Hematopoietic stem cell (HSC) transplantation is possible only because of the ability of transplanted cells to home into the bone marrow (BM) microenvironment. HSC homing is an evolving, selective process through which stem cells lodge within specific organs at specific stages of mammalian embryonic development. Homing is driven, in most part, by a discriminating process of adhesion mediated via specific interactions between HSC adhesion molecules and their counter-receptors. During embryonic development, HSC migrate between hematopoietic tissues then home to the BM where they reside throughout postnatal life. However, through unknown mechanisms, HSC can egress from the BM to the periphery under the influence of mobilizing regimens. We believe that during ontogeny, progression of hematopoiesis from the yolk sac to the liver and finally to the BM is governed by the expression of adhesion molecules and counter-receptor sets on HSC and stromal elements in these organs. We also believe that HSC homing to, and egress from adult BM is a regulatable process tightly associated with cell cycle regulation of HSC and directly influenced by modulation of expression and function of adhesion molecules and/or their counter receptors. To better understand the mechanisms of homing of HSC mammalian embryonic development and postnatal trafficking of these cells, the following specific aims will be tested: 1) We will investigate the nature of developmental changes involving acquisition of adhesion molecules and counter-ligand sets by embryonic HSC and stromal elements of fetal liver and BM enabling stem cells to home to specific hematopoietic tissues during development. 2) We will examine whether HSC egress from BM without their entry into active phases of cell cycle, and whether modulation of expression of adhesion molecules on HSC traversing into active phases of cell cycle render these cells inferior to mitotically quiescent cells in their homing and engraftment potential. 3) We propose to use the expression of adhesion molecules on primitive progenitor cells for further refinement of the selection process of HSC and to examine, in an animal model, the relationship between homing capacity and hematopoietic potential. Examination of these goals will contribute to our understanding of normal hematopoiesis and the mechanisms that govern homing of HSC and engraftment potential of candidate populations of stem cells.
