HEMATOPOIETIC COMMITMENT OF HUMAN EMBRYONIC STEM CELLS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 目的：促进人类胚胎干细胞及其衍生物向 治疗血液病的临床应用。 了解调控造血干细胞发育的机制 对进一步改善造血干细胞在肿瘤学和临床中的应用至关重要 基因疗法。该项目的总体目标是确定和描述 通往造血干细胞的祖细胞和分子途径的层级 从人类胚胎(HES)和诱导多能干细胞(IPS)发育而来。 在我们的实验室里，我们建立了一个有效的造血分化系统。 通过与OP9骨髓基质细胞共培养获得HES细胞。使用这个系统 我们能够直接将hes细胞分化为所有主要血统的细胞。 (红系、髓系和淋巴系)，以及识别不同阶段的 造血术的承诺。我们发现最早的造血祖细胞 人类(HPS)出现在CD34+人群中，最终可能由以下因素定义 白涎素(CD43)的表面表达。此外，在CD43+人群中，我们 鉴定具有分化能力的LIN-CD34+CD43+CD45-造血祖细胞 包括淋巴细胞在内的所有血统，表明它们的等级 接近造血干细胞。然而，HES Lin的分子图谱- CD34+CD43+CD45-细胞表达相关基因发生改变 造血干细胞的自我更新和存活，反映了有限的植入 胚胎干细胞来源的造血祖细胞的潜能。此外，我们还确定了一个 间充质干细胞和内皮细胞间充质单血管母细胞的新前体。 随着人们对HES细胞衍生物潜在的治疗应用越来越感兴趣， 造血干细胞发育所必需基因的鉴定和鉴定 多样化尤为重要。所描述的实验系统设置了一个 朝着这个方向前进的坚实平台。 这项研究使用了WNPRC干细胞资源。 出版物： 马福达，于军，张旭，田S，斯图尔特R，汤姆森JA，Slukvin II.中胚层- 间充质干细胞和内皮细胞的衍生前体。干细胞。2010年 12月3日；7(6)：718-29。PMID：21112566，PMC3033587。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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 hierarchy of progenitors and molecular pathways leading to hematopoietic stem cell development from human embryonic (hES) and induced pluripotent stem (iPS) cells. 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. In addition we identified a novel precursor for mesenchymal stem and endothelial cells mesenchymonangioblast. 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. PUBLICATION: Vodyanik MA, Yu J, Zhang X, Tian S, Stewart R, Thomson JA, Slukvin II. A mesoderm- derived precursor for mesenchymal stem and endothelial cells. Cell Stem Cell. 2010 Dec 3;7(6):718-29. PMID: 21112566, PMCID: PMC3033587.