Generating blood stem and progenitor cells from haemogenic endothelium

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.

Stem cells are crucial in tissue homeostasis, regeneration and repair. The current interest in stem cell-based therapies has emphasised the importance of understanding how tissue specific stem cells are specified in development. Here, we aim to obtain a mechanistic understanding of the birth of blood stem cells in mouse development. We will build on our previous work in which we have made advances towards unravelling the cis-regulatory complexity of Runx1, a critical regulator of the endothelial-to-haematopoietic transition (EHT), and obtained important new insights on the timeline and process of early haematopoietic commitment. In this programme we will continue our analysis of the Runx1 cis-regulatory logic through application of state-of-the-art technologies, and identify upstream regulators that converge on these cis-elements. In addition, we aim to identify the gene regulatory network that underlies blood stem and progenitor generation in vivo, through genome wide expression and chromatin analyses of primary mouse embryo cells. Together with studies into the developmental origin of the haemogenic endothelium, these experiments will shed light on the spatiotemporal factors and signals that are active in haematopoietic specification and differentiation from gastrulation onwards. This knowledge will inform the development of robust in vitro models for generating definitive haemogenic endothelium and blood stem and progenitor cells from ESC/iPSCs.