Defining Mesodermal Origins of Hematopoietic Stem Cells

描述(由申请人提供)： 具有造血潜能的中胚层细胞在胚胎发育过程中出现在不同的时间和位置。现在普遍认为，胚胎的卵黄囊和腹主动脉旁的内脏胸膜/主动脉-性腺-中肾区域是独立的造血发育部位。大多数研究表明，来自这两个地点的造血祖细胞在产生各种造血谱系的能力和产生长期再填充干细胞(LTRSC)的能力方面显示出不同的潜力。因此，这两个地点可能包含不同的人口，在发展过程中具有独特的功能。这项实验的总体目标是绘制这些造血细胞群体的中胚层起源图，目的是从培养中分化的胚胎STAR(ES)细胞产生LTRSC，这里提出的研究建立在对体外ES分化模型中早期造血承诺步骤的广泛分析和理解的基础上。表达中胚层基因brachyury位点GFP的ES细胞将被用作从体外分化的ES细胞中分离中胚层群体的工具。从ES细胞产生LTRSC的能力将为干细胞开发研究建立一个强大的系统，可用于治疗许多疾病。具体目标是：目的1.不同的中胚层亚群是否会产生不同的造血计划？目的2.特定的中胚层亚群是否产生LTRSCs？

DESCRIPTION (provided by applicant): Cells of mesodermal origin with hematopoietic potential appear at distinct times and locations during embryonic development. It is now generally accepted that the extra-embryonic yolk sac and the paraaortic splanchnopleura / aorta-gonad-mesonephros regions of the embryo represent independent sites of hematopoietic development. Most studies indicate that hematopoietic progenitors from these two locations display differential potential in their ability to produce the various hematopoietic lineages and in their capacity to give rise to the long-term repopulating stem cell (LTRSC). These two sites could therefore contain different populations with unique functions during development. The overall goals of the experiments in this proposal are to map the mesodermal origins of these hematopoietic cell populations with the aim of generating the LTRSC from embryonic stern (ES) cells differentiated in culture, The studies proposed here build on extensive analysis and understanding of the early hematopoietic commitment steps in the in vitro ES differentiation model. ES cells that express GFP from the mesodermal gene brachyury locus will be used as a tool to isolate mesodermal populations from in vitro differentiated ES cells. The ability to generate the LTRSC from ES cells will establish a powerful system for the study of stem cell development, which can be used to treat many diseases. The specific aims are: Aim 1. Do Different subpopulations of mesoderm give rise to different hematopoietic programs? Aim 2. Does a specific subpopulation of mesoderm give rise to LTRSCs?