Interactions of hemopoietic stem cells with their particular microenvironments in specific anatomic sites throughout development and in adult life are instrumental for their survival, proliferation/differentiation and their migration patterns. The VLA-4 integrin (a4/p1) is widely expressed in hemopoietic cells and exerts decisive roles in many of their functions by affecting not only the migration patterns of stem/progenitor cells, but critically controlling the recruitment, migration and function of mature immunoregulatory cells to sites of inflammation. In fact, the latter characteristic of VLA-4 has been clinically exploited for therapeutic purposes in man. Most of the in vitro and in vivo studies on cc4 integrin have relied on the use of anti-functional antibodies, as gene targeting leads to embryonic lethality. Studies in chimeric mice provided limited data and many were divergent from those described with the use of antibodies. We have generated a conditional a4-knockout model and provided novel observations on the impact of a.4 integrin absence on several aspects of hemopoietic cell regulation in adults. In this application, we will investigate unexplored issues of a.4 deficiency in fetal hemopoiesis, using a new permissive animal model (SA #1A); and in lymphoid trafficking and regeneration post stress during postnatal life (SA#1B). Using parabiotic pairs with or without perturbations of cell trafficking, fundamental biological issues regarding the fate and turnover of circulating stem/progenitor cells or the exchange of specific lymphocyte pools will be addressed (SA#2). The consequences of a4 integrin absence from endothelial cells for the regeneration of the """"""""vascular niche"""""""" in bone marrow, or the neovascularization in other tissues, as well as the migration patterns of BM-derived endothelial cells will be studied (SA#3A and B). Finally, whether absence of a4 integrin from hemopoietic cells affects their trans-marrow interstitial migration and lodgment to """"""""endosteal niches"""""""" thereby influencing their self-renewal ability will be explored (SA#4). We believe that the proposed studies will enhance our understanding and provide a more comprehensive picture of the influence of
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