SDF-1对小鼠骨髓源性内皮祖细胞数量及功能的影响

目的:观察基质细胞衍生因子-1(SDF-1)对体外培养的小鼠骨髓源性内皮祖细胞(EPC s)数量及功能的影响。方法:以密度梯度离心法获取小鼠骨髓单个核细胞(M NC s),由BS-1和D iI-acLDL荧光双染鉴定。加入不同浓度SDF-1 a培养48 h,然后分别采用M TT法、改良的Boyden小室和粘附能力测定来观察EPC s的增殖、迁移和粘附能力;采用血清饥饿法和紫杉醇诱导EPC s凋亡,TUNEL法和流式细胞仪检测SDF-1a对EPC s凋亡率的影响。结果:SDF-1a剂量依赖性增加EPC s数量(P<0.01),并显著改善了EPC s的粘附、迁移和增殖能力(P<0.01),显著降低EPC s凋亡率(P<0.01)。结论:SDF-1a可增加小鼠骨髓源性EPC s的数量并改善EPC s功能。     

贝那普利对高血压患者内皮祖细胞凋亡及氧化应激的影响

目的探讨贝那普利对高血压患者内皮祖细胞(EPC)凋亡和氧化应激的影响。方法入选符合《中国高血压防治指南》诊断标准的1级高血压患者15例,同时选取年龄、性别相匹配的健康体检者15名为对照组。所有受试者抽取外周血,常规密度梯度离心法分离单个核细胞,将经鉴定的正在分化的EPC培养5 d后用于实验。将分离、培养获得的每一例高血压患者EPC培养5 d后将细胞平行分为5份,每份细胞根据不同的刺激处理条件分为高血压组、不同浓度贝那普利(1、10和100μmol/L)干预组、贝那普利(10μmol/L)+基质细胞衍生因子/受体趋化因子4(SDF-1/CXCR4)拮抗剂AMD3100干预组。上述干预24 h后进行EPC凋亡检测:用Annexin-V/PI法;氧化应激检测:黄嘌呤氧化法测定上清液中超氧化物歧化酶活力,硫代巴比妥酸法测定丙二醛含量。结果 (1)与对照组比较,高血压组外周血EPC凋亡率明显增加(t早=6.6334,t晚=3.812;均为P<0.01),氧化应激反应明显增高(tSOD=8.258,tMDA=6.6806;均为P<0.01);(2)随着贝那普利干预浓度的增加(1、10和100μmol/L),EPC凋亡率也随之降低(F早=17.39,F晚=51.65;均为P<0.05),氧化应激反应也随之降低,呈浓度依赖性(FSOD=14.56,FMDA=7.859;均为P<0.05)。与10μmol/L贝那普利干预组比较,10μmol/L贝那普利+AMD 3100干预组的EPC凋亡率增加(t早=3.551,t晚=5.333;均为P早、晚<0.05),氧化应激反应增高(tSOD=1.931,tMDA=0.6407;均为P<0.05)。结论贝那普利能显著改善高血压患者体外EPC凋亡及氧化应激反应,并可能通过SDF-1/CXCR4轴发挥作用。     

SDF-1/CXCR-4对内皮祖细胞生物学功能的影响

内皮祖细胞（EPC）移植或动员内源性EPC可加速损伤血管的再内皮化。基质细胞衍生因子-1（SDF-1）能通过其受体CXCR4促进骨髓干细胞向EPC方向分化,抑制EPC凋亡。升高外周血SDF-1浓度可动员EPC进入外周血。SDF-1/CXCR4系统在EPC迁移、捕获及归巢过程中起重要作用,参与促进缺血性血管生成。     

生理性雌激素对骨髓源性内皮祖细胞迁移功能的影响

目的研究生理性雌激素对骨髓源性内皮祖细胞（BM—EPCs）迁移功能的影响及其机制。方法雌性BALB／C小鼠随机分成卵巢切除组、假手术组和正常组。ELISA法检测各组血清雌激素浓度。取胫骨和股骨骨髓,培养、鉴定BM—EPCs。Transwell小室检测各组BM．EPCs经或未经CXCR4抑制剂AMD3100处理后向基质细胞衍生因子-1α（SDF-1α）的迁移功能。RT—PCR和流式细胞术检测各组BM-EPCsCXCR4的表达。结果卵巢切除组血清雌激素浓度明显低于假手术组和正常组（P〈0．01）。卵巢切除组BM—EPCs向SDF-1α迁移的数量明显低于假手术组和正常组（P〈0．01）。AMD3100明显抑制BM—EPCs向SDF-1α的迁移功能。卵巢切除组BM—EPCsCXCR4的表达明显低于假手术组和正常组（P〈0．01）。结论生理性雌激素通过调节BM—EPCsCXCR4的表达而增强其迁移功能。     

