Chinese Journal of Tissue Engineering Research ›› 2022, Vol. 26 ›› Issue (7): 1137-1142.doi: 10.12307/2022.157
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Fan Yiming, Liu Fangyu, Zhang Hongyu, Li Shuai, Wang Yansong
Received:
2020-11-11
Revised:
2020-11-14
Accepted:
2020-12-07
Online:
2022-03-08
Published:
2021-10-29
Contact:
Wang Yansong, MD, Chief physician, Fifth Department of Orthopedics, the First Affiliated Hospital of Harbin Medical University, Harbin 150000, Heilongjiang Province, China
About author:
Fan Yiming, Master candidate, Fifth Department of Orthopedics, the First Affiliated Hospital of Harbin Medical University, Harbin 150000, Heilongjiang Province, China
Supported by:
CLC Number:
Fan Yiming, Liu Fangyu, Zhang Hongyu, Li Shuai, Wang Yansong. Serial questions about endogenous neural stem cell response in the ependymal zone after spinal cord injury[J]. Chinese Journal of Tissue Engineering Research, 2022, 26(7): 1137-1142.
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2.1 脊髓损伤 脊髓损伤可分为原发性脊髓损伤和继发性脊髓损伤。原发性脊髓损伤是指外界直接因素或间接因素作用于脊髓造成轴突断裂、神经元死亡等不可逆的损伤。由于原发性损伤后局部血流减少、血脊髓屏障功能丧失以及大量炎症细胞浸润等因素造成的进一步持续性损伤称为继发性损伤。活性氧、兴奋性神经递质及促凋亡因子的急性升高是导致幸存神经元、少突胶质细胞等细胞死亡的早期因素[10]。损伤部位的血管痉挛、局灶性微出血以及血栓形成造成了血脊髓屏障通透性的改变以及细胞膜及离子泵/转运蛋白周围电解稳态的改变,正是这种变化导致了病变部位的脊髓水肿和缺血,而强烈的炎症反应以及抑制性生长因子的释放加剧了这种级联事件的负面影响[10-11]。研究发现,继发性损伤的进展可以通过人为调控,目前的研究都是以此为基础,目的是为了改善受损脊髓的恶劣微环境,增强神经元的再生能力[12]。既往对脊髓损伤机制的研究主要集中在幸存的神经元及少突细胞上,随着对干细胞研究的深入,人们发现在中枢神经系统中有一些具有分化为神经元潜能的ENSCs,利用脊髓中的ENSCs来修复脊髓损伤具有其独特的优势。 2.2 内源性神经干细胞 成人脊髓内存在3种增殖细胞类型:星形胶质细胞(GFAP+/Sox9+/Cx30+)、少突胶质细胞祖细胞(NG2+/OLIG2+)和室管膜细胞(CD133+/FoxJ1+)[13-14]。在生理条件下,少突胶质细胞前体细胞是成人脊髓中主要的增殖细胞。然而,少突胶质细胞前体细胞和星形胶质细胞都没有表现出多向分化能力,其分化的后代分别局限于少突胶质细胞谱系和星形胶质细胞谱系[15-16]。有研究在小鼠的第三脑室室管膜和脊髓中央管中发现了CD133+室管膜细胞,并且体外实验证实这些细胞可以形成神经球,并具有向星形胶质细胞、少突细胞及神经元分化的能力[17]。