Characterization of the hematopoietic stem cell lineage

造血干细胞谱系的表征

• 批准号: 9153958
• 负责人: MARK B LEWANDOSKI
• 金额: $ 21.76万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9153958
• 关键词: Adult; Aorta; Autoimmune Diseases; Biology; Blood; Bone Marrow; Boxing; Cell Lineage; Cells; Complement; Data; Disease; Embryo; Embryonic Development; Endothelium; Fetal Liver; Gene Expression; Genes; Goals; Gonadal structure; Hematological Disease; Hematopoietic stem cells; Immune System Diseases; Immune system; Lymphoid; Malignant Neoplasms; Mesonephric structure; Molecular; Mus; Myelogenous; Paper; Placenta; Primitive foregut structure; Publishing; Stem cells; Syndrome; Testing; Tissues; cell behavior; fighting; improved; leukemia/lymphoma; mouse development; novel marker; novel strategies; progenitor; receptor; research study; transcription factor

In order to understand diseases of the blood, such as leukemias, lymphomas and autoimmune diseases, it is essential to understand the full complement of gene expression that occurs the hematopoietic stem cells (HSCs) that give rise to the blood lineage. Although in the adult, HSCs are found primarily in the bone marrow, in the embryo they can be traced to the fetal liver, the aorta-gonad-mesonephros and the endothelium of the placenta. In 2011 we published a paper (Dev Dynamics 240:2290) in which we characterized the embryonic lineage during mouse development that is marked by the expression of the Tbx4 gene, which encodes a transcription factor of the "T-box" class. This paper also characterized a useful mouse line, called Tbx4-Cre, that we have since used, in a collaborative effort, to demonstrate that Roundabout receptors are critical for foregut separation from the body wall during embryogenesis (Dev Cell 24: 52) Our analysis of the Tbx4 lineage in the extraembryonic tissue inspired us to speculate that Tbx4 expression marked early cells into two compartments, each giving rise to an endothelium, only one of which is capable of generating HSCs ("hemogenic endothelium"). If this hypothesis is correct, Tbx4 expression may be one of the earliest known markers useful in isolating and purifying cells that will generate hemogenic endothelium. Therefore, this year we have embarked on experiments to test this hypothesis and have generated data that demonstrates that Tbx4 either is a superior to other commonly used markers of hemogenic endothelium or, when combined with these other markers, vastly improves our ability to isolate this crucial cellular subtype. We are now embarking on experiments to use this new approach to isolate and characterize the genes that are expressed in these cells. Such data will allow us to understand the biology of the HSC.

为了了解白血病、淋巴瘤和自身免疫性疾病等血液疾病，有必要了解产生血液谱系的造血干细胞 (HSC) 的完整基因表达。虽然在成人中，造血干细胞主要存在于骨髓中，但在胚胎中，它们可以追溯到胎儿肝脏、主动脉-性腺-中肾和胎盘内皮。 2011 年，我们发表了一篇论文 (Dev Dynamics 240:2290)，其中我们描述了小鼠发育过程中胚胎谱系的特征，该谱系以 Tbx4 基因的表达为标志，该基因编码“T-box”类转录因子。本文还描述了一种有用的小鼠品系，称为 Tbx4-Cre，我们随后在合作中使用该品系来证明 Roundabout 受体对于胚胎发生过程中前肠与体壁分离至关重要 (Dev Cell 24: 52)。我们对胚胎外组织中 Tbx4 谱系的分析启发我们推测 Tbx4 表达将早期细胞标记为两个区室，每个区室仅产生内皮细胞 其中之一能够产生HSC（“造血内皮细胞”）。如果这一假设正确，Tbx4 表达可能是最早已知的可用于分离和纯化生成造血内皮细胞的标记物之一。因此，今年我们开始进行实验来检验这一假设，并生成数据证明 Tbx4 优于其他常用的造血内皮标记物，或者与这些其他标记物结合时，极大地提高了我们分离这种关键细胞亚型的能力。我们现在正在进行实验，利用这种新方法来分离和表征这些细胞中表达的基因。这些数据将使我们能够了解 HSC 的生物学特性。