ADHESION ANALYSIS OF CYCLING STEM CELLS THROUGH ONTOGENY

造血干细胞（HSC）移植之所以成为可能，仅仅是因为移植细胞能够回到骨髓（BM）微环境中。造血干细胞归巢是一种进化的、选择性的过程，通过这种过程，干细胞在哺乳动物胚胎发育的特定阶段进入特定的器官。在大多数情况下，归巢是由HSC粘附分子与其对抗受体之间的特异性相互作用介导的粘附鉴别过程驱动的。在胚胎发育过程中，造血干细胞在造血组织之间迁移，然后在出生后的整个生命中回到骨髓。然而，通过未知的机制，在动员方案的影响下，HSC可以从基底膜转移到外周。我们认为，在个体发育过程中，造血从卵黄囊到肝脏，最后到骨髓的进展是由粘附分子和抗受体组在HSC和这些器官间质元件上的表达所控制的。我们还认为，HSC归巢和从成人BM中退出是一个可调节的过程，与HSC的细胞周期调节密切相关，并直接受粘附分子和/或其对抗受体的表达和功能调节的影响。为了更好地理解哺乳动物胚胎发育中造血干细胞的归巢机制和这些细胞的出生后运输，我们将测试以下特定目标：1)我们将研究胚胎造血干细胞获得粘附分子和反配体集的发育变化的本质，以及胚胎肝脏和骨髓间质元件使干细胞在发育过程中能够归巢到特定的造血组织。2)我们将研究HSC是否在没有进入细胞周期活动性阶段的情况下从BM中退出，以及在HSC进入细胞周期活动性阶段时，粘附分子的表达调节是否会使这些细胞的归巢和着床潜能低于有丝分裂静止细胞。3)我们建议利用粘附分子在原始祖细胞上的表达来进一步完善HSC的选择过程，并在动物模型中检验归巢能力与造血潜能之间的关系。检查这些目标将有助于我们理解正常造血，以及控制造血干细胞归巢和候选干细胞群体移植潜力的机制。

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.