ALFARO-CERVELLO等[18]在脊髓中央管区中发现了一群CD133+/FoxJ+双表达的细胞,他们证实正是这群细胞在脊髓神经的继续生长中发挥关键性作用。PFENNINGER等[19]发现脊髓中央管中存在一群CD133+/CD24-细胞,这群细胞不仅在形态学上表现出神经干细胞的潜能,而且高表达干细胞相关基因。1996年,WEISS等[20]首次从成年哺乳动物脊髓室管膜区分离出具有自我更新能力的神经干细胞,这些细胞具有分化为神经元、少突胶质细胞和星形胶质细胞的能力。因此,室管膜细胞代表一个潜在的神经干细胞群,既往被认为是成熟脊髓中的ENSCs[14]。在未发生损伤的成年哺乳动物脊髓中,中央管内的室管膜细胞增殖率低,无多能性,仅通过自我更新来维持室管膜细胞的数量。 2.2.1 脊髓中央管内的室管膜细胞 脊髓中央管腔周围的室管膜区存在多种形态的室管膜细胞,根据其形态的不同可分为3种类型:立方体室管膜细胞、放射状室管膜细胞以及室管膜伸展细胞[13]。室管膜区内的大部分细胞呈多纤毛立方型,是中央管结构的支撑点。一小部分细胞为室管膜伸展细胞,是一种胶质细胞,具有单个纤毛,被认为有助于脑脊液和血管之间的物质运输[21]。立方体室管膜细胞是数量最多的多纤毛细胞,而放射状室管膜细胞的数目较少。放射状室管膜细胞位于室管膜区的背侧和腹侧,其和室管膜伸展细胞被认为是室管膜区主要的干细胞类型[22]。室管膜细胞在室管膜区延伸出顶突,与脑脊液接触,可以通过跨膜钠通道检测脑脊液的流量,并通过该膜通道激活Erk级联反应来调节细胞的增殖[23]。 2.2.2 室管膜细胞的异质性 研究表明,室管膜细胞具有异质性,表达放射状神经胶质细胞标记物(例如RC1和BLBP)、神经细胞标记物(例如CD15、GFAP、PSA-NCAM、Musashi1、CD133/prominin-1、Sox2、Sox3、Sox9)以及波形蛋白和巢蛋白(Nestin蛋白)[24-25]。Nestin蛋白是ENSCs的特异性蛋白,其在室管膜细胞的背侧和腹侧表达,在背侧区域表达CD15和BLBP [26]。在成年小鼠脊髓中,含Nestin蛋白的细胞在颈椎1-7节数量最多,在胸椎1-12节中次之,在腰椎1-5节中最少[27]。 2.3 脊髓损伤后的ENSCs 脊髓损伤后,ENSCs经历3个步骤:激活、迁移和分化。 2.3.1 ENSCs的激活 正常情况下室管膜细胞保持静止状态或非常缓慢增殖状态[28-29]。室管膜细胞、星形胶质细胞和少突胶质细胞前体细胞都在损伤刺激后激活[30]。受损脊髓的神经细胞生长速度比正常完整的脊髓快三四倍[14]。当子代细胞离开中央管并促进胶质瘢痕形成时,一些室管膜细胞标记物如Sox2、Sox3和FoxJ1下调。研究表明,脊髓损伤后大鼠中央管中Nestin+/Sox2+细胞数量明显增加。使用25G针刺模拟大鼠脊髓损伤后可检测出中央管内ENSCs标志物Nestin的表达明显上调[31]。 微环境的变化,如某些可溶性因子以及免疫应答水平的增加,也可能有助于脊髓损伤后ENSCs的激活。表皮细胞生长因子和成纤维细胞生长因子等促细胞分裂剂在体外和体内均可促进脊髓ENSCs激活与增殖,表皮细胞生长因子也可促进其从中央管迁移[32-33]。研究表明,小鼠腹腔内注射成纤维生长因子蛋白,可以促进脊髓损伤后ENSCs激活、增殖和分化。血管内皮生长因子在脊髓损伤后表达水平升高,可通过VEGFR2和EGFR信号通路激活ENSCs增殖[31]。有研究表明,脊髓匀浆液在体外可通过提高Notch1和Hes1的表达促进胚胎大鼠ENSCs的激活与增殖[34]。 2.3.2 迁移 被激活的室管膜细胞从中央管远端向病变部位的迁移可在脊髓损伤后3 d被检测到[13,35]。迁移的细胞会改变形态,并失去FoxJ1、Sox2和Sox3的表达[13]。激活转录因子3 (activatingtranscriptionfactor 3,ATF3)最近被认为是ENSCs迁移的一个新的核标记[36]。ATF3定位于静止的室管膜细胞的细胞质中,并在从中央管迁移到相邻白质的腹侧和背侧的活化细胞中强烈表达。