DECIPHERING THE BIOLOGICAL CHARACTERISTICS OF HUMAN HAEMOGENIC ENDOTHELIUM

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。这些细胞在治疗血液恶性肿瘤的骨髓移植中确保血液系统的重建。不幸的是，骨髓供体短缺或缺乏兼容的供体导致患者在移植等候名单上停留太长时间。可用于临床移植的血液干细胞的另一种来源依赖于多能干细胞的体外分化。然而，只有充分了解分化过程和临床有用细胞群的彻底特征，才能实现这一治疗目标。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。在胚胎时期，包括成人造血干细胞在内的所有血细胞都是由称为造血内皮的前体细胞产生的。然而，尽管造血内皮在建立血液系统中具有重要的基础作用，但我们对这种细胞群仍然知之甚少。在本项目中，我们拟从体外分化的人多能干细胞中探索这一祖细胞群的分子和细胞特征。首先，我们将研究在体外分化过程中产生的造血内皮细胞群的异质性水平。接下来，我们将探讨造血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变过程中的渐进变化。该项目的成功完成将有助于更好地表征多能干细胞分化产生的造血内皮。该项目的研究结果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。

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.