Chinese Journal of Tissue Engineering Research ›› 2014, Vol. 18 ›› Issue (14): 2250-2256.doi: 10.3969/j.issn.2095-4344.2014.14.019
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Da Yang1, Meng Qiu-hong2, Liu Hong-bao3, Xue Wu-jun4
Received:
2014-01-28
Online:
2014-04-02
Published:
2014-04-02
Contact:
Liu Hong-bao, M.D., Department of Nephrology, Xijing Hospital, the Fourth Military Medical University, Xi’an 710032, Shaanxi Province, China
Corresponding author: Xue Wu-jun, Chief physician, Professor, Department of Renal Transplantation, Center of Nephropathy, the First Affiliated Hospital, Medical College of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
About author:
Da Yang, Fifth Team of Trainee Brigade at Grade 2009, the Fourth Military Medical University, Xi’an 710032, Shaanxi Province, China
Meng Qiu-hong, Studying for master’s degree, Graduate Management Brigade at Grade 2013, the Fourth Military Medical University, Xi’an 710032, Shaanxi Province, China
Da Yang and Meng Qiu-hong contributed equally to this paper.
Supported by:
the National Natural Science Foundation of China, No. 81370016, 81000309; Midwest Outstanding Young Foundation of Chinese Medical Association, No. 2012
CLC Number:
Da Yang, Meng Qiu-hong, Liu Hong-bao, Xue Wu-jun. Therapeutic potential of stem cells for ischemic kidney injury: functional characteristics of a stromal cell-derived factor 1-CXCR4/CXCR7 axis[J]. Chinese Journal of Tissue Engineering Research, 2014, 18(14): 2250-2256.
2.1 基质细胞衍生因子1-CXCR4/CXCR7轴概述 2.1.1 基质细胞衍生因子1(CXCL12)的生物学特性 人基质细胞衍生因子1基因定位于人染色体10q11.1。基质细胞衍生因子1 有基质细胞衍生因子1α和基质细胞衍生因子1β两个亚型,分别含有89个和93个氨基酸残基。与其他趋化因子不同,即使无病原体侵入,基质细胞衍生因子1也在体内稳定表达,而不是由炎症等刺激所诱导。除了骨髓基质细胞外,某些间皮细胞、上皮细胞、肿瘤细胞和肿瘤间质细胞也可以分泌基质细胞衍生因子1。基质细胞衍生因子1表达于人体多种组织中,包括心脏、肺脏、肝脏、胰腺、脾脏、肾脏、肠、脑、胎盘、卵巢和免疫细胞等。基质细胞衍生因子1与其受体(CXCR4和CXCR7)之间构成的信号通路在维持胚胎发育、介导免疫及炎症反应、造血干/祖细胞的动员和归巢、肿瘤发生和转移、免疫细胞的发育与活化、循环系统及中枢神经系统的发育等多种生理和病理过程中发挥重要作用。 