Abstract 18167: MCP-1/CCR2 Desensitizes the SDF-1/CXCR4 Signaling in Bone Marrow Stem/Progenitor Cells
Background: SDF-1/CXCR4 axis plays a pivotal role in the regulation of bone marrow (BM) stem/progenitor cell trafficking, thereby contributing to the ischemic tissue repair. CCR2 receptor is also widely expressed in the BM mononuclear cells, and the MCP-1/CCR2 axis has been shown to regulate the migration of these cells during inflammation. More recent evidence suggests that CCR2 and CXCR4 can form hetero-dimmers; however, the biological significance of the crosstalk between these two chemotactic pathways is not clear. Here, we hypothesize that MCP-1/CCR2 suppresses BM stem/progenitor cell trafficking through desensitization of SDF-1/CXCR4 signaling.
Methods and Results: By using MCP1-RFP/CXCR4-eGFP double transgenic mice, we examined the endocytosis of MCP-1 in BM cells after systemic injection of lipopolysaccharide (LPS) and found that MCP-1 endocytosis occurred predominantly in CXCR4-positive stem/progenitor cells. Then we measured the MCP-1- and/or SDF-1-induced intracellular calcium transient by Fura2-based calcium imaging in the isolated BM cells. Our results showed that more than 80% of MCP-1-responsive cells also responded to SDF-1 treatment. However, in the cells pretreated with escalating doses of MCP-1 (10, 20, and 40 nM), a dose-dependent desensitization of SDF-1 activity was observed (p<0.05, 20 nM vs. 10 nM; p<0.001, 40 nM vs. 10 nM or 20 nM). Moreover, systemic administration of AMD3100 in mice significantly increased CCR2-positive stem/progenitor cells in the peripheral blood (n=4 each; p<0.01).
Conclusions: Activation of MCP-1/CCR2 desensitizes SDF-1/CXCR4 signaling in BM stem/progenitor cells; targeting MCP-1/CCR2 axis may enhance the effectiveness of CXCR4-mediated stem/progenitor cell homing and tissue repair in ischemic heart disease.
- © 2013 by American Heart Association, Inc.