent roles of Ldb1 and functional redundancy with Ldb2 in mammalian retinogenesis[J].Development,2016,143(22):4182-4192.
[39]Nelson CM,Ackerman KM,O'Hayer P,et al.Tumor necrosis factoralpha is produced by dying retinal neurons and is required for müller glia proliferation during zebrafish retinal regeneration[J].J Neurosci,2013,33(15):6524-6539.
[40]Genini S,Beltran WA,Aguirre GD.Up-regulation of tumor necrosis factor superfamily genes in early phases of photoreceptor degeneration[J].PLo S One,2013,8(12):e85408.
[41]Gesslein B,Hkansson G,Gustafsson L,et al.Tumor necrosis factor and its receptors in the neuroretina and retinal vasculature after ischemia-reperfusion injury in the pig retina[J].Mol Vis,2010,16:2317-2327.
[42]Ooto S,Akagi T,Kageyama R,et al.Potential for neural regeneration after neurotoxic injury in the adult mammalian retina[J].Proc Natl Acad Sci U S A,2004,101(37):13654-13659.
[43]Takeda M,Takamiya A,Jiao JW,et al.alpha-Aminoadipate induces progenitor cell properties of Müller glia in adult mice[J].Invest Ophthalmol Vis Sci,2008,49(3):1142-1150.
[2]Bringmann A,Pannicke T,Grosche J et al.Müller cells in the healthy and diseased retina[J].Prog Retin Eye Res,2006,25(4):397-424.
[3]Kassen SC,Ramanan V,Montgomery JE,et al.Time course analysis of gene expression during light-induced photoreceptor cell death and regeneration inalbino zebrafish[J].Dev Neurobiol,2007,67(8):1009-1031.
[4]Thummel R,Kassen SC,Montgomery JE,et al.Inhibition of Müller glial cell division blocks regeneration of the light-damaged zebrafish retina[J].Dev Neurobiol,2008,68(3):392-408.
[5]Fischer AJ,Reh TA.Muller glia are a potential source of neural regeneration in the postnatal chicken retina[J].Nat Neurosci,2001,4(3):247-252.
[6]Chang ML,Wu CH,Jiang-Shieh YF,et al.Reactive changes of retinal astrocytes and Müller glial cells in kainate-induced neuroexcitotoxicity[J].J Anat,2007,210(1):54-65.
[7]Close JL,Liu J,Gumuscu B,et al.Epidermal growth factor receptor expression regulates proliferation in the postnatal rat retina[J].Glia,2006,54(2):94-104.
[8]Wan J,Ramachandran R,Goldman D.HB-EGF is necessary and sufficient for Muller glia dedifferentiation and retina regeneration[J].Dev Cell,2012,22(2):334-347.
[9]Nelson CM,Ackerman KM,O'Hayer P,et al.Tumor necrosis factoralpha is produced by dying retinal meurons and is required for müller glia proliferation during zebrafish retinal regeneration[J].J Neurosci,2013,33(15):6524-6539.
[10]Todd L,Volkov LI,Zelinka C,et al.Heparin-binding EGF-like growth factor(HB-EGF)stimulates the proliferation of Müller gliaderived progenitor cells in avian and murine retinas[J].Mol Cell Neurosci,2015,69:54-64.
[11]Karl MO,Hayes S,Nelson BR,et al.Stimulation of neural regeneration in the mouse retina[J].Proc Natl Acad Sci U S A,2008,105(49):19508-19513.
[12]Fischer AJ,Mc Guire CR,Dierks BD,et al.Insulin and fibroblast growth factor 2 activate a neurogenic program in Muller glia of the chicken retina[J].J Neurosci,2002,22(21):9387-9398.
[13]Todd L,Squires N,Suarez L,et al.Jak/Stat signaling regulates the proliferation and neurogenic potential of Müller glia-derived progenitor cells in the avian retina[J].Sci Rep,2016,6:35703.
[14]Jayaram H,Jones MF,Eastlake K,et al.Transplantation of photoreceptors derived from human Müller glia restore rod function in the P23H rat[J].Stem Cells Transl Med,2014,3(3):323-333.
[15]Giannelli SG,Demontis GC,Pertile G,et al.Adult human müller glia cells are a highly efficient source of rod photoreceptors[J].Stem Cells,2011,29(2):344-356.
[16]Singhal S,Bhatia B,Jayaram H,et al.Human müller glia with stem cell characteristics differentiate into retinal ganglion cell(RGC)precursors in vitro and partially restore RGC function in vivo following transplantation[J].Stem Cells Transl Med,2012,1(3):188-199.
[17]Conner C,Ackerman KM,Lahne M,et al.Repressing Notch Signaling and Expressing TNFα?Are Sufficient to Mimic Retinal Regeneration by Inducing Muller Glial Proliferation to Generate Committed Progenitor Cells[J].J Neurosci,2014,34(43):14403-14419.
[18]Hayes S,Nelson BR,Buckingham B,et al.Notch signaling regulates regeneration in the avian retina[J].Dev Biol,2007,312(1):300-311.
[19]Ghai K,Zelinka C,Fischer AJ.Notch signaling influences neuroprotective and proliferative properties of mature müller glia[J].J Neurosci,2010,30(8):3101-3112.
[20]Muto A,Iida A,Satoh S,et al.The group E Sox genes Sox8 and Sox9 are regulated by Notch signaling and are required for Müller glial cell development in mouse retina[J].Exp Eye Res,2009,89(4):549-558.
