Gli2 信号分子在调控 脊髓损伤后再生修复过程中 NSCs分化 的机制研究

Gli2 信号分子在调控 脊髓损伤后再生修复过程中 NSCs分化 的机制研究

朱双芳 * 黄学良 2 林雨聪 3 林杰钊 4 周初松 通讯作者

国家癌症中心 / 国家肿瘤临床医学研究中心 / 中国医学科学院 北京协和医学院 肿瘤医院深圳医 院 骨与软组织科 、 * 南方医科大学珠江医院 脊柱外科 ； 广东 深圳 5 18117

通讯作者：南方医科大学珠江医院脊柱外科 广东 广州 510280

摘要：脊髓损伤的预后非常差，病人多伴有终身残疾或瘫痪，干细胞移植被一致认为是治疗SCI极具潜力的选择。神经干细胞有助于脊髓损伤后的修复，直接输入神经干细胞虽最为理想，然而在临床上实施却困难重重、效果有限。利用内源性修复机制刺激组织再生达到按组织自身结构与功能要求去修复脊髓意义重大；然而，探索ENSCs增殖和分化的关键靶点和网络通路一直是医学界亟待解决的一大难题。Gli2基因编码的蛋白质是一种转录因子，关于脊髓损伤后再生修复过程中NSCs分化的分子机制仍未阐明，Gli2的潜在分子机制和关键下游靶点目前仍尚未完全了解。本文就Gli2信号分子在调控脊髓损伤后再生修复过程中NSCs分化的研究机制进展综述如下。

关键词：Gli2;信号通路;神经干细胞；脊髓损伤；

Gli2 signaling molecule regulates the mechanism of NSCs differentiation during the regeneration and repair after spinal cord injury

Author:Shuangfang Zhu¹ Xueliang Huang² Yucong Lin³ Jiezhao Lin⁴ Chusong Zhou^#

#Corresponding author: Chusong Zhou^#

Work unit name: ^*National Cancer Center / National Clinical Research Center for Cancer / Cancer Hospital & Shenzhen Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen,Department of Bone and Soft Tissue;^*Spine Surgery, Zhujiang Hospital, Southern Medical University; Shenzhen, Guangdong; Postcode: 518117; China Address: No. 113, Baohe Road, Longgang District, Shenzhen, Guangdong Province.

Corresponding author: Spine Surgery, Zhujiang Hospital, Southern Medical University; Guangzhou; zip code: 510280; China; Address: Guangzhou City Industrial Road 253, Guangdong Province.

Abstract: The prognosis of spinal cord injury is very poor, and patients are often associated with lifelong disabilities or paralysis. Stem cell transplantation is unanimously considered as a very promising option for the treatment of SCI. Neural stem cells are helpful for repair after spinal cord injury. Although direct input of neural stem cells is the most ideal, it is difficult to implement clinically and has limited effect. It is of great significance to use endogenous repair mechanisms to stimulate tissue regeneration to repair the spinal cord according to the tissue's own structural and functional requirements; however, exploring key targets and network pathways for the proliferation and differentiation of ENSCs has always been a major problem in the medical community. The protein encoded by the Gli2 gene is a transcription factor. The molecular mechanism of NSCs differentiation during spinal cord injury regeneration has not yet been elucidated. The potential molecular mechanism and key downstream targets of Gli2 are still not fully understood. This article summarizes the research progress of Gli2 signaling molecules in regulating the differentiation of NSCs during the regeneration and repair of spinal cord injury as follows.

Keywords: Gli2; signaling pathway; neural stem cells; spinal cord injury;

正文

脊髓损伤后，脊髓再生主要依赖于脊髓神经干细胞的增殖与分化。寻找脊髓损伤后修复中内源性神经干细胞及其信号通路分子调控机制，该研究结果将为临床治疗 SCI 寻找新策略,具有重要的意义。关于脊髓损伤后再生修复过程中NSCs分化的分子机制仍未阐明，Gli2的潜在分子机制和关键下游靶点目前仍尚未完全了解。这篇综述主要阐述Gli2信号分子在调控脊髓损伤后再生修复NSCs分化方面的研究进展。

1.调控NSCs在脊髓损伤后修复及重建中的作用

目前，脊髓损伤（SCI）是一种综合性疾病，不仅会导致肢体感觉或运动功能的丧失，还会导致其他脏器的功能障碍，如膀胱、肾脏、肠道功能受损，心血管以及呼吸功能障碍等^[1]。神经干细胞存在于成人及哺乳动物中枢神经系统之中，包括脊髓和其他非神经发生区域^[2]。有研究表明，外源性移植脊髓神经干细胞可以有效修复啮齿类动物的脊髓损伤^[3]。

对于临床治疗中，内源性神经干细胞（ENSCs）再生能力不足是脊髓损伤（SCI）难以修复的重要原因。由于外源性神经干细胞移植后修复功效有限，因此调控ENSCs的增殖与分化以促进SCI原位再生修复有其重要意义。目前，在SCI领域调控神经干细胞增殖或分化的研究中已发现Wnt通路对神经干细胞增殖与分化具有调控作用。而为实现这一目标，需要一方面促进脊髓神经干细胞的增殖；同时另一方面促使脊髓神经干细胞朝向神经元和少突胶质细胞的方向分化，促进神经新生。

