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视神经再生的研究进展

Research progress of optic nerve regeneratio

来源期刊: 眼科学报 | 2022年1月 第37卷 第1期 14-24 发布时间: 收稿时间:2022/9/27 16:03:35 阅读量:6231
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关键词:
视神经视神经节细胞保护轴突再生视功能重建
optic nerves retinal ganglion cell protection axon regeneration visual function reconstruction
DOI:
10.3978/j.issn.1000-4432.2021.09.02
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视神经属于中枢神经的一部分,损伤后难以再生。视神经损伤通常伴随视网膜神经节细胞(retinal ganglion cells,RGCs)的持续性凋亡及视神经变性坏死,引起视力损害甚至完全失明。目前针对视神经再生的基础研究主要集中于保护和维持视神经损伤后RGCs的存活、促进RGCs轴突再生及重建视神经功能。本文以RGCs保护、轴突再生及视神经功能重建等为关键词,查询国内外最新视神经再生研究类文献,并分析整理,从抗氧化应激、提供外源性细胞因子、炎症刺激、抗胶质瘢痕、基因调控等方面阐述近年的视神经再生研究进展,以期对后续的基础研究开展及临床转化有所帮助。
Optic nerves are a part of the central nervous system, which is difficult to regenerate after injury. Optic nerve injury is usually accompanied by continuous apoptosis of retinal ganglion cells (RGCs) and degeneration or necrosis of optic nerves, resulting in visual impairment or even complete blindness. At present, the basic research on optic nerve regeneration mainly focuses on protecting and maintaining the survival of RGCs after optic nerve injury, promoting RGCs axon regeneration, and reconstructing optic nerve function. In this paper, RGCs protection,axon regeneration, and optic nerve function reconstruction are used as key words to collect the latest domestic and foreign literatures on optic nerve regeneration. The research progress of optic nerve regeneration in recent years was reviewed from the aspects of antioxidant stress, provision of exogenous cytokines, inflammatory stimulation, anti-glial scar, gene regulation and so on, in order to help the follow-up basic research and clinical translation.
    人类所获知的感知信息80%来源于视觉,因此依赖于视神经进行传递的视觉信息对人类至关重要,而视神经由于其胚胎起源和细胞组成而成为中枢神经系统(central nervous system,CNS)不可或缺的部分,并且像大多数成熟哺乳动物的CNS一样,视神经如果受到损伤,其再生能力远远低于周围神经(peripheral nervous system,PNS)的再生[1]。由青光眼、颅脑外伤以及各种缺血性、遗传性、神经性疾病等造成的视神经损伤,使视功能严重受损[2-4],而这种损伤往往导致视网膜神经节细胞(retinal ganglion cells,RGCs)原发性或继发性死亡,最终视神经变性坏死而致盲。因此针对视神经损伤后再生的基础研究对于重建患者失去的视功能具有重大意义。很长时间以来,研究者们一直认为包括视神经在内的CNS较弱的再生能力是中枢神经元细胞的固有特点,但Richardson等[5]的研究结果证实:中枢神经轴突可以再生并长入周围神经移植物内,暗示损伤局部微环境因素,如炎症信号、神经营养因子、凋亡和抗凋亡稳态失衡等,同样影响着CNS轴突再生,这个重大发现改变了人们的看法并尝试进行CNS轴突再生研究。由于视神经独特的可及性,相对简单的解剖结构和功能评价的便利性,其已成为CNS轴突再生主要的研究对象之一[6]近年来,研究者们从多方面开展了视神经保护和损伤修复的深入研究,并取得了一定成果。本文将从调控炎症刺激、不同方式提供内源性或外源性细胞因子抑制凋亡等促进视神经再生、抗氧化药物应用减少氧化应激保护RGCs、干细胞营养或分化补充凋亡的RGCs,以及基因调控RGCs重编程促进再生等方面对视神经损伤后修复再生进行综述。

