scholarly journals Stromal-Cell-Derived Factor-1 (SDF-1)/CXCL12 as Potential Target of Therapeutic Angiogenesis in Critical Leg Ischaemia

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Teik K. Ho ◽  
X. Shiwen ◽  
D. Abraham ◽  
J. Tsui ◽  
D. Baker
Keyword(s):  
Skeletal Muscle ◽  
Chemokine Receptors ◽  
Stromal Cell ◽  
Therapeutic Angiogenesis ◽  
Limb Amputation ◽  
Western World ◽  
High Morbidity ◽  
Biologic Effects ◽  
Inflammatory Processes ◽  
Stromal Cell Derived Factor

In the Western world, peripheral vascular disease (PVD) has a high prevalence with high morbidity and mortality. In a large percentage of these patients, lower limb amputation is still required. Studies of ischaemic skeletal muscle disclosed evidence of endogenous angiogenesis and adaptive skeletal muscle metabolic changes in response to hypoxia. Chemokines are potent chemoattractant cytokines that regulate leukocyte trafficking in homeostatic and inflammatory processes. More than 50 different chemokines and 20 different chemokine receptors have been cloned. The chemokine stromal-cell-derived factor-1 (SDF-1 aka CXCL12) is a constitutively expressed and inducible chemokine that regulates multiple physiological processes, including embryonic development and organ homeostasis. The biologic effects of SDF-1 are mediated by chemokine receptor CXCR4, a 352 amino acid rhodopsin-like transmembrane-specific G protein-coupled receptor (GPCR). There is evidence that the administration of SDF-1 increases blood flow and perfusion via recruitment of endothelial progenitor cells (EPCs). This review will focus on the role of the SDF-1/CXCR4 system in the pathophysiology of PVD and discuss their potential as therapeutic targets for PVD.

Hypoxia-Inducible Factor 1 in Lower Limb Ischemia

Vascular ◽  
2006 ◽  
Vol 14 (6) ◽  
pp. 321-327 ◽  
Author(s):  
Teik K. Ho ◽  
David J. Abraham ◽  
Carol M. Black ◽  
Daryll M. Baker
Keyword(s):  
Skeletal Muscle ◽  
Lower Limb ◽  
Target Genes ◽  
Therapeutic Potential ◽  
Hypoxia Inducible Factor ◽  
Limb Ischemia ◽  
Limb Amputation ◽  
Western World ◽  
High Morbidity ◽  
Activity Increase

In the Western world, peripheral vascular disease (PVD) has a high prevalence and is associated with high morbidity and mortality. More patients are presenting with critical limb ischemia (CLI), the end stage of PVD, because of an increased life expectancy owing to improved medical care. In a large percentage of these patients, lower limb amputation is still required, despite current advances in surgery and interventional radiology. Studies of ischemic skeletal muscles disclosed evidence of endogenous angiogenesis and adaptive skeletal muscle metabolic changes in response to hypoxia. Many of the genes responsible for these responses are regulated by hypoxia-inducible factor (HIF)-1. HIF-1, consisting of HIF-1α and HIF-1β subunits, is a major transcription factor that functions as a master regulator of oxygen homeostasis that plays essential roles in cellular and systemic pathophysiology. HIF-1α expression and HIF-1 transcriptional activity increase exponentially as cellular oxygen concentration is decreased. More than 60 target genes that are transactivated by HIF-1 have been identified. Many of the target genes, such as vascular endothelial growth factor, have been studied extensively, especially in tumors. However, only recently that interest in HIF-1 is growing in relation to ischemic diseases. Most of the studies concentrated mainly on the angiogenic property of HIF-1. In contrast, there is a lack of information on the role of HIF-1 in skeletal muscle metabolic adaptive changes as the end-organ in PVD. This review aims to summarize our current understanding of HIF-1 roles and the therapeutic potential in PVD.