内皮素-1对大鼠骨髓内皮前体细胞增殖、细胞周期及NO分泌功能的影响

目的探讨内皮素-1（ET-1）对大鼠骨髓内皮前体细胞（EPC）增殖、细胞周期及一氧化氮（NO）分泌功能的影响。方法采用密度梯度离心法获取大鼠骨髓单核细胞,在M199培养液中培养扩增EPC并进行鉴定。不同浓度ET-1（A组:0mol/L、B组:10-9mol/L、C组:10-8mol/L、D组:10-7mol/L、E组:10-6mol/L）作用于EPC,MTT法检测ET-1对EPC增殖能力的影响,流式细胞仪检测ET-1对EPC细胞周期的影响,硝酸还原酶法检测细胞培养液中NO含量的变化,观察ET-1对EPC的NO分泌功能的影响。结果与对照组（A组,0.405±0.017）相比,ET-1浓度C组（0.434±0.016）、D组（0.463±0.016）、E组（0.473±0.015）EPC增殖能力显著增高（n=8,P<0.01）。EPC的G0/G1期细胞百分数C组（57.28±3.65）%、D组（44.99±3.19）%、E组（40.29±3.74）%较对照组（70.55±1.37）%明显降低（n=5,P<0.01）,EPC的S期细胞百分数C组（26.75±2.87）%、D组（32.79±2.41）%、E组（35.74±2.94）%较对照组（20.04±1.64）%明显升高（n=5,P<0.01）,EPC的G2/M期细胞百分数C组（15.96±1.71）%、D组（22.22±2.22）%、E组（23.64±2.86）%较对照组（9.41±0.81）%明显升高（n=5,P<0.01）。EPC培养液中NO含量（μmol/L）ET-1浓度C组（11.70±1.80）、D组（15.69±1.86）、E组（16.89±1.55）较对照组（7.45±2.41）明显增加（n=8,P<0.01）。B组检测结果与对照组相比,各项指标均无统计学差异。结论ET-1能够促进EPC的增殖,促进细胞向S期和G2期的转化,并提高细胞NO分泌功能,可能参与缺血性疾病的血管再生过程。     

冠状动脉严重狭窄SAP患者的侧支循环、EPCs、SDF-1α变化及意义

目的探讨冠状动脉严重狭窄稳定型心绞痛（SAP）患者循环内皮祖细胞（EPCs）及基质细胞衍生因子（SDF）-1α与冠状动脉侧支循环（CCC）形成的关系,为冠心病的治疗提供新思路。方法研究对象为同期收治的92例冠状动脉严重狭窄的SAP患者（CCC良好42例、不良50例）,均采集外周血测定EPC数量、体外生成血管能力,并用ELISA法检测其血浆SDF-1α水平,采用直线相关和Pearson检验分析CCC良好与不良者各指标间及与CCC分级的相关性;同上分离92例患者外周血单个核细胞并随机分为6组,分别加入含有PBS、SDF-1α（10、50、100ng／ml）、SDF-1α（100ng／ml）＋CXCR4拮抗剂AMD3100、SDF-1α（100ng／ml）＋血管内皮生长因子（VEGF）特异性受体酪氨酸激酶抑制剂K18751的培养液,培养至第7天同上测定EPCs数量、体外生成血管能力,采用ELISA法检测培养液中VEGF水平。结果与CCC不良者比较,CCC良好者EPCs集落形成数量增加、体外生成血管能力增强,且血浆SDF-1α水平增加,三指标间及与CCC分级均呈显著正相关（P均〈0．01）;与PBS及SDF-1α＋AMD3100、SDF-1α＋K18751干预者比较,SDF-1α可呈剂量依赖性显著上调EPCs数量、增强其体外生成血管能力及VEGF水平（P〈0．05、0．01）。结论冠状动脉严重狭窄的SAP患者CCC形成情况与循环EPCs及血浆SDF-1α水平有关,VEGF可能参与此过程的调节;提高VEGF及SDF-1α活性可能对冠心病患者有益。     

