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.

为了了解血液疾病，如白血病、淋巴瘤和自身免疫性疾病，了解产生血统的造血干细胞(HSCs)的基因表达完全互补是至关重要的。虽然在成人中，造血干细胞主要在骨髓中发现，但在胚胎中，它们可以追溯到胎儿肝脏、主动脉-性腺-中肾和胎盘的内皮细胞。2011年，我们发表了一篇论文(Dev Dynamic 240：2290)，其中我们描述了小鼠发育过程中以Tbx4基因表达为标志的胚胎谱系，Tbx4基因编码“T-box”类转录因子。这篇论文还描述了一个有用的小鼠系，称为Tbx4-Cre，我们后来在合作努力中用它来证明RoundAbout受体对于胚胎发生期间前肠和体壁的分离至关重要(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的表达将早期细胞分成两个隔室，每个隔室产生一层内皮，其中只有一层能够生成肝星状细胞(“血源性内皮”)。如果这一假设是正确的，Tbx4的表达可能是已知最早的标记之一，用于分离和纯化将产生血源性内皮的细胞。因此，今年我们开始了实验来验证这一假设，并产生了数据，证明Tbx4要么优于其他常用的血液内皮标志物，要么与这些其他标志物结合在一起，极大地提高了我们分离这一关键细胞亚型的能力。我们现在正在进行实验，使用这种新的方法来分离和鉴定在这些细胞中表达的基因。这样的数据将让我们了解HSC的生物学。