Role Of SDF-1 Research Articles

The role of SDF-1 in fracture repair

The role of SDF-1 in fracture repair

Increased Susceptibility to Severe Chronic Liver Damage in CXCR4 Conditional Knock-Out Mice

The chemokine SDF-1 and its receptor CXCR4 are essential for the proper functioning of multiple organs. In the liver, cholangiocytes and hepatic progenitor cells (HPCs) are the main cells that produce SDF-1, and SDF-1 is thought to be essential for HPC-stimulated liver regeneration. In this study, CXCR4 conditionally targeted mice were used to analyze the role of SDF-1 in chronically damaged liver. Chronic liver damage was induced in MxCre CXCR4(f/null) mice and the control MxCre CXCR4(f/wt) mice by CCl(4). Serum markers were analyzed to assess liver function and damage, the number of cytokeratin-positive cells as a measure of HPCs, and the extent of liver fibrosis. Additional parameters relating to liver damage, such as markers of HPCs, liver function, MMPs, and TIMPs were measured by real-time PCR. Serum ALT was significantly higher in MxCre CXCR4(f/null) mice than MxCre CXCR4(f/wt) mice. The number of cytokeratin-positive cells and the area of fibrosis were also increased in the MxCre CXCR4(f/null) mice. The expression of mRNAs for several markers related to hepatic damage and regeneration was also increased in the liver of MxCre CXCR4(f/null) mice, including primitive HPC marker prominin-1, MMP9, TNF-α, and α-SMA. MxCre CXCR4(f/null) mice were susceptible to severe chronic liver damage, suggesting that SDF-1-CXCR4 signals are important for liver regeneration and preventing the progression of liver disease. Modulation of SDF-1 may therefore be a promising treatment strategy for patients with chronic liver disease.

Action of SDF-1/CXCR4 axis in liver metastasis of colorectal cancer.

530 Background: It has recently been suggested that the SDF-1/CXCR4 axis is involved in tumor progression, angiogenesis, metastasis, and survival in various cancer. In this study, we investigate the possible role of SDF-1/CXCR4 axis in colorectal liver metastasis. Methods: Both primary colorectal tumors and liver metastatic tumors were obtained from 12 patients with colorectal liver metastasis. Expression levels of CXCR4 and SDF-1 were determined using RT-PCR. In 4 patients with benign liver disease, the expression level of SDF-1 in normal liver tissues was also determined. We divided the 12 patients into two groups; high expression group (n=6) and low expression group (n=6) according to each expression level of SDF-1 and CXCR4, and compared the clinicopathological factors between the two groups. Results: 1. CXCR4 expression levels in primary tumor: The frequency of the peritoneal dissemination in the CXCR4 high expression group was higher than in the low expression group (p=0.07). Moreover, overall survival rate in the CXCR4 high expression group was significantly lower than that in the low expression group (3 year-survival rate: 67% vs. 100%, p<0.05). 2. CXCR4 in metastatic tumor tissues and SDF-1 in non-tumor liver tissues: The expression level of SDF-1 in non-tumor liver tissues was significantly higher than that in normal liver tissues (p<0.01). A significant correlation between the CXCR4 expression levels in metastatic tumor tissues and SDF-1 expression levels of non-tumor liver tissues (p<0.05). The number of metastatic liver tumors in the SDF-1 high expression group tended to be larger than that in the low expression group (p=0.12). Conclusions: The present data suggest that there is a significant association of the SDF-1/CXCR4 axis with enhanced liver metastasis and poor prognosis of the patients with colorectal liver metastasis. Furthermore, an enhanced expression of SDF-1 in non-tumor liver tissues may have an important role in the formation of liver metastasis.

