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Stromal cell-derived factor-1alpha (SDF-1alpha) has pleiotropic effects on hematopoietic progenitor …

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- The Many Facets of SDF-1alpha CXCR4 Agonists and Antagonists on Hematopoietic Progenitor Cells


Stromal cell-derived factor-1 (SDF-1 or CXCL12) is a multifunctional cytokine that is constitutively expressed and secreted by several tissues, including endothelium and stromal cells [1, 2]. It has a single open reading frame of 282 nucleotides encoding a polypeptide of 93 amino acids. SDF- 1 arises in two forms, SDF-1α (amino acids 24–88) and SDF-1β (amino acids 24–93), by differential splicing [3–5]. SDF-1α is so far the only proven chemoattractant for primitive hematopoietic progenitor cells (HPC) [6–8]. Accordingly, SDF-1α is considered as one of the key regulators for hematopoietic progenitor cell trafficking between the peripheral circulation and bone marrow [54]. Our group and others have demonstrated that SDF-1α induces polarization and podia formation of HPC and leukemic cells [9, 10], two properties that represent prerequisites for directed locomotion. SDF-1α alone showed a moderate effect on cell proliferation in CD34+ cells [11], and its effect on survival or apoptosis of HPC has remained controversial [12–15]. Furthermore the SDF-1α/CXCR4 axis plays a crucial role in regulation of homing and adhesion to the supportive cellular microenvironment in the stem cell niche [16]. The receptor for SDF-1α has been identified as the 7- transmembrane receptor CXCR4 which is also a coreceptor for the HIV type 1 virus [17, 18]. SDF-1α/CXCR4 interaction was reported to play an important role during embryonic development, especially in hematopoiesis, vascular development, and cardiogenesis. CXCR4 expression on bone marrow endothelial cells is important for internalization of circulating SDF-1α, resulting in its translocation into the bone marrow [2]. CXCR4 is also expressed on primitive CD34+ HPC [11]. Signal transduction pathways initiated by the binding of SDF-1α to CXCR4 are not fully understood. Mechanisms involved in CXCR4 signaling include Gi-protein-mediated activation of PI3K and the phospholipase C cascade [6, 19, 20].

The function of SDF-1α can be mimicked by small peptide agonists [21]. Such molecules have several advantages over the natural one such as the ease of manufacturing and that they can be more resistant to serum modification and inactivation [22]. CTCE-0214, for example, is an analog in which the C-terminal of SDF-1α is connected to the N-terminal region by a short bifunctional linker. A recent publication suggested that CTCE-0214 might improve ex vivo expansion and engraftment of HPC in a mouse model [23]. CTCE-0214 has also been reported to increase circulating HPC concentrations when administered to a murine model, indicating that this SDF-1α peptide agonist could be used for mobilization [24]. CTCE-9908 is another small peptide analog that comprises a dimerized sequence of the disordered N-terminal region of SDF-1α and was designed to block the CXCR4 receptor. Furthermore, nonpeptide compounds have been used to interfere with the SDF- 1α/CXCR4 axis. AMD3100, for example, is a bicyclam in which the two cyclam rings are tethered by an aromatic bridge. It was first designed as an inhibitor of virus replication of HIV-1 and HIV-2 [25]. However, AMD3100 has been shown to be a very potent and selective inhibitor of CXCR4 and both experimental and clinical data suggest that AMD3100 might mobilize a more primitive and hence multipotent HPC population than G-CSF [26, 27]. The different peptide and nonpeptide analogs might have a more selective effect with respect to the different functions of the native molecule SDF-1α (Figure 1). Here, we have compared effects of SDF-1α, CTCE-0214, CTCE-9908, and AMD3100 on polarization, migration, adhesion, proliferation, and CXCR4 receptor internalization in human CD34+ cells.

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