Chinese Journal of Tissue Engineering Research ›› 2013, Vol. 17 ›› Issue (19): 3538-3545.doi: 10.3969/j.issn.2095-4344.2013.19.019
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Wu Ling-feng, Wu Xiao-mu
Received:
2013-02-21
Revised:
2013-03-27
Online:
2013-05-07
Published:
2013-05-07
Contact:
Wu Xiao-mu, M.D., Chief physician, Professor, Department of Neurology, People’s Hospital of Jiangxi Province, Nanchang 330006, Jiangxi Province, China
wuxm79@163.com
About author:
Wu Ling-feng☆, Studying for doctorate, Associate chief physician, Department of Neurology, People’s Hospital of Jiangxi Province, Nanchang 330006, Jiangxi Province, China
wusky2000@126.com
CLC Number:
Wu Ling-feng, Wu Xiao-mu. Adult neural stem cells and the microenvironment[J]. Chinese Journal of Tissue Engineering Research, 2013, 17(19): 3538-3545.
2.1 成体神经干细胞的定义 神经干细胞是存在于成体脑组织中的一种干细胞,是具有分裂潜能和自我更新能力的母细胞,可以通过不对等的分裂方式产生神经组织的各类细胞,可分化成神经元、星形胶质细胞、少突胶质细胞,也可转分化成血细胞和骨骼肌细胞。神经干细胞具有位置特异性的分化潜能,其增殖、分化和迁移,与细胞外基质有非常密切的关系[7]。 2.2 微环境的定义 微环境是保持干细胞的自我更新及避免分化的特定三维空间结构。干细胞微环境的共同特点:①干细胞微环境由干细胞定居的特异组织的细胞组成,不同的组织干细胞微环境有许多保守的成分[8]。②干细胞微环境主要功能之一是锚定干细胞[9]。③干细胞微环境细胞可以产生调控干细胞命运的信号,并通过对干细胞染色体的修饰和重构起作用[10]。④干细胞微环境为非对称的结构,这种结构与干细胞的非对称分裂有关[8]。维持干细胞静止和活动的平衡是微环境的一个特点[11]。 2.3 微环境的构成 2.3.1 微环境中的神经干细胞 神经干细胞微环境中存在有3种不同状态干细胞类型(静息期、自我更新、增殖或分化),其组成了干细胞池:A型(神经母细胞)、B型(神经干/祖细胞)、C型(短暂增殖细胞)。 干细胞能通过自我更新保持其数目稳定,相对静息期的神经干细胞(B型细胞),能自我更新或分化增殖细胞(C型细胞)。C型细胞可以分化为迁徙神经母细胞(A型细胞),进入嘴侧迁徙流。 神经干细胞的标志物:处于不同时期的神经干细胞,其表达的标志物不同[12]。 巢蛋白属于第Ⅵ类中间丝蛋白,其表达始于神经胚形成时,当神经干细胞迁移基本完成,巢蛋白的表达量逐渐减少,并随神经干细胞分化的完成停止表达[13]。 