1 抑制视神经再生的因素

    视神经再生研究一般包含如下3个方面:1)避免视神经损伤后的RGCs凋亡,即RGCs保护。在视神经损伤后常伴随炎症及氧化损伤,可激活RGCs的凋亡程序,促使RGCs凋亡,而大量RGCs凋亡必然影响视神经功能,因此避免RGCs凋亡至关重要。2)促使RGCs轴突沿视神经方向再生,即轴突定向生长。视神经损伤后,轴突断裂,视神经变性坏死失去功能,需要新生轴突重建功能。3 )重建新生轴突的视觉信号转导功能,即视功能重建。在促使RGCs轴突定向再生形成新生神经元后,还需要与脑部建立功能性连接以转导视觉信号,才能改善受损的视功能。视神经再生研究策略示意图见图1。
    视神经再生存在许多限制因素,可分为内在因素和外在因素。内在因素主要表现为RGCs在分化成熟的同时,其细胞内程序向抑制增殖转变[7]。例如环磷酸腺苷(cAMP)、mTOR/PTEN、Kruppel样因子4(Kruppel-like factors 4,KLF4)等可诱导转录级联和表观遗传改变,这些改变与中枢神经系统成熟密切相关[8-10]
    外在因素主要体现在视神经再生的抑制性微环境,主要包括慢性炎症及氧化损伤、神经营养因子缺乏、RGCs损伤凋亡、髓鞘蛋白高表达和损伤处神经胶质瘢痕形成等。视神经损伤后,轴突运输功能障碍导致神经营养因子缺乏,引起RGCs凋亡。而RGCs凋亡会上调凋亡相关信号通路(p53、Bax)的下游因子,增加RGCs氧化应激水平,进一步促进RGCs凋 亡[4,11]。在正常情况下,髓鞘能够隔离轴突,并加速电传导。在中枢神经系统中,髓鞘由少突胶质细胞产生,受到损伤后少突胶质细胞继续表达髓鞘蛋白。而这些髓鞘蛋白碎片已被验证为中枢神经系统中轴突生长的最主要抑制剂之一。例如,Vajda等[12]报道少突胶质细胞上高度表达的髓鞘相关蛋白(Nogo)是中枢神经系统轴突再生的一个主要抑制剂。此外,其他髓鞘蛋白如髓鞘相关糖蛋白(myelin-associated glycoprotein,MAG)、少突胶质细胞髓鞘相关糖蛋白(OMgp)、酪氨酸蛋白激酶B3(ephrin B3)等都被证明与抑制轴突生长相关[6,13-16]。同时中枢神经系统损伤后髓鞘碎片清除效率降低容易导致外环境髓鞘蛋白堆积,髓鞘蛋白不仅能够抑制轴突再生,更能够激活凋亡级联,进一步促进神经元凋亡[15]
    视神经损伤后神经胶质细胞包括少突胶质细胞、星形胶质细胞及小胶质细胞被激活,上调多种轴突生长抑制因子,并促进硫酸软骨素蛋白聚糖及反应性星形胶质细胞形成胶质瘢痕[17-18]。神经胶质瘢痕中含有多种抑制轴突再生因子包括硫酸软骨素蛋白聚糖(chondroitin sulfate proteoglycan,CSPG)、信号蛋白3A(Sema3A)和腱生蛋白-R(TN-R)等,是视神经轴突再生的不适宜环境,也是其生长的物理屏障[19-22]
    基于上述的困难和限制,近年来开展了许多相关的基础研究并取得较好的成果。表1对近年来视神经再生研究策略及研究结果进行了汇总。
20221214110706_8176.png
图1 视神经再生研究策略示意图
Figure 1 Research strategies for optic nerve regeneration

