G-CSF induces up-regulation of CXCR4 expression in human hematopoietic stem cells by beta-adrenergic agonist

Abstract

Introduction C-X-C chemokine receptor type 4/stromal-derived factor-1 (CXCR4/SDF-1) axis dynamically mediates hematopoietic stem cell trafficking in the bone marrow (BM). Granulocyte colony-stimulating factor (G-CSF) as the most effective mobilizing agent induces SDF-1 secretion from BM stromal cells into circulation that recruit CXCR4 cells such as hematopoietic stem cells (HSCs) into circulation. However, the direct effect of G-CSF on CXCR4 expression of HSC remains unknown. The nervous system regulates HSC migration with effecting on adrenergic receptors. On the other hand, interaction of G-CSF and catecholamines has been demonstrated; hence, we examined the direct effect of G-CSF and catecholamine on CXCR4 expression. Material and methods After enrichment of CD34 HSCs from the cord blood with magnetic-activated cell sorting (MACS), these cells were exposed to G-CSF (100 ng/ml), epinephrine (10 µM), isoproterenol (10 µM), and propranolol (1 µM) separately and together. Results Our results showed that G-CSF have no direct effect on CXCR4 expression on human CD34 cells in vitro and treating HSCs with epinephrine leads to significantly increased CXCR4 in 1, 3, and 5 hours. Epinephrine and G-CSF-induced up-regulation of CXCR4 mRNA is dependent on beta receptors, so incubation of HSCs with propranolol led to inhibition of such increased expression. In addition, isoproterenol and agonist of beta receptors would significantly increase the expression of CXCR4 approximately 4- and 12-fold after 1-hour incubation, respectively. Discussion Co-stimulation of enriched HSCs with G-CSF and isoproterenol resulted to a further enhanced CXCR4 levels. In general, G-CSF-induced CXCR4 expression is the indirect mechanism and is specifically regulated through beta-adrenergic receptors.

Immunological effects of a low‑dose cytarabine, aclarubicin and granulocyte‑colony stimulating factor priming regimen on a mouse leukemia model

“…G-CSF has been widely used in the treatment of refractory and relapsed AML together with chemotherapeutic drugs, and has improved the CR rate ( 13 ). Although it is well-established that G-CSF has an important influence on the BMM ( 22 ), there is little research regarding the effect of G-CSF priming chemotherapy on the BMM. G-CSF can promote leukemia cells to be released from the bone marrow into the peripheral circulation by blocking the interaction of SDF-1α and CXCR4, thus enhancing the anti-leukemia effect ( 13 ).…”

“…Inhibition of the SDF-1α/CXCR4 axis using the CXCR4 antagonist, AMD3100, has been indicated to induce leukemia cells to enter the peripheral circulation and induce higher sensitivity to chemotherapeutic drugs ( 21 ). G-CSF, an effective stem cell-mobilizing agent, induces SDF-1α secretion from bone marrow stromal cells into the blood, thus recruiting CXCR4 + cells, including HSCs, into the peripheral circulation ( 22 ). It has been established that G-CSF can promote the expression of transcriptional repressor growth factor independence-1 (Gfi-1), which binds to DNA sequences upstream of the CXCR4 gene and reduces CXCR4 expression in myeloid cells ( 23 ).…”

New role of hypoxia in pathophysiology of multiple myeloma through miR-210

“…The malignant plasma cells in the niche of multiple myeloma attach to stromal elements using several adhesion receptors. One of the most extensively studied adhesion molecules is CXCR4 and its receptor, stromal cell-derived factor-1 (SDF-1) (Saba et al, 2014[ 31 ]). SDF-1 is produced by osteoblast cells and its receptor, CXCR4, is expressed on myeloma cells.…”

“…CXCR4 facilitates homing of MM cells to the BM and leads to adhesion of myeloma cells to the stromal cells, such as osteoblasts and extracellular matrix components; these, in turn, support the growth, survival, and progression of myeloma cells (Alsayed et al, 2007[ 3 ]; Azab et al, 2009[ 8 ]). Studies have shown that CXCR4 is involved in the cross-talk between MM cells and the BM microenvironment (Alsayed et al, 2007[ 3 ]; Azab et al, 2009[ 8 ]; Saba et al, 2014[ 31 ]). Furthermore, VLA-4 integrin plays an important role in the localization of myeloma cells to BM by interacting with its ligands, such as vascular cell adhesion protein-1 (VCAM-1) and connecting segment-1 (CS-1)/fibronectin (Uchiyama et al, 1993[ 36 ]).…”

Inhibition of CD34+ cell migration by matrix metalloproteinase-2 during acute myocardial ischemia, counteracted by ischemic preconditioning

“…Exploiting the beneficial effect of the SDF-1α/CXCR4 axis in cardiac repair has been performed by repeated injections of granulocyte-colony stimulating factor (G-CSF) applied in patients, which aims to release the stem and premature cells from BM and activate the cellular CXCR4 expression of the reparative cells by interrupting the BM-SDF-1α/CXCR4 axis 3 . However, despite the enhanced cell release and migration, and stimulation of the endogenous cardiac progenitor cells, the efficacy of clinical cardiac cell-based therapy in patients with recent acute myocardial infarction (AMI) led to ambiguous results 4 , especially if the regenerative cell therapy was performed very early after ischemic injury 5 .…”