2.1.2 CXCR4的生物学特性 CXCR4是一个编码352个氨基酸且高度保守的G蛋白耦联7次跨膜蛋白受体,属于G蛋白偶联受体家族。其编码基因位于染色体2q21,有1个胞外的N端,3个胞内环,3个胞外环和1个胞内的C端。其胞外N端及胞外环与基质细胞衍生因子1都具有较高的亲和力;胞内区则与G蛋白偶联;C端位于胞浆内,含有丝氨酸/苏氨酸可以磷酸化,与受体配体结合无关,主要参与信号转导。CXCR4表达于骨髓、脐血和动员的外周血CD34+细胞表面,还可在多种非造血细胞和器官上表达。CXCR4与基质细胞衍生因子1具有高度亲和力,二者的结合所形成基质细胞衍生因子1/CXCR4轴是实现其生物学功能的基础。近期的大量研究结果表明,基质细胞衍生因子1/CXCR4轴的生物学功能主要包括以下5点:①介导了炎症和免疫反应。②关联于艾滋病病毒感染;③参与了胚胎发育的过程。④涉及了恶性肿瘤转移和浸润。⑤调控了干细胞归巢和迁移。在关于基质细胞衍生因子1/CXCR4轴生物学功能的相关研究中,日益引起重视的基质细胞衍生因子1/CXCR4轴与成体干细胞或其前体细胞的迁移和归巢之间的关系,随着大量深入研究的开展,学者们已经开始意识到利用基质细胞衍生因子1/CXCR4轴去调控干细胞或其前体细胞的迁移方向和部位,从而有利于受损组织的再生和重建。 2.1.3 CXCR7的生物学特性 CXCR7最初发现于狗甲状腺cDNA库,命名为狗受体基因1,随后狗受体基因1又被命名为孤儿受体或清道夫受体。最近Burns等[12]发现CXCR4基因敲除小鼠胚胎第13天的胎肝细胞仍能结合基质细胞衍生因子1,进一步鉴定证实这个新位点就是狗受体基因1分子,因此将其重新命名为CXCR7。CXCR7是一个编码362个氨基酸且高度保守的G蛋白耦联七次跨膜蛋白受体,属G蛋白偶联受体家族。与CXCR4有31%的同源性,也包含有1个胞外的N端,3个胞内环,3个胞外环和1个胞内的C端。在第3个跨膜螺旋和第2个胞内环存在一个DRY结构,在第7个跨膜螺旋上存在一段CxNPxxY序列,在细胞外存在4个保守的半胱氨酸残基。小鼠的基因定位于1号染色体,紧邻CXCR1、CXCR2和CXCR4;人类定位于染色体2q37.3。CXCR7单克隆抗体能识别位于N端7-21号的抗原,和CXCR4竞争结合基质细胞衍生因子1。与CXCR4相比较,CXCR7与基质细胞衍生因子1结合更紧密。除了基质细胞衍生因子1外,CXCR7还有另一个配体干扰素诱导的T细胞化学诱导物(也叫CXCL11),但其结合力不如基质细胞衍生因子1。CXCR7在转化细胞以及人和鼠的胚胎发育过程中高表达。此外,CXCR7蛋白也表达于胎盘和肿瘤细胞内。尽管CXCR7分子一般不表达在正常细胞的表面,但在其细胞内却可能表达CXCR7 mRNA。 2.2 低氧对成体干细胞基质细胞衍生因子1-CXCR4/ CXCR7轴的影响 通过重组基质细胞衍生因子1蛋白对骨髓间充质干细胞进行预处理,提高了在体外缺氧条件下和移植入缺血组织后骨髓间充质干细胞的存活和增殖[20]。CXCR4阻断剂AMD3100抑制了基质细胞衍生因子1的促存活能力,而PI3K/Akt通路的活化参与其中。预处理也增加了骨髓间充质干细胞抗凋亡和血管生成相关细胞因子的释放。基质细胞衍生因子1预处理在缺血组织中细胞再生、血管生成和细胞存活方面产生积极效果,更快地引起组织修复。 一个软组织缺血小鼠模型显示,低氧诱导因子1调控了内皮细胞的基质细胞衍生因子1基因表达[21]。基质细胞衍生因子1高表达于低氧压的缺血组织[22]。低氧梯度通过低氧诱导因子1诱导基质细胞衍生因子1的表达调控着CXCR4阳性祖先细胞向再生组织募集。Wang等[23]利用中脑动脉闭塞脑缺血模型显示,低氧诱导了骨髓间充质干细胞的CXCR4表达;CXCR4阻断剂AMD3100减少了GFP标记的骨髓间充质干细胞向缺血脑组织的移动。 有趣地是,骨髓间充质干细胞在连续的体外传代后细胞表面CXCR4表达进行性降低[24-25]。Wynn等[26]证实少数骨髓间充质干细胞表面表达活化的CXCR4,用Triton X-100增加细胞膜通透性后,CXCR4表达明显增加,因此认为CXCR4 mRNA大量表达在骨髓间充质干细胞内部。低氧可以刺激CXCR4从细胞内转移到细胞表面。CXCR4表达上调的机制可能包括:通过血小板衍生膜微粒转移CXCR4到细胞表面从而增强它们的定居和迁移能力[27];或者在低氧、照射和化疗刺激下使CXCR4的合成增加[28-30]。重要的是,研究发现低氧也上调了基质细胞衍生因子1和CXCR7[30-32]。