Stromal cell-derived factor-1 enhances pro-angiogenic effect of granulocyte-colony stimulating factor

OBJECTIVE: Granulocyte colony-stimulating factor (G-CSF) mobilizes bone marrow mononuclear cells into the peripheral circulation. Stromal cell-derived factor-1 (SDF-1) enhances the homing of progenitor cells mobilized from the bone marrow and augments neovascularization in ischemic tissue. We hypothesize that SDF-1 will boost the pro-angiogenic effect of G-CSF. METHODS AND RESULTS: NIH 3T3 cells retrovirally transduced with SDF-1alpha gene (NIH 3T3/SDF-1) were used to deliver SDF-1 in vitro and in vivo. Endothelial progenitor cells (EPCs) co-cultured with NIH 3T3/SDF-1 cells using cell culture inserts migrated faster and were less apoptotic compared to those not exposed to SDF-1. NIH 3T3/SDF-1 (10(6) cells) were injected into the ischemic muscles immediately after resection of the left femoral artery and vein of C57BL/6J mice. G-CSF (25 mug/kg/day) was injected intraperitioneally daily for 3 days after surgery. Blood perfusion was examined using a laser Doppler perfusion imaging system. The perfusion ratio of ischemic/non-ischemic limb increased to 0.57+/-0.03 and 0.50+/-0.06 with the treatment of either SDF-1 or G-CSF only, respectively, 3 weeks after surgery, which was significantly higher than the saline-injected control group (0.41+/-0.01, P<0.05). Combined treatment with both SDF-1 and G-CSF resulted in an even better perfusion ratio of 0.69+/-0.08 (P<0.05 versus the single treatment groups). Mice were sacrificed 21 days after surgery. Immunostaining and Western blot assay of the tissue lysates showed that the injected NIH 3T3/SDF-1 survived and expressed SDF-1. CD34(+) cells were detected with immunostaining, capillary density was assessed with alkaline phosphatase staining, and the apoptosis of muscle cells was viewed using an in situ cell death detection kit. More CD34(+) cells, increased capillary density, and less apoptotic muscle cells were found in both G-CSF and SDF-1 treated group (P<0.05 versus other groups). CONCLUSION: Combination of G-CSF-mediated progenitor cell mobilization and SDF-1-mediated homing of EPCs promotes neovascularization in the ischemic limb and increases the recovery of blood perfusion.     

Stromal cell-derived factor-1 genotype, coreceptor tropism, and HIV type 1 disease progression

This study used a well characterized cohort of human immunodeficiency virus type 1 (HIV-1)-infected hemophiliacs to define the relationship between the SDF1-3'A allele, the plasma HIV-1 coreceptor tropism, and the natural history of HIV-1 disease. Subjects heterozygous or homozygous for the SDF1-3'A allele experienced higher rates of decline in CD4+ T cell counts over time than did those without the allele (P=.009). Moreover, they had an increased risk of progression to acquired immunodeficiency syndrome and death, a relationship that persisted even when baseline plasma HIV-1 RNA levels and CD4+ T cell counts or CCR5 Delta 32 and CCR2-64I genotype were controlled for. This relationship was even stronger in a subgroup of subjects for whom tropism data were available. Subjects with the SDF1-3'A allele were also more likely to have detectable X4-tropic viruses (P=.012), and, when tropism was included in the survival analyses, the effect of the SDF1-3'A allele on disease progression was no longer significant. Therefore, the increased frequency of X4-tropic viruses in subjects carrying the SDF1-3'A allele may explain the observed adverse effect that this allele has on the natural history of HIV-1 disease.     

不稳定型心绞痛患者血浆胰岛素生长因子-1与胰岛素抵抗的关系

目的:探讨无糖尿病的不稳定型心绞痛(UAP)患者血浆胰岛素(INS)样生长因子(IGF)-1与INS抵抗(IR)的关系。方法:42例无糖尿病的UAP患者(UAP组)与30例非冠心病患者(对照组)比较,行75g葡萄糖口服耐量试验,测定空腹、餐后30min、餐后120min血糖、INS、IGF-1水平。结果:UAP组和对照组伴IR患者分别为26例和12例(P<0·05),UAP组中,伴IR与不伴IR者比较,空腹、餐后30min、餐后120minIGF-1明显降低(均P<0·05);HOMA-INS敏感指数(HOMA-ISI)、HOMA-IR指数(HOMA-IRI)分别明显增高和降低(P<0·05)。相关分析显示HOMA-IRI与体质指数(BMI)呈正相关(r=0·353,P<0·05);与空腹及餐后120minIGF-1和IGF-1曲线下面积(IGF-1AUC)呈负相关。多重逐步回归分析显示,HOMA-IRI=0·45722BMI-0·34285IGF-1空腹。结论:IGF-1与无糖尿病的UAP患者IR存在密切关系。     