表1 视神经再生研究进展
Table 1 Research progress of optic nerve regeneration

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20221214110846_3128.png

2 抗氧化药物减少氧化应激

    视神经轴突富含线粒体,因此对缺血、缺氧更为敏感。视神经损伤后,由于缺乏氧气及炎症激发,损伤视神经发生严重的活性氧(reactiveoxygen,ROS)积累,产生氧化应激损伤。氧化应激可导致RGCs自噬失衡,并进一步诱导炎症升级,促进RGCs凋亡。使用抗氧化药物减轻ROS积累及氧化应激损伤,有助于保护RGCs存活。维生素C能抑制细胞释放超氧根离子,提高谷胱甘肽过氧化酶(glutathione peroxidase,GSH-Px)活性,从而清除细胞内外的氧自由基。维生素C和维生素E合用有协同作用,可有效防止脂类过氧化,有效降低视神经损伤后RGCs的氧化应激水平,减少RGCs凋亡。Zanon-Moreno等[35]的研究表明:血液中高水平维生素C和维生素E能够降低青光眼患病风险,保护视神经功能。此外,Ekicier Acar等[23]发现:局部联合使用辅酶Q10与维生素E能有效降低视神经损伤后视网膜内Iba1(小胶质细胞/巨噬细胞特异性蛋白)的表达,并能够上调Bcl-xL蛋白水平从而减少RGCs的凋亡。Williams等[23]报道维生素B3能在糖代谢中发挥重要作用,可以维持线粒体的活性,避免RGCs的凋亡。除了应用维生素类药物,也有研究[25,36-37]通过递送其他抗氧化药物如超氧化物歧化酶(SOD)、曲美他嗪(TMZ)、氨基
葡萄糖(GlcN)等抵抗损伤后RGCs中的氧化应激,提高RGCs的存活率。然而视神经损伤后,损伤的视神经长期处于慢性炎症及氧化应激状态,抗氧化药物的应用仅能在短时间内缓解RGCs的氧化损伤,无法长期发挥作用。

3 提供外源性细胞因子

    细胞因子是由免疫细胞或者非免疫细胞经刺激而合成、分泌的一类具有广泛生物学活性的小分子蛋白质,具有调节细胞生长、分化成熟、功能维持、调节免疫应答、参与炎症反应、创伤愈合和肿瘤消长等功能[38]
    红细胞生成素(erythrogenin,EPO)是一种内源性的糖蛋白激素,属于细胞因子I型超家族,有多篇研究报道EPO能对中枢神经系统和周围神经系统产生神经保护和抗凋亡作用,并能在损伤后缓解神经毒性或缺血[39-41]。而后,Hernández等[42]报道了EPO产生神经保护和抗凋亡作用的机制可能是通过JANUS激酶2( JAK2)磷酸化,激活PI3-K、MAPK和STAT5通路,并通过Wnt1维持线粒体膜电位、磷酸化和促进Bad从线粒体向细胞质的易位、减少Bad/Bcl-xL复合物的形成和增加Bcl-xL/Bax复合物的形成,从而调节凋亡级联。此外,Kucuk等[41]报道EPO在包括视网膜和视神经在内的不同组织中具有抗炎、神经保护和神经营养作用。随后,在Kashkouli等[39]进行的临床试验中,使用EPO对外伤性视神经病变(traumatic optic neuropathy,TON)具有显著的治疗效果,与对照组相比在矫正视力和色觉上具有显著差异且无明显的不良反应。
    神经营养因子(nerve growth factor,NGF)是一类由神经元靶细胞分泌的蛋白质或多肽分子,包括脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)、成纤维细胞生长因子-2(fibroblast growth factor-2,FGF-2)、碱性成纤维细胞生长因子(basic fibroblast growth factor,bFGF)和睫状神经营养因子(ciliary neurotrophic factor,CNTF)等,能与相应受体特异性结合,被轴突末端摄取,经轴浆逆行运输至神经元胞体,发挥维持神经元存活和促进神经生长的作用[43]。视神经损伤后RGCs发生凋亡,而视网膜过表达BDNF能够有效保护RGCs的存活[44-46]。Sánchez-Migallón等[27]发现BDNF能够显著改善视神经夹伤动物模型的RGCs存活数量。在Duprey-Díaz等[47]的报道中,FGF-2和FGF受体上调对RGCs轴突再生具有重要意义。CNTF在过去通常被用来治疗肌萎缩侧索硬化症。直到1994年,Unoki等[48]报道了视网膜损伤后CNTF与CNTF受体表达均会上调,发现了CNTF在视网膜及视神经再生的应用潜能。随后,Vega-Meléndez等[49]在2014年报道在视神经横断后给予CNTF能够抑制RGCs的凋亡并促进轴突再生。Wang等[50]发现CNTF发挥作用可能与RhoA通路相关,通过使用生长抑制因子如Nogo、OMgp和MAG激活RhoA信号通路可显著降低CNTF对RGCs存活和再生的积极作用。
    目前,NGF已应用于临床,并取得了较好的疗效[51-53]。相关的临床试验如重组人神经生长因子治疗视神经损伤也在进行中(临床研究编号:CTR20191810、CTR20201202、NCT04232332)。但NGF治疗也存在较多局限,例如NGF缓解RGCs凋亡效果较为短暂,需要持续给药维持效果;同时NGF难以通过血眼屏障,需要频繁进行玻璃体腔内注射,也给患者带来了痛苦。为解决此问题,也有研究采用转基因高表达的方式提供内源性NGF以达到持续给药的目的[46]

