影响神经干细胞增殖及分化的主要因素
2021-07-01李策张备姜从玉胡瑞萍
李策 张备 姜从玉 胡瑞萍
摘 要 近年来,应用干细胞治疗神经系统疾病逐渐成为神经科学领域的研究热点。本文概要介绍影响神经干细胞增殖及分化的主要因素。
关键词 神经干细胞 分子机制 中枢神经系统疾病
中图分类号:R329.28 文献标志码:A 文章编号:1006-1533(2021)07-0021-05
*基金项目:①国家自然科学基金资助项目(82002390);②上海市卫生和计划生育委员会重要薄弱学科建设项目(2015ZB0401)
The factors influencing the proliferation and differentiation of neural stem cells*
LI Ce**, ZHANG Bei, JIANG Congyu, HU Ruiping***
(Department of Rehabilitation, Huashan Hospital, Fudan University, Shanghai 200040, China)
ABSTRACT Recently, stem cell therapy for the treatment of nervous system diseases has gradually become a hotspot in the field of neuroscience. This paper summarizes the factors influencing the proliferation and differentiation of neural stem cells in vivo.
KEy WORDS neural stem cells; molecular mechanism; central nervous system diseases
在成人脑组织中,主要有两个区域可观察到神经干细胞的存在,即脑室下区和海马体齿状回。在人类中,由脑卒中诱导的神经再生似并不能导致患者的神经功能在脑卒中后得到足够程度的恢复,但目前还不清楚这是否是因为神经干细胞的数量太少的缘故。不过,近年来,神经干细胞移植已被研究用于多种神经系统疾病的治疗,如脑外伤[1]、脑卒中[2]和帕金森病[3]等。
神经干细胞的分化依赖于其周围的神经细胞、基质细胞和细胞外基质。基于神经干细胞所处微环境的不同,同一来源的神经干细胞可分化为不同种类的神经细胞,其分化过程涉及自我调节和外源信号物质的调节。适当诱导内源性或外源性神经干细胞向神经元增殖和分化,以补偿神经元的损失,这被认为是一种潜在的有效促进神经再生及其损伤修复的方法。因此,优化神经干细胞移植的微环境,使神经干细胞发生特异性分化,对神经功能恢复具有重要的作用。本文概要介绍影响神经干细胞增殖及分化的主要因素。
1 激素
1.1 糖皮质激素
许多激素均已被证实可影响神经干细胞的增殖及分化,如糖皮质激素[4]、生长激素和催乳素[5]等。有研究表明,低氧诱导的大鼠海马体糖皮质激素水平增高是海马体齿状回神经及其可塑性受损的原因之一[6]。氯倍他索为糖皮质激素类药物,广泛用于湿疹[7]、银屑病[8]、扁平苔藓[9]等皮肤病治疗。然而,体内研究发现,氯倍他索可促进神经干细胞向少突胶质前体细胞(oligodendrocyte precursor cells, OPCs)分化,并促进OPCs分化为少突胶质细胞,进而促进髓鞘形成[10-11],而神经干细胞分化为星形胶质细胞的比例则相应下降[12]。
TREK-1是一种双孔钾离子通道,其已被证实参与了抑郁症的发病[13],机制与神经干细胞的增殖有关。TREK-1抑制剂布比卡因和姜黄素能显著增强胚胎神经干细胞的生存和增殖能力,糖皮质激素类药物地塞米松则可显著提高TREK-1及其蛋白mRNA的表达水平,进而导致神经干细胞的增殖能力下降,但地塞米松的此效应能被氟西汀所逆转[14]。氟西汀是一种选择性5-羟色胺再摄取抑制剂,是一种具有TREK-1抑制作用的抗抑郁药物[15],能显著抑制TREK-1的表达,从而改善地塞米松诱导的神经干细胞增殖能力下降现象[14]。抗抑郁药物艾司西酞普兰也是通过减少TREK-1的表达,进而促进海马体齿状回神经干细胞的增殖,使脑卒中后抑郁大鼠体重增加、运动能力得到改善的[16]。此外,抑制TREK-1的活性可减少脑皮质缺氧大鼠的神经元凋亡[17]、抑制星形胶质细胞增殖[18],提示TREK-1和压力导致的糖皮质激素水平增高与神经再生减少有关,而5-羟色胺或抗抑郁药物水平增高则与神经再生增加有关[19]。
综合以上研究结果可以推知,由于糖皮质激素既能抑制神经干细胞增殖,又能促进神经干细胞向少突胶质细胞分化,故其在神经干细胞移植治疗脱髓鞘病变性中枢神经系统疾病中可能有很好的临床应用价值,但仍需进行进一步的深入研究。
