Developmental origins and niches of the haematopoietic system

Hematopoietic stem cells (HSCs) are important cells from a biological and therapeutic perspective. They are responsible for the life-long production of all blood cells. Our work focuses on the first origins of HSCs during their initial generation in the embryo. We aim to obtain a better understanding of the molecules and mechanisms that
are involved in HSC generation, function and maintenance. The transcription factor Runx1 was shown to play a critical role in HSC generation in the embryo. In humans, mutations and translocations of RUNX1 are found in approximately 25% of acute leukaemias, indicating the importance of RUNX1 also for the maintenance of normal
haematopoiesis. In our studies we will examine how Runx1 exerts its crucial role in the first HSCs of the embryo, by identification of the genes and pathways regulated by Runx1, and by identification of the pathways that regulate Runx1 expression. These studies are expected to increase our insight into the biology of HSCs, and can
contribute to a better understanding of leukaemogenesis and ultimately the development of new therapies.

To harness the full therapeutic potential of haematopoietic stem cells (HSCs) and lineage-restricted progenitors to treat blood-related disorders, we aim to better understand their birth in the embryo. Haematopoietic stem and progenitor cells are generated in asynchronous waves from haemogenic endothelium in the yolk sac and the dorsal aorta through a process termed endothelial-to-haematopoietic transition (EHT). EHT is critically dependent on the transcription factor Runx1. In our past work, we have progressed towards fully unravelling the CIS regulatory complexity of Runx1 during EHT and obtained new insights on the timeline and process of early haematopoietic commitment. In our future programme, we will take advantage of new tools we developed and available cutting edge technologies to perform a series of complementary studies that will transform our ability to gain a deep level mechanistic understanding of early blood development. We will combine our unique Runx1 enhancer-reporter transgenic models with chromatin conformation analysis, single cell omics and functional assays to
i) discern the principles of Runx1 regulation during the establishment of haematopoiesis,
ii) deconstruct the HSC-generative niche with the aim to recreate critical components in vitro, and finally,
iii) to elucidate the developmental trajectories of mesoderm contributing to yolk sac and AGM blood cells and their contribution tothe haemato-immune system. Our studies will offer exciting opportunities for translational applications into human models of normal and perturbed developmental haematopoiesis.