Chinese Journal of Tissue Engineering Research ›› 2014, Vol. 18 ›› Issue (14): 2269-2274.doi: 10.3969/j.issn.2095-4344.2014.14.022
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Feng Tao, Kao Xiao-ming, Ji Wu
Received:
2014-03-14
Online:
2014-04-02
Published:
2014-04-02
Contact:
Ji Wu, M.D., Chief physician, Professor, Doctoral supervisor, Research Institute of General Surgery, Jinling Hospital, Clinical School of Medicine, Nanjing University/Nanjing General Hospital of Nanjing Military Command of PLA, Nanjing 210002, Jiangsu Province, China
About author:
Feng Tao, Studying for master’s degree, Research Institute of General Surgery, Jinling Hospital, Clinical School of Medicine, Nanjing University/Nanjing General Hospital of Nanjing Military Command of PLA, Nanjing 210002, Jiangsu Province, China
Supported by:
the Scientific Development Plan of Nanjing City, No. 201104027
CLC Number:
Feng Tao, Kao Xiao-ming, Ji Wu. Clinical application of stem cells: a lack of large animal models and human trials[J]. Chinese Journal of Tissue Engineering Research, 2014, 18(14): 2269-2274.
2.1 干细胞治疗血液疾病 血液系统疾病包括一系列因血液细胞谱系的改变而导致的急性或慢性血液病,例如白血病、贫血、多发性骨髓瘤、淋巴瘤和黑色素瘤等。到目前为为止,造血干细胞移植仍然是治疗某些血液系统遗传疾病惟一可行、有效的治疗方案[5-6]。多发性骨髓瘤对传统化疗反应率低,并且大剂量化疗加重了患者免疫功能缺陷,中位生存期为二至三年,沙利度胺及其衍生物和硼替佐米等新药联合自体造血干细胞移植显著延长了患者的缓解率及总生存率,为多发性骨髓瘤患者的治疗带来了新的希望[7-8]。治疗非遗传性血液疾病,如再生障碍性贫血,因为没有病理突变存在,诱导性多能干细胞衍生的造血干细胞非常适合自体移植,而不必进行任何遗传操作。对于遗传性血液疾病,如地中海贫血、镰状细胞性贫血,在患者的诱导性多能干细胞中修复病理突变对于基因校正是必须的。迄今大多数的基因校正工作是在患有血红蛋白病的患者诱导性多能干细胞中进行的。因基因突变致病的基因校正多是在原位通过同源重组进行基因修复或者是在一个安全的基因位点通过转基因技术导入健康的基因[9-12]。 2.2 干细胞治疗神经退行性疾病 由于神经元或者是神经胶质细胞功能障碍引起的神经系统疾病,如帕金森病、肌萎缩性侧索硬化症、亨廷顿氏病以及脑卒中等通常后果严重,甚至危及生命[13-15]。目前尚无有效治疗方案治愈这些疾病,但是细胞替代疗法可以明显缓解症状,是将来最具疗效的治疗方案。帕金森病是目前研究最充分和效果最肯定的,由于帕金森病的病变主要是黑质多巴胺神经元的变性导致纹状体内多巴胺水平下降所致,目前的药物治疗和外科手术均不能从根本上解决这个问题,近来发展较快的治疗方法则包括干细胞移植及基因治疗等[16]。另据报道,将能够产生多巴胺受体神经元的人类胚胎干细胞/诱导性多能干细胞移植到啮齿类动物帕金森病模型可以明显改善动物行为障碍[17-19]。应用锌指核酸酶、转录激活因子样效应核酸酶、定期聚集空隙短回文重复(CRISPR)/CRISPR相关系统(CAS)[20-21],或依赖辅助腺病毒载体等基因校正技术可进一步提高利用诱导性多能干细胞治疗神经系统疾病的缓解率,而引起微弱的免疫排斥反应[22-23],以上研究表明,应用干细胞替代疗法治疗帕金森病或其他神经系统疾病能有效地纠正致病性的遗传缺陷。 2.3 干细胞治疗心脏疾病 心脏衰竭是因各种原因,包括心肌梗死和慢性心功能障碍等导致的病理损伤性疾病。成年哺乳动物心肌细胞先天的再生能力非常有限,这使得心脏损伤后的恢复极其困难。传统的治疗方法,例如药物干预和心脏移植等起到的疗效欠佳,而可以抢救心力衰竭患者的干细胞治疗已经在世界范围内引起了极大的关注[24],诱导性多能干细胞使再生心肌细胞治疗心脏衰竭等成为可能[5]。