胰腺癌及胰腺星状细胞中基质细胞衍生因子SDF-1及其受体CXCR4的表达

目的 检测基质细胞衍生因子(SDF-1)及其受体CXCR4在胰腺癌组织、细胞株及星状细胞(PSC)中的表达.方法 采用免疫组织化学方法 检测37例胰腺癌及10例癌旁正常胰腺组织SDF-1、CXCR4、α-SMA蛋白表达以及细胞株AsPC-1、PSC的SDF-1、CXCR4蛋白表达.RT-PCR检测AsPC-1、BxPC3、SW1990及PSC的SDF-1、CXCR4 mRNA表达.结果 37例胰腺癌CXCR4表达(+)8例、(++)20例、(+++)9例;10例癌旁正常胰腺组织CXCR4表达(-)2例、(+)7例、(++)1例,两者差异显著(P<0.01).胰腺癌的间质组织SDF-1的表达高于癌旁间质组织(P<0.01),并随α-SMA表达的增加而增加.胰腺癌细胞株AsPC-1有CXCR4蛋白表达,而PSC有SDF-1蛋白表达.AsPC-1、BxPC3、SW1990细胞株均有CXCR4 mRNA的表达,而无SDF-1 mRNA的表达;PSC有SDF-1 mRNA表达,CXCR4 mRNA微弱表达.结论 胰腺癌组织及细胞系表达CXCR4,PSC表达SDF-1,PSC有可能通过SDF-1/CXCR4轴促进胰腺癌的侵袭转移.     

基质细胞衍生因子及其受体对造血作用的研究进展

骨髓基质细胞衍生因子 (Ｓｔｒｏｍａｌｃｅｌｌ ｄｅｒｉｖｅｄｆａｃｔｏｒ 1 ,ＳＤＦ 1 )是趋化因子ＣＸＣ家族中的一个成员 ,又称前Ｂ细胞刺激因子 (Ｐｒｅ Ｂ ｃｅｌｌｇｒｏｗｔｈ ｓｔｉｍｕ ｌａｔｉｎｇｆａｃｔｏｒ,ＰＢＳＦ ) ,最初是从小鼠骨髓细胞中提取 ,继而从小鼠基质细胞的上清中纯化获得。ＳＤＦ 1与其受体ＣＸＣＲ4协同 ,参与介导炎性反应 ,对胚胎存活、心脏等器官的发生、Ｂ淋巴细胞的生成、骨髓造血、骨髓纤维化等均起重要作用。此外 ,ＳＤＦ 1能介导淋巴细胞及单核细胞的迁移 ,通过淋巴细胞内肌动蛋白 (ａｃｔｉｎ)的…     

基质细胞衍生因子-1/趋化因子受体CXCR4轴与支气管哮喘

基质细胞衍生因子-1（stromal cell—derived factor-1,SDF-1）是趋化因子亚家族的成员之一,SDF1与趋化因子受体CXCR4（CXCR4）作用,构成SDF-1／CXCR4反应轴,在介导造血干细胞迁移及归巢、恶性肿瘤浸润转移、HIV感染、胚胎发育、免疫与炎症反应等方面发挥着重要作用。SDF1／CXCR4通过调节炎症细胞、血管形成、气道高反应性（AHR）等方面参与支气管哮喘（哮喘）的发生发展。     

基质细胞衍生因子1及其受体CXCR4生物轴与缺血性心脏病

缺血性心脏病(IHD)是一种在世界范围内高发的疾病,近年来其治疗研究的进展突飞猛进,其中应用干细胞治疗该病的报道越来越多,而如何提高该治疗手段的疗效成为许多医疗工作者关注的焦点.基质细胞衍生因子1(SDF-1)是目前已知的唯一与干细胞动员有关的趋化因子,它可以通过与其特异性受体CXCR4结合激活一系列信号通路,从而在组织缺血后起到炎症调节、促进干细胞动员、诱导血管再生的作用,引起了研究者们极大的兴趣.本文介绍了SDF-1/CXCR4轴在不同类型缺血性心脏病中的病理生理变化及临床应用.     