Stromal cell–derived factor-1 and macrophage-derived chemokine: 2 chemokines that activate platelets

Blood ◽  
2000 ◽  
Vol 96 (1) ◽  
pp. 50-57 ◽  
Author(s):  
M. Anna Kowalska ◽  
Mariusz Z. Ratajczak ◽  
Marcin Majka ◽  
Jianguo Jin ◽  
Satya Kunapuli ◽  
...  
Keyword(s):  
Chemokine Receptors ◽  
Stromal Cell ◽  
Platelet Rich Plasma ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Creatine Phosphate ◽  
Polymerase Chain ◽  
Stromal Cell Derived Factor ◽  
Induced Aggregation ◽  
Second Wave

Platelets play roles in both thrombosis and inflammation, and chemokines that are released at sites of inflammation could potentially activate platelets. Among the chemokine receptors expressed on platelets, the CXCR4 is the receptor for chemokine stromal cell-derived factor-1 (SDF-1), and the CCR4 is the receptor for macrophage-derived chemokine (MDC). Of the chemokines tested, SDF-1 and MDC were the only 2 that activated platelets. Both are weak agonists, but they enhanced response to low-dose adenosine 5′-diphosphate (ADP), epinephrine, or serotonin. When SDF-1 and MDC were added together, full and brisk platelet aggregation occurred. Platelet activation by these 2 chemokines appears to involve distinct pathways: SDF-1 inhibited an increase in cyclic adenosine monophosphate (cAMP) following prostaglandin (PG) I2, while MDC had no effect. In contrast, MDC, but not SDF-1, lead to Ca++mobilization by platelets. Further, second-wave aggregation induced by MDC in platelet-rich plasma was inhibited by aspirin, ADP scavenger creatine phosphate/creative phosphokinase (CP/CPK), and ARL-66096, an antagonist of the ADP P2TAC receptor involved in adenylyl cyclase inhibition. But the aggregation was not affected by A3P5PS, an inhibitor of the ADP P2Y receptor. SDF-1–induced aggregation was inhibited by aspirin, but it was only slightly affected by CP/CPK, ARL-66096, or A3P5PS. Finally, the presence of chemokines in platelets was determined. Reverse transcriptase–polymerase chain reaction studies with platelet RNA did not detect the presence of SDF-1 or MDC. In summary, SDF-1 and MDC are platelet agonists that activate distinct intracellular pathways. Their importance in the development of thrombosis at sites of inflammation needs to be further evaluated.

scholarly journals Stromal cell-derived factor-1 (SDF-1) as a target in liver diseases

2016 ◽  
Vol 311 (2) ◽  
pp. G203-G209 ◽  
Author(s):  
Anke Liepelt ◽  
Frank Tacke
Keyword(s):  
Liver Injury ◽  
Chemokine Receptors ◽  
Liver Diseases ◽  
Stromal Cell ◽  
Current Knowledge ◽  
Suppressor Cells ◽  
Cancer Therapies ◽  
Liver Sinusoidal Endothelial Cells ◽  
Chronic Injury ◽  
Stromal Cell Derived Factor

The chemokine stromal cell-derived factor-1 (SDF-1) or CXCL12 is constitutively expressed in healthy liver. However, its expression increases following acute or chronic liver injury. Liver sinusoidal endothelial cells (LSEC), hepatic stellate cells (HSC), and malignant hepatocytes are important sources of SDF-1/CXCL12 in liver diseases. CXCL12 is able to activate two chemokine receptors with different downstream signaling pathways, CXCR4 and CXCR7. CXCR7 expression is relevant on LSEC, while HSC, mesenchymal stem cells, and tumor cells mainly respond via CXCR4. Here, we summarize recent developments in the field of liver diseases involving this chemokine and its receptors. SDF-1-dependent signaling contributes to modulating acute liver injury and subsequent tissue regeneration. By activating HSC and recruiting mesenchymal cells from bone marrow, CXCL12 can promote liver fibrosis progression, while CXCL12-CXCR7 interactions endorse proregenerative responses in chronic injury. Moreover, the SDF-1 pathway is linked to development of hepatocellular carcinoma (HCC) by promoting tumor growth, angiogenesis, and HCC metastasis. High hepatic CXCR4 expression has been suggested as a biomarker indicating poor prognosis of HCC patients. Tumor-infiltrating myeloid-derived suppressor cells (MDSC) also express CXCR4 and migrate toward CXCL12. Thus CXCL12 inhibition might not only directly block HCC growth but also modulate the tumor microenvironment (angiogenesis, MDSC), thereby sensitizing HCC patients to conventional or emerging novel cancer therapies (e.g., sorafenib, regorafenib, nivolumab, pembrolizumab). We herein summarize the current knowledge on the complex interplay between CXCL12 and CXCR4/CXCR7 in liver diseases and discuss approaches on the therapeutic targeting of these axes in hepatitis, fibrosis, and liver cancer.