The Function Role of SDF-1/CXCR4 Signaling in Osteoarthritis

The Function Role of SDF-1/CXCR4 Signaling in Osteoarthritis

The Role of Endogenous Stromal Cell-Derived Factor-1 in the Survival and Growth of Acute Myeloid Leukemia Cells

Abstract 1502Stromal cell-derived factor-1 (SDF-1) is constitutively expressed and produced by stromal cells in the bone marrow (BM). The protein exerts its functions by binding to its receptor CXCR4, thus guiding the homing of hematopoietic stem/progenitor cells and leukemia cells to the BM. CD34+ cells purified from normal adult peripheral blood have been shown to express and produce SDF-1, which exerted an antiapoptotic effect on CD34+ cell through an autocrine/paracrine loop. Acute myeloid leukemia (AML) cells have also been shown to express and produce SDF-1, but the role of SDF-1 in this context is largely unknown. Thus, the aim of the present study was to determine the function of SDF-1 produced by AML cells. Using siRNA technology, SDF-1 was knocked-down in AML cells and subsequent biological alterations occurring in the cells were evaluated in vitro. All AML cell lines used in this study (U937, K562, KG1a, HL-60 and MO7e) as well as primary CD34+ cells obtained from the BM of 5 patients with AML expressed SDF-1 mRNA at various levels, as revealed by semi-quantitative and real time RT-PCR analysis. SDF-1 was detected by Western blotting analysis and ELISA allowed for the detection of SDF-1 in the supernatants of cultures of AML cells grown for 3 days in a serum-free medium, indicating that AML cells, similar to normal CD34+ cells, are able to produce and secrete SDF-1. Exogenous SDF-1 (added at a concentration of up to 200 ng/mL) alone had no discernible effects on the survival or proliferation of either the cell lines or the primary CD34+ AML cells maintained in a serum-free medium, but was able to induce the internalization of CXCR4 and CXCR7. Transfection of five AML cell lines with SDF-1 siRNA diminished the SDF-1 mRNA levels by up to 90%. The knock-down cells were stable for at least 3 days. SDF-1 knock-down did not affect the serum deprivation-induced apoptosis of the cells. Cell surface expression of CXCR4 was not changed, whereas cytoplasmic CXCR4 was significantly upregulated along with the upregulation of SDF-1 mRNA. Neither cell surface nor cytoplasmic expression of CXCR7 was affected by the knock-down of SDF-1. Conversely, the knock-down of CXCR7, but not CXCR4, upregulated the SDF-1 mRNA expression in the transfected cells. No changes in the transmembrane and trnasendothelial migration of the knock-down cells were observed. In contrast, the knock-down of SDF-1 inhibited the spontaneous proliferation of the U937, K562, and KG1a cells by 20–30% during a 3-day incubation in a serum-free medium. These results indicate that endogenous SDF-1 of AML cells functions as an autocrine growth factor. Disclosures:No relevant conflicts of interest to declare.

The roles of SDF-1/CXCR4 axis and its relationship with apoptosis in the myelodysplastic syndromes

We performed flow cytometric analysis of CD34(+) cell apoptosis in 22 patients with myelodysplastic syndrome (MDS) and 7 patients with de novo acute myeloid leukemia (AML) using annexin V-FITC, which binds to exposed phosphatidylserine on apoptotic cells. Apoptosis was significantly increased in low-grade MDS group (IPSS score ≤ 1.0) compared with high-grade MDS group (21.33 vs. 7.27%, P < 0.001) and patients with de novo AML (21.33 vs. 7.53%, P < 0.001). There was no correlation between apoptosis and patient's age or gender. Our results confirmed that CD34(+) cell apoptosis was significantly increased in low-grade MDS, which was featured as bone marrow failure. CXCR4 protein expression on CD34(+) cell surface in the low-grade MDS was lower than high-grade MDS (10.42 vs. 16.97, P = 0.014) and AML group (10.42 vs. 20.26, P < 0.001). But there was no statistical significance between low-grade MDS and the control group (P = 0.496). Furthermore, we measured SDF-1 levels in BM plasma from patients by enzyme-linked immunosorbent assay (ELISA), and no difference was found. We found a negative correlation between apoptosis and CXCR4 expression. Our data indicate that CXCR4 might be the prognostic marker of MDS.