Stromal cells in lymph nodes attract B-lymphoma cells via production of stromal cell-derived factor-1

Stromal cell-derived factor-1 (SDF-1) is a chemokine produced by bone marrow stromal cells which plays an important role in B-lymphopoiesis and the homing of hematopoietic stem cells to the bone marrow. In the present study, we investigated the role of SDF-1 and its receptor, CXCR4, in the chemotactic interaction between non-Hodgkin B-lymphoma cells and lymph node stromal cells. SDF-1 mRNA was abundantly expressed in stromal cells isolated from the lymph nodes of patients with malignant lymphoma. All B-lymphoma cells freshly isolated from these patients and most laboratory B-lymphoma cell lines, including follicular, diffuse large, and Burkitt's lymphoma cells, expressed surface CXCR4 and migrated in the presence of recombinant human SDF-1alpha. Chemotaxis assays revealed that CXCR4-positive (but not CXCR4-negative) B-lymphoma cells migrated towards lymph node stromal cells, and this migration was almost completely inhibited by the addition of anti-CXCR4 monoclonal antibody to the lymphoma cells or of anti-SDF-1 neutralizing antibody to the culture supernatant of the stromal cells. Down-regulation of surface CXCR4 was detected in B-lymphoma cells which migrated towards the stromal cells but not in those which showed no migratory response. In addition, contact between the lymphoma cells and the stromal cells resulted in down-regulation of surface CXCR4 on the lymphoma cells. These data strongly suggest that SDF-1/CXCR4 is the main chemokine system involved in the chemotactic interaction between B-lymphoma cells and lymph node stromal cells.     

SDF-1/CXCR4轴在肝脏干细胞移植中的应用

基质细胞衍生因子-1(stromal cell-derivedfactor-1, SDF-1)及其受体CXCR4构成SDF-1/CXCR4轴体系统.近年来随着该领域科研的不断深入, 越来越多的研究发现SDF-1/CXCR4轴体系统在组织损伤及修复中起着重要的作用.本文主要对SDF-1/CXCR4轴体系统的生物学特性及其在肝脏干细胞移植中的作用进行综述.     

Stromal cell-derived factor-1alpha/CXCL12-induced chemotaxis of T cells involves activation of the RasGAP-associated docking protein p62Dok-1

Events mediating stromal cell-derived factor-1 (SDF-1alpha/CXCL12) chemotaxis of lymphocytes are not completely known. We evaluated intracellular signaling through RasGAP-associated protein p62Dok-1 (downstream of tyrosine kinase [Dok-1]) and associated proteins. SDF-1alpha/CXCL12 stimulated Dok-1 tyrosine phosphorylation and association with RasGAP, adaptor protein p46Nck, and Crk-L in Jurkat T cells. The phosphorylation of Dok-1 was blocked by pretreatment of cells with the src kinase inhibitor PP2. Src kinase family member Lck was implicated. SDF-1alpha/CXCL12 did not phosphorylate Dok-1 in J.CaM1.6 cells, a Jurkat derivative not expressing Lck, but did phosphorylate Dok-1 in J.CaM1.6 cells expressing Lck. SDF-1alpha/CXCL12 induced the tyrosine phosphorylation of Pyk2 and the association of Pyk2 with zeta chain-associated protein-70 kilodaltons (Zap-70) and Vav. SDF-1alpha/CXCL12 enhanced the association of RasGAP with Pyk2. CXCR4-expressing NIH3T3 and Baf3 cells transfected with full-length Dok-1 cDNA were suppressed in their responses to SDF-1alpha/CXCL12-induced chemotaxis; mitogen-activated protein (MAP) kinase activity was also decreased. Chemotaxis to SDF-1/CXCL12 was significantly enhanced in Dok-1(-/-) CD4+ and CD8+ splenic T cells. These results implicate Dok-1, Nck, Crk-L, and Src kinases-especially Lck, Pyk2, Zap-70, Vav, and Ras-GAP-in intracellular signaling by SDF-1alpha/CXCL12, and they suggest that Dok-1 plays an important role in SDF-1alpha/CXCL12-induced chemotaxis in T cells.     