2.Gli2信号分子与Wnt信号通路之间的联系

研究发现，脊椎动物Gli家族是一种转录因子家族，由三种不同基因Gli1、Gli2和Gli3组成^[4-7]。SHH途径成员很多，包括SHH、PTCH1、SMO、Gli1、Gli2、Gli3和SUFU^[8]，其中Gli2在SHH信号转录调节中起着至关重要的作用^[9-12]，但关于Gli2的潜在分子机制和关键下游靶点目前仍尚未完全了解。

Gli2在大多数肿瘤细胞中表达活性增强，而且Gli2的高活性也能促进肿瘤进一步生长、侵袭和转移^{[13, 14]}。有研究者发现，在肺癌^{[15, 16]}、宫颈癌^[17]、胰腺癌^{[18, 19]}、乳腺癌^[20]、肝癌^{[21, 22]}、前列腺癌^[23]、骨肉瘤^[24]、胃癌^{[25, 26]}、结肠癌^[27]、侵袭性血管瘤^[28]、胶质瘤^{[29, 30]}等肿瘤细胞中均有发现Gli2蛋白的表达提高；而且，Gli2、Gli1和SHH的表达水平与肿瘤细胞的恶性表型呈正相关性^[31]。研究也报道，Gli2和SmoM2都诱导Wnt6在小鼠脂肪库中的表达，Wnt6是一种已知的抗肥胖因子；SHH/Gli2信号不仅可抑制脂肪细胞分化，还可抑制脂肪细胞的脂肪生成^[32]。Gli转录因子可以调节软骨细胞和成骨细胞的分化^[33]。细胞内Gli2的表达对组织纤维化有着一定影响，Gli2和Gli1的表达受抑制有可能引起肌成纤维细胞部分转化成成纤维细胞和胶原形成的减少^[34]。皮肤色素沉着的形成有可能部分与通过Smo-Gli2信号传导有关。miR-141-3p对骨肉瘤细胞增殖和凋亡的影响是通过Gli2途径实现的,这一点可能为骨肉瘤的治疗提供新的靶点^[24]。Gli1和Gli2蛋白在肿瘤侵袭前沿的微血管细胞中表达^[35]；此外，Gli2在哺乳动物的CNS和四肢发育中也起着重要作用^[36]；通过体外细胞实验发现，Gli1在中脑外侧区表达，而Gli2和Gli3在背外侧表达，并由Ptch1的腹外侧表达补充^[37]。

研究显示，在爪蟾神经嵴细胞的生长和发育中，Gli2是一种关键的转录激活因子,Gli2可以通过减少神经嵴中的凋亡而不影响其细胞增殖状态，还可促进神经嵴迁移和衍生物如颅面软骨、黑素细胞和颅神经节等形成^[38]。Gli3是干细胞增殖的抑制剂，影响成人后舌中成熟味觉细胞的数量和功能^[39]；然而，Gli2是SHH信号的主要转录调节因子，抑制SHH/Gli2信号传导可以抑制小鼠神经干细胞P19的细胞分化，并可以改变细胞增殖和凋亡之间的平衡^[40]。有研究表明，11β-羟基类固醇脱氢酶2型( 11β-HSD2 )在人类怀孕维持和正常胎儿发育中起着关键作用；敲除Gli2而非Gli1和Gli3将显著减弱SHH诱导的11β-HSD2表达和活性，仅Gli2激活剂的过度表达就足以诱导11β-HSD2表达和活性,故Gli2可能也参与人类怀孕和胎儿发育所需^[41]。研究者也发现，SHH信号通过Smo激活Gli家族成员，RTK信号通过PI3K-AKT介导的GSK3失活或RAS - STIL1介导的SUFU失活增强Gli活性，而GPCR信号通过腺苷酸环化酶介导的PKA活化抑制Gli活性

