Chinese Journal of Tissue Engineering Research ›› 2017, Vol. 21 ›› Issue (9): 1470-1476.doi: 10.3969/j.issn.2095-4344.2017.09.02
Liu Jie1, Zhang Guo-hua2
Online:
2017-03-28
Published:
2017-03-31
Contact:
Zhang Guo-hua, Associate professor, Chief physician, Master’s supervisor, Department of Neurology, First Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010059, Inner Mongolia Autonomous Region, China
About author:
Liu Jie, Studying for master’s degree, Inner Mongolia Medical University, Hohhot 010059, Inner Mongolia Autonomous Region, China
CLC Number:
Liu Jie, Zhang Guo-hua. Effect and mechanism of umbilical cord blood stem cells in the treatment of stroke[J]. Chinese Journal of Tissue Engineering Research, 2017, 21(9): 1470-1476.
2.1 脐血干细胞的基础研究 从1974年knudtzon首先证明了脐血中存在成熟的造血干细胞[9],直到1989年Broxmeyer等[10]的研究表明,脐血中富含造血干细胞和祖细胞并且可用于临床。同年,Gluckman等[11]第1次用同胞脐血来源造血干细胞代替骨髓治疗范尼可贫血取得成功,开启了脐血干细胞临床研究的新道路。此后,超过20 000例的脐血干细胞移植在全世界范围内进行,超过1 000 000脐血被保存在几个公共脐血世界银行[12]。而这种来源于脐血的祖细胞被证明是间充质干细胞[13]。 造血干细胞作为脐血干细胞的主要成员,具有分化为各种血细胞前体细胞的能力。造血干细胞在形态学方面无法与其他单核细胞区别,CD34作为造血细胞调节因子,黏附于造血微环境的基质细胞,是造血干细胞的阳性标志[14-15]。脐血干细胞中CD34阳性的细胞承担了主要的造血功能。据报道,虽然脐血中的CD34阳性细胞仅占有核细胞的1%,骨髓中CD34阳性细胞占有核细胞的1%-3%。但最原始造血干细胞却不表达HLA-DR和CD38,CD34+HLA-DR-和CD34+CD38-细胞在脐血中的比例明显高于骨髓[15]。所以,固然脐血中CD34阳性细胞数少于骨髓,但脐血中的造血干细胞更原始、增殖能力更强,被广泛应用于疑难血液系统疾病(如镰刀形细胞病和再生障碍性贫血)、恶性肿瘤和遗传性疾病等[16]。 脐血间充质干细胞是脐血中的非造血组织多能干细胞,不仅可分化为中胚层来源的多种细胞如脂肪细胞、成骨细胞及肌细胞等,还可分化为内胚层来源的肝细胞和外胚层来源的神经细胞[17]。间充质干细胞的发现源于1970年,Friedenstein首次在骨髓中发现一群具有支持造血和分化为骨细胞等功能的祖细胞,4年后将这类细胞进行体外培养并获得成功[18]。Haynesworth等[19]用人骨髓间充质干细胞免疫鼠,首次揭示了间充质干细胞的特异性抗原:SH2,SH3和SH4。但脐血中是否存在间充质干细胞却一直存在争议,直到2000年Erices将脐血单个核细胞经培养获得破骨细胞和类似骨髓的间充质样细胞,这些细胞表达SH2、SH3、SH4,认为脐血中含有丰富的间充质干细胞[20]。