CXCR7 Expression Restricts CXCR4/SDF-1 Mediated Hematopoietic-Supporting Activity of Stromal Cells by Decreasing Extracellular SDF-1 Availability.

Abstract 1452

Poster Board I-475

Stromal cell-derived factor 1 (SDF-1)/CXCR4 axis plays a major role in regulating the interactions between hematopoietic stem and progenitor cells (HPSC) and their stromal microenvironment within the bone marrow. A second SDF-1/CXCL12 receptor, CXCR7 binds SDF-1 with high affinity but little is known about its function in hematopoiesis. In the present study, we demonstrate that the activity of CXCR7 is crucial for proper maintenance of hematopoietic activity on stromal layers. Using quantitative reverse transcription-PCR analysis, we demonstrate that CXCR7 is highly expressed in stromal cells in contrast to hematopoietic cells showing that it functions primarily in the stromal microenvironment compartment. CXCR7 stable expression in UT7 hematopoietic cells fails to support SDF-1 induced migration and signalling but inhibits migration of CXCR4 expressing cells in paracrine manner. Overexpression of CXCR7 in MS-5 stromal cells lead to a reduction of SDF-1 concentration in the supernatants. In addition, supernatants from these cells had substantially lower efficiency in promoting integrin alpha-4 beta-1–mediated adhesion and migration of Mo7e cells to vascular cell adhesion molecule-1 (VCAM-1) and CS-1/fibronectin than their control GFP counterparts. Moreover, human cord blood CD34+ hematopoietic progenitor cells displayed SDF-1–dependent reduced responses in chemotaxis, transendothelial migration, and up-regulation of adhesion to VCAM-1 when supernatants from CXCR7 expressing MS-5 cells were used compared with supernatants from GFP expressing cells. Finally, phenotypical primitive murine cells displayed reduced hematopoietic activity when cultured on CXCR7 expressing MS-5 cells. This reduced hematopoietic activity is partly reverted when recombinant SDF-1 was added to CXCR7 overexpressing MS-5 cells. Taken together, our results indicate that CXCR7-controlled disponibility of SDF-1 expression influences BM cell migration, adhesion and hematopoietic activity and thus behaves as a decoy receptor regulating the SDF-1 level.