Lung defects in neonatal and adult stromal-derived factor–1 conditional knockout mice

Stromal-derived factor (SDF)-1/CXCL12 is a cytokine that is involved in organogenesis, hematopoiesis, chemoattraction, and wound healing. An SDF-1 knockout mouse (SDF-1(-/-)) has provided important insights into the role of SDF-1 in fetal development. Because the SDF-1 knockout is lethal in the perinatal period, we have created a conditional SDF-1 knockout mouse. In the present study, we induced conditionally knocked out SDF-1 in neonatal mice and found that lung development was compromised; neonatal lungs showed increased alveolar airspace and abnormal ultrastructure. Conditional knockout of SDF-1 in adult mice resulted in an emphysemic morphology, with increased alveolar airspace and thickened alveolar septa. Fluorescence angiography showed pulmonary vessel hyperdilation. To determine whether the hyperdilation involved nitric oxide, we inhibited endothelial nitric oxide synthase (eNOS) with N (G)-nitro-L- arginine methyl ester. This resulted in the inhibition of pulmonary vessel hyperdilation. Western blot results showed increased phosphorylation of eNOS in our induced SDF-1 knockout mice, indicating that eNOS is normally repressed in the presence of SDF-1, and that activation of eNOS contributes to pulmonary pathology. Thus, a conditional knockout mouse has been successfully created for SDF-1; initial characterization indicates that SDF-1 is intimately involved in lung development and physiology.

Role of SDF-1 and CXCR4 axis in LPS stimulated bone resorption

Role of SDF-1 and CXCR4 axis in LPS stimulated bone resorption

Preliminary study on CXCR4 nuclear localization sequence in metastatic renal cell carcinoma

Objective:To investigate the role of SDF-1/CXCR4 in metastasis of renal cell carcinoma and to observe the intracellular location of different CXCR4 segments in renal carcinoma cells.Methods:The potential nuclear localization sequences of different CXCR4 were discovered by nuclear localization software and experiments.Full length and truncated forms of CXCR4 were fused with green fluorescent protein pEGFP-N1 and their influence on subcellular localization was examined by confocal microscopy after transfecting them into renal carcinoma cell line A498.Results:Analysis with PSORT Ⅱ Prediction revealed that the nuclear localization sequence region of CXCR4 was located between amino acids 146 and 149(RPRK).Expression products of the recombinant plasmids with SDF-1 stimulation,including EGFP-CXCR4(1-510 bp),EGFP-CXCR4(1-765 bp) and wild-type EGFP-CXCR4,were mainly located in the cell nuclei.However,expression product of EGFP-CXCR4(1-267 bp) with SDF-1 stimulation was mainly located in the renal cell cytoplasm.Expression product of wild-type EGFP-CXCR4 full length plasmid without SDF-1 stimulation was mainly located in the cell cytoplasm;these results accorded with the results of bioinformatics analysis.Conclusion:Nuclear localization sequence of CXCR4 is located in the amino acids 90 to 170,which provides a theoretical basis for further clarifying the nuclear localization sequences of CXCR4 in renal cell carcinoma cells and for finding new potential target for inhibiting the metastasis of renal cell carcinoma.

Stromal Cell-Derived Factor-1/CXCL12 Contributes to MMTV-Wnt1 Tumor Growth Involving Gr1+CD11b+ Cells