基质细胞衍生因子1α介导小鼠内皮祖细胞修复损伤血管内膜

目的探讨损伤血管局部表达的基质细胞衍生因子1α是否能介导内皮祖细胞参与损伤血管的再内皮化,抑制新生内膜的增生。方法培养、获取小鼠骨髓源性内皮祖细胞,采用改良的Boyden小室测定基质细胞衍生因子1α诱导的内皮祖细胞迁移及AMD3100(CXCR4的拮抗剂)对其的影响。分别将内皮祖细胞培养基、内皮祖细胞及AMD3100孵育过的内皮祖细胞经心脏穿刺注射给颈动脉损伤小鼠,在14天后取损伤血管检测内皮祖细胞募集情况、再内皮化情况及新生内膜增生情况。结果基质细胞衍生因子1α能诱导内皮祖细胞迁移(与对照组比较P<0.01),AMD3100能有效阻断该作用(AMD3100组与对照组比较P>0.05)。较多注射的内皮祖细胞成功归巢到损伤血管处(14.2±3.6个/切片),AMD3100孵育过的内皮祖细胞仅少量可成功归巢(4.0±2.5个/切片);内皮祖细胞注射能加速损伤血管的再内皮化(内皮祖细胞移植组比对照组:83.45%±5.44%比66.46%±6.16%,P<0.01),AMD3100孵育过的内皮祖细胞注射则无效(68.02%±6.68%,与对照组比较P>0.05);内皮祖细胞移植组新生内膜增生厚度(19237±1875μm2)和内膜中膜比值(0.94±0.12)均小于对照组(34676±2412μm2和1.77±0.18)及AMD3100组(32451±2081μm2和1.60±0.17)(P<0.01)。结论基质细胞衍生因子1/CXCR-4在介导移植的内皮祖细胞修复损伤血管内膜中起重要作用。     

基质细胞衍生因子-1及其受体对大鼠主动脉血管平滑肌细胞增殖与凋亡的影响

目的研究基质细胞衍生因子-1(SDF-1)对氧化低密度脂蛋白(ox-LDL)诱导的血管平滑肌细胞(VSMC)增殖与凋亡的影响。方法选用体外培养的大鼠主动脉VSMC,并分为正常对照组、ox-LDL组[动脉粥样硬化(AS)模型]、SDF-1组(AS模型+SDF-1)、SDF-1+12G5组(AS模型+SDF-1+CXCR4单克隆抗体)和12G5组(AS模型+CXCR4单克隆抗体),应用MTT法测VSMC细胞增殖,TUNEL法测细胞凋亡率,RT-PCR法测凋亡基因bax、bcl-2mRNA的表达。结果ox-LDL组的增殖率0.38±0.01,明显高于正常对照组0.28±0.02(P<0.01),明显低于SDF-1组0.44±0.02(P<0.01),与SDF-1+12G5组和12G5组比较差异无显著性(P>0.05);ox-LDL组的凋亡率24.2±2.4,高于正常对照组19.8±2.7和SDF-1组20.7±2.8(P<0.05),而与SDF-1+12G5组和12G5组比较差异无显著性(P>0.05);ox-LDL组bcl-2和bax的比值明显低于正常对照组和SDF-1组(P<0.01),而与SDF-1+12G5组和12G5组差异无显著性(P>0.05)。结论SDF-1可明显促进ox-LDL诱导的VSMC增殖,并抑制细胞凋亡;SDF-1及其受体CXCR4构成的生物学轴可能通过bcl-2/bax途径影响VSMC凋亡。     

低频脉冲电磁场对CRP作用下大鼠EPC增殖、凋亡及NO分泌的影响

目的观察不同强度、不同作用时间的低频脉冲电磁场对C反应蛋白（CRP）作用下大鼠骨髓来源内皮祖细胞（EPC）增殖、凋亡及NO分泌能力的影响。方法密度梯度离心法获得SD雄性大鼠的骨髓EPC,实验分为10组,即空白对照组、12mg/LCRP组以及CRP+不同强度、不同作用时间（0.2mT2h、4h;0.6mT2h、4h;1.0mT2h、4h;1.4mT2h、4h）低频脉冲电磁场组。MTT法检测CPR对EPC增殖能力的影响,流式细胞仪检测CRP对EPC凋亡率的影响,硝酸还原酶法检测EPC培养液中NO含量的变化。结果与空白对照组相比,12mg/LCRP可明显抑制EPC增殖及NO分泌能力,促进EPC凋亡（P<0.05）,0.6mT4h;1.0mT2h两组EPC增殖、NO分泌能力显著高于CRP组,EPC凋亡显著低于CRP组（P<0.05）。其余各组与CRP组相比无明显差异。结论12mg/LCRP可抑制EPC的增殖及NO分泌,促进其凋亡;0.6mT4h和1.0mT2h电磁场可拮抗CRP对EPC的作用,磁场对CRP环境下EPC的作用无强度及时间依赖性。     