Stromal cell–derived factor-1 and macrophage-derived chemokine: 2 chemokines that activate platelets

Blood ◽  
2000 ◽  
Vol 96 (1) ◽  
pp. 50-57 ◽  
Author(s):  
M. Anna Kowalska ◽  
Mariusz Z. Ratajczak ◽  
Marcin Majka ◽  
Jianguo Jin ◽  
Satya Kunapuli ◽  
...  
Keyword(s):  
Chemokine Receptors ◽  
Stromal Cell ◽  
Platelet Rich Plasma ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Creatine Phosphate ◽  
Polymerase Chain ◽  
Stromal Cell Derived Factor ◽  
Induced Aggregation ◽  
Second Wave

Abstract Platelets play roles in both thrombosis and inflammation, and chemokines that are released at sites of inflammation could potentially activate platelets. Among the chemokine receptors expressed on platelets, the CXCR4 is the receptor for chemokine stromal cell-derived factor-1 (SDF-1), and the CCR4 is the receptor for macrophage-derived chemokine (MDC). Of the chemokines tested, SDF-1 and MDC were the only 2 that activated platelets. Both are weak agonists, but they enhanced response to low-dose adenosine 5′-diphosphate (ADP), epinephrine, or serotonin. When SDF-1 and MDC were added together, full and brisk platelet aggregation occurred. Platelet activation by these 2 chemokines appears to involve distinct pathways: SDF-1 inhibited an increase in cyclic adenosine monophosphate (cAMP) following prostaglandin (PG) I2, while MDC had no effect. In contrast, MDC, but not SDF-1, lead to Ca++mobilization by platelets. Further, second-wave aggregation induced by MDC in platelet-rich plasma was inhibited by aspirin, ADP scavenger creatine phosphate/creative phosphokinase (CP/CPK), and ARL-66096, an antagonist of the ADP P2TAC receptor involved in adenylyl cyclase inhibition. But the aggregation was not affected by A3P5PS, an inhibitor of the ADP P2Y receptor. SDF-1–induced aggregation was inhibited by aspirin, but it was only slightly affected by CP/CPK, ARL-66096, or A3P5PS. Finally, the presence of chemokines in platelets was determined. Reverse transcriptase–polymerase chain reaction studies with platelet RNA did not detect the presence of SDF-1 or MDC. In summary, SDF-1 and MDC are platelet agonists that activate distinct intracellular pathways. Their importance in the development of thrombosis at sites of inflammation needs to be further evaluated.

scholarly journals BCR activated CLL B cells use both CR3 (CD11b/CD18) and CR4 (CD11c/CD18) for adhesion while CR4 has a dominant role in migration towards SDF-1

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0254853
Author(s):  
Zsuzsa Nagy-Baló ◽  
Richárd Kiss ◽  
Judit Demeter ◽  
Csaba Bödör ◽  
Zsuzsa Bajtay ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukaemia ◽  
Stromal Cell ◽  
Lymphocytic Leukaemia ◽  
Dominant Role ◽  
Leukemic Cells ◽  
Western World ◽  
Stromal Cell Derived Factor ◽  
Unfavourable Prognostic Factor

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in the western world. In previous studies, various proportion of patients was found to carry CD11b+ or CD11c+ B cells whose presence was an unfavourable prognostic factor. The exact mechanism however, how these receptors contribute to the pathogenesis of CLL has not been revealed so far. Here we analysed the role of CD11b and CD11c on B cells of CLL patients in the adhesion to fibrinogen and in the migration towards stromal cell derived factor-1 (SDF-1) and studied the role of CR4 in the adherence of the CD11c+ B cell line BJAB. We observed that both CR3 and CR4 mediate adhesion of the malignant B cells. Moreover, we found, that CR4 was strongly involved in the migration of the leukemic cells towards the chemoattractant SDF-1. Our data suggest that CR3 and CR4 are not only passive markers on CLL B cells, but they might contribute to the progression of the disease. Since the role of SDF-1 is prominent in the migration of CLL cells into the bone marrow where their survival is supported, our findings help to understand how the presence of CD11c on leukemic B cells can worsen the prognosis of chronic lymphocytic leukaemia.