4 炎症刺激激活再生

    炎症刺激对于视神经再生而言是一把双刃剑,一方面,过度的炎症刺激会促进细胞凋亡及胶质瘢痕的形成阻碍轴突在损伤部位的再生[54];另一方面,适宜的炎症刺激也会带来重要的细胞信号,激活RGCs轴突再生通路。例如在诱导眼内炎(如晶状体损伤、酵母聚糖注射)情况下,炎症刺激可促进多种利于轴突再生的细胞因子释放,如
CNTF、白血病抑制因子和白细胞介素6(IL-6)等。同时,炎症刺激持续激活了多种信号通路,如JAK/STAT3和PI3K/AKT/mTOR,表现出了RGCs保护和轴突再生的作用[55]。此外,视神经损伤后向玻璃体腔内注射酵母多糖能够上调癌调蛋白的表达。癌调蛋白是一种钙结合蛋白,由视网膜上巨噬细胞和中性粒细胞分泌,能够协同cAMP促进视神经轴突再生,相较单独使用cAMP或其他生长因子,视神经再生效果显著提升[30,56]。然而,对于癌调蛋白是否是酵母聚糖诱导视神经再生的关键因素仍然存在巨大争议,并且炎症刺激是如何通过复杂调控实现再生的也需要更多研究探索。

5 抗胶质瘢痕形成

    神经损伤处胶质瘢痕形成是一个复杂的生理过程,伴有胶质细胞、免疫细胞和神经元细胞的参与。当中枢神经系统损伤区的神经元细胞死亡时,小胶质细胞和外周的单核细胞、中性粒细胞、软脑膜细胞及纤维母细胞向损伤灶周围聚集,成为胶质基质层的组成部分[57]。损伤引起炎症反应,活化的炎症细胞释放细胞因子,促进了损伤区星形胶质细胞的增生并向损伤部位的迁移,最终形成胶质瘢痕。
    胶质瘢痕是中枢神经包括视神经在内轴突再生的巨大障碍,如CSPG能够显著抑制轴突再生。但在单层的星形胶质细胞上,神经细胞的突起能很好地生长。这是由于星形胶质细胞具有合成和分泌营养因子的功能。现有观点[58]认为以星形胶质细胞为主的胶质瘢痕对于再生轴突重建具有阻碍轴突穿越的作用,但同时星形胶质细胞能够分泌神经营养因子对中枢神经轴突再生起促进作用。已有研究[59-63]表明参与胶质瘢痕形成的细胞因子有转化生长因子-β(TGF-β)、bFGF、FGF-2、IL-1β、IL-6、结缔组织生长因子(connective tissue growth factor,CTGF)、胶质细胞成熟因子、血栓素、表皮生长因子、血小板源性生长因子等,其中部分细胞因子具有一定的促进RGCs存活和轴突再生的作用。因此无法单纯通过去除星形胶质细胞以抑制胶质瘢痕形成。而如何在抑制胶质瘢痕产生的同时保留星形胶质细胞对神经元细胞的营养作用是当下研究的重点。Pearson等[18]发现:通过芳基硫酸酯酶B能够有效降低视神经损伤后胶质瘢痕形成及CSPG对视神经轴突的再生抑制作用,显著增强了酵母聚糖促进视神经轴突再生的作用。Frik等[58]发现减少单核细胞浸润能有效促进星型胶质细胞增殖,减少胶质瘢痕生成并保留星形
胶质细胞的营养效果。

