Background. The first haematopoietic stem cells (HSCs) emerge in the embryonic aorta-gonad-mesonephros (AGM) region through a process called endothelial-to-haematopoietic transition (EHT). We previously showed that secreted molecules in the AGM region are spatially polarized and some of them support HSC development (2,3). However, the full impact of this complex polarized microenvironment on haematopoietic development remains unclear. We propose that spatial intersections of secreted factors define the efficacy and specifics of EHT within the AGM region.
Objectives. We will investigate how spatial patterning of secreted molecules in the AGM region impacts on haematopoietic development (EHT). Using human ES cells, we will model the HSC niche by spatially patterned combinatorial expression of secreted molecules. Results will be obtained and analysed using fluorescent reporters, single cell RNAseq, flow cytometry and computer modelling. In the longer term, these analyses will facilitate generation of human HSCs for clinical needs.
Techniques and skills to be employed/ acquired. This project will be carried out in a highly collaborative environment. The student will learn cutting-edge and multidisciplinary methods including human ES cell differentiation, live imaging, micropatterning, confocal microscopy, flow cytometry, CRISPR/Cas9 gene editing; gene expression profiling (RNAseq) and bioinformatics.
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