ATF3是CREB蛋白家族的应激诱导适应性反应基因,是MAPK-p38和JNK/c-Jun信号通路的下游靶点。研究表明,在脊髓损伤后室管膜细胞中,除了Jak/Stat通路外,VEGF/MAPK通路也被激活并在调节细胞迁移、分化和胶质瘢痕形成中发挥作用[37]。 2.3.3 分化 少突胶质细胞前体细胞和星形胶质细胞是成熟脊髓中主要的增殖分裂细胞[14]。脊髓损伤后少突胶质细胞前体细胞及星形胶质细胞活化,但由于缺乏多能性,少突胶质细胞前体细胞和活化的星形胶质细胞不被认为是干细胞。 BARNABE-HEIDER等[14]通过构建遗传图谱进一步证明新生成的胶质瘢痕细胞来自于室管膜细胞。室管膜细胞在完整的脊髓中很少分裂,但在体外培养时它们开始不规则地分裂,并展现出三系分化的特性。脊髓损伤引起了室管膜细胞强烈的、持续性的增殖,在脊髓损伤后3-7 d达到高峰[38]。室管膜细胞被激活并迁移至损伤部位产生大量的星形胶质细胞以形成胶质瘢痕,少量少突胶质细胞及神经元,研究发现与瘢痕相关的星形胶质细胞主要来自室管膜细胞。长期以来,脊髓损伤后形成的瘢痕被认为阻碍了轴突再生。胶质瘢痕细胞产生抑制因子如硫酸软骨素前突聚糖、髓磷脂相关蛋白等,被证实抑制了轴突的生长。密集堆积的星形胶质细胞对再生的轴突形成了物理屏障[39]。然而,随着对胶质瘢痕更深入的研究以及更多对胶质瘢痕有益的报道,人们对室管膜分化的星形胶质细胞的看法变得矛盾。为了研究室管膜细胞分化的胶质瘢痕成分的特定功能,SABELSTR?M等[40]对小鼠进行了所有Ras基因的诱导敲除,Ras基因敲除后ENSCs不能增殖,使得ENSCs来源的胶质无法形成。当ENSCs增殖被阻断时,脊髓损伤后病灶处出现囊肿,而正常ENSCs功能的小鼠未出现囊肿,这一结果表明,ENSCs分化的后代在形成胶质瘢痕中起着支架的作用,限制损伤进一步扩大[14,41];其次,小鼠脊髓损伤后没有来自ENSCs的瘢痕细胞,幸存的轴突也将进一步损伤[42-43]。总的来说,胶质瘢痕形成了物理屏障及分子屏障虽然限制了轴突的生长及再生,但也限制了炎症的扩散,避免了损伤进一步扩大。如何调控ENSCs分化的瘢痕细胞向更利于神经再生、修复方向发展需要进一步的探究。 脊髓损伤恢复受限的主要原因是神经元的丧失及再生能力弱,而影响脊髓损伤恢复的关键是ENSCs分化成神经元的比例。许多动物研究表明,内源性和外源性移植的神经干细胞很少分化为神经元,而是在损伤部位主要分化为星形胶质细胞[44-45],这极大地影响了神经干细胞对脊髓损伤修复的治疗效果。ENSCs的分化受到脊髓损伤后微环境中存在的抑制因子的影响,这些因子会促进ENSCs分化为更多的星形胶质细胞,抑制轴突的再生,包括神经轴突生长抑制因子Nogo以及少突胶质细胞髓磷脂糖蛋白和髓磷脂相关糖蛋白在内的髓磷脂相关抑制剂已被确定为不良微环境的主要成分[46]。研究发现,髓磷脂相关抑制剂除了抑制轴突再生外,还抑制ENSCs向神经元分化。Nogo-A是一种强力的髓鞘相关蛋白,主要在少突胶质细胞中表达,已被确定为神经轴突生长的抑制剂[47]。在细胞表面表达的Nogo-A活性片段(Nogo-66)抑制了ENSCs的神经元分化,并促进了ENSCs分化为星形胶质细胞。Nogo-66受体是与糖基磷脂酰肌醇连接的轴突表面蛋白,它也在ENSCs中表达,并以高亲和力结合Nogo-66抑制轴突的生长[48]。如何调控脊髓损伤后的微环境,使得ENSCs更多地分化为神经元是近年来研究的热点。ZHAO等[49]鉴于髓磷脂相关抑制剂可激活EGFR信号通路,使用胶原支架栓系抗EGFR抗体来减弱髓磷脂相关抑制剂对神经元分化的抑制作用,为ENSCs创造一个更利于向神经元分化的微环境,而微环境中其他对ENSCs分化的影响因子及其机制,更需要进一步的研究。 2.4 继发性脊髓损伤对ENSCs的影响 脊髓继发性损伤的概念首次提出于1911年,此后被广泛应用于解释脊髓损伤后发生的一系列复杂的分子和生化级联事件。继发性损伤是多种研究的基础,旨在针对阻止幸存细胞进一步损伤、设计改善损伤脊髓的恶劣微环境以及增强轴突再生、促进神经功能恢复[50-51]。