6 干细胞移植

    视神经再生的干细胞移植研究可分为2种。一种是移植具有分化潜能的多功能干细胞,包括胚胎干细胞(embryonic stem cells,ESCs)和视网膜干细胞(retinal stem cells,RSCs)等,并通过诱导分化使其移行整合到宿主的视网膜上,补充凋亡的RGCs及生成新生的轴突;一种是通过移植间充质干细胞包括脂肪干细胞(adipose-derived stem cells,ADSCs)、牙髓干细胞(dental pulp stem cells,DPSCs)、脐血干细胞(umbilical cord blood stem cells,UCBSCs)等,对损伤后的神经元细胞给予炎症调节、营养和神经保护支持[32,64-68]
    ESCs是从早期胚胎或者早期性腺分离出的一类干细胞,早在1998年便可被分离和克隆。ESCs可分化为视网膜祖细胞,形成形态类似RGCs和表达RGCs特性的细胞,并能够与宿主视网膜结合。RSCs在正常视网膜的微环境下处于相对静默状态,但在特殊的环境下可以分化为RGCs。RSCs分化能力的激活可能与Wnt和Shh信号途径在睫状体边缘区域的高表达相关。基于ESCs、RSCs具有分化RGCs的潜能,有研究者[67,69]将ESCs或RSCs诱导分化培养成视网膜器官,有望运用于视网膜、视神经疾病的治疗。但多功能干细胞分化治疗仍面临巨大的障碍,例如细胞移行与宿主视网膜的整合、神经元轴突的定向再生、移植干细胞的增生调控等[70]
    多种来源的间充质干细胞如骨髓、脂肪组织、脐带血和牙齿(牙髓和牙周膜)来源的干细胞能在视神经损伤动物模型中起到促进RGCs存活和神经保护的作用[32,45,71-72]。Cen等[32]在视神经夹伤大鼠的玻璃体腔内注射人牙周膜干细胞,发现其能够显著提高视神经损伤后RGCs的存活并促进轴突再生,同时在体外与视网膜外植体共培养也能促进RGCs存活及轴突再生且不发生炎症反应。然而Chen等[66]认为虽然间充质干细胞的确对视神经损伤后的RGCs具有保护和轴突再生的积极作用,但只是短暂的促进作用,在更长期的观察中与对照无明显差异。