在成人心肌组织中包含有表达酪氨酸激酶受体的心脏干细胞,自我更新、克隆性、多功能性是其三大属性。心脏干细胞最终可以分化为3种主要的心肌细胞,即肌细胞、血管平滑肌细胞及内皮细胞。在心肌梗死后心力衰竭动物模型中进行心脏干细胞移植可以显著减弱心肌细胞重塑,并可以显著改善急慢性心肌梗死患者的左心室功能[25-26]。另有研究表明,对心肌纤维化患者进行胚胎干细胞移植可以显著抑制心肌细胞凋亡和心肌纤维化,进而逆转心肌重塑和改善心肌梗死后患者心脏功能。这一系列治疗效果得益于胚胎干细胞移植后胶原蛋白沉积的减少、心肌再生的增加以及胚胎干细胞潜在的旁分泌因子,包括抗细胞凋亡蛋白半胱氨酸蛋白酶抑制剂C、骨桥蛋白、凝聚素以及抗组织纤维化金属蛋白酶抑制剂1[27-28]。骨髓间充质干细胞移植可以通过影响心肌细胞形成和心肌血管再生,改善心脏结构的重构和心功能,自体移植应用时无免疫排斥反应,可在体外大量扩增,避免伦理争论。另外骨髓间充质干细胞治疗心肌梗死的研究仍处于初期阶段,随着研究深入,如果找到临床应用有效、安全的剂量,其必将为防治缺血性心脏病提供全新的治疗手段[29]。间充质干细胞可以向心肌细胞及脉管系统分化,在心血管疾病的治疗过程中越来越体现出其优越性,其可通过旁分泌作用分泌一系列的细胞活素类物质及生长因子,并且动员内在的心肌干细胞,从而起到改善心功能,诱导逆向重塑,降低心梗面积的作用[30]。 2.4 干细胞治疗肠道疾病 炎症性肠病、放射性肠炎、肝移植相关性肠病等利用传统方法治疗疗效欠佳,且常产生严重的不良反应及并发症。干细胞具有强大的增殖分化能力、多向分化潜能以及向损伤组织定向修复的功能,因而在细胞移植方面具有广阔的应用前景。肠道干细胞主要位于肠黏膜隐窝内,其与肠道黏膜上皮的更新和修复密切相关。研究影响肠道干细胞增殖分化的因素,进而分离、获取、培养肠道干细胞,用于有关肠道损伤疾病的治疗具有重要的临床价值。当前,相关研究的最大障碍是缺乏特异性的肠道干细胞标志物,近年来有研究结果表明Lgr5、Bmi1、Musashi-1等可以作为公认的肠道干细胞标志物,尤其是Lgr5特异性较高[31-32]。在过去的5年中关于干细胞疗法治疗消化道疾病的实验研究数量增加了10倍之多,其中在克罗恩病、各种消化道瘘、肝衰竭等方面取得了突破性进展,有些已进入了三期临床研究阶段[33-34]。研究表明对于难治性炎症性肠病,特别是肠瘘患者,进行骨髓间充质干细胞移植可以显著减轻患者痛苦,提高患者生活质量。骨髓间充质干细胞移植也应用于治疗放射性肠炎,取得了良好的效果[35]。骨髓间充质干细胞移植对Th-1或Th-17异常激活导致的炎症性肠病主要是通过以下几个方面:①归巢并在受伤部位存活。②发挥免疫调节作用,控制炎症进展。③加速肠黏膜再生。④促进Th-1细胞和Th-17细胞向Th-2细胞转化并增强调节性T细胞在肠组织对局部炎症的抑制[36]。有研究发现骨髓间充质干细胞移植对胃肠道手术后吻合口有促进愈合作用,作用主要体现在吻合口张力强度增加、羟脯氨酸水平表达增加、局部新生血管形成以及骨髓间充质干细胞释放的旁分泌介质因子——血管内皮生长因子、肝细胞生长因子、白细胞介素6等[37]。对乙肝肝硬化失代偿期患者进行自体骨髓间充质干细胞移植,结果表明在传统口服核苷类似物抗病毒等综合治疗乙肝肝硬化基础上联合自体骨髓间充质干细胞经肝动脉移植治疗失代偿期肝硬化,能更有效地改善肝功能和凝血功能,患者症状明显好转[38]。 2.5 其他应用 在肾移植的后续治疗中,基于抗体的诱导治疗和钙调神经磷酸酶抑制剂显著降低了移植肾急性排斥反应的发生率,但是机会性感染及钙调神经磷酸酶抑制剂毒性反应仍然不容忽视。Tan等[39]研究发现,自体间充质干细胞移植联合抗白细胞介素2受体抗体诱导治疗能够显著降低肾移植患者急性排斥反应的发生率及机会性感染,并且1年后肾功能较对照组有显著改善,这主要是利用间充质干细胞的抑制T细胞增殖、单核细胞分化为树突状细胞,调节B细胞功能以及抑制自然杀伤细胞毒作用等免疫调节活性。危重症患者中,急性肺损伤或者急性呼吸窘迫综合征是导致急性肺衰竭最常见原因之一,因间充质干细胞可以分泌生长因子等可溶性因子来调节内皮细胞和上皮细胞的通透性、抗炎性因子以及抗菌肽等,间充质干细胞移植被认为是将来治疗急性肺损伤或者急性呼吸窘迫综合征的理想选择[40]。另有研究表明,间充质干细胞移植在一定程度上能改善慢性阻塞性肺通气功能障碍患者肺功能,这主要是通过以下几点实现:①下调促炎递质(肿瘤坏死因子α、白细胞介素1β、单核细胞趋化蛋白1和白细胞介素6)及蛋白酶(基质金属蛋白酶9和基质金属蛋白酶12)。②上调血管内皮生长因子、血管内皮生长因子受体2及降低肺细胞凋亡的转化生长因子β1[41]。干细胞在眼科也得到了应用,在眼角膜受到外伤后,角膜间充质干细胞可以迁移分化为角膜基质细胞,这使得其在角膜生物再生工程中备受青睐[42]。干细胞工程的兴起为视网膜变性、视网膜光毒性损伤、晚期青光眼等难治性疾病的治疗展现了新的曙光,干细胞具有视网膜组织修复和再生的潜能,是目前眼科学领域的研究热点之一[43]。干细胞在感觉神经性耳聋及组织工程化骨等领域也有着应用[44-45],推动了组织工程学的发展。"
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