Analysis of biomechanical forces in the embryonic development of haematopoietic stem cells

血液干细胞(也称为造血干细胞，HSCs)可以在我们的一生中在人体内产生各种类型的血细胞。造血干细胞是研究最广泛的干细胞类型，也是分析其他类型干细胞的模型。造血干细胞在临床上被广泛用于治疗血液疾病。这些强大的“永生”细胞在生物体中的重要性引起了科学界和普通公众的极大关注。尽管在这一领域取得了重大进展，但造血干细胞在胚胎中产生的确切机制仍然知之甚少。了解人体最初是如何产生造血干细胞的，将有助于我们制定在实验室中培养和生产这些细胞的策略。众所周知，造血干细胞首先在胚胎中从称为背主动脉的大血管中产生，通过一个称为内皮细胞到造血细胞的转变(EHT)的过程。尽管在这一领域取得了进展，但如果没有强有力的基因干预，在实验室中不可能从多能胚胎干细胞(ESCs)中产生HSCs。尽管胚胎干细胞可以产生身体的所有类型的细胞，但这一事实仍然存在。在实验室条件下生长的细胞中EHT的这种缺陷可能是因为我们无法准确地复制发育中的胚胎中存在的条件。在这里，我们建议将重点放在过去二十年来越来越受到关注的物理力量，这些力量在调节胚胎发育、组织结构和功能方面发挥着关键作用。我们认为，胚胎中存在的物理线索在EHT和HSC的发育过程中起着重要的作用，如果不能复制作用于胚胎的关键物理力量，可能会导致体外血液发育不足。我们将研究胚胎背主动脉的物理环境，已知HSC在那里发育，并建立这些物理信号如何在EHT和HSC发育过程中启动重要基因，反过来，我们将研究一些基因如何影响背主动脉的物理特性。这是一个结合了生物医学工程、物理学、干细胞生物学和生物信息学的多学科项目。我们将整合发育成HSCs的细胞谱系与其环境的物理和分子相互作用的复杂图景。我们的研究将揭示驱动血液系统发育的基本机制，并从长远来看，可能为临床环境下产生可移植的人类造血干细胞铺平道路。

Blood stem cells (also known as haematopoietic stem cells, HSCs) can generate all types of blood cells in the body throughout our lifetime. HSCs are the most extensively studied stem cell type and serve as a model for analysis of other types of stem cell. HSCs are widely used in clinics to treat blood disorders. The importance of these potent "immortal" cells in the organism attracts considerable attention both from the scientific community and the general public. Despite significant progress in this field, the exact mechanisms whereby HSCs emerge in the embryo remain poorly understood. Knowing how the body first generates HSCs will help us to develop strategies for growing and producing these cells in the laboratory. It is known that HSCs first emerge in the embryo from the large vessel called the dorsal aorta, through a process called endothelial-to-haematopoietic transition (EHT). Despite progress in this area, it has not been possible to generate HSCs from pluripotent embryonic stem cells (ESCs) in the laboratory without drastic genetic intervention. This is despite the fact that ESCs can generate all cell types of the body. This deficiency of EHT in cells growing under laboratory conditions could be caused by our inability to exactly reproduce conditions that exist in the developing embryo. Here we propose to focus on physical forces that have come under increasing attention in the past two decades as a key player in regulating embryo development, tissue architecture and function. We propose that physical cues existing in the embryo play an important role during EHT and HSC development and that the failure to reproduce key physical forces acting in the embryo may result in deficient blood development in vitro. We will investigate the physical environment of the embryonic dorsal aorta where HSCs are known to develop and establish how these physical cues switch on important genes during EHT and HSC development, and conversely, we will investigate how some genes may impact the physical characteristics of the dorsal aorta. This is a multidisciplinary project which combines biomedical engineering, physics, stem cell biology and bioinformatics. We will integrate a complex picture of physical and molecular interactions of the cell lineage that develops into HSCs with their environment. Our study will reveal fundamental mechanisms that drive development of the blood system and in the longer term may pave a way to the generation of transplantable human HSCs for clinical settings.