BackgroundHistological examinations of MMTV-Wnt1 tumors reveal drastic differences in the tumor vasculature when compared to MMTV-Her2 tumors. However, these differences have not been formally described, nor have any angiogenic factors been implicated to be involved in the Wnt1 tumors.Methodology/Principal FindingsHere, we show that MMTV-Wnt1 tumors were more vascularized than MMTV-Her2 tumors, and this correlated with significantly higher expression of a CXC chemokine, stromal cell-derived factor-1 (SDF1/CXCL12) but not with VEGFA. Isolation of various cell types from Wnt1 tumors revealed that SDF1 was produced by both tumor myoepithelial cells and stromal cells, whereas Her2 tumors lacked myoepithelial cells and contained significantly less stroma. The growth of Wnt1 tumors, but not Her2 tumors, was inhibited by a neutralizing antibody to SDF1, but not by neutralization of VEGFA. Anti-SDF1 treatment decreased the proportion of infiltrating Gr1+ myeloid cells in the Wnt1 tumors, which correlated with a decrease in the percentage of endothelial cells. The involvement of Gr1+ cells was evident from the retardation of Wnt1 tumor growth following in vivo depletion of these cells with an anti-Gr1-specific antibody. This degree of inhibition on Wnt1 tumor growth was comparable, but not additive, to the effect observed with anti-SDF1, indicative of overlapping mechanisms of inhibition. In contrast, Her2 tumors were not affected by the depletion of Gr1+ cells.Conclusions/SignificanceWe demonstrated that SDF1 is important for Wnt1, but not for HER2, in inducing murine mammary tumor and the role of SDF1 in tumorigenesis involves Gr1+ myeloid cells to facilitate growth and/or angiogenesis.

Role of the SDF-1/CXCR4 System in Myocardial Infarction

Myocardial infarction (MI) is accompanied by an inflammatory response, leading to the recruitment of leukocytes and subsequent myocardial injury and healing. Chemokines are potent chemoattractant cytokines that regulate leukocyte trafficking in inflammatory processes. Recent evidence indicates that chemokines play a role not only in leukocyte trafficking but also in angiogenesis and cardioprotection. In particular, stromal cell-derived factor-1alpha (SDF-1alpha) has generated considerable interest for its role in the pathophysiology of MI. This review will focus on the role of SDF-1 and its receptor CXC chemokine receptor 4 (CXCR4; ie, the SDF-1/CXCR4 system) in the pathophysiology of MI and discuss their potential as therapeutic targets for MI.

Mechanism of primitive duct formation in the pancreas and submandibular glands: a role for SDF-1

BackgroundThe exocrine pancreas is composed of a branched network of ducts connected to acini. They are lined by a monolayered epithelium that derives from the endoderm and is surrounded by mesoderm-derived mesenchyme. The morphogenic mechanisms by which the ductal network is established as well as the signaling pathways involved in this process are poorly understood.ResultsBy morphological analyzis of wild-type and mutant mouse embryos and using cultured embryonic explants we investigated how epithelial morphogenesis takes place and is regulated by chemokine signaling. Pancreas ontogenesis displayed a sequence of two opposite epithelial transitions. During the first transition, the monolayered and polarized endodermal cells give rise to tissue buds composed of a mass of non polarized epithelial cells. During the second transition the buds reorganize into branched and polarized epithelial monolayers that further differentiate into tubulo-acinar glands. We found that the second epithelial transition is controlled by the chemokine Stromal cell-Derived Factor (SDF)-1. The latter is expressed by the mesenchyme, whereas its receptor CXCR4 is expressed by the epithelium. Reorganization of cultured pancreatic buds into monolayered epithelia was blocked in the presence of AMD3100, a SDF-1 antagonist. Analyzis of sdf1 and cxcr4 knockout embryos at the stage of the second epithelial transition revealed transient defective morphogenesis of the ventral and dorsal pancreas. Reorganization of a globular mass of epithelial cells in polarized monolayers is also observed during submandibular glands development. We found that SDF-1 and CXCR4 are expressed in this organ and that AMD3100 treatment of submandibular gland explants blocks its branching morphogenesis.ConclusionIn conclusion, our data show that the primitive pancreatic ductal network, which is lined by a monolayered and polarized epithelium, forms by remodeling of a globular mass of non polarized epithelial cells. Our data also suggest that SDF-1 controls the branching morphogenesis of several exocrine tissues.