Stromal cell-derived factor-1 and hematopoietic cell homing in an adult zebrafish model of hematopoietic cell transplantation

In mammals, stromal cell-derived factor-1 (SDF-1) promotes hematopoietic cell mobilization and migration. Although the zebrafish, Danio rerio, is an emerging model for studying hematopoietic cell transplantation (HCT), the role of SDF-1 in the adult zebrafish has yet to be determined. We sought to characterize sdf-1 expression and function in the adult zebrafish in the context of HCT. In situ hybridization of adult zebrafish organs shows sdf-1 expression in kidney tubules, gills, and skin. Radiation up-regulates sdf-1 expression in kidney to nearly 4-fold after 40 Gy. Assays indicate that zebrafish hematopoietic cells migrate toward sdf-1, with a migration ratio approaching 1.5 in vitro. A sdf-1a:DsRed2 transgenic zebrafish allows in vivo detection of sdf-1a expression in the adult zebrafish. Matings with transgenic reporters localized sdf-1a expression to the putative hematopoietic cell niche in proximal and distal renal tubules and collecting ducts. Importantly, transplant of hematopoietic cells into myelosuppressed recipients indicated migration of hematopoietic cells to sdf-1a-expressing sites in the kidney and skin. We conclude that sdf-1 expression and function in the adult zebrafish have important similarities to mammals, and this sdf-1 transgenic vertebrate will be useful in characterizing the hematopoietic cell niche and its interactions with hematopoietic cells.     

Multiple actions of the chemokine stromal cell-derived factor-1alpha on neuronal activity

The chemokine SDF-1alpha and its cognate receptor CXCR4 are expressed in several neuronal populations. This review focuses on our current knowledge about the actions of this chemokine on neuronal excitability, through CXCR4 or other yet unknown pathways. In various neuronal populations (CA1 neurons of the hippocampus, granular and Purkinje cells of the cerebellum, melanin-concentrating hormone neurons of the lateral hypothalamus, vasopressinergic neurons of the supraoptic and the paraventricular nucleus of the hypothalamus, and dopaminergic neurons of the substantia nigra), SDF-1alpha can modulate the activity of neurons by multiple regulatory pathways including and often combining: (i) modulation of voltage-dependent channels (sodium, potassium, and calcium), (ii) activation of the G-protein-activated inward rectifier potassium current, and (iii) increase in neurotransmitter release (gamma-amino butyric acid (GABA), glutamate, and dopamine), often through Ca-dependent mechanisms. The possible mechanisms underlying these effects and their consequences in terms of modulation of neuroendocrine systems and physiopathology are discussed.     

Stromal cell-derived factor 1alpha increases polyploidization of megakaryocytes generated by human hematopoietic progenitor cells

The alpha chemokine receptor CXCR4 has been shown to be expressed on human hematopoietic progenitor cells and during the megakaryocytic differentiation pathway. Stromal cell-derived factor 1 (SDF-1) is the ligand for CXCR4. In this study, the role of SDF-1alpha in megakaryocytopoiesis was investigated. CD34(+) progenitors purified from peripheral blood were grown in serum-free liquid suspension culture supplemented with thrombopoietin to obtain a virtually pure megakaryocytic progeny. In this condition, the addition of SDF-1alpha gives rise to megakaryocytes (MKs) showing an increased DNA content and a rise of lobated nuclei, as compared with untreated cells: at day 5, approximately 20% of the cells already showed the presence of more than one nuclear lobe versus fewer than 5% in the control cells; at day 12, approximately 85% of the cells were of large size and markedly polyploid, whereas approximately 60% of the control cells were polyploid, showed fewer lobes, and were a smaller size. This effect was dose-dependent and did not affect the megakaryocytic proliferation. Experiments with the mitogen-activated protein kinase (MAPK) inhibitor PD98059 suggested a role for MAPK pathway on SDF-1alpha-induced endomitosis. Furthermore, SDF-1alpha induced a significant increase in the number of proplatelet-bearing MKs and promoted the migration of megakaryocytic cells. Treatment with SDF-1alpha caused reduction in CXCR4 abundance on the plasma membrane, seemingly owing to receptor internalization. Furthermore, the presence of SDF-1alpha did not affect the expression of megakaryocytic markers, indicating that differentiation and polyploidization are independently regulated events.     

