Efficient homing of hematopoietic stem cells (HSC) in bone marrow (BM) is a prerequisite for establishment of hematopoiesis during development and following transplantation. However, the cellular and molecular pathways that control the homing of HSCs, in particular, of fetal HSCs are still not well understood. Of integrin receptors, the role of integrin α4 receptor during embryonic hematopoiesis has been established by using gene ablated chimeric mice and function blocking antibodies. However, the specific function of integrin α4 in homing of fetal liver HSPC remains less well defined. We have previously found that integrin α6 mediates human hematopoietic stem and progenitor cell (HSPC) adhesion to and migration on its specific ligands, laminin-8 and laminin-10/11 in vitro (Gu et al, Blood, 2003; 101:877). Furthermore, integrin α6 is required for adult mouse HSC homing to BM in vivo (Qian et al., Blood, 2006; 107:9). We have found that the integrin α6 and α4, like in adult HSCs, is ubiquitously (>99%) expressed also in fetal liver HSPCs (lin-Sca-1+c-Kit+, LSK). Here we studied the contribution of α6 and α4 integrins in homing of fetal liver hematopoietic cells into adult BM by using function-blocking antibodies and an integrin α6 knockout mouse model. We found an ubiquitous expression of integrin α6 on fetal liver LSK HSPCs. Genetic ablation of integrin α6 resulted in reduced homing of fetal liver progenitors to BM of lethally irradiated adult recipients. In agreement with this, the integrin α6 antibody inhibited homing of fetal liver progenitors into BM and spleen. The role of integrin α6 in homing and engraftment of fetal liver HSCs was studied by a competitive repopulation assay by using integrin α6−/− or α6+/+ fetal liver cells. Absence of α6 integrin in fetal liver cells did not cause any engraftment defect as compared to wildtype cells. Consistent with this, anti-integrin α6 antibody did not either reduce BM homing of short-term or long-term HSCs. In contrast, homing of fetal liver HSCs and HPCs to BM was virtually abrogated after treatment with integrin α4 antibody. These results show that α6 integrin acts as a homing receptor during fetal liver progenitor cell homing to BM, whereas homing and engraftment of multilineage repopulating HSCs is independent of α6 integrin function. In contrast, integrin α4 receptor is crucial for homing of all HSPCs, indicating distinct roles for each integrin during fetal hematopoieisis. (Qian, et al., 2006, ASH abstract, Qian et al., Blood, 2007 in press)