Lymphopoietic development in the extra-embryonic yolk sac

胚胎外卵黄囊的淋巴细胞发育

基本信息

项目摘要

PROJECT SUMMARY/ABSTRACT The overall goal of the present work is to determine the mechanisms that permit the emergence of B lymphoid cells in the extraembryonic yolk sac and the para aortic splanchnopleura (P-Sp) and facilitate the homing of these cells into the peritoneal cavity. Though the extraembryonic yolk sac is the first site of primitive red blood cell, megakaryocyte, and macrophage production, it is controversial whether it is a site of B lymphoid emergence. An intraembryonic site, the aorta-gonad-mesonephros (AGM) region derived from the P-Sp, is currently recognized as the first site of production of HSCs capable of repopulating the hematopoietic compartment of lethally irradiated adult mice and is reported to possess the potential to give rise to B lymphoid cells upon in vitro co-culture with a certain stromal cell line. However, after the systemic circulation has commenced, it remains unclear and unproven whether the B cell progenitors are moving from the yolk sac into the P-Sp or vice versa. Indeed, the most formidable obstacle encountered when attempting to define the onset of B lymphopoiesis in the developing murine embryo, is the onset of cardiac contractions and establishment of the circulation. We have developed a novel approach that permits determination of exactly where and when hematopoietic cells emerge in the yolk sac and P-Sp. Ncx1 encodes a sodium-calcium exchange protein that is expressed only in cardiomyocytes through embryonic day (E) 11.0. Embryos lacking Ncx1 are unable to initiate cardiac contractions preventing the onset of the systemic circulation. Lack of blood flow is initially tolerated without evidence of maldevelopment, however embryos demonstrate growth retardation by E10.0 and die by E11.0. Using Ncx1 mutant and wild type (WT) mice, we have recently reported that all hematopoietic definitive progenitor cells that seed the E 10.0 fetal liver are yolk sac-derived. We have also reported that the potential for forming B lymphoid cells is present in the E 9.5 yolk sac and P-Sp of wild type and Ncx1 null mice; confirming that B lymphoid cells arise autonomously in the yolk sac and P-Sp. A host of questions now emerge that we address in the following aims: Aim 1: To delineate the temporal and spatial emergence of B lymphoid cells in the yolk sac and P-Sp and to define B cell specification to B1 and/or B2 lymphoid lineages from the emergent cells in these sites. Aim 2: To define the growth factor signaling pathways required for yolk sac and P-Sp B lymphopoiesis. Aim 3: Define the molecular pathway for yolk sac and P-Sp derived B cell homing to the peritoneal cavity. These studies will define the mechanism of B lymphocyte emergence, determine whether differences in B cell specification are intrinsic and restricted, and may clarify the origin of the B1 lymphocytes that secrete natural antibodies; a population of cells important in human development of autoimmune diseases and leukemia. PROJECT NARRATIVE This project aims to determine the factors required to permit the emergence of B lymphoid cells in the murine yolk sac and within the embryo and to define the molecules that are necessary for yolk sac and intraembryonic B lymphoid cells to home to the peritoneal cavity.
项目总结/摘要 目前工作的总体目标是确定允许B出现的机制 淋巴样细胞在胚胎外卵黄囊和主动脉帕拉内脏胸膜(P-Sp),并促进 这些细胞归巢到腹膜腔。虽然胚外卵黄囊是胚胎发育的第一个原始部位, 红细胞、巨核细胞和巨噬细胞的产生,但它是否是B淋巴样细胞的一个部位仍有争议 出现。胚胎内的一个部位,即来源于P-Sp的性腺-中肾(AGM)区域, 目前被认为是第一个能够重新增殖造血干细胞的造血干细胞产生位点。 在致死性照射的成年小鼠的隔室中,据报道具有产生B淋巴样 细胞在与特定基质细胞系体外共培养后的细胞。然而,在体循环已经 开始时,仍然不清楚和未经证实的是,B细胞祖细胞是否从卵黄囊进入卵黄囊。 P-SP或反之亦然。事实上,在试图定义发病时遇到的最大障碍是 在发育中的小鼠胚胎中,B淋巴细胞生成的第一阶段是心脏收缩的开始, 流通。 我们开发了一种新的方法,可以确定确切的时间和地点 造血细胞出现在卵黄囊中,P-Sp. Ncx 1编码一种钠钙交换蛋白, 仅在胚胎第11.0天的心肌细胞中表达。缺乏Ncx 1的胚胎无法启动 心脏收缩阻止体循环的开始。缺乏血流最初是可以忍受的 没有发育不良的证据,然而,胚胎在E10.0时表现出生长迟缓,并在E10.0时死亡。 E11.0使用Ncx 1突变型和野生型(WT)小鼠,我们最近报道,所有造血决定性 接种E10.0胎肝的祖细胞是卵黄囊来源的。我们还报告说, 在野生型和Ncx 1基因敲除小鼠的E 9.5卵黄囊和P-Sp中存在形成B淋巴样细胞的特异性抗体; 证实了B淋巴细胞在卵黄囊和P-Sp中自主产生。 我们将致力于实现以下目标: 目的1:描述卵黄囊和P-Sp中B淋巴细胞的时空出现, 从这些部位的出现细胞中确定B细胞对B1和/或B2淋巴谱系的特异性。 目的2:明确卵黄囊和P-Sp B淋巴细胞生成所需的生长因子信号通路。 目的3:明确卵黄囊和P-Sp来源的B细胞归巢至腹腔的分子途径。 这些研究将明确B淋巴细胞出现的机制,确定B细胞是否存在差异, 特异性是内在的和受限制的,并且可以澄清分泌天然B1淋巴细胞的起源。 抗体;在人类自身免疫性疾病和白血病的发展中起重要作用的细胞群。项目叙述 本项目旨在确定允许小鼠中出现B淋巴细胞所需的因素。 卵黄囊和胚胎内,并确定卵黄囊和胚胎内所必需的分子 B淋巴细胞回到腹膜腔。