scholarly journals Role of stromal cell-derived factor 1 (SDF1/CXCL12) in regulating anterior pituitary function

2007 ◽  
Vol 38 (3) ◽  
pp. 383-389 ◽  
Author(s):  
Federica Barbieri ◽  
Adriana Bajetto ◽  
Carola Porcile ◽  
Alessandra Pattarozzi ◽  
Gennaro Schettini ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Pituitary Adenomas ◽  
Chemokine Receptors ◽  
Stromal Cell ◽  
Immune Surveillance ◽  
Brain Parenchyma ◽  
Pituitary Function ◽  
Pituitary Cells ◽  
Stromal Cell Derived Factor

Chemokines are key factors involved in the regulation of immune response, through the activation and control of leukocyte traffic, lymphopoiesis and immune surveillance. However, a large number of chemokines and their receptors are expressed in central nervous system (CNS) cells, either constitutively or induced by inflammatory stimuli, playing a role in many neuropathological processes. Stromal cell-derived factor 1 (SDF1) is a chemokine whose extra-immunological localization and functions have been extensively studied. SDF1 and its receptor CXCR4 were identified in both neurons and glia of many brain areas, including the hypothalamus, as well as at the pituitary level. Importantly, SDF1 and CXCR4 expression is increased in brain tumors in which their activity induced tumor cell proliferation and brain parenchyma invasion. Despite their localization, to date very few reports addressed the role of CXCR4 and SDF1 in the modulation of the hypothalamus/pituitary axis and their possible involvement in the development of pituitary adenomas. In this review, we discuss previous literature data on the role of chemokines in normal and adenomatous pituitary cells, focusing on recent data from our group showing that CXCR4 activation controls proliferation and both prolactin and GH release in the pituitary adenoma cell line GH4C1 through a complex network of intracellular signals. Thus, the SDF1/CXCR4 system together with other chemokinergic ligand–receptor pairs, may represent a novel regulatory pathway for pituitary function and, possibly, be involved in pituitary adenoma development. These lines of evidence suggest that the inhibition of chemokine receptors may represent a novel pharmacological target for the treatment of pituitary adenomas.

scholarly journals Spatial and Temporally Restricted Expression of Chemokines and Chemokine Receptors in the Developing Human Kidney

2002 ◽  
Vol 13 (4) ◽  
pp. 957-967 ◽  
Author(s):  
Hermann-Josef Gröne ◽  
Clemens D. Cohen ◽  
Elisabeth Gröne ◽  
Claudia Schmidt ◽  
Matthias Kretzler ◽  
...  
Keyword(s):  
Chemokine Receptors ◽  
Stromal Cell ◽  
Kidney Development ◽  
Human Kidney ◽  
Reverse Transcription Pcr ◽  
Inducible Protein ◽  
Stromal Cell Derived Factor ◽  
Injury And Repair ◽  
Key Events ◽  
Migration Of Cells

ABSTRACT. The directed migration of cells, cell-cell adhesion, and the control of proliferation are key events during metanephric development. The chemokines are a family of proteins that selectively control aspects of cell migration, activation, proliferation, and adhesion. The expression of a series of chemokines and chemokine receptors during human renal development was investigated by using immunohistochemical analyses and real-time reverse transcription-PCR assays of defined laser-microdissected metanephric structures. The results demonstrate that mononuclear cell-like cells within the nephrogenic blastema focally express interferon-inducible protein-10/CXCL10, a ligand for CXCR3. Mononuclear-like cells dispersed through the developing organ express CX3CR1. Expression of CXCR4, the receptor for stromal cell-derived factor-1/CXCL12, is also limited to stromal CD34-positive cells. In contrast, the expression of stromal cell-derived factor-1/CXCL12, fractalkine, and CXCR3 is first observed in the comma- or S-shaped body stage. The intensity of this expression becomes stronger in the capillary loop stage, and expression is mainly observed in the mesangial stalk and endothelial cells of the glomeruli. These proteins may play modulatory roles in kidney development. Because genes that are expressed during ontogeny often play a role in tissue regeneration, these embryonal chemokine/chemokine receptor patterns may be important in renal injury and repair.

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