The SDF-1/CXCR4 Axis Is a Novel Driver of Vascular Development of the Glomerulus

Spatial and temporal control of developing glomerular capillaries is complex and requires coordinated cross-talk between various cell types. Recent advances in our understanding of the processes that regulate glomerular morphogenesis reveal some mediators are essential for the emerging tuft, particularly vascular endothelial growth factor (VEGF) and PDGF.1–4 In search of additional crucial mediators, Takabatake et al. 5 examine the role of CXC chemokine ligand 12 (CXCL12; stromal cell–derived factor 1 [SDF-1]) and its receptor, CXCR4, in this issue of JASN . Traditional SDF-1 signaling is involved primarily in the homing of hematopoietic stem cells to their niche within the bone marrow and in hematopoietic stem cell quiescence. A role for SDF-1/CXCR4 is also described for chemotaxis of T lymphocytes and monocytes, B cell development, cardiac and cerebellar development, and cancer stem cell migration.6 This study was triggered by a previous report, which analyzed mice deficient in SDF-1 or CXCR4 and the requirement for this ligand-receptor system in vascularization of the gastrointestinal tract.7 In their beautiful study, Takabatake et al. 5 demonstrate the SDF-1/CXCR4 axis is a novel and essential signaling system for blood vessel formation in the kidney, particularly within the glomerulus. The …

Signalling Pathway Mediated by CXCR7, an Alternative Chemokine Receptor for Stromal‐Cell Derived Factor‐1α, in AtT20 Mouse Adrenocorticotrophic Hormone‐Secreting Pituitary Adenoma Cells

Stromal cell-derived factor (SDF)-1 and its receptor, CXCR4, have been identified in both neurones and glia of many brain areas. Previous studies have mainly focused on the role of SDF-1 and CXCR4 in modulating the hypothalamic-pituitary axis and their possible involvement in the development of pituitary adenomas. An alternative SDF-1 receptor, CXCR7, has recently been identified, but it has not been studied in the context of pituitary adenomas. The present study aimed to investigate the distribution and function of CXCR7 in pituitary adenomas. The expression of CXCR7, normalised to β-actin, was assessed by tissue microarray analysis of 62 adenomas, including 23 growth hormone (GH)-producing adenomas, 22 nonfunctioning adenomas, seven prolactin (PRL)-producing adenomas, six adrenocorticotrophic hormone-producing adenomas and four thyroid-stimulating hormone-producing adenomas. In vitro functional studies used RNA interference (RNAi) and cDNA microarray analysis to evaluate the CXCR7 signalling pathway in AtT-20 mouse pituitary adenoma cells treated with recombinant mouse SDF-1α and transfected with RNAi against Cxcr7 or control RNAi. In tissue microarray analysis, prominent expression of CXCR7 was observed in GH-producing adenomas and PRL-producing adenomas, and in macroadenomas (P < 0.05). Intracellular signalling via CXCR7 up-regulated Bub1, Cdc29 and Ccnb1, and down-regulated Asns, Gpt, Pycr1, Cars and Dars. The present study demonstrates that the SDF-1α ⁄ CXCR7 signalling pathway regulates genes involved in cell cycle control, amino acid metabolism and ligase activity, which comprise targets that are distinct from those of CXCR4.

Characterization of Angiogenic Potential of Late Endothelial Progenitor Cells on Human Cord Blood and Bone Marrow