7 基因及转录因子调控

    随着生长发育的成熟,RGCs再生能力下降,其可能机制为基因表达改变促使成熟RGCs抑 制生长环境形成及发育依赖性的再生能力下降。因此,通过调控特定基因及信号通路,可以逆转视神经轴突的再生抑制,从而促进视神经再生。目前,对于视神经再生的基因及信号通路的基础研究较多,例如cAMP、PTEN/mTOR、APC-Cdh1、KLF-4、Melanopsin/GPCR、MDM4/MDM2-p53-IGF1等都被报道与中枢神经发育依赖性生长能力下降和促进神经轴突再生相关[17,73-74]。重组腺相关病毒(adeno-associated virus,AAV)载体是目前眼科基因治疗研究中最常用的载体,通过将治疗基因导入病毒编码序列并转染宿主细胞,过表达或沉默相关基因,从而促进RGCs的存活及轴突再生[32]。Park等[75]发现激活mTOR通路可以促进中枢神经保护和轴突再生,此积极作用与PTEN基因下调关系密切。之后,Sun等[34]进一步报道分别激活mTOR、JAK/STAT通路或敲除SOCS3、PTEN均可
以促进视神经轴突显著再生,但再生效率在2周后发生下降。而同时敲除SOCS3和PTEN可以显著增强RGCs轴突再生能力,说明SOCS3和PTEN是两个相互独立的通路,可以协同促进视神经轴突的再生。Liu等[74]将A AV-mela注入玻璃体腔感染视网膜中的RGCs,使其高表达黑色素(melanopsin),并上调M1-M3 ipRGCs的mTOR表达,能够有效保护视神经损伤大鼠RGCs的存活并促进轴突的再生。Chiha等[76]发现:在玻璃体腔内注射A AV-BDNF或A AV-CRMP2能够保护视神经损伤后RGCs,稳定轴突及髓鞘。Sinclair课题组[33]通 过A AV介 导Oct4(Pou5f1)、Sox2和Klf4基因(OSK)在小鼠RGCs中异位表达,促进损伤后轴突的再生,并逆转青光眼小鼠和老年小鼠的视力丧失。
    KLF是一类具有锌指结构的转录因子,广泛参与细胞增殖、凋亡、分化以及胚胎发育等多个生命活动的调控。Moore等[77]研究发现:KLF家族成员能在不同程度上抑制或增强了中枢神经系统轴突的生长,其中有几种生长抑制KLF在出生后上调,而生长促进KLF则下调。同时,KLF4是RGCs和其他中枢神经系统神经元轴突生长的转录抑制因子,KLF4敲除能在体外及体内促进视神经损伤后RGCs轴突的再生。随后,Qin等[78]报道KLF4敲除是通过JAK- STAT3信号通路诱导视神经损伤后RGCs轴突再生的。同时,采用外源性细胞因子处理或去除内源性JAK-STAT3通路抑制剂(SOCS3)可加强此积极效应。但由于目前技术及操作难以在实际临床的应用中做到准确的条件性基因敲除,因此此种方式仅限于基础研究未在临床上得到广泛应用。

8 定向诱导轴突再生

    尽管上述方式能够较好地保护RGCs并有效促进轴突再生,但轴突再生仍然缺少定向生长,即向颅脑靶区生长的能力。如Pernet等[79]发现通过AAV2-CNTF的基因治疗能够有效保护神经并促进轴突再生,然而在更长时间后新生轴突生长方向出现了U型迂回,向视网膜中生长,并在视网膜内表面形成了密集的神经丛。因此,成功的视神经再生不仅是促进视神经轴突再生,还需要能够诱导再生轴突定向生长的信号。外加直流电场刺激在1981年便被报道为具有能够有效刺激中枢神经系统轴突定向再生的应用潜能[80]。之后,Gokoffski等[81]报道了外加直流电场能够促进视网膜外植体新生轴突向阴极方向生长,此种趋电效应与Rho GTPase信号的激活密切相关。然而外加直流电场在视神经方面应用还仅限于体外方面,体内应用仍存在巨大的限制和难点。
    近年来,在神经营养因子的作用下,纳米图案化或三维支架有望能引导轴突定向再生。Ellis-Behnke等[82]报道了一种自组装肽纳米纤维支架能够为轴突再生创造了一个有利环境,新生轴突不仅可以通过急性损伤部位,还可以与脑组织连接在一起,以促进视觉功能的恢复。此外,Yang等[83]利用纳米图案化技术构建了一个模拟体外组织微结构的支架,成功引导人类诱导多能干细胞(iPSC)衍生的RGCs轴突沿着支架沟槽定向生长。