^[42]。在众多信号分子的传导之中，Wnt信号通路和SHH途径之间具有着错综复杂的联系；两者信号分子之间既能相互促进，有时候也能互相抑制^[43]；在肿瘤的生长和转移过程中，SHH/Gli2信号通路和Wnt/β-catenin信号通路之间相互影响，如一方面Gli2是β-catenin的调节因子之一；另一方面β-catenin也可以反馈激活SHH信号^{[44, 45]}。研究者也报道，在乳腺癌骨转移的过程中，Wnt信号可以调节诱导骨破坏的肿瘤细胞中的Gli2表达，转化生长因子-β(TGF-β)部分通过转录因子Gli2能刺激甲状旁腺激素相关蛋白( PTHrP )的产生，Gli2和PTHrP、Wnt3a和TGF-β信号之间存在显著的串扰关系^[46]。研究发现，人类鞭毛内转运80 (IFT80 )沉默细胞中的Gli2过度表达促进了软骨形成，通过调节SHH和Wnt信号通路，IFT80对软骨细胞分化至关重要^[47]。小鼠胚胎成纤维细胞中的蛋白sFRP-1表达依赖于Gli1和Gli2^[48]。P19细胞中Gli2的过度表达也足以上调Foxc1/2转录水平并诱导骨骼肌发生^[49]。之前的研究曾表明，在胚胎和神经发育过程中，Wnt和SHH信号作为关键调节因子，具有一定的协同作用^[50]。Gli蛋白参与了SHH和FGF信号在神经和中胚层发育中的调节。在中胚层发育过程中,Wnt蛋白中的Wnt8和Wnt11能促进Gli2和Gli3的表达；同时抑制Wnt信号可以抑制Gli2和Gli3的表达，但不能抑制中胚层的发育。因此，Gli2和Gli3通常可以协调这两种Wnt蛋白的共同作用于其下游的信号分子^[51]。目前，已经发现许多已知对NSC自我更新有着至关重要的转录因子，包括 Sox2、Pax6、Tlx和Id4，以及Wnt、SHH，Notch及相关通路中转录效应因子TCF4、Gli2、Gli3、Yap1和Tead2等^[52]。研究还发现，SHH被认为参与大脑和中脑多巴胺能神经元的发育，其中Gli2可能参与构成红核( RN )子集的神经元的分化^[50]。以上研究表明，Gli2和MASH基因的表达在神经干细胞分化方面具有可调控性，然而如何寻找关键靶点并有效调控以上信号分子，促进NSCs的分化，解决这些难题仍需进一步的深入探究。

3.Gli2与NSCs分化之间的潜在联系

Wnt信号传导有助于维持和分化许多发育和成体干细胞，包括肠上皮和毛囊中的干细胞。在CNS中，Wnt/β-catenin 信号传导是在生长发育过程中信号通路中的关键^[1]。Wnt/β-catenin 信号传导的重要性可能在于其在维持神经干/祖细胞（NSC）增殖中的作用；抑制Wnt/β-catenin 信号传导将减少神经球中的NSC增殖^[53]。 经典Wnt信号的激活可选择性刺激少突胶质细胞系的增殖，导致少突胶质细胞生成的大量增加而不改变神经原性克隆内的谱系选择或增殖^[54]。外源性补充Wnt-3a可以改善受损脊髓中的轴突传导和脊髓功能，补充的Wnt-3a会导致原有神经元的数目增多，表明这些细胞可以来源于神经前体和干细胞^[55]。Wnt-3a、稳定的β-catenin以及抑制GSK-3β均能激活这类细胞中的Wnt/β-catenin信号通路的某些基因；此外，Wnt-3a和β-catenin分离能够促进hNPCs中的神经增殖^[56]，这表明由Wnt-3a诱导的神经分化并不依赖于β-catenin 的转录；而HES5的过表达可以有效地阻断了Wnt-3a诱导的神经分化，其伴随着MASH1的强烈下调，因此直接将HES5抑制或诱导MASH1，这可能与Wnt-3a促进神经干细胞分化有一点联系^[57]。之前的报道表明，Wnt-3a能不同程度的调控HES5的表达，而与NICD1和GSK3β的表达无关；并且当予以NICD1抑制剂处理后，Wnt-3a仍然能够调节HES1/5的 表达；因此，这表明其他分子可能参与Wnt-3a对HES5表达的调节。之前的报道表明，MASH-1是早期神经分化的关键基因之一^[58]；在无维甲酸( RA )的情况下，Wnt-1的过度表达可以引导胚胎癌P19细胞中基因Mash-1和Ngn-1表达上调，同时促进其向神经元方向分化并抑制胶质细胞的生长^[59]。研究者也发现，Wnt-1可以通过激活HES-1和细胞周期蛋白D1并抑制MASH-1来阻断PC12细胞的分化并增强其增殖^[60]。

Gli2基因编码的蛋白质是一种转录因子，存在于细胞质中；而且，Gli2属于Gli家族C2H2型锌指蛋白亚类，而且这个亚类的成员的特征是通过锌指基序结合DNA的转录因子。Wnt信号传导能调节成纤维细胞中的Gli2激活^[61]。 研究者也发现，Gli2可以调控MASH的表达，从而促使老鼠干细胞株分化成为神经细胞^[62]。所以，在Gli2也有可能通过Wnt信号通路共同参与调控脊髓损伤后再生修复过程中NSCs的分化，但Gli2作用的潜在分子机制和关键下游靶点但仍需进一步的研究。

小结

目前，神经干细胞增殖和分化的关键靶点和网络通路的研究尚未成熟，多限于基础实验和动物模型的研究；在SCI领域调控神经干细胞增殖或分化的研究中已发现Wnt通路对神经干细胞增殖与分化具有调控作用，Gli2的潜在分子机制和关键下游靶点目前仍尚未完全了解，Gli2有可能通过Wnt信号通路参与调控脊髓损伤后再生修复过程中NSCs分化。随着科技的不断创新与进步，困难会被解决，这一难题也终将被解开，探索ENSCs增殖和分化的关键靶点和网络通路会是人类脊髓损伤后修复治疗的新策略之一。

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