1.2 生长激素
一项研究发现,使用生长激素刺激可导致小鼠胚胎神经干细胞增殖,且脑缺血小鼠同侧脑室下区中生长激素受体的免疫反应活性显著增高[20]。运动训练可提高学习记忆能力,此与其能增加生长激素的分泌,进而促进神经干细胞的增殖有关,但运动训练不能促进生长激素受体缺失小鼠神经干细胞的增殖[21]。这些发现提示,与生长激素及其受體有关的神经干细胞增殖在运动训练诱导的神经再生及预防神经退化中起着重要的作用,但具体机制还不十分清楚。
Devesa等[22]使用生长激素联合康复治疗方法治疗了1例9月龄大的尾端退化综合征(caudal regression syndrome)患儿,治疗共持续5年。治疗6个月后,患儿的粗大运动功能测试88项(Gross Motor Function Measure-88 item, GMFM-88)评估结果提高至39.48%,感觉和运动功能明显改善;治疗18个月后,患儿的感觉神经支配完成,并已可控制括约肌;治疗3年后,患儿开始拄拐行走,但足底屈曲,GMFM-88评估结果为78.48%。该研究表明,使用生长激素促进神经干细胞增殖,进而治疗中枢神经系统损伤性疾病具有较好的临床应用前景。
1.3 促肾上腺皮质激素释放激素(corticotropinreleasing hormone, CRH)
CRH是哺乳动物应激反应的主要介质,也是成人脑中的关键神经调节因子,是海马体区神经干细胞增殖及分化所必需的物质。CRH基因缺陷会损害海马体区神经干细胞对环境刺激的反应能力,减少神经形成,影响空间记忆能力,而暴露于CRH则可促进神经形成[23]。不过,有关CRH对神经干细胞增殖及分化影响的研究很少,需进一步研究以明确CRH促进神经形成的机制。
2 神经递质
2.1 5-羟色胺
以往研究表明,抗抑郁药物可通过增加神经祖细胞的增殖、加速树突的生长、提高新生神经元的存活率来促进成人海马体区的神经形成[24]。最近研究则发现,运动训练诱导的5-羟色胺是神经再生的参与者,对运动训练诱导的神经再生至关重要[25],能直接促进神经干细胞的增殖[26]。5-羟色胺转运蛋白在运动训练诱导的神经再生过程中也是必不可少的[27]。
尽管已知运动训练可导致脑中的5-羟色胺水平增高[28-29],但目前还不清楚5-羟色胺是如何促进神经干细胞增殖的。氟西汀是一种选择性5-羟色胺再摄取抑制剂类抗抑郁药物。以往研究表明,非典型蛋白激酶C参与了神经形成和氟西汀的抗抑郁作用过程[30]。近年研究还发现,氟西汀也可通过蛋白激酶Mζ介导的信号通路增加海马体区神经干细胞的增殖,并经作用于1A型5-羟色胺受体而激活丝裂原活化的蛋白激酶信号通路下游的磷酸化[31]。不过,氟西汀只能特异性地增加海马体腹侧的神经干细胞增殖,对海马体背侧的神经干细胞没有显著影响。即使在海马体腹侧,氟西汀亦仅能特异性地诱导Ⅱ型神经干细胞和成神经细胞的增殖,而Ⅰ型神经干细胞的有丝分裂活性未发生改变[32]。
5-羟色胺与其受体相互作用后可增加成人大脑皮质中神经前体细胞的增殖。研究表明,给予1A型5-羟色胺受体激动剂可增加成人脑室下区和海马体齿状回中的神经前体细胞数量[33],而使用药物降低5-羟色胺水平则可抑制成年动物脑中神经前体细胞的增殖[34]。不同亚型5-羟色胺受体参与的神经发育阶段也不同,如神经再生、凋亡,以及轴突分支和树突的形成等[35]。例如,3A型5-羟色胺受体在运动训练诱导的海马体区神经形成和抗抑郁治疗中起着关键作用,但对学习能力没有显著影响[29];2A型5-羟色胺受体是脑中表达最广泛的5-羟色胺受體之一,其在神经元分化及其树突成熟过程中起着重要作用[35],同时也是运动训练治疗偏瘫患者运动功能障碍有效的潜在机制之一[36]。因此,似可通过激活不同亚型的5-羟色胺受体来诱导神经干细胞定向分化为不同类型的神经细胞。
2.2 多巴胺
多巴胺系统具有调控行为表型的生理学功能,如运动控制、奖赏、焦虑和抑郁等。研究表明,多巴胺可增加成人脑中海马体区新生神经元的数量,而去除多巴胺能神经元则会减少海马体齿状回颗粒下区中神经干细胞的增殖[37],提示多巴胺具有促进成人脑中神经干细胞及祖细胞增殖和分化的作用[38],机制可能与多巴胺D1受体和Wnt/β-连环蛋白信号通路的激活有关[39]。脑多巴胺神经营养因子(cerebral dopamine neurotrophic factor, CDNF)是一种可能具有保护和恢复多巴胺能神经元作用的关键蛋白,给予CDNF可改善帕金森病大鼠的运动功能,并增加其脑室下区中表达双皮质素的神经母细胞数量,促进神经干细胞向受损的纹状体迁移[40]。一项研究将多巴胺功能化于通过三维打印制成的甲基丙烯酸明胶生物支架上,神经干细胞被用作此支架的主要干细胞来源,其最终能分化为多种神经细胞类型,包括神经元、星形胶质细胞和少突胶质细胞,由此形成的多巴胺-甲基丙烯酸明胶生物支架具有高孔隙度和互联的三维环境,有利于神经干细胞增殖[41]。