Background: The identification of circulating endothelial progenitor cells (EPCs) has revolutionized approaches to cell-based therapy for injured and ischemic tissues. Recently, we have demonstrated that there are 2 distinct types of EPCs from UCB having different biologic properties for angiogenic capabilities in vitro and in vivo. In present study, the aim is to directly compare umbilical cord blood (UCB)- and BM-derived late EPC surface phenotypes and in vitro functional capacity.Methods: Mononuclear cells from UCB and BM cultured using EGM-2 medium with VEGF, IGF-1 and FGF for 21 days. Late outgrowing endothelail cells(late OECs) which were in peak growth at third weeks of culture were analyzed for expression of various surface markers by flow cytometry/RT-PCR/IF, tube formation in Matrigel plates, proliferation assay, endothelial colony assay and the role of SDF-1/VEGF on migration.Results: The adherent cells after culture of 7 days exhibited a fibroblast like shape in BM and a cobblestone shaped cells in UCB. Although two sources of OECs were comparable in expression of endothelial and various adhesion molecule markers, BM-derived OECs contained higher proportion of cells expressing smooth muscle cell markers(SMMHC), several adhesion molecule(CD49d, CD62L and VCAM-1), whereas the expression of CXCR-4, PECAM-1 and CD62E and expression of mRNA on endothelial marker genes were higher in UCB-derived OECs. UCB-OECS stained positive for uptake of acetylated low-density lipoprotein and had more migratory ability in the presence of SDF-1 and VEGF compared with BM-OECs. Both sources OECs effectively formed capillary tubes in Matrigel plates.Conclusion: We directly compared OECs derived from UCB and BM and two source of OECs differ in aspect of several adhesion molecule and angiogenic potential in vitro. These difference of UCB render it potentially advantageous for human therapeutic OECs applications for potential applications for a “cell therapy” in the situations on vascular injuries when compared with patients-derived BM.

Short-Term Ex Vivo Expansion of CD133+ Cells by Co-Culture with Mesenchymal Stem Cells: Role of SDF-1/CXCL12

CD133 (prominin-1) is the first in a class of novel pentaspan membrane proteins identified in humans and mice, and studies have since confirmed the utility of CD133 as a marker of stem cells with hematopoietic and non-hematopoietic lineage potential. A number of human transplantation studies have documented hematopoietic reconstitution from CD133+ stem cells from mismatched donors, with a suggested advantage over standard grafts in avoidance of graft versus host disease. We have developed a novel hematopoietic culture system (Long-Term Stem Cell Culture or LTSCC) to investigate the potential of human mesenchymal stem cells (MSC) to form stroma that can support short- and long-term hematopoiesis derived from cord blood (CB)-derived CD133+ cells. In addition, we analyzed the effect of stromal derived factor-1 (SDF-1/CXCL12) on survival and short-and long-term colony-forming capacity of CD133+ hematopoiesis. LTSCC induced stroma-like changes in the MSC feeder layer, with adipocyte formation, thought to be needed for formation of stem cell niches, and supported long-term (>9 weeks) survival of CB-CD133+ cells. Cobblestone areas of active CD133-derived hematopoiesis were seen in LTSCC for up to 9 weeks of culture. SDF-1/CXCL12 acted as a survival factor for CB-CD133+ cells and induced a significant ex vivo cell expansion at weeks 3 and 4 of LTSCC (maximal 500-fold increase), while maintaining the capacity for CFU-Mix and BFU-E colony formation up to 7 weeks. Long-term hematopoiesis was assessed by enumeration of long-term culture initiating cells (LTC-IC). When SDF-1/CXCL12 was added to LTSCC, we found a significant increase in LTC-IC: 0.3% (+SDF-1/CXCL12) vs. 0.05% (-SDF-1/CXCL12). Finally, homing capacity, as defined by SDF-1/CXCL12-induced adhesion and migration of CB-CD133+ cells, was maintained and even increased during the first 3 weeks of LTSCC. In summary, MSC can be maintained in LTSCC medium, and this simplified feeder layer is able to provide niches for cobblestone area forming cells derived from CB-CD133+ cells. SDF-1/CXCL12 is critical to support the survival and expansion of CD133+ cells, either directly or indirectly by paracrinesignaled retention of CD133+ cells in contact with specialized MSC niches. We suggest that expansion of CD133+ cells from cord blood may be useful in clinical transplantation limited by insufficient numbers of stem cells.

