Chinese Journal of Tissue Engineering Research ›› 2013, Vol. 17 ›› Issue (1): 167-172.doi: 10.3969/j.issn.2095-4344.2013.01.027
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Wang Kun, Ha Xiao-qin
Received:
2012-04-28
Revised:
2012-05-18
Online:
2013-01-01
Published:
2013-01-01
Contact:
Ha Xiao-qin, M.D., Chief physician, Department of Laboratory Medicine, the General Hospital of Lanzhou Military Area Command of Chinese PLA, Lanzhou 730050, Gansu Province, China Haxq@yahoo.com
About author:
Wang Kun★, Studying for master’s degree, Department of Laboratory Medicine, the General Hospital of Lanzhou Military Area Command of Chinese PLA, Lanzhou 730050, Gansu Province, China 163wk1029r@163.com
Supported by:
Supported by: the Medical Science and Technology Foundation of Chinese PLA during Twelfth "Five-Year" Development Period (General Program), No.CWS11C229
CLC Number:
Wang Kun, Ha Xiao-qin. Research and clinical application of mesenchymal stem cells modified by cytokines[J]. Chinese Journal of Tissue Engineering Research, 2013, 17(1): 167-172.
2.1 纳入文献基本情况 纳入的35篇文献中,中文文献10篇,英文文献25篇。文献[1-4]主要是对间充质干细胞的介绍,文献[5-9]涉及间充质干细胞的免疫原性,文献[10-18]探讨间充质干细胞的主要功能,文献[19-35]探讨细胞因子对间充质干细胞的修饰。 2.2 间充质干细胞的弱免疫原性 但凡在各类疾病的治疗过程中,只要进行组织移植,那么移植物多少都会引起宿主本身的免疫排斥。但是,若移植物是间充质干细胞,那么情况将有所改变。间充质干细胞目前没有明显的特异性抗原标志,它既有间充质细胞的表面抗原,又有内皮细胞、上皮细胞、肌肉细胞的表面抗原。研究发现, 间充质干细胞可以高表达MHC-1类抗原,低表达CD86(B7-2),不表达MHC-2类抗原及CD(B7-1)。而只有在T淋巴细胞识别间充质干细胞上的MHC-2类抗原的基础上,才能对抗原产生免疫应答,且T淋巴细胞对其的表面标志识别能力差,所以它是通过抑制T淋巴细胞的殖值来达到免疫耐受的。这种表达模式并不会随着细胞的分化成熟而明显改变,同时激活T淋巴细胞所必须的协同刺激分子,这些特性减少了间充质干细胞移植以后免疫排斥反应和相关并发症的发生[5-6]。 间充质干细胞抑制T淋巴细胞的增殖的方式是通过旁分泌的途径来达成的,激活T淋巴细胞的凋亡从而起到免疫抑制作用[7-8]。