ADHESION ANALYSIS OF CYCLING STEM CELLS THROUGH ONTOGENY

造血干细胞(HSC)移植是可能的，因为移植的细胞能够回到骨髓微环境中。HSC归巢是一个进化的、选择性的过程，在哺乳动物胚胎发育的特定阶段，干细胞通过这个过程寄宿在特定的器官中。归巢在很大程度上是由HSC黏附分子和它们的对抗性受体之间的特定相互作用介导的黏附的区分过程所驱动的。在胚胎发育期间，HSC在造血组织之间迁移，然后回到BM，它们在出生后的整个生命中都居住在那里。然而，在动员方案的影响下，HSC可以通过未知的机制从骨髓向外扩散。我们认为，在个体发育过程中，从卵黄囊到肝脏最后到骨髓的造血过程是由这些器官中HSC和基质元素上的黏附分子和反受体集的表达控制的。我们还认为，HSC归巢和离开成人骨髓是一个可调节的过程，与HSC的细胞周期调控密切相关，并直接受到黏附分子和/或其对应性受体表达和功能调节的影响。为了更好地了解HSC哺乳动物胚胎发育的归巢机制和这些细胞在出生后的运输，我们将测试以下特定目标：1)我们将研究胚胎HSC和胎肝基质元素获得黏附分子和反配体集的发育变化的本质，使干细胞能够在发育过程中定位于特定的造血组织。2)我们将研究HSC是否在没有进入细胞周期活动期的情况下离开BM，以及HSC上黏附分子表达的调节是否使这些细胞在归巢和植入能力上逊于有丝分裂静止的细胞。3)我们建议利用原始祖细胞上黏附分子的表达来进一步完善HSC的选择过程，并在动物模型中检测归巢能力和造血力之间的关系。对这些目标的研究将有助于我们理解正常的造血和控制HSC归巢的机制以及候选干细胞群体的植入潜力。

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.