Musashi-1为一种RNA结合蛋白[14],Sox2为核转录因子[15],CD133是细胞表面蛋白[16],双肾上腺皮质激素为转录因子[17],均可作为神经干细胞的标志物,星形胶质细胞以几种不同的种群存在于成体干细胞微环境中,神经胶质酸性蛋白虽然是星形胶质细胞标志物,但干细胞池中的这些细胞的形态学和功能均不同于成熟的星形胶质细胞,也被认为是神经干细胞的标志物[18]。 多聚唾液酸-神经黏附因子是神经母细胞的标记物,对神经干细胞迁移、轴突生长和成束有重要意义,常被用来标识神经干细胞的迁移情况[19]。继巢蛋白之后,即起始于神经迁移完成时, 出现的是波形蛋白,分化完成后表达下降,属于第Ⅲ类中间丝蛋白,可作为神经祖细胞的标记[20]。 神经干细胞分布:成体哺乳动物中枢神经系统中主要存在2个神经干细胞聚集区:侧脑室壁的室管膜下区和海马齿状回的颗粒下层[21-22]。另外大脑皮质、海马、纹状体、嗅球、脑室沿线包括侧脑室、第三脑室和第四脑室、间脑、中脑、小脑、脊髓、视网膜均存在神经干细胞[23-27]。 2.3.2 微环境的其他结构 血管及其内皮细胞:神经干细胞微环境中主要的成分之一是血管[28-29]。在神经发生过程中,包括神经祖细胞、神经母细胞、神经胶质细胞和内皮祖细胞组成的增殖集落被发现与海马小毛细血管相联系。相似的这种联系在侧脑室区也可以见到。这种联系在病理条件下如卒中时为明显,神经祖细胞在此类血管微环境可以提高它们自身增殖和分化能 力[30]。 当各种来源的内皮细胞和神经祖细胞在体外共同培养时,内皮细胞促进了神经祖细胞自我更新、并抑制其分化,但当分化发生后,则促进神经元的分化[31]。血管也提供了一种特殊的基底层(fractones,一种细胞外基质结构),是微环境的一种至关重要的组成成分[32]。通过电镜检测发现fractones与神经干细胞和神经祖细胞相联系,提示其在神经发生中起作用,fractones可增加神经干细胞微环境中生长因子的活性[33]。 体外将内皮细胞和神经祖细胞共同培养,发现神经祖细胞促进了内皮细胞管的形成和稳定,而内皮细胞则促进了神经祖细胞的增殖。研究显示将缺血诱导的皮质神经祖细胞被移植入卒中大脑后,内皮细胞能增加移植神经祖细胞的生存、增殖和神经元分化率,并导致皮质功能轻度增加[34]。神经祖细胞调控内皮细胞的作用也可以在短暂性脑缺血的小鼠模型中见到,神经祖细胞移植后可见微血管密度明显增加[35]。 Gómez-Gaviro等[36]研究发现,小鼠大脑干细胞微环境内的血管内皮细胞能产生β-细胞素,导致神经干细胞增殖并形成新的神经细胞而促进大脑再生;相反,当给小鼠施加阻断β-细胞素活性的抗体时,则可抑制新神经元产生。 以上研究说明血管内皮细胞与神经干细胞两者在微环境中相互依存,互不可少。 星形胶质细胞:微环境中星形胶质细胞表达的几种因子:血管内皮生长因子、干细胞因子、基质衍生因子1α、单核细胞趋化蛋白1会影响在生理和病理条件下神经干细胞性能,能促进神经母细胞的迁移[37]。 Lim等[38]发现,在体外新生或成体分离的室管膜下区细胞与单层星形胶质细胞培养中,可明显增加室管膜下区神经干细胞的增殖并分化至神经母细胞。成体海马的神经祖细胞在层粘连蛋白外涂料的微型聚合物基质中培养,神经祖细胞与星形胶质细胞共培养证实了能增加神经祖细胞的分化,使β-Ⅲ微管蛋白表达的增加了2倍[39]。 神经干细胞对星形胶质细胞功能也有影响。外源性神经祖细胞被移植至帕金森病模型黑质和纹状体中,内源性神经祖细胞的增殖、神经元的分化并迁徙至受损部位增加,并表达各种不同的神经营养因子,包括对微环境中星形胶质细胞功能有关键作用的音速小子(Sonic hedgehog)等[40-41]。 说明在调控神经干细胞微环境中星形胶质细胞起了一种关键作用。微环境中星形胶质细胞的移植能足够改变中枢神经系统非神经再生区域的微环境。星形胶质细胞可作为间断体内神经干细胞扩增和分化的一种有用的工具。 