目前的研究结果证明,脐血间充质干细胞不仅具有多向分化潜能,还可联合造血干细胞,提高造血重建能力和发挥部分免疫调节作用。 首先,脐血间充质干细胞具有多分化潜能,尤其是在特定诱导条件下可分化为神经干细胞,而神经干细胞是中枢神经系统的多能细胞,具有自我更新和多方向分化的能力。2001年Sanchez-Ramos等[21]首先报道了人脐血干细胞在维甲酸和神经生长因子的诱导下,可表达Musashi-1及微管蛋白Ⅲ等在神经元形成早期所表达的标记物,并发现胶质纤维酸性蛋白在诱导后的细胞及未处理的细胞中均有表达。2002年,侯玲玲等[22]将脐血间充质干细胞分别经β-巯基乙醇、二甲基亚砜和丁化羟基苯甲醚等抗氧化剂体外诱导后,70%表达神经丝蛋白和神经元特异性烯醇化酶等典型的神经元样表型,且有神经元特有结构尼氏体的形成。Buzańska等[23]对磁珠分选去除CD34+细胞的脐血单个核细胞进行研究,发现低密度接种后,细胞形成表达巢蛋白Nestin的集落。脐血间充质干细胞的神经分化潜能呗广泛应用于脑血管疾病[24-25]、神经退行性疾病(阿尔茨海默病、帕金森病)[26-27]、脊髓损伤[28]、儿童神经变性性疾病(Krabble病、脑白质营养不良)等中枢神经系统疾病的治疗。 除此之外,脐血间充质干细胞的造血支持作用也引起了许多学者的关注。脐血是造血干细胞的主要来源,但由于脐血中的造血干细胞数量少,移植存活率低,中性粒细胞和血小板恢复时间长,影响着脐血干细胞移植的成功率。一方面,脐血间充质干细胞通过分泌多种具有造血支持作用的细胞因子,促进造血干细胞的扩增和增殖;另一方面,脐血间充质干细胞表达与造血细胞相互作用的黏附分子,调控造血细胞与基质细胞的黏附,在造血细胞植入和归巢中起着重要作用[29]。于是,许多实验表明,联合移植脐血间充质干细胞和造血干细胞,可提高造血干细胞移植的成功率[30-31]。 最后,间充质干细胞可能通过抑制淋巴细胞的增殖、抑制B细胞分化成熟及其抗原呈递作用、抑制细胞毒性T淋巴细胞形成,发挥其免疫调控功能。因此,脐血间充质干细胞输注可能是预防和治疗移植物抗宿主病的来源[31]。 2.2 脐血干细胞应用于脑卒中的实验 随着人们不断深入对脐血干细胞神经分化的研究,使得脐血干细胞成为神经系统疾病治疗领域的研究热点。目前,已有一些脑卒中细胞移植的实验性治疗,取得了理想疗效,并对脐血干细胞的作用机制、移植途径和时间限制进行了分析。 目前虽有许多应用脐血干细胞移植治疗出血性及缺血性脑卒中的实验性治疗,但尚未有学者对脐血干细胞治疗出血性和缺血性脑卒中进行对比的分析。Chen等[32]通过静脉输注移植脐血干细胞治疗短暂大脑中动脉闭塞大鼠模型,观察到大鼠的行为功能明显改善,大脑损伤同侧(皮质和纹状体)的脐血干细胞数量显著大于对侧,说明移植细胞可透过血脑屏障迁移至脑损伤区域。同时利用免疫组化方法测得有星形胶质细胞标记物胶质纤维酸性蛋白、神经元标记物NeuN和微管相关蛋白2的表达,说明移植的细胞有分化为神经干细胞的潜能。 此后Taguchi等[33]证明了移植脐血来源的CD34+治疗缺血性脑卒中,可诱导缺血区域新生血管的形成,直接或间接的为神经再生创造适宜的环境。另外有学者将神经营养因子GDNF基因转染至脐血干细胞,不仅可提高梗死区神经细胞的存活率,而且有助于脐血干细胞改善缺血性脑卒中后缺血性再灌注损伤[34]。说明基因介入与细胞联合治疗更有利于脑卒中的治疗。 同样,脐血干细胞也广泛应用于出血性脑卒中。例如,Kim等[24]在胶原酶诱导的脑出血模型中输注脐血间充质干细胞,获得神经功能改善的同时,对脐血间充质干细胞的作用机制进行了探讨,即除了神经和血管再生,减轻继发性的炎症损伤也是脐血间充质干细胞发挥作用的关键。总之脐血干细胞治疗出血性和缺血性脑卒中的机制与神经重塑、血管再生、抗炎反应相关,但脐血干细胞应用于两种疾病的差异尚需大量的实验进行探讨研究。 目前,脐血干细胞移植治疗脑卒中的最适途径仍然存在争议。