Multi-layered spatial transcriptomics identify secretory factors promoting human hematopoietic stem cell development

Haematopoietic stem cells (HSCs) first emerge in the embryonic aorta-gonad-mesonephros (AGM)region. Studies on model organisms defined intersecting signalling pathways that converge to promote HSC emergence predominantly in the ventral domain of the dorsal aorta. Much less is known about mechanisms driving HSC development in human. Here, to identify secreted signals underlying human HSC development, we combined spatial transcriptomics analysis of dorso-ventral polarised signalling in the aorta with gene expression profiling of sorted cell populations and single cells. Our analysis revealed a subset of aortic endothelial cells with down regulated arterial signature and a predicted lineage relationship with the emerging HSC/ progenitor population. Analysis of the ventrally polarised molecular landscape identified endothelin 1 as an important secreted regulator of human HSC development. The obtained gene expression datasets will inform future studies on mechanisms of HSC development in vivo and on the generation of clinically relevant HSCs in vitro.