项目成果

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Mervin C. YODER其他文献

Mervin C. YODER的其他文献

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{{ truncateString('Mervin C. YODER', 18)}}的其他基金

Lymphopoietic development in the extra-embryonic yolk sac
胚胎外卵黄囊的淋巴细胞发育
  • 批准号:
    7994151
  • 财政年份:
    2008
  • 资助金额:
    $ 35.45万
  • 项目类别:
Lymphopoietic development in the extra-embryonic yolk sac
胚胎外卵黄囊的淋巴细胞发育
  • 批准号:
    7751826
  • 财政年份:
    2008
  • 资助金额:
    $ 35.45万
  • 项目类别:
Lymphopoietic development in the extra-embryonic yolk sac
胚胎外卵黄囊的淋巴细胞发育
  • 批准号:
    7565153
  • 财政年份:
    2008
  • 资助金额:
    $ 35.45万
  • 项目类别:
Lymphopoietic development in the extra-embryonic yolk sac
胚胎外卵黄囊的淋巴细胞发育
  • 批准号:
    8389561
  • 财政年份:
    2008
  • 资助金额:
    $ 35.45万
  • 项目类别:
Cord Blood Stem Cell Expansion Ex Vivo With Endothelial Progenitor Cells
使用内皮祖细胞进行脐带血干细胞体外扩增
  • 批准号:
    6993884
  • 财政年份:
    2005
  • 资助金额:
    $ 35.45万
  • 项目类别:
Role of Endothelial Progenitors in Hematopoietic Stem Cell Expansion
内皮祖细胞在造血干细胞扩增中的作用
  • 批准号:
    7081088
  • 财政年份:
    2005
  • 资助金额:
    $ 35.45万
  • 项目类别:
Core B- Cell and Vector Core
核心 B 细胞和载体核心
  • 批准号:
    7081096
  • 财政年份:
    2005
  • 资助金额:
    $ 35.45万
  • 项目类别:
ENDOTHELIAL CELL ROLE IN YOLK SAC STEM CELL DEVELOPMENT
内皮细胞在卵黄囊干细胞发育中的作用
  • 批准号:
    6184767
  • 财政年份:
    1999
  • 资助金额:
    $ 35.45万
  • 项目类别:
Endothelial Cell Role in Yolk Sac Stem Cell Development
内皮细胞在卵黄囊干细胞发育中的作用
  • 批准号:
    7045963
  • 财政年份:
    1999
  • 资助金额:
    $ 35.45万
  • 项目类别:
Endothelial Cell Role in Yolk Sac Stem Cell Development
内皮细胞在卵黄囊干细胞发育中的作用
  • 批准号:
    7391197
  • 财政年份:
    1999
  • 资助金额:
    $ 35.45万
  • 项目类别:

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