Characterization of the first HSCs during mouse ontogeny

小鼠个体发育过程中第一个 HSC 的表征

• 批准号: 8816081
• 负责人: ELAINE A DZIERZAK
• 金额: $ 30.38万
• 依托单位: UNIVERSITY OF EDINBURGH
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8816081
• 关键词: Adult; Aorta; Biological Assay; Blood; Blood Cells; Blood Circulation; Bone Marrow; Cell Line; Cell surface; Cells; Clinical; Collection; Data; Development; Developmental Process; Disease; Dorsal; Dose; Dyes; Embryo; Endothelial Cells; Endothelium; Erinaceidae; Event; Funding; GATA2 transcription factor; Gene Transfer Techniques; Generations; Genetic Recombination; Gonadal structure; Growth; Haploidy; Hematopoiesis; Hematopoietic; Hematopoietic Cell Growth Factors; Hematopoietic System; Hematopoietic stem cells; Interleukin-3; Investigation; LacZ Genes; Lead; Life; Maps; Mesenchymal; Mesonephric structure; Methods; Molecular; Mus; Oils; Placenta; Play; Production; Research; Role; Running; Staging; System; Technology; Therapeutic; Thromboplastin; Tissues; Transgenic Mice; Transplantation; Trauma; Yolk Sac; base; bone morphogenetic protein 4; cell motility; cytokine; embryo culture; hematopoietic tissue; implantation; improved; insight; leukemia; novel; research study; transcription factor

DESCRIPTION (provided by applicant): The continuous life-long production of all mature blood cells in the circulation and hematopoietic tissues is contingent on hematopoietic stem cells (HSC). These rare cells reside in the bone marrow of the adult and are the clinically important cells in transplantation therapies for blood-related diseases and leukemias. The manipulation of limited numbers of adult HSCs has been difficult, since ex vivo expansion of these cells has not yet been achieved. Despite the identification and use of many hematopoietic growth factors, HSCs can at best be maintained, not expanded. We hypothesized that at some early stage in ontogeny HSCs are generated and expanded in a unique embryonic microenvironment. An understanding of the developmental processes leading to HSC emergence in the embryo should provide novel insights and improved methods for the ex vivo expansion of HSCs for clinical use. To this end, our long-term research objective has been to determine the cellular and molecular mechanisms by which HSCs are generated/expanded within the mammalian embryo. We have shown that the mouse aorta-gonad-mesonephros (AGM) region autonomously generates the first fully potent HSCs in close association with the aortic endothelium. We have demonstrated that Runxl and GATA-2 transcription factors are required for the generation and expansion of these HSCs. However, more factors have yet to be identified. In various preliminary studies of the AGM microenvironment, IL-3, BMP-4 and hedgehog factors have been implicated as effectors of AGM HSC emergence, but these factors must be further characterized. Thus, we will examine each factor for its role in the induction and expansion of HSCs in the midgestation mouse aorta. Using classical embryologic methods, we will deliver factors to whole cultured mouse embryos by bead/cell pellet implantation and transgenesis, to determine their effect on AGM HSCs. In similar factor manipulation experiments, we aim to establish the lineage relationships of precursors to AGM HSCs by dye marking of aortic endothelium. We will also investigate the long-term fate of the HSCs generated in the mouse AGM by Cre-lox recombination technology. If indeed embryonic aorta-derived HSCs migrate and colonize the adult bone marrow, our insights into their generation and expansion should lead to novel methods for clinical HSC expansion and thus, improve transplantation therapies.

描述（由申请人提供）：循环和造血组织中所有成熟的血细胞的连续生产是造血干细胞（HSC）的。这些稀有细胞驻留在成年人的骨髓中，是与血液相关疾病和白血病的移植疗法中临床重要的细胞。由于尚未实现这些细胞的离体扩展，因此对有限数量的成年HSC进行操作一直很困难。尽管鉴定和使用了许多造血生长因素，但HSC充其量可以维持，而不是扩展。我们假设在某个早期阶段，HSC的某个早期阶段是在独特的胚胎微环境中产生和扩展的。对导致胚胎中HSC出现的发育过程的理解应提供新颖的见解和改进的HSC扩展供临床使用的方法。为此，我们的长期研究目标是确定在哺乳动物胚胎中生成/扩展HSC的细胞和分子机制。我们已经表明，小鼠主动脉主动脉 - 肾小球（AGM）区域自动生成第一个完全有效的HSC与主动脉内皮密切相关。我们已经证明了这些HSC的生成和扩展需要RunXL和GATA-2转录因子。但是，尚未确定更多因素。在AGM微环境的各种初步研究中，IL-3，BMP-4和刺猬因子已被视为AGM HSC出现的效应因子，但必须进一步表征这些因素。因此，我们将检查每个因素在中间小鼠主动脉中HSC的诱导和扩展中的作用。使用经典的胚胎学方法，我们将通过珠/细胞颗粒植入和转基因为整个培养的小鼠胚胎传递因子，以确定它们对AGM HSC的影响。在类似的因素操纵实验中，我们旨在通过主动脉内皮的染料标记来建立前体与AGM HSC的谱系关系。我们还将研究Cre-Lox重组技术在小鼠AGM中产生的HSC的长期命运。如果确实胚胎主动脉衍生的HSC迁移并定居成年骨髓，那么我们对它们的产生和扩张的见解应导致临床HSC扩张的新方法，从而改善移植疗法。

项目成果

Placenta as a source of hematopoietic stem cells.

• DOI: 10.1016/j.molmed.2010.05.005
• 发表时间: 2010-08
• 期刊: Trends in molecular medicine
• 影响因子: 13.6
• 作者: Dzierzak E;Robin C
• 通讯作者: Robin C

The placenta as a haematopoietic organ.

胎盘作为造血器官。

• DOI: 10.1387/ijdb.093057ko
• 发表时间: 2010
• 期刊: The International journal of developmental biology
• 作者: Ottersbach,Katrin;Dzierzak,Elaine
• 通讯作者: Dzierzak,Elaine

The biochemistry of hematopoietic stem cell development.

• DOI: 10.1016/j.bbagen.2012.10.004
• 发表时间: 2013-02
• 期刊: BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
• 影响因子: 3
• 作者: Kaimakis, P.;Crisan, M.;Dzierzak, E.
• 通讯作者: Dzierzak, E.

In vivo single cell analysis reveals Gata2 dynamics in cells transitioning to hematopoietic fate.

• DOI: 10.1084/jem.20170807
• 发表时间: 2018-01-02
• 期刊: The Journal of experimental medicine
• 作者: Eich C;Arlt J;Vink CS;Solaimani Kartalaei P;Kaimakis P;Mariani SA;van der Linden R;van Cappellen WA;Dzierzak E
• 通讯作者: Dzierzak E

Identification of Cdca7 as a novel Notch transcriptional target involved in hematopoietic stem cell emergence.

• DOI: 10.1084/jem.20131857
• 发表时间: 2014-11-17
• 期刊: The Journal of experimental medicine
• 作者: Guiu J;Bergen DJ;De Pater E;Islam AB;Ayllón V;Gama-Norton L;Ruiz-Herguido C;González J;López-Bigas N;Menendez P;Dzierzak E;Espinosa L;Bigas A
• 通讯作者: Bigas A