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IntroductionHematopoietic stem cells migrate during embryonic development from the fetal liver through the blood circulation, home to the bone marrow (BM) microenvironment, and repopulate it with immature and maturing blood cells of all lineages. Similarly, in clinical and experimental stem cell transplantation protocols, hematopoietic stem cells, which are infused into the blood circulation of patients and experimental animals, home and repopulate the BM. 1 The molecular mechanisms that regulate the homing and repopulation processes are crucial for stem cell function and development. [2][3][4][5] The CXC chemokine stromal cell-derived factor 1 (SDF-1) plays a major role in migration, proliferation, differentiation, and survival of many cell types including human and murine hematopoietic stem/progenitor cells. 6,7 SDF-1 is produced by multiple BM stromal cell types and by epithelial cells in many organs 8,9 and is highly expressed by human and murine BM endothelium. [10][11][12] CXCR4, the 7-transmembrane receptor of SDF-1, is widely expressed by a variety of hematopoietic cell types, neuronal cells, and different stromal cells. 13 SDF-1 is a chemotactic agent for human lymphoid, myeloid, and immature CD34 ϩ progenitor cells. 6,7,14,15 This chemokine induces integrin-dependent adhesion of CXCR4 ϩ human T lymphocytes 16 and immature CD34 ϩ CXCR4 ϩ cells 17 under shear flow and also mediates transendothelial migration of human progenitors. 18 In vivo cell migration and localization are also mediated by SDF-1/CXCR4 interactions. Murine T cells overexpressing human CXCR4 and CD4 accumulated in the BM of transgenic mice. 19 Prevention of CXCR4 expression by introducing SDF-1 intrakine blocked in vitro migration and in vivo dissemination of a T-cell hybridoma. 20 More important, mice reconstituted with progenitor cells expressing SDF-1-intrakine suffered impaired lymphoid and myeloid hematopoiesis, whereas transplantation of progenitors overexpressing SDF-1 led to increased myeloid and B-lymphoid hematopoiesis. 21 The key role of SDF-1 and CXCR4 in embryonic development was demonstrated by knockout studies in mice. The lack of either SDF-1 or its receptor in murine fetuses results in multiple lethal defects including impaired BM hematopoiesis. [22][23][24][25] Recently, Wright and colleagues have demonstrated that SDF-1 is the sole chemokine mediating in vitro migration of purified adult murine BM stem cells. 26 This important study suggests a major role for SDF-1/CXCR4 interactions also in adult murine stem cell migration and development.We demonstrated the essential role of SDF-1/CXCR4 interactions in both homing and high-level multilineage repopulation of nonobese diabetic/severe combined immunodeficient (NOD/SCID) 10,27,28 The antihuman CXCR4-neutralizing monoclonal antibody (mAb; clone 12G5) binds CXCR4 on the first and second extracellular domain as its ligand SDF-1, interfering with SDF-1 binding and signaling. 29,30 Coinjecting enriched human CD34 ϩ cells with neutralizing anti-CXCR4 mAb blocked homing and re...