除了低氧之外,CXCR7表达可能受肿瘤坏死因子α和白细胞介素6调节。Tarnowski等[33]证实低氧可以提高胚胎横纹肌肉瘤细胞的CXCR4和CXCR7启动子活性和受体表达。几个研究发现低氧可以诱导血管内皮细胞和某些肿瘤细胞CXCR4和CXCR7表达的增加[34-35]。 作者先前的研究提示,体积分数3%的体外低氧预处理24 h,明显增加了骨髓间充质干细胞的CXCR4和CXCR7的蛋白和mRNA表达[16-17]。低氧预处理也改善了骨髓间充质干细胞的体外迁移、黏附、存活和旁分泌能力。通过针对CXCR4或CXCR7的中和性抗体预处理以及基因过表达证实,基质细胞衍生因子1-CXCR4轴调控了低氧预处理骨髓间充质干细胞增强的迁移能力,基质细胞衍生因子1-CXCR7轴调控了低氧预处理骨髓间充质干细胞增强的存活能力,而基质细胞衍生因子1-CXCR4轴和基质细胞衍生因子1-CXCR7轴共同调控了低氧预处理骨髓间充质干细胞增强的黏附和旁分泌能力,提示了CXCR4和CXCR7在骨髓间充质干细胞迁移、黏附、存活和旁分泌能力方面的本质而差异性作用。此外,作者也首次证实了PI3K/Akt-HIF-1α-CXCR4/ CXCR7通路在骨髓间充质干细胞上述功能中的调控作用。 2.3 基质细胞衍生因子1-CXCR4/CXCR7轴在干细胞募集和定居中的作用 2.3.1 基质细胞衍生因子1/CXCR4轴在干细胞募集和定居中的作用 首先,基质细胞衍生因子1/CXCR4轴影响干细胞的动员和迁移。研究证实骨髓来源的CD34+干细胞高表达CXCR4,减少骨髓内基质细胞衍生因子1浓度或者增加骨髓外基质细胞衍生因子1浓度[36-38],形成基质细胞衍生因子1的骨髓内外浓度梯度,从而促进骨髓来源干细胞动员入血,然后在化学因子的影响下向靶器官迁移。 其次,基质细胞衍生因子1/CXCR4轴影响干细胞的黏附能力。动员和迁移的干细胞到达靶器官后,基质细胞衍生因子1可以激活靶细胞表面的各种黏附分子(例如淋巴细胞功能相关抗原1、晚期活化抗原4和晚期活化抗原5)[39],促进干细胞黏附到血管内皮细胞上[40]。 第三,基质细胞衍生因子1/CXCR4轴影响干细胞分泌细胞因子。部分研究显示,基质细胞衍生因子1诱导了干细胞分泌大量的一氧化氮、某些促进血管生长的因子(例如血管内皮细胞生长因子等)和基质金属蛋白酶9 [41-43],这些酶和因子均参与了干细胞向血管内皮细胞黏附、横穿血管壁基底膜,进而到达靶组织的过程。 第四,基质细胞衍生因子1/CXCR4轴影响干细胞的存活和增殖,干细胞只有在损伤部位长期存活并扩增才能发挥其修复能力。基质细胞衍生因子1在这方面的作用仍存在争议,某些研究证实基质细胞衍生因子1能够促进造血细胞和外周血CD34+细胞的增殖和存活[44-45]。CD34+CD38+骨髓单核细胞也可以自分泌基质细胞衍生因子1并维持细胞的存活[37]。Bhakta等[46]用反转录病毒体外转染使骨髓间充质干细胞过表达CXCR4,通过transwell迁移试验证实,转染CXCR4的骨髓间充质干细胞向基质细胞衍生因子1(30 μg/L)的迁移率在3 h和6 h时分别是未转染组的3倍和5倍之多;但是,通过流式细胞术的膜联蛋白V/PI双染色法进行凋亡测定发现,在正常或无血清培养基培养2 d或7 d,CXCR4转染没有改善骨髓间充质干细胞的存活能力。 第五,基质细胞衍生因子1/CXCR4轴涉及某些细胞因子动员和迁移干细胞。干细胞因子可以增加靶细胞的CXCR4表达而提高基质细胞衍生因子1诱导的干细胞迁移。集落刺激因子动员骨髓造血干细胞入血的机制也是与促进造血干细胞CXCR4表达增高和骨髓内基质细胞衍生因子1表达降低相关[37]。 2.3.2 基质细胞衍生因子1/CXCR7轴在干细胞募集和定居中的作用 最早认为基质细胞衍生因子1/CXCR4轴在斑马鱼的原始干细胞迁移中发挥关键作用,目前证实基质细胞衍生因子1另一受体CXCR7也关联于原始干细胞的定向迁移[47]。基质细胞衍生因子1诱导干细胞持续迁移,正常机体则阻滞干细胞的移动,CXCR7结合并灭活基质细胞衍生因子1,从而适时清除基质细胞衍生因子1;当机体缺乏CXCR7,基质细胞衍生因子1就会导致干细胞迁移紊乱[48]。可见CXCR7就是清道夫,对个体发育发展极其重要。在斑马鱼侧翼的形成中,基质细胞衍生因子1与CXCR4和CXCR7结合直接控制头尾部细胞的迁移。