室管膜细胞:室管膜细胞是位于中枢神经系统脑室壁上的特殊神经胶质细胞,产生脑脊液。一层纤毛覆盖在这些细胞的顶端,与脑脊液循环的有 关[42]。 Mirzadeh等[42]利用共焦显微镜观察结构,发现大鼠室管膜下区室管膜细胞层上有许多独特纸风车结构,在核心包含神经干细胞的一个顶部末端,在外缘为2种室管膜细胞包绕,说明神经干细胞参与了室管膜的构成。室管膜细胞开始被认为是室管膜区的固定干细胞,但是现在研究认为成体大鼠大脑中这些细胞是细胞有丝分裂后期的,并无自我更新的能力,不能被培养后分化为神经元。 Carlen等[43]证明室管膜细胞在正常情况下成体再生过程并没有起到作用,但在卒中情况下具有分化为神经母细胞和星形胶质细胞的潜能。 虽然室管膜细胞在正常情况下不是神经干细胞,但能在干细胞微环境中发挥了作用。室管膜细胞生成的色素上皮源性因子,能促进体内和体外神经干细胞的自我更新和增殖。室管膜细胞生成的头蛋白,一种骨形态发生蛋白拮抗物,可通过干预神经胶质细胞阻止神经发生[44-45]。另外,室管膜细胞在离开微环境的新生神经母细胞迁徙中发挥了作 用[46]。 细胞外基质:细胞外基质是组成间质和上皮血管中基质的不溶性结构成分,神经干细胞微环境中的细胞外基质主要由透明质酸所组成,构成了透明质酸网络,其与糖蛋白和蛋白聚糖相连,锚泊细胞表面至基质上[47]。 神经干细胞与细胞外基质紧密结合是通过细胞间黏附分子来实现的,干细胞能表达层粘连蛋白α6β1整联蛋白等受体,与细胞外基质包含的细胞粘合素C、纤维连接蛋白、层粘连蛋白、血小板反应蛋白和胶原蛋白Ⅳ相连接[48],成体动物室管膜下区干细胞通过抑制α6β1整联蛋白来阻止它们与内皮细胞的粘合,从而改变自身位置和增生情况。α6β1膜整连蛋白对成熟的室管膜下区神经干细胞与它的血管生存环境具有重要的作用。 通过对转基因小鼠大脑内神经干细胞的编码Id(DNA结合的抑制因子)蛋白质基因敲除,发现在该蛋白缺如小鼠出生后24 h内即死亡,对其大脑的进一步研究发现其大脑内神经干细胞增殖能力显著下降,而且干细胞的数量也明显减少。研究发现Id蛋白质分子直接调控一种称作Rap1GAP蛋白(小分子G蛋白Rap1的三磷酸鸟苷酶激活蛋白)的生成,而这种Rap1GAP蛋白会再反过来控制Rap1(转录因子阻遏激活蛋白,一种主要的细胞黏附调控因子,能够调节整合素信号以及调节细胞粘附),导致神经干细胞不能粘附在包含有层粘连蛋白或纤连蛋白的细胞外基质上。证明Id-Rap1GAP-Rap1信号通路是神经干细胞锚定于它们的微环境所必须的[49]。 以上研究说明细胞外基质在神经干细胞锚定、生长、增殖、分化、迁移方面起了作用,而支架结构是细胞外基质的特性。 对调控神经干细胞微环境的进一步研究将需要考虑使用组合的方法来模似多种微环境。将有可能包括设计好的细胞外基质支架与神经干细胞共培养,再与其它微环境成分或溶解的微环境因子相作用是今后研究热点。 2.4 微环境中神经干细胞的分化、增殖及调控 成体神经干细胞在正常生理情况下,可能面临多种命运的选择:处于静止状态、自我更新、增殖、分化或者凋亡。干细胞的各种命运决定于精细调控,各种命运之间的选择存在动态平衡。神经干细胞像其它部位干细胞一样,在微环境中基本处于静息或慢周期状态,极少发生增殖,大部分细胞保持于细胞周期G0/G1期,分化基因处于沉默状态,并始终保持干细胞池的稳定[50]。否则干细胞的过度增殖最终可能导致癌变。 2.4.1 神经干细胞与细胞因子关系 当有神经细胞需要自我更新和有病变发生时,则有各种转录因子出现,导致分化基因发生激活,产生细胞增殖;其中过程受到各种信号因子的调节。在神经干细胞的自然分化中,碱性成纤维细胞生长因子主要使神经干细胞分化为神经元。而表皮生长因子主要使神经干细胞分化为神经胶质细胞。 