此外,间充质干细胞还可通过各种方式作用于抗原提呈细胞、树突状细胞、T淋巴细胞、B淋巴细胞和自然杀伤细胞(NK细胞),以影响机体免疫状态。当自然杀伤细胞数量高于干细胞时,干细胞发挥不了免疫抑制作用,活化的自然杀伤细胞可直接溶解间充质干细胞[9]。 2.3 间充质干细胞在组织修复中的作用及功能 在一定的诱导条件下,间充质干细胞具有向成骨细胞、脂肪细胞,骨骼肌、软骨细胞平滑肌、肌腱细胞[10],造血支持基质等中脑层细胞分化的能力;同时可以向外胚层的星形胶质细胞、神经元、血管内皮细胞和心肌细胞分化。近期研究表明,间充质干细胞还能分化为胰岛素分泌细胞[11]。其跨系、甚至跨胚层横向分化的可塑性及其强大的分化潜能使得它可为组织修复提供可能性。 干细胞可能通过旁分泌的机制来促使缺血局部的血管生长[12]。在实验中发现,间充质干细胞在缺氧条件下,一系列有关血管生成的细胞因子的表达上调且分泌在培养基中。内皮细胞和平滑肌细胞的增生在这种培养基中被加强。而当这些培养基注射进动物的后肢缺血部位后,加速了缺血区的侧支建立,改善了局部功能,降低了肌肉萎缩。 机体组织损伤后,不论是内源性还是外源性间充质干细胞都会归巢至损伤处,发挥修复作用。通常认为损伤的组织细胞引起趋化细胞因子,CK)的释放,同时表达趋化细胞因子特异性受体或配体引导对应的干细胞迁移并黏附于损伤处。基质细胞衍生因子1是一种只对其受体CXCR4作出移动反应的趋化因子。研究发现,表达CXCR4的间充质干细胞对基质细胞衍生因子1的浓度梯度有强列的趋化作用并且提高CXCR4的表达水平,能更加有效的促进干细胞的迁移。胰岛素样生长因子1也可以通过提高CXCR4受体的表达水平,增强间充质干细胞的迁移率[13]。Son等[14]发现,培养维持到15-18代的间充质干细胞在表达CXCR4的同时还表达基质金属蛋白,而后者是一种能够降解基质有助于干细胞动员和迁移归巢的酶。经发现,粒细胞集落刺激因子也可提高间充质干细胞向基质细胞衍生因子1的迁移能力,但这一过程是通过CD44与其受体结合实现的,与基质细胞衍生因子1受体CXCR4无关。 据研究表明,CD44与透明质酸酶相互作用有利于间充质干细胞归巢至受损的肾组织[15]。间充质干细胞在分泌大量的相关细胞因子,可能有助于改善和治疗股骨头坏死[16]。而且人骨髓间充质干细胞对胶原诱导的关节炎也有良好的效用[17]。间充质干细胞在与多巴胺神经元细胞联合应用后,可能会促进干细胞对帕金森病的治疗[18]。 2.4 细胞因子对间充质干细胞的修饰作用 间充质干细胞联合各种细胞因子在研究及临床应用方面越来越受到关注。经过细胞因子修饰,不但能够同时发挥两者的作用,还能在一定程度上增强干细胞的功能。这类细胞因子有很多,其中包括低氧诱导因子1、肝细胞生长因子等。 2.4.1 低氧诱导因子1对间充质干细胞的修饰 低氧诱导因子1作为细胞对缺氧适应性反应的上游关键性转录因子,通过对血管内皮生长因子、血小板衍生生长因子、血管生成素、促红细胞生成素)、血红素加氧酶1等多种靶基因的转录调控参与了血管新生、红细胞生成等病理生理过程。应用具有组成型表达活性的低氧诱导因子1α基因治疗可诱导生理功能完整的血管新生。低氧诱导因子1α诱导的新生血管具有无明显炎症反应、不渗漏、不引起组织水肿的特点。因此低氧诱导因子1α被认为是最具有前景的促血管新生治疗的基因之一。 低氧条件下,细胞核产生的低氧诱导因子1α为氧调节蛋白,其调节作用受到机体内氧分压的控制,在正常氧分压下,通过pVHL介导的泛素化蛋白酶体途径,低氧诱导因子1α迅速降解;但在低氧分压下,其的降解途径受阻,导致其在细胞核内聚集,使其表达增高。pVHL具有E3泛素-蛋白酶活性,它可直接与该因子的ODDD区结合,二者结合后就会与ElonginB、ElonginC等因子形成E3蛋白酶复合体。