CXCR4和CXCR7的不均匀分布是始基迁移方向的基础,在头部只表达CXCR4而无CXCR7,当细胞迁移达肌隔水平时CXCR7开始微弱表达,并逐渐增高,此时基质细胞衍生因子1-CXCR7占优势发挥作用,始基尾部继续迁移并开始分离,使组织得以伸缩。可见,CXCR4蛋白在始基前端2/3表达增强,而尾部1/3则表达CXCR7而使CXCR4下调。因此,始基内CXCR4、CXCR7具有时间、空间上的不均匀分布,两者是相互补充、相互对抗的,任何一个基因的反常表达,均可产生细胞迁移的紊乱[47,49-50]。 当然,干细胞迁移是一个复杂的过程,受多种因素调控。除基质细胞衍生因子1-CXCR4/CXCR7轴外,肝细胞生长因子、白血病抑制因子、血管内皮生长因子、碱性成纤维细胞生长因子等对干细胞的迁移可能都有一定调控作用。 2.4 基质细胞衍生因子1-CXCR4/CXCR7轴在缺血缺氧性肾脏疾病中的作用 2005年Togel等[19]首次报道了基质细胞衍生因子1/CXCR4轴在肾脏急性缺血再灌注损伤的修复过程中的重要作用,它可以募集和促进肾外循环血中的CXCR4表达阳性的干细胞发生定向迁移。作者发现:①基质细胞衍生因子1几乎表达在缺血再灌注损伤后肾脏的所有肾皮质和外层髓质的残存细胞中。②肾脏急性缺血再灌注损伤24 h后缺血肾脏和血浆内基质细胞衍生因子1水平升高而骨髓内降低,继而外周血和骨髓内的基质细胞衍生因子1浓度梯度形成,形成了驱动外周干细胞发生定向迁移的先决条件。③肾脏急性缺血再灌注损伤后,外周血表达CXCR4的骨髓来源CD34+细胞数目急剧增多,占粒细胞总量的7%(正常动物循环血中CD34+细胞占粒细胞数总量约1%),这说明随着基质细胞衍生因子1可以引起外周血液循环中CD34+细胞增多。④体外和体内实验中,抗CXCR4抗体抑制了CD34+细胞向肾脏的迁移。⑤实验同时证实这些从骨髓向外周血迁移继而募集到缺血肾脏的CD34+细胞正是修复损伤肾组织的修复细胞;从而表明损伤肾脏中基质细胞衍生因子1是CXCR4阳性细胞迁移和归航的介质。2008年3个研究组进行了肾损伤中基质细胞衍生因子1/CXCR4轴的研究。Ohnishi等[18]将GFP转基因雄性小鼠全骨髓移植入野生型同系小鼠5周后建立双侧肾脏急性缺血再灌注损伤模型,发现肾脏缺血加重时骨髓来源细胞和基质细胞衍生因子1增加,给予抗基质细胞衍生因子1受体IgG (抗-CXCR4 IgG)后,肾小管和肾间质中骨髓来源细胞减少;因此作者推断急性肾功能衰竭修复期间,基质细胞衍生因子1/CXCR4负责骨髓来源细胞的迁移。Mazzinghi等[51]证实人肾脏祖先细胞高度表达基质细胞衍生因子1受体CXCR4和CXCR7,横纹肌溶解诱导急性肾衰竭小鼠的肾脏坏死区域周围的常驻细胞中基质细胞衍生因子1显著上调;静脉内注射肾脏祖先细胞后,明显地向受损肾组织迁移并改善肾功能,并且这个效果受CXCR4中和抗体或CXCR7中和抗体预处理的抑制;体外实验证实仅CXCR4介导肾脏祖先细胞向基质细胞衍生因子1梯度的迁移;CXCR4和CXCR7共同介导了肾脏祖先细胞黏附到内皮细胞和跨内皮趋化作用;仅CXCR7介导基质细胞衍生因子1诱导的肾脏祖先细胞的存活。Lotan等[52]对IgA肾病、微小病变肾病综合征、局灶性肾炎、膜增生性肾小球肾炎、慢性肾盂肾炎和急性肾小管坏死患者的肾脏组织进行基质细胞衍生因子1α、CXCR4和CD45(全造血标记)染色,发现基质细胞衍生因子1主要定位于患者肾脏的末梢小管和集合管,而CXCR4定位于末梢和近曲小管;仅在急性肾小管坏死患者的肾脏组织中发现CXCR4+细胞浸润,并且仅定位于缺血急性肾小管坏死的皮髓交界处,它与基质细胞衍生因子1相关联,基质细胞衍生因子1α对CXCR4+细胞的趋化作用仅见于人急性肾小管坏死中。 作者先前的研究证实,基质细胞衍生因子1高表达在缺血再灌注损伤后肾脏;与常氧培养的骨髓间充质干细胞相比,低氧预处理的骨髓间充质干细胞在移植后 24 h明显向缺血肾组织募集,但是这个效果被CXCR4中和性抗体而不是CXCR7中和性抗体所抑制[16-17]。此外,与常氧培养的骨髓间充质干细胞移植相比较,低氧预处理的骨髓间充质干细胞明显改善了肾功能、增加了细胞增殖和减少了细胞凋亡,这个改善的治疗学效果是被基质细胞衍生因子1-CXCR4轴和基质细胞衍生因子1-CXCR7轴共同调节的,提示了基质细胞衍生因子1-CXCR4/CXCR7轴在低氧预处理的骨髓间充质干细胞救治肾脏缺血再灌注中治疗学效果中的作用。"
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