HEMATOPOIETIC COMMITMENT OF HUMAN EMBRYONIC STEM CELLS

人胚胎干细胞的造血功能

• 批准号: 8173080
• 负责人: Igor I. Slukvin
• 金额: $ 3.1万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8173080
• 关键词: Blood; Bone Marrow; CD34 gene; CD43 molecule; Cells; Coculture Techniques; Computer Retrieval of Information on Scientific Projects Database; Development; Embryo; Engraftment; Erythroid; Funding; Gene Expression; Genes; Goals; Grant; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; In Vitro; Institution; Laboratories; Lymphoid; Lymphoid Cell; Modeling; Molecular; Molecular Profiling; Myelogenous; Pathway interactions; Population; Research; Research Personnel; Resources; Solid; Source; Staging; Stem Cell Development; Stem cells; Stromal Cells; Surface; System; Therapeutic; To specify; United States National Institutes of Health; clinical application; embryonic stem cell; gene therapy; human embryonic stem cell; interest; oncology; progenitor; self-renewal; Blood; Bone Marrow; CD34 gene; CD43 molecule; Cells; Coculture Techniques; Computer Retrieval of Information on Scientific Projects Database; Development; Embryo; Engraftment; Erythroid; Funding; Gene Expression; Genes; Goals; Grant; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; In Vitro; Institution; Laboratories; Lymphoid; Lymphoid Cell; Modeling; Molecular; Molecular Profiling; Myelogenous; Pathway interactions; Population; Research; Research Personnel; Resources; Solid; Source; Staging; Stem Cell Development; Stem cells; Stromal Cells; Surface; System; Therapeutic; To specify; United States National Institutes of Health; clinical application; embryonic stem cell; gene therapy; human embryonic stem cell; interest; oncology; progenitor; self-renewal

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Objective: To advance human embryonic stem cells and their derivatives towards clinical application for treatment of blood disease. Understanding the mechanisms that regulate hematopoietic stem cell development is essential for further improvement of hematopoietic stem cell use in oncology and gene therapy. The overall goal of this project is to identify and characterize the earliest hematopoietic progenitors in humans to specify cellular and molecular pathways leading to hematopoietic stem cell development using in vitro hESC differentiation system as a model. Directed hematopoietic differentiation of ES cells reproduces many aspects of embryonic hematopoiesis, and provides a unique opportunity to study molecular and cellular pathways of hematopoietic development in humans. In our laboratory, we established a system for efficient hematopoietic differentiation of hES cells through coculture with OP9 bone marrow stromal cells. Using this system we were able to directly differentiate hES cells into cells of all major blood lineages (erythroid, myeloid and lymphoid), as well as identify different stages of hematopoietic commitment. We found that the earliest hematopoietic progenitors (HPs) in humans arise within CD34+ population and could be ultimately defined by surface expression of leukosialin (CD43). In addition, within CD43+ population, we identified lin-CD34+CD43+CD45- hematopoietic progenitors capable of differentiating toward all blood lineages including lymphoid cells, suggesting their hierarchical proximity to hematopoietic stem cells. However, molecular profiling of hES lin-CD34+CD43+CD45- cells revealed altered expression of genes associated with hematopoietic stem cell self-renewal and survival, reflecting limited engraftment potential of ES cell-derived hematopoietic progenitors. With increasing interest in potential therapeutic application of hES cell derivates, identification of genes essential for hematopoietic stem cell development and diversification is of particular importance. The described experimental system sets a solid platform to advance in this direction. This research used WNPRC Stem Cell Resources.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 目的：将人类胚胎干细胞及其衍生物推向血液疾病治疗的临床应用。 了解调节造血干细胞发育的机制对于进一步改善造血干细胞在肿瘤学和基因治疗中的使用至关重要。该项目的总体目标是识别和表征人类中最早的造血祖细胞，以指定使用体外HESC分化系统作为模型的细胞和分子途径，从而导致造血干细胞的发育。 ES细胞的定向造血分化再现了胚胎造血的许多方面，并为研究人类造血发育的分子和细胞途径提供了独特的机会。在我们的实验室中，我们建立了一个通过与OP9骨髓基质细胞共培养的HES细胞有效造血分化的系统。 使用该系统，我们能够直接将Hess细胞分化为所有主要血统（红细胞，髓样和淋巴样）的细胞，并鉴定造血剂量的不同阶段。我们发现，人类中最早的造血祖细胞（HPS）是在CD34+种群中出现的，最终可以通过白细胞素的表面表达来定义（CD43）。 此外，在CD43+种群中，我们鉴定了LIN-CD34+CD43+CD45-造血祖细胞，能够区分所有血统，包括淋巴样细胞，表明它们与造血干细胞的层次接近。然而，HES LIN-CD34+CD43+CD45-细胞的分子分析显示，与造血干细胞自我更新和存活相关的基因表达改变了，这反映了ES细胞衍生的造血祖细胞的植入潜力有限。 随着对HES细胞衍生的潜在治疗应用的兴趣越来越多，对造血干细胞发育必不可少的基因鉴定和多样化至关重要。所描述的实验系统设定了一个坚实的平台，以朝这个方向前进。 这项研究使用了WNPRC干细胞资源。