Rapid mobilization of hematopoietic progenitors by AMD3100 and catecholamines is mediated by CXCR4-dependent SDF-1 release from bone marrow stromal cells

Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K (Impact Factor: 10.43). 04/2011; 25(8):1286-96. DOI: 10.1038/leu.2011.62
Source: PubMed


Steady-state egress of hematopoietic progenitor cells can be rapidly amplified by mobilizing agents such as AMD3100, the mechanism, however, is poorly understood. We report that AMD3100 increased the homeostatic release of the chemokine stromal cell derived factor-1 (SDF-1) to the circulation in mice and non-human primates. Neutralizing antibodies against CXCR4 or SDF-1 inhibited both steady state and AMD3100-induced SDF-1 release and reduced egress of murine progenitor cells over mature leukocytes. Intra-bone injection of biotinylated SDF-1 also enhanced release of this chemokine and murine progenitor cell mobilization. AMD3100 directly induced SDF-1 release from CXCR4(+) human bone marrow osteoblasts and endothelial cells and activated uPA in a CXCR4/JNK-dependent manner. Additionally, ROS inhibition reduced AMD3100-induced SDF-1 release, activation of circulating uPA and mobilization of progenitor cells. Norepinephrine treatment, mimicking acute stress, rapidly increased SDF-1 release and progenitor cell mobilization, whereas β2-adrenergic antagonist inhibited both steady state and AMD3100-induced SDF-1 release and progenitor cell mobilization in mice. In conclusion, this study reveals that SDF-1 release from bone marrow stromal cells to the circulation emerges as a pivotal mechanism essential for steady-state egress and rapid mobilization of hematopoietic progenitor cells, but not mature leukocytes.

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    • "This leads us to hypothesize that CPCs might have already migrated to damaged tissue, although MMP-9 levels were still elevated. In this context, it is important to mention how catecholamines (Katayama et al., 2006; Dar et al., 2011), which are highly elevated during exercise, affect the bone marrow (Walsh et al., 2011a). Ultra-endurance exercise is associated with activation of the sympathetic system, the HPA axis, and the systemic inflammatory response (Fig. 4; Tables 3 and 4) (Ronsen et al., 2004; Mastorakos & Pavlatou, 2005; Cooper et al., 2007). "
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    • "Immun. (2015), b 2 AR-agonist, and that increased circulating PC numbers correlate with circadian sympathetic oscillations (Katayama et al., 2006; Spiegel et al., 2007; Mendez-Ferrer et al., 2008; Dar et al., 2011). Further, both murine and human PCs express functional adrenergic receptors (Muthu et al., 2007; Spiegel et al., 2007). "
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    • "We are the first to analyze the biologically active form [26] of free (unconjugated) NE, which is probably more relevant for an influence on CPC functionality. Benschop et al. [27] and Dar et al. [28] showed that increased catecholamines lead to elevated leucocytes and hematopoietic stem and progenitor cells (HSPCs) in peripheral blood. Accordingly, mice with reduced NE production failed to respond to HSPC mobilization by G-CSF [29]. "
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