睾酮通过SDF-1α/CXCR4轴调控骨髓内皮祖细胞迁移

目的　探讨雄激素睾酮对小鼠骨髓源性内皮祖细胞（BM-EPC）迁移功能的影响及其机制。方法　6周龄雄性BALB/C小鼠,切除双侧睾丸,饲养4周,培养、鉴定BM-EPC。收集贴壁细胞随机分为8组：分别添加0、1、10、100　nmol/L睾酮以及相应浓度睾酮加氟他胺（雄激素受体阻断剂）预处理。Transwell实验检测各组BM-EPC经或未经趋化因子受体4（CXCR4）抑制剂AMD3100处理后向基质细胞衍生因子1α（SDF-1α）的迁移。逆转录聚合酶链反应和Western　blot检测各组BM-EPC　CXCR4的表达。Transwell实验检测BM-EPC的迁移。结果　与对照组相比,睾酮呈浓度依赖性促进BM-EPC向SDF-1α迁移（放大200倍视野下,A组：61.80±9.31;B组：83.20±6.53;C组：107.00±12.85;D组：134.80±8.64;P＜0.05）。与对照组相比,睾酮呈浓度依赖性促进BM-EPC　CXCR4　mRNA的表达（CXCR4　mRNA的相对表达量：A组：0.065±0.005;B组：0.114±0.002;C组：0.149±0.019;D组：0.209±0.013;P＜0.05）。睾酮呈浓度依赖性促进BM-EPC　CXCR4蛋白的表达（CXCR4与Actin表达量之比：A组：0.23±0.06;B组：0.40±0.02;C组：0.62±0.04;D组：0.77±0.05;P＜0.05）,但此作用被雄激素受体阻断剂氟他胺阻断。AMD3100阻断了不同浓度睾酮对BM-EPC的迁移作用。结论　睾酮通过雄激素受体途径作用于SDF-1α/CXCR4轴,上调BM-EPC　CXCR4的表达而增强其迁移功能。     

SDF-1alpha/CXCR4 decreases endothelial progenitor cells apoptosis under serum deprivation by PI3K/Akt/eNOS pathway

Recent studies have demonstrated that stromal cell-derived factor-1alpha (SDF-1alpha)/CXCR4 interaction regulates multiple cell signal pathways and a variety of cellular functions such as cell migration, proliferation, survival and angiogenesis. In present study, we aimed to determine the effect of SDF-1alpha on endothelial progenitor cells (EPCs) apoptosis induced by serum deprivation and the implication of phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinases (MAPKs) signaling in this effect. EPCs were isolated and characterized. SDF-1alpha decreased EPCs apoptosis induced by serum deprivation in a dose-dependent manner and the inhibitory effect was CXCR4 dependent as confirmed by the total abolishment by AMD3100, a CXCR4-specific peptide antagonist. SDF-1alpha treatment also significant decreased caspase-3 expression and activity. The inhibitory effect of SDF-1alpha on EPCs apoptosis was nearly completely abolished by PI3K inhibitors (either Wortmannin or LY294002) and partially abolished by NOS inhibitor, N(G)-nitro-arginine methyl ester, whereas inhibitors of MAPKs had no significant effect on this inhibitory effect. The treatment of EPCs with SDF-1alpha resulted in time-dependent Akt, eNOS, extracellular-regulated kinase (ERK1/2), p38 MAPK and c-Jun N-terminal kinase (JNK) phosphorylations. These findings suggest that PI3K/Akt/eNOS activation, but not MAPKs activation, is required for the inhibitory effect of SDF-1alpha on EPCs apoptosis.     