基质细胞衍生因子-1及其受体CXCR4在骨髓干细胞治疗脑梗死中的作用

脑组织损伤后修复是一个复杂的过程.随着干细胞领域基础研究的迅速发展,外源性骨髓干细胞移植和内源性骨髓干细胞动员的临床应用逐渐成为治疗缺血性脑血管疾病有效方法 之一.基质细胞衍生因子-1(stromal cell-derived factor-1,SDF-1)及其特异性受体CXCR4 (CXC chemokine receptor 4)结合后形成的SDF-1/CXCR4轴,在脑梗死时骨髓干细胞的迁移、募集过程中起着关键作用.通过调控SDF-1/CXCR4轴,增加干细胞的治疗效果,将成为治疗缺血性脑血管病一个新的干预靶点.本文就脑梗死的干细胞治疗,以及SDF-1/CXCR4轴在骨髓干细胞的迁移、募集和脑梗死修复过程中的作用作一综述.     

基质细胞衍生因子-1/CXCR4轴与肝脏疾病

基质细胞衍生因子-1(SDF-1)/CXCR4轴及其介导的细胞信号转导通路在肝脏疾病中的作用是国内外研究的热点.研究发现SDF-1/ CXCR4信号转导途径与肝脏再生、炎症、肝硬化以及肿瘤等疾病有关,但其具体机制尚未完全清楚.在细胞微环境中,SDF-1/CXCR4相互作用促进肝癌细胞生长,增强肿瘤的迁移、浸润以及转移能力.本文就SDF-1/CXCR4通路在肝再生、炎症、肿瘤疾病中的病理特征和致病机制的研究进展作一综述.     

房颤对外周血CD34+造血祖细胞的影响及SDF-1/CXCR4在心房中的表达

目的:研究不同类型的房颤(AF)对人外周血CD34+造血祖细胞（CD34+HPCs）的影响,以及持续心房快速起搏犬心肌基质细胞衍生因子-1（SDF-1）及其受体CXCR4的表达,初步探讨CD34+HPCs及SDF-1/CXCR4在AF时心肌损伤修复中的作用。方法: 应用流式细胞术测定阵发性AF患者组(n=35)、持续性AF患者组(n=35)及窦性心律者对照组(n=30)外周血中CD34+HPCs的百分含量;并对持续性AF患者组中24例患者成功进行体外直流电复律后48 h,测定外周血中CD34+HPCs的百分含量。另外,将成年健康杂种犬13条随机分为两组:即快速起搏组(n=7)和假手术组(n=6),均开胸后于右心耳缝植AOO型起搏器,快速起搏组以400次/min起搏6周,假手术组不起搏。应用RT-PCR测定左心耳和左心房CXCR4 mRNA的表达水平,用蛋白质免疫印迹法检测左心房SDF-1蛋白的表达。结果: 持续性AF患者组外周血中CD34+HPCs的百分含量明显高于阵发性AF患者组和对照组（P<0.05）;而后两组间无差别。持续性AF患者成功进行体外直流电复律后48 h,外周血中CD34+HPCs的百分含量较复律前明显下降（P<0.05）。快速起搏组犬左心耳和左心房CXCR4 mRNA表达的水平明显高于假手术组（P<0.05）,左心耳增高16.7%,左心房增高18.8%;SDF-1蛋白质表达的水平亦明显高于假手术组（P<0.01）。结论: 持续性AF患者外周血中CD34+HPCs的数量增加;心房快速起搏犬心房SDF-1/CXCR4的表达增加。CD34+HPCs和SDF-1/CXCR4可能参与了持续性AF患者心房损伤时心肌组织的修复过程。     