Wang等[35]比较了脑内局部、脑室内和静脉输注3重不同途径移植神经干细胞治疗大脑中动脉闭塞大鼠的效果,发现静脉输注途径较前两者到达损伤部位的神经干细胞数量较少,但操作简便、损伤小,可反复输注,弥补数量上的不足。脑内局部移植虽然会造成局部机械性损伤和轻微的占位效应,但移植的细胞集中,可直接到达损伤部位发挥作用,更有利于脑卒中的远期恢复[36]。脑室内移植的干细胞随着脑脊液循环到达脑损伤区域,较局部移植损伤小,较静脉输注更易到达脑损伤区域,由于血脑屏障的作用,副作用也较小,被广泛应用于临床治疗[37]。 除此之外,脐血干细胞治疗脑卒中还受“时间窗”的影响。Guan等[38]在移植同种异体骨髓间充质干细胞治疗短暂大脑中动脉闭塞大鼠时发现,24 h移植组梗死面积显著下降,行为测试、干细胞的统计数、神经营养因子和趋化因子水平明显高于其他实验组。Darsalia等[39]进一步发现,在脑卒中48 h内移植的细胞较6周后(恢复期)移植的细胞存活率高,但延迟移植并没有影响细胞迁移、增殖和神经元分化,并且过多的干细胞移植并不能增加细胞存活率和神经元分化。所以在脑卒中早期,尤其是炎症反应之前,移植细胞和选择适宜的细胞移植量直接影响移植的成功率,这对临床治疗具有很大的指导意义。 总之,脐血间充质干细胞在神经病学、血液学、基因治疗和组织工程学中具有重要的研究价值,正如前文所述,基于脐血干细胞的多向分化潜能,其被广泛应用于神经系统疾病,例如出血性和缺血脑卒中、神经退行性或变性性疾病和脊髓损伤等;利用脐血间充质干细胞的造血支持作用与造血干细胞联合治疗血液系统疾病,例如贫血、恶性肿瘤等;就其免疫调控作用,展开了对移植物抗宿主病新治疗途径的探索。除此之外,脐血干细胞中的内皮祖细胞,可作为基因传递的基础,比传统的载体和病毒基因治疗有很多优势,因其具有透过血脑屏障和向疾病部位归巢的特性。Achyut等[40]用脐血内皮祖细胞转染携带人钠碘转运体基因注入胶质瘤大鼠体内,观察到细胞向病灶的迁移和转基因的表达,说明脐血内皮细胞作为基因运载工具有希望应用于临床治疗。但目前对于脐血间充质干细胞的研究仍处在起步阶段,还有许多问题尚待解决,比如脐血间充质干细胞作为造血基质细胞,随着造血部位的转移,从脐血逐渐向骨髓转移,以致孕晚期脐血中的间充质干细胞含量很低,给培养和移植带来很大的困难;而且脐血间充质干细胞分化成神经干细胞的机制尚不清楚,尚且缺乏鉴定间充质干细胞的统一标准,这些问题有待于大量的实验及临床研究去探讨。 2.3 脐血干细胞移植治疗脑卒中的可能机制 研究发现,移植的干细胞仅有1%-8%表达神经元及星形胶质细胞的特异性标记。这说明脐血干细胞的修复机制不仅在于替代缺损的神经细胞、重建神经联系。大多数学者认为,脐血干细胞修复神经功能的机制可能与血管再生、神经重塑、分泌营养因子和减轻炎症反应有关。 2.3.1 血管再生 通常情况下,老年人在脑卒中后神经功能恢复较差,这可能与新生血管少有关。脑血管密度高的患者较低者功能恢复更好,生存时间更长。这说明神经功能的维持依赖于局部血流量,因此促进血管再生是治疗脑卒中的关键措施。血管再生发生在缺血边缘带,从缺血后数小时开始延续到数周。一氧化氮被认为是引发血管舒张和血管生成的第一步[41]。一氧化碳与血管内皮生长因子共同作用,使血管的通透性增加,血浆蛋白外渗,为内皮细胞建立一个临时的支架,促进血管生芽。第二步涉及包绕着成熟血管平滑肌细胞的解离和细胞外基质的松动。这其中,血管生成素2、Tie2信号转导的抑制剂,可能参与促进血管内皮周围细胞解离,而基质金属蛋白酶家族的蛋白酶降解基质分子进一步削弱血管完整性[42]。 一旦血管发芽的路径已启动,增殖的内皮细胞向前移动及后续细胞增生而形成一条细胞索,逐渐形成新生的毛细血管,进而彼此吻合构成毛细血管网。一系列的分子信号,包括血管内皮生长因子、血管内皮生长因子受体和胎盘生长因子共同参与了这个过程。一旦毛细血管网形成,促血管生成素1通过激活Tie2受体,进一步稳定这一网络结构。