近年来,许多研究已经证明脊髓室管膜区存在具有分化潜能的ENSCs,其在脊髓损伤后活化,对脊髓的修复发挥关键性作用[40],而这些细胞是如何对继发性损伤后微环境成分做出反应,仍然鲜有报道。最近的研究表明,级联损伤后的许多生物化学成分可能会触发ENSCs的激活、增殖和影响其分化。 2.4.1 谷氨酸 脊髓继发性损伤的特征之一是在损伤部位释放高浓度的兴奋性神经递质谷氨酸到细胞外。谷氨酸与神经细胞和胶质细胞上的多种靶受体结合,导致细胞内钙的毒性流入,进而导致细胞死亡。然而,最近的研究表明谷氨酸对ENSCs具有矛盾的作用。在体外研究中,与脊髓损伤后体内水平相当的高浓度谷氨酸可促进ENSCs增殖和提高其生存率[52];其次,在体外浓度高达1 mmol/L的谷氨酸对ENSCs也没有毒性[53]。目前还没有研究表明这种体外效应是否也发生在体内,在这种情况下,它可能有助于脊髓损伤后ENSCs的激活和增殖。谷氨酸刺激ENSCs增殖和存活的机制仍然是未知的。成熟ENSCs表达功能受体AMPA、kainate和NMDA[53]。研究表明AMPA受体可能在谷氨酸调节成人脊髓ENSCs反应中起中心作用[54-55]。在中枢神经系统中,AMPA受体已被证明可以增加脑损伤动物模型中脑源性神经营养因子水平并促进ENSCs向神经元分化。ENSCs也能够产生脑源性神经营养因子,并且对外源性脑源性神经营养因子治疗有积极的反应[56]。由此推断AMPA受体介导的促进ENSCs增殖和存活可能依赖于其自分泌脑源性神经营养因子的机制,然而还需要更多的研究以确定这一反应的下游途径。 2.4.2 炎症因子 脊髓损伤后,巨噬细胞和小胶质细胞的激活以及其他受损细胞ATP和核蛋白的释放会引发强烈的炎症反应。脊髓损伤后促炎递质和抗炎递质似乎对ENSCs产生了不同的作用。小鼠ENSCs与促炎M1巨噬细胞共培养导致诱导型一氧化氮合酶、肿瘤坏死因子α和白细胞介素1β mRNA水平上调,并通过MAPK-Sox2信号促进增殖,而与抗炎M2细胞共培养则上调了精氨酸酶和白细胞介素10 mRNA水平,降低了细胞增殖能力,并促进向神经元分化[57]。脊髓损伤之后M1反应通常占主导地位,而发生M2反应的时间较短,这与损伤后ENSCs的剧烈增殖反应一致。从另一个角度来看,上调M2细胞因子除了降低继发性损伤对ENSCs的影响以外,还提供了一种促进ENSCs向神经元分化的途径。在脊髓损伤后ATP大量释放,并通过传导嘌呤能信号导致进一步的炎症反应。核苷酸可激活两类嘌呤能受体:离子门控性P2X受体和代谢性G蛋白偶联P2Y受体,两者均在ENSCs中表达。GóMEZ-VILLAFUERTES等[58]在培养的大鼠室管膜细胞中,模拟脊髓损伤可以诱导P2Y1受体的下调和P2Y4受体的上调。P2Y1受体激活被认为可以促进ENSCs的增殖和迁移,而P2Y4受体在ENSCs分化过程中表达增强,可能与谷氨酸神经元亚型标记物有关。研究表明,P2X4受体与激活的小胶质细胞和巨噬细胞有关,因此敲除或抑制P2X4受体可减少炎症反应、改善组织紊乱。P2X7受体被认为在ENSCs凋亡中发挥作用,因此其下调可能提高ENSCs存活率[59]。总的来说,脊髓损伤后的嘌呤能信号传导可能在调节ENSCs存活、激活、迁移及增殖和分化中发挥重要作用,值得进一步研究。 2.4.3 活性氧 脊髓损伤后早期可能发生自由基和活性氧的释放。由于神经细胞和神经胶质细胞具有较高的氧化代谢率、较低的抗氧化能力以及含有高水平的不饱和脂肪酸,因此它们对氧化应激非常敏感。对小鼠和人的脑室下带区ENSCs的研究表明,这些细胞维持高活性氧状态,受NADPH氧化酶和PI3k/Akt信号的调节。低水平的外源性活性氧(2-4 μmol/L)促进了细胞的增殖和向神经元的分化,而抑制活性氧的主要来源——NADPH氧化酶,在体内、体外均可降低ENSCs的数量与活性[60]。在分化培养基中,高浓度的活性氧(100 μmol/L H2O2)可以促进神经前体细胞分化为神经元和少突胶质细胞。总之,氧化应激已经被认为可以促进ENSCs向神经元分化[61]。 