Stromal cell-derived factor-1alpha stimulates tyrosine phosphorylation of multiple focal adhesion proteins and induces migration of hematopoietic progenitor cells: roles of phosphoinositide-3 kinase and protein kinase C

The stromal cell-derived factor-1 (SDF-1) is an alpha chemokine that binds to the CXCR4 receptor. Knock-out studies in mice demonstrate that this ligand-receptor pair is essential in hematopoiesis. One function of SDF-1 appears to be the regulation of migration of hematopoietic progenitor cells. We previously characterized signal transduction pathways induced by SDF-1alpha in human hematopoietic progenitors and found tyrosine phosphorylation of focal adhesion components, including the related adhesion focal tyrosine kinase (RAFTK), the adaptor molecule p130 Cas, and the cytoskeletal protein paxillin. To better understand the functional role of signaling molecules connecting the CXCR4 receptor to the process of hematopoietic migration, we studied SDF-1alpha-mediated pathways in a model hematopoietic progenitor cell line (CTS), as well as in primary human bone marrow CD34(+) cells. We observed that several other focal adhesion components, including focal adhesion kinase (FAK) and the adaptor molecules Crk and Crk-L, are phosphorylated on SDF-1alpha stimulation. Using a series of specific small molecule inhibitors, both protein kinase C (PKC) and phosphoinositide-3 kinase (PI-3K) appeared to be required for SDF-1alpha-mediated phosphorylation of focal adhesion proteins and the migration of both CTS and primary marrow CD34(+) cells, whereas the mitogen-activated protein kinases ERK-1 and -2 were not. These studies further delineate the molecular pathways mediating hematopoietic progenitor migration and response to an essential chemokine, SDF-1alpha. (Blood. 2000;95:2505-2513)     

Platelets and stromal cell-derived factor-1 in progenitor cell recruitment

Stromal cell-derived factor-1 (SDF-1) is a CXC chemokine that binds to its sole counterreceptor, CXCR4. It is well reported that the SDF-1/CXCR4 signaling pathway is of vital importance to human development and to various pathophysiological phenomena, including hematopoiesis, angiogenesis, atherosclerosis, cancer growth, metastasis, and human immunodeficiency virus infection. SDF-1 promotes mobilization of bone marrow-derived endothelial progenitor cells (EPCs) to the circulation in response to vascular injury. Recently, we found that platelets express and release SDF-1 into the microcirculation upon activation and we observed that platelet-derived SDF-1 is functionally involved in recruitment of EPCs to arterial thrombi in vivo. This review discusses the unique functions of this chemokine and the newly discovered impact of platelet-derived SDF-1 into the recruitment of progenitor cells to vascular injury areas, and its subsequent effects in atherosclerosis, vascular repair, and angiogenesis.     

Depression and 1-year prognosis in unstable angina

BACKGROUND: Depression is common after acute myocardial infarction and is associated with an increased risk of mortality for at least 18 months. The prevalence and prognostic impact of depression in patients with unstable angina, who account for a substantial portion of acute coronary syndrome admissions, have not been examined. METHODS: Interviews were carried out in hospital with 430 patients with unstable angina who did not require coronary artery bypass surgery before hospital discharge. Depression was assessed using the 21-item self-report Beck Depression Inventory and was defined as a score of 10 or higher. The primary outcome was 1-year cardiac death or nonfatal myocardial infarction. RESULTS: The Beck Depression Inventory identified depression in 41.4% of patients. Depressed patients were more likely to experience cardiac death or nonfatal myocardial infarction than other patients (odds ratio, 4.68; 95% confidence interval, 1.94-11.27; P<.001). The impact of depression remained after controlling for other significant prognostic factors, including baseline electrocardiographic evidence of ischemia, left ventricular ejection fraction, and the number of diseased coronary vessels (adjusted odds ratio, 6.73; 95% confidence interval, 2.43-18.64; P<.001). CONCLUSIONS: Depression is common following an episode of unstable angina and is associated with an increased risk of major cardiac events during the following year.