A critical role of Src family kinase in SDF-1/CXCR4-mediated bone-marrow progenitor cell recruitment to the ischemic heart

The G protein-coupled receptor CXCR4 and its ligand stromal-cell derived factor 1 (SDF-1) play a crucial role in directing progenitor cell (PC) homing to ischemic tissue. The Src family protein kinases (SFK) can be activated by, and serve as effectors of, G proteins. In this study we sought to determine whether SFK play a role in SDF-1/CXCR4-mediated PC homing. First, we investigated whether SDF-1/CXCR4 signaling activates SFK. Bone-marrow mononuclear cells (BM MNCs) were isolated from WT and BM-specific CXCR4-KO mice and treated with SDF-1 and/or CXCR4 antagonist AMD3100. SDF-1 treatment rapidly induced phosphorylation (activation) of hematopoietic Src (i.e., Lyn, Fgr, and Hck) in WT cells but not in AMD3100-treated cells or CXCR4-KO cells. Then, we investigated whether SFK are involved in SDF-1/CXCR4-mediated PC chemotaxis. In a combined chemotaxis and endothelial-progenitor-cell (EPC) colony assay, Src inhibitor SU6656 dose-dependently inhibited the SDF-1-induced migration of colony-forming EPCs. Next, we investigated whether SFK play a role in SDF-1/CXCR4-mediated BM PC homing to the ischemic heart. BM MNCs from CXCR4_BAC:eGFP reporter mice were i.v. injected into WT and SDF-1_BAC:SDF1-RFP transgenic mice following surgically-induced myocardial infarction (MI). eGFP⁺ MNCs and eGFP⁺c-kit⁺ PCs that were recruited in the infarct border zone in SDF-1_BAC:SDF1-RFP recipients were significantly more than that in WT recipients. Treatments of mice with SU6656 significantly reduced eGFP⁺ and eGFP⁺c-kit⁺ cell recruitment in both WT and SDF-1_BAC:RFP recipients and abrogated the difference between the two groups. Remarkably, PCs isolated from BM-specific C-terminal Src kinase (CSK)-KO (Src activated) mice were recruited more efficiently than PCs from WT PCs in the WT recipients. In conclusion, SFK are activated by SDF-1/CXCR4 signaling and play an essential role in SDF-1/CXCR4-mediated BM PC chemotactic response and ischemic cardiac recruitment.     

Soluble factors released by endothelial progenitor cells promote migration of endothelial cells and cardiac resident progenitor cells

Circulating endothelial progenitor cells (EPC) are incorporated into newly formed capillaries, enhance neovascularization after hind limb ischemia and improve cardiac function after ischemic injury. Incorporated progenitor cells may also promote neovascularization and cardiac regeneration by releasing factors, which act in a paracrine manner to support local angiogenesis and mobilize tissue residing progenitor cells. Therefore, we analyzed the expression profile of cytokines in human peripheral blood-derived EPC as opposed to human umbilical vein endothelial cells (HUVEC), human microvascular endothelial cells (HMVEC), and CD14(+) monocytes by microarray technology. A gene tree analysis revealed a distinct expression pattern of angiogenic growth factors in EPC, mature endothelial cells, and CD14(+) monocytes. VEGF-A, VEGF-B, SDF-1, and IGF-1 mRNA levels were higher in EPC as compared to HUVEC or HMVEC. The enhanced mRNA expression was paralleled by a significant release of VEGF, SDF-1, and IGF-1 protein into the cell culture supernatant of EPC. Moreover, immunohistological analysis of ischemic limbs from nude rats revealed that VEGF is also released from recruited human EPC in vivo. As a functional consequence, conditioned medium of EPC induced a strong migratory response of mature endothelial cells, which was significantly inhibited by VEGF and SDF-1 neutralizing antibodies. Finally, conditioned medium of EPC significantly stimulated the migration of cardiac resident c-kit(+) progenitor cells in vitro. Taken together, EPC exhibit a high expression of angiogenic growth factors, which enhanced migration of mature endothelial cells and tissue resident cardiac progenitor cells. In addition to the physical contribution of EPC to newly formed vessels, the enhanced expression of cytokines may be a supportive mechanism to improve blood vessel formation and cardiac regeneration after cell therapy.     

SDF-1 involvement in endothelial phenotype and ischemia-induced recruitment of bone marrow progenitor cells

Chemokine stromal derived factor 1 (SDF-1) is involved in trafficking of hematopoietic stem cells (HSCs) from the bone marrow (BM) to peripheral blood (PB) and has been found to enhance postischemia angiogenesis. This study was aimed at investigating whether SDF-1 plays a role in differentiation of BM-derived c-kit(+) stem cells into endothelial progenitor cells (EPCs) and in ischemia-induced trafficking of stem cells from PB to ischemic tissues. We found that SDF-1 enhanced EPC number by promoting alpha(2), alpha(4), and alpha(5) integrin-mediated adhesion to fibronectin and collagen I. EPC differentiation was reduced in mitogen-stimulated c-kit(+) cells, while cytokine withdrawal or the overexpression of the cyclin-dependent kinase (CDK) inhibitor p16(INK4) restored such differentiation, suggesting a link between control of cell cycle and EPC differentiation. We also analyzed the time course of SDF-1 expression in a mouse model of hind-limb ischemia. Shortly after femoral artery dissection, plasma SDF-1 levels were up-regulated, while SDF-1 expression in the bone marrow was down-regulated in a timely fashion with the increase in the percentage of PB progenitor cells. An increase in ischemic tissue expression of SDF-1 at RNA and protein level was also observed. Finally, using an in vivo assay such as injection of matrigel plugs, we found that SDF-1 improves formation of tubulelike structures by coinjected c-kit(+) cells. Our findings unravel a function for SDF-1 in increase of EPC number and formation of vascular structures by bone marrow progenitor cells.     

