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

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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.