房颤对外周血CD34＋造血祖细胞的影响及SDF-1／CXCR4在心房中的表达

目的：研究不同类型的房颤（AF）对人外周血CD34＋造血祖细胞（CD34＋HPCs）的影响,以及持续心房快速起搏犬心肌基质细胞衍生因子-1（SDF-1）及其受体CXCR4的表达,初步探讨CD34＋HPCs及SDF-1/CXCR4在AF时心肌损伤修复中的作用。方法： 应用流式细胞术测定阵发性AF患者组（n=35）、持续性AF患者组（n=35）及窦性心律者对照组（n=30）外周血中CD34＋HPCs的百分含量;并对持续性AF患者组中24例患者成功进行体外直流电复律后48 h,测定外周血中CD34＋HPCs的百分含量。另外,将成年健康杂种犬13条随机分为两组：即快速起搏组（n=7）和假手术组（n=6）,均开胸后于右心耳缝植AOO型起搏器,快速起搏组以400次/min起搏6周,假手术组不起搏。应用RT-PCR测定左心耳和左心房CXCR4 mRNA的表达水平,用蛋白质免疫印迹法检测左心房SDF-1蛋白的表达。结果： 持续性AF患者组外周血中CD34＋HPCs的百分含量明显高于阵发性AF患者组和对照组（P〈0.05）;而后两组间无差别。持续性AF患者成功进行体外直流电复律后48 h,外周血中CD34＋HPCs的百分含量较复律前明显下降（P〈0.05）。快速起搏组犬左心耳和左心房CXCR4 mRNA表达的水平明显高于假手术组（P〈0.05）,左心耳增高16.7%,左心房增高18.8%;SDF-1蛋白质表达的水平亦明显高于假手术组（P〈0.01）。结论： 持续性AF患者外周血中CD34＋HPCs的数量增加;心房快速起搏犬心房SDF-1/CXCR4的表达增加。CD34＋HPCs和SDF-1/CXCR4可能参与了持续性AF患者心房损伤时心肌组织的修复过程。     

基质细胞衍生因子1α通过上调CXCR4表达促进单核—内皮细胞粘附

目的研究基质细胞衍生因子1α对CXCR4表达及THP-1单核细胞与内皮细胞粘附的影响。方法逆转录聚合酶链反应检测CXCR4 mRNA的表达,免疫印迹检测其蛋白表达变化;用0、50、100和200μg/L基质细胞衍生因子1α处理内皮细胞30min后,将THP-1单核细胞与内皮细胞共孵育后洗脱检测THP-1与内皮细胞的粘附,并加用10mg/L的CXCR4抗体阻断。结果100μg/L基质细胞衍生因子1α显著上调THP-1单核细胞上CXCR4的表达(P<0.05),基质细胞衍生因子1α能促进内皮细胞与THP-1单核细胞的粘附,且随着作用浓度的增加粘附细胞数也增加,但可被CXCR4抗体所抑制。结论基质细胞衍生因子1α可上调THP-1单核细胞上CXCR4表达,并能促单核细胞与内皮细胞粘附,其机制与上调单核细胞CXCR4表达有关。     

基质细胞衍生因子-1及其受体CXCR4轴介导内皮祖细胞参与血管损伤修复的研究进展

<正>内皮祖细胞(endothelial progenitor cells,EPCs)能够参与血管损伤修复,给再生医学治疗带来了希望。Asahara等[1]从人类外周血中分离出内皮前体细胞,发现这种细胞参与缺血组织的血管新生。多项研究证实,EPCs通过分化成新生内皮细胞替代损伤的血管内皮,参与血管损伤修复[2-3]。EPCs参与血管损伤修复过程涉及EPCs动员、迁移、分化等一系列过程,期间多种因子通过多种途径参与调节此     