Effects of benazepril on functional activity of endothelial progenitor cells from hypertension patients

The effect of angiotensin-converting enzyme inhibitors on hypertension patients regarding endothelial progenitor cell (EPC) functions is poorly understood. The aim of this study was to investigate the effects of benazepril on the proliferation, adhesion and migration capacity of EPCs and its possible mechanism. The functions of EPCs from hypertension patients were obviously reduced compared with control group, and this could be improved by benazepril in a dose-dependent manner, whereas this improvement were obviously blocked when AMD3100 were used together. Therefore, benazepril could obviously improve functions of EPCs from hypertension patients, and the potential mechanism may be related to SDF-1/CXCR4 axis.     

AMD3100对胰腺癌细胞AsPC-1及其移植瘤血管生成的影响

目的 探讨非肽类特异性CXCR4拮抗剂AMD3100对胰腺癌细胞株AsPC-1细胞增殖及其移植瘤生长的影响.方法 AsPC-1细胞分为对照组、基质细胞衍生因子-1(SDF-1α)处理组、AMD3100处理组和SDF-1α+AMD3100处理组,MTT法检测细胞增殖,Western blotting检测血管内皮生长因子(VEGF)表达.建立AsPC-1细胞裸鼠移植瘤模型,应用AMD3100瘤内及瘤周注射,观察移植瘤的生长,免疫组化法检测裸鼠移植瘤的微血管密度(microvessel density,MVD).结果 SDF-1α可明显促进AsPC-1细胞增殖(1.430±0.122对1.002±0.001,P<0.05),而同时应用AMD3100处理能抑制这种增殖反应(0.983±0.068对1.430±0.122,P<0.05);SDF-1α亦可促进AsPC-1细胞VEGF的表达(0.565±0.047对0.439±0.034,P<0.05),而同时用AMD3100处理可抑制这种效应(0.450±0.071对0.565±0.047,P<0.05).AMD3100可抑制AsPC-1细胞皮下移植瘤的生长,第24天的抑瘤率达59.5%,移植瘤的MVD显著减少(28.56±6.94对98.75±20.60,P<0.01).结论 AMD3100在体外和体内均可抑制AsPC-1细胞增殖及其移植瘤的血管生成.     

S1P promotes murine progenitor cell egress and mobilization via S1P1-mediated ROS signaling and SDF-1 release

The mechanisms of hematopoietic progenitor cell egress and clinical mobilization are not fully understood. Herein, we report that in vivo desensitization of Sphingosine-1-phosphate (S1P) receptors by FTY720 as well as disruption of S1P gradient toward the blood, reduced steady state egress of immature progenitors and primitive Sca-1(+)/c-Kit(+)/Lin(-) (SKL) cells via inhibition of SDF-1 release. Administration of AMD3100 or G-CSF to mice with deficiencies in either S1P production or its receptor S1P(1), or pretreated with FTY720, also resulted in reduced stem and progenitor cell mobilization. Mice injected with AMD3100 or G-CSF demonstrated transient increased S1P levels in the blood mediated via mTOR signaling, as well as an elevated rate of immature c-Kit(+)/Lin(-) cells expressing surface S1P(1) in the bone marrow (BM). Importantly, we found that S1P induced SDF-1 secretion from BM stromal cells including Nestin(+) mesenchymal stem cells via reactive oxygen species (ROS) signaling. Moreover, elevated ROS production by hematopoietic progenitor cells is also regulated by S1P. Our findings reveal that the S1P/S1P(1) axis regulates progenitor cell egress and mobilization via activation of ROS signaling on both hematopoietic progenitors and BM stromal cells, and SDF-1 release. The dynamic cross-talk between S1P and SDF-1 integrates BM stromal cells and hematopoeitic progenitor cell motility.