此外,体外实验证明,脑源性神经营养因子、胰岛素样生长因子、神经生长因子、血小板源性生长因子和视黄酸等因子[51-52],通常可以增加神经干细胞向神经元表型方向的分化。其他细胞因子,如白细胞介素6超家族细胞因子和骨形态蛋白家族细胞因子通过协调作用诱导神经干细胞定向分化。这些信号分子彼此相互影响,存在相互拮抗和协同的效应。 2.4.2 神经干细胞的基因调控 虽然神经干细胞在体内所受到的各类细胞因子的影响,最终还需通过信号途径将在基因水平的调控环节发挥作用。 神经干细胞的基因调控包括正负双重调节。负性调节主要包括Notch信号等途径,通过对称性分裂增加神经干细胞的数量,使神经干细胞不分化。正性调节则通过不对称性分裂使神经干细胞分化,其中碱性螺旋-环-螺旋基因起了重要作用。Wnt基因对神经干细胞的增殖和分化均起关键调节作用。Singh等[53]发现少量的Wnt信号可使按细胞维持在多能状态,而大量的Wnt信号则起相反作用,促进细胞分化。 Notch 信号系统的作用是通过旁路抑制机制实现的,细胞上的Notch受体与其邻近细胞上的配体DSL(delta-serrate-Lag-2)结合,Notch信号系统被激活,通过抑制神经干细胞分化为神经元和胶质细胞,从而间接维持干细胞的多能性和更新能力[54]。当Notch信号系统被抑制时,促进神经元分化,发育为功能细胞[55]。另外Aguirre等[56]研究发现神经干细胞微环境中,表皮生长因子受体信号通过Notch信号作用的调控来调节神经干细胞的数目和自我更新。 碱性螺旋-环-螺旋基因编码产生碱性螺旋-环-螺旋转录因子,其转录因子包括Mash1、Neurogenins、NeuroD和Math家族,参与对神经干细胞的正负性调控。碱性螺旋-环-螺旋转录因子主要调节神经元及胶质细胞命运的选择,转录因子可以产生Notch受体,受Notch信号系统的调节[57]。 Wnt基因功能主要是通过调节细胞与细胞之间的相互作用,参与细胞命运的特化、细胞粘附和迁移、细胞极性的形成以及细胞的增殖。Wnt信号可能是干细胞自身分泌并通过自分泌途径来控制干细胞的增殖。Wnt信号通路可在多个水平上对抗Notch信号,从而影响神经干细胞的增殖和分化[58]。 2.4.3 神经干细胞内在程序化与微环境诱导的相关性 干细胞的增殖分化行为一方面被细胞本身预先程序化,另一方面受其所处的微环境的影响[59]。Veizovic等[60]报告,将大鼠神经干细胞注入成年鼠脑内神经发生正在进行的部位如嗅球、海马,则主要化分为神经元;而注入至成年鼠纹状体、黑质等非神经发生性环境时,主要分化为星型胶质细胞质。说明微环境能诱导神经干细胞分化为神经元或其他的神经细胞。 进一步研究表明移植部位的特异微环境对神经干细胞分化影响是相对的[61-62]。Nishino等[63]将大鼠胚胎中脑和皮质来源的神经干细胞分别植入单侧黑质毁损后的大鼠纹状体,发现中脑来源的神经干细胞能分化为多巴胺能神经元,但皮质来源的神经干细胞在纹状体既不能分化为多巴胺能神经元也不能改善动物的旋转行为。揭示室管膜下区中神经干细胞命运特化存在区域性的差异,与不同的培养条件或不同异型移植无关。 Kelsch等[64]通过研究哺乳动物成体神经干细胞发现,神经干细胞其内在程序预设定并不会随着周围环境而改变。虽然神经干细胞具有多能性,可以产生不同类型的神经元,但研究结果显示,神经干细胞只能不可逆地产生一种类型的神经元,而且只具有预先设定的连接模式,也就是说即使将干细胞移植到脑部其他位置,其内在程序预设定的连接模式也不会改变。这意味着特定的神经元干细胞在替代治疗中只能被有限地利用,用于替代大脑中缺失的皮质神经元的干细胞很可能不能用于替代脊髓中缺失的神经元,更何况,在大脑皮质内存在很多不同类型的神经元。"
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