Role of the CXCR4/SDF-1 chemokine axis in circulating neutrophil homeostasis

The bone marrow is the primary site for neutrophil production and release into the circulation. Because the CXC chemokine receptor-4/stromal derived factor-1 (CXCR4/SDF-1) axis plays a central role in the interactions of hematopoietic stem cells, lymphocytes, and developing neutrophils in the marrow, we investigated whether reciprocal CXCR4-dependent mechanisms might be involved in neutrophil release and subsequent return to the marrow following circulation. Neutralizing antibody to CXCR4 reduced marrow retention of infused neutrophils (45.7% +/- 0.5% to 6.9% +/- 0.5%) and was found to mobilize neutrophils from marrow (34.4% +/- 4.4%). Neutrophil CXCR4 expression and SDF-1-induced calcium flux decreased with maturation and activation of the cells, corresponding to the decreased marrow homing associated with these characteristics in vivo. Infusion of the inflammatory mediator and CXCR2 ligand KC led to mobilization of neutrophils from marrow by itself and was augmented 3-fold by low doses of CXCR4-blocking antibody that otherwise had no mobilizing effect. Examination of KC and SDF-1 calcium signaling demonstrated that the effect of KC may, in part, be due to heterologous desensitization to SDF-1. These results suggest that the CXCR4/SDF-1 axis is critical in circulating neutrophil homeostasis and that it may participate in the rapid release of neutrophils from the marrow during inflammation through a novel interaction with inflammatory CXC chemokines.     

Role of the intracellular domains of CXCR4 in SDF-1-mediated signaling

The CXCR4 chemokine receptor is a G(i) protein-coupled receptor that triggers multiple intracellular signals in response to stromal cell-derived factor 1 (SDF-1), including calcium mobilization and p44/42 extracellular signal-regulated kinases (ERK1/2). Transduced signals lead to cell chemotaxis and are terminated through receptor internalization depending on phosphorylation of the C terminus part of CXCR4. Receptor endocytosis is also required for some receptors to stimulate ERK1/2 and to migrate through a chemokine gradient. In this study, we explored the role played by the 3 intracellular loops (ICL1-3) and the C terminus domain of CXCR4 in SDF-1-mediated signaling by using human embryonic kidney (HEK)-293 cells stably expressing wild-type or mutated forms of CXCR4. ICL3 of CXCR4 is specifically involved in G(i)-dependent signals such as calcium mobilization and ERK activation, but does not trigger CXCR4 internalization after SDF-1 binding, indicating that ERK phosphorylation is independent of CXCR4 endocytosis. Surprisingly, ICL2, with or without the aspartic acid, arginine, and tyrosine (DRY) motif, is dispensable for G(i) signaling. However, ICL2 and ICL3, as well as the C terminus part of CXCR4, are needed to transduce SDF-1-mediated chemotaxis, suggesting that this event involves multiple activation pathways and/or cooperation of several cytoplasmic domains of CXCR4.     

外周血SDF-1/CXCR4轴与急性心肌梗死患者冠状动脉侧支循环形成的关系

目的 检测急性心肌梗死(acute myocardial infarction,AMI)患者外周血基质细胞衍生因子-1(stromalcell derived factor 1,SDF-1)、CXC趋化因子受体-4(C-X-C chemokine receptor 4,CXCR4)的浓度,探讨两者在AMI患者冠状动脉侧...     

The SDF-1/CXCR4 axis in stem cell preconditioning

We review the pivotal role of the stromal derived factor (SDF)-1 chemokine in tissue ischaemia and how it orchestrates the rapid revascularization of injured, ischaemic, and regenerating tissues via the CXC chemokine receptors CXCR4 and CXCR7. Furthermore, we discuss the effects of preconditioning (PC), which is a well-known protective phenomenon for tissue ischaemia. The positive effect of both hypoxic and acidic PC on progenitor cell therapeutic potential is reviewed, while stressing the role of the SDF-1/CXCR4 axis in this process.     