最近的一些研究表明,新生血管在大脑神经再生中起着重要作用。Kojima等[43]用病毒标记大鼠脑缺血损伤模型脑室下区的神经祖细胞,用EGFP标记血管,对迁移的神经祖细胞和新生血管实时成像,研究结果显示,脑室下区的神经祖细胞沿着血管支架迁移至损伤的纹状体。说明了血管作为神经祖细胞向受损脑区域迁移的支架而发挥作用。既往实验证明,脐血间充质干细胞在治疗血栓闭塞性脉管炎、下肢缺血性疾病和心肌梗死等动物模型具有明显的血管再生作用[44-46]。Kim等[44]将脐血间充质干细胞移植于脑出血大鼠,发现脐血间充质干细胞治疗组显示高水平的神经、血管再生和抗细胞凋亡作用。 2.3.2 神经重塑 在脑卒中等急性中枢神经系统损伤之后,神经功能恢复是有限的,常给患者留下终生残疾,这可能与轴突再生与神经可塑性的不足有关[47]。轴突重构开始于脑卒中后的二三周。有研究证明,在梗死灶周围幸存的皮质神经元,可通过轴突出芽恢复大脑的神经连接,促进功能恢复[48-49]。有学者通过移植脐血干细胞治疗脊髓损伤时发现,有形态正常的包绕轴突的髓鞘形成[50]。 少突胶质细胞产生髓鞘,包绕轴突,促进神经传导。而少突胶质细胞的前体在缺血性脑损伤的高风险期寄居于大脑白质,大脑白质比灰质血流量低,甚至深部白质几乎没有侧支供血,所以少突胶质细胞极易受到缺血性损害,导致脱髓鞘改变,加重神经和行为功能缺损。在短暂大脑中动脉闭塞模型中,少突胶质细胞的数量在缺血24-48 h后下降,而在梗死再灌注后一二周开始增加。众所周知,成熟少突胶质细胞是不能增殖的,缺血性损伤后,白质却含有大量的少突胶质细胞前体,说明脑卒中后有丰富的少突胶质细胞再生[51]。那么少突胶质细胞是怎么来的呢?位于脑室下区和海马齿状回的颗粒下区的神经干细胞是具有多向分化潜能的祖细胞。正常情况下,神经干细胞的数量是通过对细胞凋亡和增殖的调控完成的[52]。大脑缺血性损伤后,通过激活内源性的神经祖细胞,使其大量增生并迁移至海马回,产生各种细胞类型,包括神经元、星形胶质细胞、少突胶质细胞[53]。而且细胞疗法可以增强这种内源性神经发生,迁移和分化,促进神经功能恢复[32,54]。 2.3.3 抗炎作用 脑卒中后继发性神经缺损,被认为是由迟发性炎症反应和免疫细胞活化介导的[55]。近期许多研究表明,脐血间充质干细胞能够减少脑卒中后的缺血性损害,归因于其抑制炎症反应的作用。Newcomb等[56]静脉输注脐血干细胞治疗大脑中动脉闭塞48 h后,发现中性粒细胞和单核细胞浸润显著降低,星形胶质细胞和小胶质细胞激活也明显减少。Kim等[47]移植脐血干细胞治疗脑出血大鼠得出同样的结论,同时发现肿瘤坏死因子α、环氧合酶等炎症因子的表达比对照组明显减少。研究表明,脐血干细胞可通过抑制促炎因子的表达,包括细胞因子、肿瘤坏死因子α、环氧合酶和CD11b、CD45/B220阳性的细胞等,抑制与凝集素结合反应,发挥抑制炎症与神经保护的作用[57]。 2.3.4 营养因子的作用 干细胞治疗脑卒中的机制不仅是细胞替代受损组织,近期研究表明,脐血干细胞还通过分泌营养因子发挥营养和修复作用,降低脑卒中后的组织损伤。这些营养因子包括成纤维细胞生长因子2、表皮生长因子、脑源性神经营养因子、促红细胞生成素等。例如,无论内源性或外源性的成纤维细胞生长因子,都可以防止大脑缺血缺氧性损伤[58-59]。再灌注1 d后血管内皮生长因子的释放,被认为可减少梗死面积,促进海马齿状回和脑室下区神经祖细胞的生存与增殖并刺激血管生成[60]。局部应用胶质细胞源性神经营养因子,可减少细胞凋亡,减轻缺血性脑水肿和TUNEL阳性神经元数[61]。有学者静脉注射促红细胞生成素治疗31例脑卒中患者,结果证明促红细胞生成素安全到达大脑,治疗组神经功能评分有所改善,梗死面积缩小,这可能与减少细胞凋亡,促进神经血管再生,减少炎症反应等作用有关[62]。"
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