ADHESION ANALYSIS OF CYCLING STEM CELLS THROUGH ONTOGENY

造血干细胞（HSC）移植是可能的，只是因为移植的细胞回家到骨髓（BM）微环境的能力。 HSC归巢是一个进化的、选择性的过程，通过这个过程，干细胞在哺乳动物胚胎发育的特定阶段进入特定器官。归巢在很大程度上是由通过HSC粘附分子与其反受体之间的特异性相互作用介导的粘附的鉴别过程驱动的。 在胚胎发育过程中，HSC在造血组织之间迁移，然后回到BM，在出生后的整个生命中它们都居住在那里。 然而，通过未知的机制，HSC可以在动员方案的影响下从BM排出到外周。 我们认为，在个体发育过程中，从卵黄囊到肝脏，最后到BM的造血进展是由这些器官中HSC和基质元素上的粘附分子和反受体集的表达决定的。 我们还认为，HSC归巢和从成人BM的出口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/或其反受体的表达和功能的调节影响。 为了更好地理解HSC哺乳动物胚胎发育和这些细胞的出生后运输的归巢机制，将测试以下具体目标：1）我们将研究发育变化的性质，所述发育变化涉及胚胎HSC和胎肝和BM的基质成分获得粘附分子和反配体集，从而使干细胞能够在发育期间归巢到特定的造血组织。 2)我们将研究HSC是否从骨髓中排出而不进入细胞周期的活跃期，以及HSC上粘附分子的表达的调节是否进入细胞周期的活跃期，使这些细胞在归巢和植入潜力方面劣于有丝分裂静止细胞。 3)我们建议使用原始祖细胞上的粘附分子的表达，以进一步完善HSC的选择过程，并在动物模型中研究归巢能力和造血潜能之间的关系。 对这些目标的研究将有助于我们理解正常造血和HSC归巢的机制以及干细胞候选群体的移植潜力。

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.