SDF-1/CXCR4 and VLA-4 interaction regulates homing in Waldenstrom macroglobulinemia

Waldenstrom macroglobulinemia (WM) is characterized by widespread involvement of the bone marrow at the time of diagnosis, implying continuous homing of WM cells into the marrow. The mechanisms by which trafficking of the malignant cells into the bone marrow has not been previously elucidated. In this study, we show that WM cells express high levels of chemokine and adhesion receptors, including CXCR4 and VLA-4. We showed that CXCR4 was essential for the migration and trans-endothelial migration of WM cells under static and dynamic shear flow conditions, with significant inhibition of migration using CXCR4 knockdown or the CXCR4 inhibitor AMD3100. Similarly, CXCR4 or VLA-4 inhibition led to significant inhibition of adhesion to fibronectin, stromal cells, and endothelial cells. Decreased adhesion of WM cells to stromal cells by AMD3100 led to increased sensitivity of these cells to cytotoxicity by bortezomib. To further investigate the mechanisms of CXCR4-dependent adhesion, we showed that CXCR4 and VLA-4 directly interact in response to SDF-1, we further investigated downstream signaling pathways regulating migration and adhesion in WM. Together, these studies demonstrate that the CXCR4/SDF-1 axis interacts with VLA-4 in regulating migration and adhesion of WM cells in the bone marrow microenvironment.     

基质细胞衍化生长因子-1及其受体CXCR4在肝细胞癌和肝硬化中的表达

目的探讨肝癌患者外周血、腹水以及肿瘤组织中基质细胞衍化生长因子-1（SDF-1）及其特异性受体CXCR4的表达。方法ELISA法分别检测39例肝癌患者、16例肝硬化患者、12例肝炎患者和12名正常人的外周血和（或）腹水中的SDF-1表达水平,以免疫组织化学的方法分别检测肝癌、肝硬化和肝炎患者肝组织中CXCR4的表达。结果健康对照者SDF-1水平为（2625．38±868．37）ng/L,肝癌Ⅰ、Ⅱ期和Ⅲ、Ⅳ期患者分别为（5121．33±1021．58）ng/L和（7829．43±1443．32）ng/L,肝硬化患者（2932．83±891．28）ng/L,慢性肝炎患者（3029．56±765．38）ng/L,肝癌患者外周血SDF-1水平明显高于正常对照组和肝炎、肝硬化患者组,肝癌Ⅰ、Ⅱ期低于Ⅲ、Ⅳ期患者。肝硬化和肝炎患者与正常对照组之间差异无统计学意义。肝硬化和肝癌组腹水SDF-1水平差异无统计学意义。肝癌组织中CXCR4的表达,高分化呈弱阳性,而中、低分化呈强阳性,其表达率分别为56%,62%和67%。结论外周血SDF-1和肝癌组织的CXCR4高表达可以作为一种肝癌的肿瘤标志,而且其高表达可能与肝癌的恶性程度和转移有关。     

Rapid mobilization of functional donor hematopoietic cells without G-CSF using AMD3100, an antagonist of the CXCR4/SDF-1 interaction

Allografts from HLA-matched sibling donors were mobilized and collected without granulocyte colony-stimulating factor (G-CSF) using AMD3100, a direct antagonist of CXCR4/stromal-derived factor 1 (SDF-1/CXCL12). Donors (N = 25) were treated with AMD3100 at a dose of 240 mug/kg by subcutaneous injection, and leukapheresis was then initiated just 4 hours later. Two-thirds of the donors collected an allograft with a CD34(+) cell dose sufficient for transplantation after just one dose of AMD3100. No donor experienced more than grade 1 toxicity. After a myeloablative regimen, 20 patients with hematologic malignancies received allografts collected after AMD3100 alone. All patients engrafted neutrophils (median day 10) and platelets (median day 12) promptly. Acute graft-versus-host disease (GVHD) grades 2 through 4 occurred in 35% of patients. One patient died due to complications related to acute GVHD. No unexpected adverse events were observed in any of the recipients. All 14 patients surviving in remission have robust trilineage hematopoiesis and are transfusion-free with a median follow-up of 277 days (range, 139-964 days). Direct antagonism of CXCR4 by AMD3100 may provide a more rapid and possibly less toxic and cumbersome alternative to traditional G-CSF-based mobilization in normal donors. This trial was registered as no. NCT00241358 at www.ClinicalTrials.gov.