Involvement of the urokinase-type plasminogen activator receptor in hematopoietic stem cell mobilization

Blood ◽  
2005 ◽  
Vol 105 (5) ◽  
pp. 2198-2205 ◽  
Author(s):  
Carmine Selleri ◽  
Nunzia Montuori ◽  
Patrizia Ricci ◽  
Valeria Visconte ◽  
Maria Vincenza Carriero ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Mononuclear Cells ◽  
Serum Levels ◽  
Peripheral Blood Mononuclear ◽  
Hematopoietic Stem ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Plasminogen Activator Receptor ◽  
Cell Mobilization

AbstractWe investigated the involvement of the urokinase-type plasminogen-activator receptor (uPAR) in granulocyte–colony-stimulating factor (G-CSF)–induced mobilization of CD34+ hematopoietic stem cells (HSCs) from 16 healthy donors. Analysis of peripheral blood mononuclear cells (PBMNCs) showed an increased uPAR expression after G-CSF treatment in CD33+ myeloid and CD14+ monocytic cells, whereas mobilized CD34+ HSCs remained uPAR negative. G-CSF treatment also induced an increase in serum levels of soluble uPAR (suPAR). Cleaved forms of suPAR (c-suPAR) were released in vitro by PBMNCs and were also detected in the serum of G-CSF–treated donors. c-suPAR was able to chemoattract CD34+ KG1 leukemia cells and CD34+ HSCs, as documented by their in vitro migratory response to a chemotactic suPAR-derived peptide (uPAR84-95). uPAR84-95 induced CD34+ KG1 and CD34+ HSC migration by activating the high-affinity fMet-Leu-Phe (fMLP) receptor (FPR). In addition, uPAR84-95 inhibited CD34+ KG1 and CD34+ HSC in vitro migration toward the stromal-derived factor 1 (SDF1), thus suggesting the heterologous desensitization of its receptor, CXCR4. Finally, uPAR84-95 treatment significantly increased the output of clonogenic progenitors from long-term cultures of CD34+ HSCs. Our findings demonstrate that G-CSF–induced upregulation of uPAR on circulating CD33+ and CD14+ cells is associated with increased uPAR shedding, which leads to the appearance of serum c-suPAR. c-suPAR could contribute to the mobilization of HSCs by promoting their FPR-mediated migration and by inducing CXCR4 desensitization.

scholarly journals Specific Interference of Urokinase-type Plasminogen Activator Receptor and Matrix Metalloproteinase-9 Gene Expression Induced by Double-stranded RNA Results in Decreased Invasion, Tumor Growth, and Angiogenesis in Gliomas

2005 ◽  
Vol 280 (23) ◽  
pp. 21882-21892 ◽  
Author(s):  
Sajani S. Lakka ◽  
Christopher S. Gondi ◽  
Dzung H. Dinh ◽  
William C. Olivero ◽  
Meena Gujrati ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Tumor Growth ◽  
Plasminogen Activator ◽  
Tumor Invasion ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Antisense Approach ◽  
Plasminogen Activator Receptor ◽  
Metalloproteinase 9

We have previously demonstrated the effectiveness of adenovirus-mediated expression of antisense urokinase-type plasminogen activator receptor (uPAR) and matrix metalloproteinase-9 (MMP-9) in inhibiting tumor invasion in vitro and ex vivo. However, the therapeutic effect of the adenovirus-mediated antisense approach was shown to be transient and required potentially toxic, high viral doses. In contrast, RNA interference (RNAi)-mediated gene targeting may be superior to the traditional antisense approach, because the target mRNA is completely degraded and the molar ratio of siRNA required to degrade the target mRNA is very low. Here, we have examined the siRNA-mediated target RNA degradation of uPAR and MMP-9 in human glioma cell lines. Using RNAi directed toward uPAR and MMP-9, we achieved specific inhibition of uPAR and MMP-9. This bicistronic construct (pUM) inhibited the formation of capillary-like structures in both in vitro and in vivo models of angiogenesis. We demonstrated that blocking the expression of these genes results in significant inhibition of glioma tumor invasion in Matrigel and spheroid invasion assay models. RNAi for uPAR and MMP-9 inhibited cell proliferation, and significantly reduced the levels of phosphorylated forms of MAPK, ERK, and AKT signaling pathway molecules when compared with parental and empty vector/scrambled vector-transfected SNB19 cells. Furthermore, using RNAi to simultaneously target two proteases resulted in total regression of pre-established intracerebral tumor growth. Our results provide evidence that the use of hairpin siRNA expression vectors for uPAR and MMP-9 may provide an effective tool for cancer therapy.

