DECIPHERING THE BIOLOGICAL CHARACTERISTICS OF HUMAN HAEMOGENIC ENDOTHELIUM

破译人类造血内皮的生物学特性

• 批准号: MR/P000673/1
• 负责人: Valerie Kouskoff
• 金额: $ 63.31万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP000673%2F1
• 关键词: DECIPHERING; BIOLOGICAL; CHARACTERISTICS; HUMAN; HAEMOGENIC

The continuous production of all mature blood cells in an adult organism is sustained by a population of blood stem cells that resides in the bone marrow. Those are the cells which ensure reconstitution of the blood system upon bone marrow transplantation in the treatment of blood malignancies. Unfortunately, shortages of bone marrow donors or lack of compatible donors result in patients remaining for too long on transplant waiting lists. An alternative source of blood stem cells usable for transplantation in the clinic relies on the in vitro differentiation of pluripotent stem cells. However, this therapeutical aim will only be achieved with a full understanding of the differentiation processes and the thorough characterization of clinically useful cell populations. To date, this remains one of the principal limitations and most difficult challenge of the regenerative medicine field.During embryonic life, all blood cells including adult blood stem cells are generated from precursor cells termed haemogenic endothelium. However, despite the fundamental importance of the haemogenic endothelium in establishing the blood system, we still know very little about this cell population. In this project, we propose to explore the molecular and cellular characteristics of this progenitor population derived from the in vitro differentiation of human pluripotent stem cells. First, we will investigate the level of heterogeneity of the haemogenic endothelium population generated during the course of in vitro differentiation. Next, we will explore whether the cell fate specification of the haemogenic endothelium can be modulated by culture conditions. Finally, we will dissect at the molecular level the progressive changes involved in the transition from endothelium to blood cells. The successful completion of this project will lead to a better characterisation of haemogenic endothelium generated upon the differentiation of pluripotent stem cells. Findings from this project will advance our understanding of early human haematopoiesis and inform the design and optimization of differentiation protocols for the generation of haematopoietic cell populations usable in the clinic for regenerative medicine purposes.

在成年生物体中，所有成熟血细胞的持续生产是由一群驻留在骨髓中的血液干细胞维持的。在血液恶性肿瘤的治疗中，这些细胞确保骨髓移植后血液系统的重建。不幸的是，骨髓捐赠者短缺或缺乏相容的捐赠者导致患者在移植等待名单上停留太长时间。临床上可用于移植的另一种血液干细胞来源依赖于多能干细胞的体外分化。然而，这一治疗目标只有在充分了解分化过程和对临床有用的细胞群进行彻底表征的情况下才能实现。到目前为止，这仍然是再生医学领域的主要限制和最困难的挑战之一。在胚胎生命期间，包括成人血液干细胞在内的所有血细胞都是从被称为血源性内皮的前体细胞产生的。然而，尽管血液内皮细胞在建立血液系统中具有基本的重要性，但我们对这一细胞群体仍然知之甚少。在这个项目中，我们打算探索从人类多能干细胞体外分化而来的祖细胞群体的分子和细胞特征。首先，我们将研究在体外分化过程中产生的血液内皮细胞群体的异质性水平。接下来，我们将探索血源性内皮细胞的命运是否可以通过培养条件来调节。最后，我们将在分子水平上剖析内皮细胞向血细胞转化过程中涉及的渐进性变化。该项目的成功完成将导致对多能干细胞分化所产生的造血内皮细胞的更好的表征。该项目的发现将促进我们对早期人类造血的理解，并为设计和优化分化方案提供信息，以产生可用于临床再生医学目的的造血细胞群体。

项目成果

A novel prospective isolation of murine fetal liver progenitors to study in utero hematopoietic defects.

• DOI: 10.1371/journal.pgen.1007127
• 发表时间: 2018-01
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Draper JE;Sroczynska P;Fadlullah MZH;Patel R;Newton G;Breitwieser W;Kouskoff V;Lacaud G
• 通讯作者: Lacaud G

Regulation of RUNX1 dosage is crucial for efficient blood formation from hemogenic endothelium.

RUNX1剂量的调节对于造血内皮的有效血液形成至关重要。

• DOI: 10.1242/dev.149419
• 发表时间: 2018-03-12
• 期刊: Development (Cambridge, England)
• 作者: Lie-A-Ling M;Marinopoulou E;Lilly AJ;Challinor M;Patel R;Lancrin C;Kouskoff V;Lacaud G
• 通讯作者: Lacaud G

Single-cell transcriptomics reveal the dynamic of haematopoietic stem cell production in the aorta.

单细胞转录组学揭示了主动脉中造血干细胞产生的动态。

• DOI: 10.1038/s41467-018-04893-3
• 发表时间: 2018-06-28
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Baron CS;Kester L;Klaus A;Boisset JC;Thambyrajah R;Yvernogeau L;Kouskoff V;Lacaud G;van Oudenaarden A;Robin C
• 通讯作者: Robin C