Abstract 3747: Endothelial Specific Inactivation of CXCR4 Receptor in Adult Mice Reveals the Pivotal Role of SDF-1/CXCR4 Axis in the Development of Endothelial Progenitor Cells (EPCs) for Myocardiac Infarction

The development of endothelial progenitor cells (EPCs) is markedly modulated by vascular niche-derived factors for maintaining EPC pool in adult bone marrow. Although SDF-1a/CXCR4 axis have shown to play a critical role in maintaining hematopoietic stem cell (HSC) pool, the precise regulatory mechanism of EPC development remain unclear. In the analysis of tie-2 specific inactivation of CXCR4 in adult mice, we have found that the number of CD34(−/low)/c-kit(+)/Sca-1(+)/Lin(−) or side population (SP) stem cells is profoundly increased. In addition, EPC colony forming capacity of CD34(−)/c-kit(+)/Sca-1(+)/Lin(−) stem cells in endothelial specific CXCR4 null mice are drastically enhanced. Notably, the development of definitive EPC, a late stage of EPC development, is specifically impaired in Tie2cre-CXCR4 null mice, although the colony number of primitive EPCs, an early stage of EPC development, is profoundly increased. EPCs derived from endothelial specific CXCR4 null mice showed showed immatured EPC function, such as migration capacity, proliferation, cell survival. When cultured with SDF-1, niche-derived stem cells gave rise to promoted EPC colony forming capacity. In myocardiac infarction model, we observed the significantly reduced cardiac function,when measured by echocardiography. Furthermore, capillary density was also significantly decreased, as well as induced fibrosis in endothelial specific CXCR4 null mice. In conclusion, the present report clearly showed for the first time that the SDF-1a/CXCR4 axis plays a pivotal role in EPC maturation in special niche, suggesting that the full understanding of EPC development via regulating SDF-1-CXCR4 axis provide a key source of therapeutic tissue regeneration.

SDF-1 (CXCL12) in haematopoiesis and leukaemia: impact of DPP IV/CD26

DPP IV/CD26 contributes to cell signalling by various mechanisms: as a receptor or co-receptor, as a component of a membrane-associated signal transduction complex and by virtue of its exopeptidase activity. The presence of enzymatically active DPP IV in a variety of tissues and in plasma makes it challenging to review clinical consequences of chemokine turnover by DPP IV activity, even more so in times when the concept of DPP IV inhibition for therapeutic purposes has reached the stage of clinical application. Among the known substrates of DPP IV/CD26, Stromal cell-derived factor 1 (SDF-1, CXCL12) has gained attention in recent years as a critical mediator of chemotaxis and tissue invasion, especially in the context of malignant disease. SDF-1 and its receptor, CXCR4, differ from other chemokines and their respective receptors by a lack of redundancy and pleiotropism. Therapeutic intervention using CXCR4 antagonists has been proposed. It seems appropriate to review the role of SDF-1 in haematopoiesis and its malignant counterpart, leukaemia, and to assess the interference of DPP IV/CD26 with the SDF-1/CXCR4 axis as well as possible risks and benefits of DPP IV inhibition.

Stromal-Derived Factor-1 and Inflammatory Cytokines in Retinal Vein Occlusion

Purpose: To identify the roles of stromal-derived factor (SDF-1) and inflammatory cytokines in retinal vein occlusion (RVO). Methods: Samples were collected by vitrectomy and the levels of SDF-1, vascular endothelial growth factor, and inflammatory cytokines (interleukins [IL-1β, IL-6, IL-8, IL-10, IL-12p70]; tumor necrosis factor-α) were measured in 20 eyes with RVO, and 9 eyes with epiretinal membrane served as negative controls. Four eyes with inflammatory diseases were also investigated. Results: SDF-1 levels in active RVO (A-RVO; 4 eyes with iris neovascularization) were significantly higher than those in quiescent RVO (Q-RVO; 16 eyes without iris neovascularization) and the negative controls (p <. 01), whereas there were no significant difference between the Q-RVO and the negative controls. There were no significant correlations between the concentrations of SDF-1 and other cytokines. Conclusions: Elevation of intravitreous SDF-1 levels in A-RVO but not Q-RVO suggested a pivotal role of SDF-1 in angiogenic changes during RVO.

Critical role of SDF-1/CXCR4 in the development of boundary cap cells and CNS/PNS segregation

Critical role of SDF-1/CXCR4 in the development of boundary cap cells and CNS/PNS segregation