IDENTIFICATION OF A NOVEL ANGIOPOIETIN 2 SIGNALLING CENTRE IN THE EMBRYONIC HAEMATOPOIETIC STEM CELL NICHE

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Blood stem cells, also known as haematopoietic stem cells (HSCs), are found in adult bone marrow and they give rise to practically all blood cells throughout the entire lifespan. For many years, transplantations of HSCs have been used (~50,000 patients/year worldwide) to restore normal blood formation in patients with blood disorders and cancers. However, there is a significant shortage of donors, only 20-60% of patients on registers find a good genetic match for transplants, which affects treatment options, efficiency and outcomes. There is therefore an urgent need to find alternative sources of HSCs. One solution would be to produce HSCs in the laboratory from other readily available cell types, such as pluripotent stem cells, which are capable of producing any cell type in the body. This approach holds great promise for regenerative medicine, but currently generating HSCs in the laboratory remains a big challenge, mainly because, despite being of fundamental importance for medical sciences, we have only limited understanding of how HSCs first emerge during embryonic development. Our recent analyses have revealed a novel signaling centre, Angpt2, which we found to be a strong stimulator of HSC emergence in the mouse embryo. We observed a similar expression pattern of this factor in the human embryo, suggesting it could be an important HSC regulatory centre, which has not been described before. In this project, we will use cutting-edge techniques, including cell purification, gene expression profiling, advanced imaging, bioinformatics and transplantations, to perform a detailed investigation into the role of Ang2 signaling in driving HSC emergence in the embryo. Using novel image-based spatial correlation methods we will build the first 3D digital model of this signaling centre in mouse and human embryonic HSC development. These 3D models and associated datasets will be a valuable resource for the research field. We will further test if Angpt2 can enhance haematopoietic cell/ HSC production from pluripotent cells. In the long term, this could help development of protocols to produce HSCs in the laboratory to meet the shortage of HSCs in the clinic.