泛素化的低氧诱导因子1α会立即被26S蛋白酶体结合并被降解,而这种结合的首要条件是该因子的ODDD区564和402位脯氨酸残基被脯氨酸羟化酶羟化。脯氨酸羟化酶的羟化作用需要有氧气的参与,是氧依赖性的降解过程。所以低氧诱导因子1α只在细胞缺氧时表达,是细胞感受缺氧时最早反映因子之一,被称为“缺氧基因表达的总开关”[19]。 间充质干细胞可以被动员到暴露于短期缺氧的大鼠的外周血里,并且在一定的时间内这种动员效率可以被增加[20-21],还可高表达低氧诱导因子1在骨骼疾病[22]。软骨是无血管组织,因此它存在于一个缺氧的微环境中。在这样的缺氧环境中,间充质干细胞暴露于软骨细胞生长因子、转化生长因子和地塞米松中,其对胶原Ⅱ型表达的诱导和proteoglygan的沉积明显大于暴露于常氧状态下软骨细胞生长因子中的细胞。而当它暴露于缺氧后,低氧诱导因子1从胞浆移位到细胞核,结合其靶基因序列。同样,缺氧诱发该细胞因子上游激活物AKT和p38丝裂原活化蛋白激酶的磷酸化的增加。而且LY294002,and p38抑制剂,等降低了低氧诱导因子1缺氧介导的稳定性,让细胞暴露于该因子siRNA中,upregulation of collagen Ⅱ,sox-9和proteoglycan deposition的消失可以证明其被诱导成软骨的功能增强[23]。这也说明了低氧诱导因子1是低氧环境对间充质干细胞成软骨的一个关键调节因子。 2.4.2 肝细胞生长因子对间充质干细胞的修饰 肝细胞生长因子是至今发现的第一种能刺激肝细胞增生的蛋白质。其最大的特点是对肝细胞的作用,不仅能是肝实质细胞迅速增生,还能刺激胆管上皮细胞增生,从而加速整个肝脏的再生[24]。其肝细胞生长因子只被凋亡细胞所表达,但间充质干细胞却能揭示其受体c-Met的表达。阻断肝细胞生长因子生物活性会显著减少干细胞的迁移。而且,重组肝细胞生长因子被间充质干细胞以一种剂量依赖性的方式吸引。经其修饰的间充质干细胞,维持了原有的细胞形态及特异性细胞表型,且高表达该因子[25]。因此,细胞凋亡通过肝细胞生长因子/c-Met axis启动间充质干细胞的趋化因子,从而聚集具有再生能力的细胞到组织损伤部位[26]。 肝细胞生长因子修饰的间充质干细胞高表达该因子,而该因子也能进一步促进干细胞本身其他促血管生长因子分泌量的增加,这样可以更好的促进血管生成效应。经证实,经该因子修饰后的间充质干细胞对缺血区血流灌注恢复及组织微血管密度增高均起到了良好促进作用,且治疗效果明显好于单种干细胞的治疗。有关这方面的实验已经可以证实出联合治疗具有协同效应,能有效增加兔缺血肢体的侧支血管,改善肢体缺血状况[27]。肝细胞生长因子修饰的间充质干细胞通过自身分泌促血管生长因子量的增加,显著促进血管内皮细胞的增生、迁移及血管结构的重建,以此在体内发挥促血管新生的作用。另外,间充质干细胞移植到肺组织后,经过分化,修复肺部损伤,减轻肺纤维化[28]。而肝细胞生长因子可以明显减少肺部胶原成分的形成,将肝细胞生长因子转染到间充质干细胞中,可以应用于肺纤维化的治疗[29]。 被修饰后的间充质干细胞通过分泌不同浓度的肝细胞生长因子在组织修复中发挥关键作用。低浓度的肝细胞生长因子通过增加c-Met表达和磷酸化,激活AKT通路,增加p27,Runx2和Osterix蛋白表达,优先促进干细胞成骨分化。与此相反,高浓度的肝细胞生长因子通过诱导激活ERK 1 /2信号通路,强烈诱导其增殖。在动物实验中,肝细胞生长因子高度转染于兔间充质干细胞中,使其数量增殖。移植2周后,该因子表达水平下降,干细胞分化为成骨细胞并产生有效的组织修复功能。所以,通过连续的浓度变化,肝细胞生长因子可以控制间充质干细胞在体内的增殖和成骨分化[30]。这种功能可以被用来诱导骨的再生,也可以用来提高对股骨头缺血性坏死的治疗的药理疗效。"
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