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

造血干细胞胚胎发育过程中的生物力学力分析

• 批准号: BB/W003236/1
• 负责人: Alexander Medvinsky
• 金额: $ 92.08万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW003236%2F1
• 关键词: Analysis; biomechanical; forces; embryonic; development

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.

造血干细胞（也称为造血干细胞，HSC）可以在我们的一生中产生体内所有类型的血细胞。HSC是研究最广泛的干细胞类型，并作为分析其他类型干细胞的模型。造血干细胞在临床上广泛用于治疗血液疾病。这些强大的“不朽”细胞在生物体中的重要性吸引了科学界和公众的极大关注。尽管在这一领域取得了重大进展，但HSC在胚胎中出现的确切机制仍然知之甚少。了解身体如何首先产生HSC将有助于我们制定在实验室中生长和生产这些细胞的策略。 众所周知，HSC首先在胚胎中从称为背主动脉的大血管中出现，通过称为内皮向造血转变（EHT）的过程。尽管在这一领域取得了进展，但在实验室中从多能胚胎干细胞（ESC）产生HSC而不进行剧烈的遗传干预是不可能的。尽管事实上ESCs可以产生身体的所有细胞类型。在实验室条件下生长的细胞中EHT的这种缺乏可能是由于我们无法准确复制发育中胚胎中存在的条件。在这里，我们建议把重点放在物理力量，在过去的二十年里，越来越多的关注作为一个关键的球员在调节胚胎发育，组织结构和功能。我们认为，胚胎中存在的物理线索在EHT和HSC发育过程中起着重要作用，并且未能重现作用于胚胎中的关键物理力量可能导致体外血液发育不足。我们将研究已知HSC发育的胚胎背主动脉的物理环境，并确定这些物理线索如何在EHT和HSC发育过程中切换重要基因，相反，我们将研究一些基因如何影响背主动脉的物理特征。这是一个结合生物医学工程、物理学、干细胞生物学和生物信息学的多学科项目。我们将整合一个复杂的图片的物理和分子相互作用的细胞谱系，发展成HSC与他们的环境。我们的研究将揭示驱动血液系统发育的基本机制，从长远来看，可能为临床环境中可移植的人类HSC的产生铺平道路。