The urokinase-type plasminogen activator receptor is not required for skeletal muscle inflammation or regeneration

2007 ◽  
Vol 293 (3) ◽  
pp. R1152-R1158 ◽  
Author(s):  
Scott C. Bryer ◽  
Timothy J. Koh
Keyword(s):  
Skeletal Muscle ◽  
Plasminogen Activator ◽  
Muscle Regeneration ◽  
Inflammatory Cells ◽  
Wild Type ◽  
Neutrophil Accumulation ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Plasminogen Activator Receptor

The hypothesis of this study was the urokinase-type plasminogen activator receptor (uPAR) is required for accumulation of inflammatory cells in injured skeletal muscle and for efficient muscle regeneration. Expression of uPAR was elevated at 1 and 3 days after cardiotoxin-induced muscle injury in wild-type mice before returning to baseline levels. Neutrophil accumulation peaked 1 day postinjury in muscle from both wild-type (WT) and uPAR null mice, while macrophage accumulation peaked between 3 and 5 days postinjury, with no differences between strains. Histological analyses confirmed efficient muscle regeneration in both wild-type and uPAR null mice, with no difference between strains in the formation or growth of regenerating fibers, or recovery of normal morphology. Furthermore, in vitro experiments demonstrated that chemotaxis is not different between WT and uPAR null macrophages. Finally, fusion of cultured satellite cells into multinucleated myotubes was not different between cells isolated from WT and uPAR null mice. These results demonstrate that uPAR is not required for the accumulation of inflammatory cells or the regeneration of skeletal muscle following injury, suggesting uPA can act independently of uPAR to regulate events critical for muscle regeneration.

scholarly journals Soluble urokinase-type plasminogen activator receptor as a measure of treatment response in acute exacerbation of COPD

2018 ◽  
Vol 44 (1) ◽  
pp. 36-41 ◽  
Author(s):  
Gehan Hassan AboEl-Magd ◽  
Maaly Mohamed Mabrouk
Keyword(s):  
Treatment Response ◽  
Plasminogen Activator ◽  
Acute Exacerbation ◽  
Serum Levels ◽  
Acute Exacerbation Of Copd ◽  
Supar Level ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Plasminogen Activator Receptor ◽  
Exacerbation Of Copd

ABSTRACT Objective: To evaluate the value of soluble urokinase-type plasminogen activator receptor (suPAR) in the diagnosis of acute exacerbation of COPD (AECOPD) and in monitoring treatment response, analyzing the relationship between suPAR and fibrinogen in AECOPD. AECOPD leads to increased airway inflammation, contributing to an exaggerated release of inflammatory mediators. Methods: We recruited 45 patients with AECOPD and 20 healthy control subjects. Medical histories were taken, and all subjects underwent clinical examination, chest X-ray, pulmonary function tests, and blood gas analysis. On day 1 (treatment initiation for the AECOPD patients) and day 14 (end of treatment), blood samples were collected for the determination of serum suPAR and plasma fibrinogen. Results: Serum levels of suPAR were significantly higher in the AECOPD group than in the control group. In the AECOPD patients, there was a significant post-treatment decrease in the mean serum suPAR level. The sensitivity, specificity, and accuracy of suPAR were 95.6%, 80.0%, and 93.0%, respectively. The Global Initiative for Chronic Obstructive Lung Disease stage (i.e., COPD severity) correlated positively and significantly with serum levels of suPAR and plasma levels of fibrinogen. Conclusions: Monitoring the serum suPAR level can be helpful in the evaluation of the COPD treatment response and might be a valuable biomarker for determining the prognosis of AECOPD. Because serum suPAR correlated with plasma fibrinogen, both markers could be predictive of AECOPD.

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