[21]Del Debbio CB,Balasubramanian S,Parameswaran S,et al.Notch and Wnt signaling mediated rod photoreceptor regeneration by Muller cells in adult mammalian retina[J].PLo S One,2010,5(8):e12425.
[22]Song WT,Zhang XY,Xia XB.Atoh7 promotes the differentiation of retinal stem cells derived from Müller cells into retinal ganglion cells by inhibiting Notch signaling[J].Stem Cell Res Ther,2013,4(4):94.
[23]Jian Q,Tao Z,Li Y,et al.Acute retinal injury and the relationship between nerve growth factor,Notch1 transcription and short-lived dedifferentiation transient changes of mammalian Müller cells[J].Vision Res,2015,110(Pt A):107-117.
[24]Ramachandran R,Zhao XF,Goldman D.Ascl1a/Dkk/β-catenin signaling pathway is necessary and glycogen synthase kinase-3Beta inhibition is sufficient for zebrafish retina regeneration[J].Proc Natl Acad Sci U S A,2011,108(38):15858-15863.
[25]Meyers JR,Hu L,Moses A,et al.β-catenin/Wnt signaling controls progenitor fate in the developing and regenerating zebrafish retina[J].Neural Dev,2012,7:30.
[26]Gallina D,Palazzo I,Steffenson L,et al.Wnt/β-catenin-signaling and the formation of Müller glia-derived progenitors in the chick retina[J].Dev Neurobiol,2016,76(9):983-1002.
[27]Das AV,Mallya KB,Zhao X,et al.Neural stem cell properties of Müller glia in the mammalian retina:regulation by motch and wnt signaling[J].Dev Biol,2006,299(1):283-302.
[28]Osakada F,Ooto S,Akagi T,et al.Wnt signaling promotes regeneration in the retina of adult mammals[J].J Neurosci,2007,27(15):4210-4219.
[29]Yao K,Qiu S,Tian L,et al.Wnt Regulates proliferation and neurogenic potential of müller glial cells via a lin28/let-7 miRNAdependent pathway in adult mammalian retinas[J].Cell Rep,2016,17(1):165-178.
[30]Angbohang A,Wu N,Charalambous T,et al.Downregulation of the canonical WNT signaling pathway by TGFβ1 inhibits photoreceptor differentiation of adult human müller glia with stem cell characteristics[J].Stem Cells Dev,2016,25(1):1-12.
[31]Sanges D,Simonte G,Di Vicino U,et al.Reprogramming Müller glia via in vivo cell fusion regenerates murine photoreceptors[J].J Clin Invest,2016,126(8):3104-3116.
[32]Goureau O,Rhee KD,Yang XJ.Ciliary neurotrophic factor promotes müller glia differentiation from the postnatal retinal progenitor pool[J].Dev Neurosci,2004,26(5-6):359-370.
[33]Kassen SC,Thummel R,Campochiaro LA,et al.CNTF induces photoreceptor neuroprotection and Müller glial cell proliferation through two different signaling pathways in the adult zebrafish retina[J].Exp Eye Res,2009,88(6):1051-1064.
[34]Pinzón-Duarte G,Arango-González B,Guenther E,et al.Effects of brain-derived neurotrophic factor on cell survival,differentiation and patterning of neuronal connections and Müller glia cells in the developing retina[J].Eur J Neurosci,2004,19(6):1475-1484.
[35]曾琦,夏晓波.体外诱导大鼠视网膜Müller细胞向神经节细胞定向分化的研究[J].中华眼科杂志,2010,46(7):615-620.
[36]Harada C,Guo X,Namekata K,et al.Glia-and neuron-specific functions of Trk B signalling during retinal degeneration and regeneration[J].Nat Commun,2011,2:189.
[37]Wan J,Zheng H,Xiao HL,et al.Sonic hedgehog promotes stemcell potential of Müller glia in the mammalian retina[J].Biochem Biophys Res Commun,2007,363(2):347-354.
[38]Gueta K,David A,Cohen T,et al.The stage-dependent roles of Ldb1 and functional redundancy with Ldb2 in mammalian retinogenesis[J].Development,2016,143(22):4182-4192.
[39]Nelson CM,Ackerman KM,O'Hayer P,et al.Tumor necrosis factoralpha is produced by dying retinal neurons and is required for müller glia proliferation during zebrafish retinal regeneration[J].J Neurosci,2013,33(15):6524-6539.
[40]Genini S,Beltran WA,Aguirre GD.Up-regulation of tumor necrosis factor superfamily genes in early phases of photoreceptor degeneration[J].PLo S One,2013,8(12):e85408.
[41]Gesslein B,Hkansson G,Gustafsson L,et al.Tumor necrosis factor and its receptors in the neuroretina and retinal vasculature after ischemia-reperfusion injury in the pig retina[J].Mol Vis,2010,16:2317-2327.
[42]Ooto S,Akagi T,Kageyama R,et al.Potential for neural regeneration after neurotoxic injury in the adult mammalian retina[J].Proc Natl Acad Sci U S A,2004,101(37):13654-13659.
[43]Takeda M,Takamiya A,Jiao JW,et al.alpha-Aminoadipate induces progenitor cell properties of Müller glia in adult mice[J].Invest Ophthalmol Vis Sci,2008,49(3):1142-1150.