考虑到大脑脑室下带区与脊髓室管膜区ENSCs的相似性,很可能大脑中描述的对活性氧的许多反应也适用于脊髓中的ENSCs。然而,只有少数实验专门研究了活性氧对脊髓ENSCs的影响,并证明了这一假设。这些研究表明,与其分化的神经元相比,体外诱导ENSCs死亡需要更高水平的活性氧(500 μmol/L)[56]。综上所述,ENSCs可能比其分化的后代具有更强的抗氧化应激能力;其次,活性氧可能是脊髓损伤后ENSCs增殖、分化和存活的重要调节因子。 2.5 展望与挑战 脊髓极弱的再生能力导致了脊髓损伤的不良预后及严重的后遗症。虽然中枢神经系统有一些固有的再生能力,但相对于重建脊髓传导束来说是远远不够的。目前临床上脊髓损伤的治疗方法包括牵引固定、激素冲击治疗[1]、手术治疗及康复治疗等[62-63]。然而,这些治疗方法只能改善症状和减少并发症,并不能使损伤的脊髓完全修复。利用ENSCs治疗脊髓损伤的主要挑战是如何激活静息态的ENSCs并维持其多向分化的能力,在损伤处使其定向分化为神经元从而再生功能神经环路。LI等[64]开发出一种包裹有微管稳定剂紫杉醇脂质体的胶原微通道支架,首次证明了紫杉醇可以挽救髓磷脂抑制的ENSCs向神经元分化,并诱导ENSCs分化出比正常微环境中更高水平的神经元。当载有ENSCs的功能性胶原蛋白支架植入大鼠脊髓T8完全横切位点时,发现该支架为ENSCs向神经元分化、神经元再生以及轴突的延续提供了有利的微环境,大鼠的运动诱发电位及后肢运动得到改善。WILSON等[65]向脊髓损伤后的大鼠鞘内注射音猬因子(Shh),验证了其可以通过表达T细胞因子调控Wnt经典信号通路,并促进脊髓损伤后ENSCs的增殖,改善脊髓损伤大鼠的动物行为学评分。有研究将一种可生物降解的材料壳聚糖负载有神经营养因子3时,其能够缓释神经营养因子3。将神经营养因子3-壳聚糖支架移植到5 mm胸腰段脊髓完全切除大鼠模型中,发现会在病变区域中引起ENSCs强烈活化,并通过缓慢释放神经营养因子3吸引更多的ENSCs迁移到病变区域,分化为神经元并形成功能性神经网络,大鼠的后肢运动感觉及电生理都有明显改善[66]。随着更多功能性支架及信号通路的开发,为调控ENSCs在病变部位定向分化为神经元从而重建脊髓传导束展现出广阔的前景。 随着对干细胞研究的深入,移植干细胞治疗脊髓损伤已经成为近年来研究的热点。对于干细胞疗法这种新型治疗方案,已经在很多医学领域如治疗心肌梗死、骨关节炎、糖尿病等都有广泛的研究[67]。干细胞的旁分泌作用和营养支持是其主要功能,但干细胞移植治疗脊髓损伤的机制还尚未有统一的观点[11]。随着研究的深入,干细胞较大的体积易被肝肺组织获取、具有成瘤性、易引起排异反应及供体、受体不足等弊端,使得干细胞移植在临床中的应用差强人意[68-69]。PAL等[70]在患者外周血中可以提取到ENSCs,并在体外培养后可重新输至患者体内,有效地规避上述弊端,这为利用ENSCs治疗脊髓损伤提供了新思路。 脊髓损伤后功能恢复的关键问题是新的神经元再生与脊髓传导束的形成。改善损伤局部的微环境可以诱导ENSCs分化为神经元并形成修复受损的脊髓传导束,然而损伤后的病理分子机制尚未阐明。研究ENSCs的特性及潜能及其对脊髓损伤的反应具有重要意义,但仍有诸多难点需要解决。目前ENSCs激活的机制及影响激活的因子较多,但尚未有统一的观点。ENSCs激活后,如何调控继发性损伤后的微环境,使ENSCs向神经元方向分化,更利于脊髓损伤修复,仍是研究的难点。为了通过调节瘢痕来改善脊髓损伤的恢复,有必要研究星形胶质细胞在瘢痕形成中的特殊作用,以及星形胶质细胞分化形成的瘢痕和ENSCs分化形成的瘢痕成分之间的相互作用。继发性损伤后微环境的多种生长因子均可影响ENSCs增殖及其向神经元分化,但不同生长因子之间的协同作用尚不清楚,需要继续深入的研究,进一步明确脊髓损伤后的病理分子机制,寻找最合适的干预靶点及最佳的干预时间,研制更多可临床应用的功能生物材料支架,利用内源性干细胞与外源性干细胞联合治疗等研究为脊髓损伤的治疗提供帮助。"
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