9 新生轴突与脑靶区的连结及视功能重建

    目前的基础研究在针对视神经损伤后RGCs的保护及轴突再生方面已取得较多进展。当视神经新生轴突再生至靶组织时,如何重新建立轴突与靶组织之间的功能性联系对于视神经功能恢复至关重要。Bei等[84]报道:将PTEN和SOCS3共敲除或将骨桥蛋白、胰岛素样生长因子1、CNTF共过表达均能促进视神经损伤后轴突的生长,同时新
生的视网膜再生轴突能够抵达上丘形成功能性突触,但仅能恢复部分的视觉功能,其原因是再生轴突缺乏髓鞘而不能将动作电位从视网膜有效地传导至上丘,通过使用钾离子通道阻滞剂可恢复动作电位的传导,显著提高视觉能力。此外,视觉刺激或化学遗传刺激也被认为与RGCs的活性密切相关。Lim等[85]报道通过视觉刺激视神经,同时结合激活的mTOR通路可以促进RGCs轴突与大脑建立功能性连接,进而恢复部分视觉功能。

10 结语

    随着视神经再生研究的不断开展,逐步揭示了视神经损伤后涉及的凋亡和再生机制,但各方面研究仍存在局限性。例如抗氧化药物仅针对视神经损伤后RGCs的氧化损伤,不能够进一步地促进轴突再生,并且药物的长期递送和释放也是限制其进一步发展的原因;细胞因子尽管已部分在临床中应用,且有部分新药已进入临床III期试验阶段,但长期疗效仍有待进一步检验和提高;炎症刺激目前仅停留在基础研究方面,何种程度的炎症能够避免炎症损伤并促进轴突再生仍需要更多研究探明。而炎症刺激产生的不良反应也限制了其走向临床;胶质瘢痕的生成与许多轴突再生相关细胞因子及营养支持细胞有关,因此需要在抗胶质瘢痕生成和轴突营养再生中寻找平衡。同时单纯的抗胶质瘢痕生成难以达到促进轴突再生效果,需与其他促再生方式联合;得益于干细胞的炎症调控、营养支持以及移植替换等功能,干细胞治疗已在视神经再生的基础研究领域取得了较好的成果。但干细胞治疗的长期效果以及干细胞本身的长期跟踪也是需要未来临床应用需要面对的难题;基因治疗是目前视神经再生基础研究中促进轴突再生能力最强的方式,能够有力并且持久地促进轴突再生。目前已有基因治疗被批准应用于眼病,同时,约有25种眼科疾病基因疗法处于I期、II期或III期[86]。因此,基因治疗可能是未来最具有向临床转化前景的视神经再生方式;纳米生物材料支架有望被应用于诱导中枢神经轴突定向再生,但目前相关进展及成果大多在于脊髓或其他中枢神经系统。由于视神经相对于其他中枢神经的特殊性(胞体位于视网膜内)及支架移植困难,导致目前视神经支架诱导轴突再生的研究大多停留在体外诱导水平,相关的体内诱导研究仍然较少;而新生轴突与脑靶区的功能重建仍是目前视神经再生的核心问题,目前仅仅是观察到新生轴突穿过视交叉进入脑部区域,对此的相关研究也未能阐明功能性突触重建的机制和关键所在。因此后续仍需要更多的基础研究探索此方向。综上,目前研究的热点仍在于激活RGCs内在再生能力、逆转外在抑制生在环境,定向诱导轴突再生,以及与大脑建立功能性连接这几个方面,而如何同时协调各方面的联合治疗,从而实现视功能恢复将是未来研究的重点所在。

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1、国 家 重 点 研 发 计 划 项 目 (2016YFC1101201)。This work was supported by the National Key R&D Program of China(2016YFC1101201).()
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  • 眼科学报

    主管:中华人民共和国教育部
    主办:中山大学
    承办:中山大学中山眼科中心
    主编:林浩添
    主管:中华人民共和国教育部
    主办:中山大学
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    主管:中华人民共和国教育部
    主办:中山大学
    承办:中山大学中山眼科中心
    主编:林浩添
    主管:中华人民共和国教育部
    主办:中山大学
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