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.

为了了解血液的疾病，例如白血病，淋巴瘤和自身免疫性疾病，必须了解发生造血干细胞（HSC）的全基因表达的完整补体，从而引起血统。尽管在成年人中，HSC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 - 纳德 - 莫诺弗罗斯和胎盘的内皮。在2011年，我们发表了一篇论文（Dev Dynamics 240：2290），其中我们表征了小鼠发育过程中胚胎谱系的表征，该论文以TBX4基因的表达为标志，该基因编码了“ T-box”类的转录因子。本文还表征了一种有用的小鼠系，称为TBX4-CRE，此后我们在协作努力中使用了圆环受体对于在胚胎发生期间与身体壁分离至关重要（DEV Cell 24：52）我们的分析至关重要。在胚外组织中的TBX4谱系激发了我们推测TBX4表达将早期细胞标记为两个隔室，每个细胞都会产生一个内皮，其中只有一个能够产生HSC（“ hemegenic nemogenic nemogenic nemogenic enogenic opentic enogentic nocenogentim nepogenic openogenic openogentim e”）。如果该假设是正确的，则TBX4表达可能是最早的已知标记之一，可用于分离和纯化细胞，这些细胞会产生血液内皮。因此，今年我们已经开始了测试这一假设的实验，并生成了数据，这些数据表明TBX4要么优于其他常用的血液生成性内皮标记，或者与这些其他标记结合使用时，大大提高了我们隔离这一至关重要的能力。细胞亚型。现在，我们正在启动实验，以使用这种新方法来隔离和表征这些细胞中表达的基因。这样的数据将使我们能够了解HSC的生物学。