Adult Hemangioblast/HSC Recruitment and Maintenance

成人成血管细胞/HSC 的招募和维持

• 批准号: 7095623
• 负责人: Edward W Scott
• 金额: $ 46.52万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-15 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7095623
• 关键词: CD34 molecule; RNA interference; Retroviridae; angiogenesis; bone marrow transplantation; bromodeoxyuridine; cell differentiation; cell migration; chemokine; electroporation; gene deletion mutation; genetically modified animals; hematopoietic stem cells; histology; laboratory mouse; magnetic resonance imaging; optical tomography; particle; phenotype; polymerase chain reaction; retina; selectins; tissue /cell culture; transfection /expression vector; vascular endothelium

DESCRIPTION (provided by applicant): We have proven that the adult hematopoietic stem cell (HSC) is able to function as a hemangioblast. Using a unique model of adult retinal neovascularization, we performed a series of experiments to ask if adult HSC exhibit hemangioblast activity by contributing to both blood and blood vessel repair in response to ischemic injury. Bone marrow transplant recipients were durably reconstituted with a single donor HSC from congenic mice expressing Gfp. Ischemia was induced in one retina per animal. Physiological localization of marrow-derived progeny to retina was detected by confocal microscopy of newly differentiated vascular tufts composed of Gfp+ endothelial cells. Both FACS and fluorescent microscopy confirmed full multilineage hematopoietic reconstitution of the transplant recipients. This study is the first to prove that an adult stem cell can exhibit functional plasticity in a transplant setting. In this proposal we seek to utilize this unique model to address the following hypotheses: Aim 1. Hypothesis: Remodeling of the endothelial niche by hemangioblast activity is the initial step in bone marrow remodeling following bone marrow transplant. Aim 2. Hypothesis: HSC hemangioblast activity produces a developmental hierarchy of cells with the potential to differentiate into endothelial cells. With our model we can define the lineage relationships and phenotypes of this new hematopoietic activity. Aim 3. Hypothesis: HSC are the source of circulating endothelial progenitors. Therefore, factors that affect HSC or leukocyte migration will affect EPC production and recruitment.

描述（由申请人提供）：我们已经证明成体造血干细胞（HSC）能够发挥成血管细胞的功能。使用成人视网膜新生血管形成的独特模型，我们进行了一系列实验，以探究成人 HSC 是否通过响应缺血性损伤而促进血液和血管修复而表现出成血管细胞活性。骨髓移植受者使用来自表达 Gfp 的同源小鼠的单个供体 HSC 进行持久重建。在每只动物的一个视网膜中诱导缺血。通过共聚焦显微镜检测由 Gfp+ 内皮细胞组成的新分化的血管簇，检测骨髓来源的子代到视网膜的生理定位。 FACS 和荧光显微镜都证实了移植受者的完全多谱系造血重建。这项研究首次证明成体干细胞在移植环境中可以表现出功能可塑性。在本提案中，我们试图利用这种独特的模型来解决以下假设： 目标 1.假设：成血成血管细胞活性对内皮微环境的重塑是骨髓移植后骨髓重塑的第一步。目标 2. 假设：HSC 成血管细胞活性产生具有分化为内皮细胞潜力的细胞发育层次。通过我们的模型，我们可以定义这种新造血活动的谱系关系和表型。目标 3. 假设：HSC 是循环内皮祖细胞的来源。因此，影响HSC或白细胞迁移的因素将影响EPC的产生和募集。