2.3 谷氨酸
神经可塑性降低和谷氨酸能神经递质在突触间隙的积聚是导致脑卒中后抑郁的主要病理学因素。脑卒中后抑郁患者星形胶质细胞中谷氨酸转运蛋白-1水平的下降会刺激神经干细胞向星形胶质细胞分化,也会影响谷氨酸代谢并抑制功能性突触的形成[42]。代谢型谷氨酸受体-2/3表达于增殖的来自人前脑的神经干细胞及其分化产生的神经元和星形胶质细胞上,激活这些受体可刺激神经干细胞增殖,但不会显著影响神经干细胞的分化[43],提示谷氨酸及其受体在神经干细胞调控中起着重要作用。
2.4 组胺
组胺在中枢神经系统中起着神经递质的作用。体外研究表明,透明质酸可通过激活1型组胺受体而增加神经干细胞分化为神经元的数量,机制可能与皮质上皮祖细胞中prospero-1和neurogenin-1基因的表达水平增高有关[44]。未来应进一步研究组胺对神经干细胞分化的影响及其机制。
3 转录因子
3.1 Sox2
Sox2对神经干细胞的生存和脑发育至关重要[45]。螺羟吲哚1a(spirooxindole 1a)是一种在研小分子抗肿瘤化合物,其能通过降低Sox2和提高β-微管蛋白Ⅲ水平来诱导神经干细胞分化,治疗胶质瘤可能有效[46]。
3.2 sonic hedgehog(Shh)
在胚胎发育过程中,Shh信号通路的短暂激活对少突胶质细胞祖细胞的产生及其在大脑和脊髓中的分化和成熟至关重要,且Shh信号通路的激活可促进神经干细胞的增殖[47]。研究表明,使用小分子抑制剂GANT61对神经干细胞中Shh信号通路的转录因子——胶质瘤相关致癌基因-1进行短暂和部分抑制可产生迁移能力更强的OPCs,并使之更早地向产生髓鞘蛋白的少突胶质细胞分化[48]。
4 生长因子和神经营养因子
4.1 生长因子
神经干细胞的增殖及分化受周围环境的调控。当从培养基中去除生长因子后,神经干细胞的增殖便会停滞并分化为神经元和胶质细胞[49]。研究表明,胰岛素样生长因子-1[50]和血管内皮生长因子[51]在运动训练诱导的神经形成增加过程中起着重要的作用。各种营养和化学因子能与生长因子协同作用,共同促进神经干细胞分化为神经元[52]。
4.2 神经营养因子
睫状神经营养因子(ciliary neurotrophic factor, CNTF)是脑室下区和海马体区神经形成的主要决定因子[53]。一项研究将一种基于CNTF的生物活性区域设计的11聚多肽(即肽6)注入健康成年小鼠的外周皮下,结果发现小鼠海马体区神经祖细胞的增殖及其分化为神经元的数量均增加,且记忆也获改善[54]。
膠质细胞源性神经营养因子(glial cell line-derived neurotrophic factor, GDNF)具有保护多巴胺能神经元、挽救运动神经元的作用,可用于退行性神经系统疾病治疗。一项研究利用重组腺相关病毒载体构建了整合有GDNF基因的改良神经干细胞,然后将此神经干细胞移植至小鼠海马体CA1区,结果发现此改良神经干细胞可在维持GDNF表达的同时向海马体齿状回区迁移并分化为神经元细胞[55],提示人神经祖细胞移植有治疗脑损伤和退行性神经系统疾病的潜力。
中脑星形胶质细胞源性神经营养因子(mesencephalic astrocyte-derived neurotrophic factor, MANF)在神经系细胞中呈高表达状态。MANF缺失的神经干细胞虽可增殖,但在神经元分化过程中轴突的扩展方面存在缺陷,而体内去除MANF后也会导致神经元迁移减慢及其轴突生长受损[56],表明MANF是哺乳动物大脑皮质发育过程中神经元迁移及其轴突生长的一种重要调节因子。
5 其他
β-雌激素受体调节因子参与了细胞黏附、轴突引导、notch和γ-氨基丁酸受体的信号传导,以及神经元前体细胞分化为多巴胺能神经元和少突胶质细胞的过程。研究表明,β-雌激素受体是胚胎干细胞分化为中脑神经元的一种重要介质,能防止新生的少突胶质细胞的早熟[57]。芳烃受体是一种可由环境激动剂和饮食色氨酸代谢物激活的配体依赖性转录因子,也会参与免疫反应和细胞周期的调节。
6 结语
影响神经干细胞增殖及分化的因素很多。遗憾的是,目前还不能确定有效、精准地诱导神经干细胞增殖并分化为脑中特定类型的神经细胞所必需的精确的分子信号组合,也不清楚内源性和外源性神经干细胞的发育过程是否相同。未来需进行更深入的研究,以明确影响神经干细胞增殖及分化的关键机制,为神经干细胞移植更好地应用于临床提供理论依据。
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