DECIPHERING THE BIOLOGICAL CHARACTERISTICS OF HUMAN HAEMOGENIC ENDOTHELIUM

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The continuous production of all mature blood cells in an adult organism is sustained by a population of blood stem cells that resides in the bone marrow. Those are the cells which ensure reconstitution of the blood system upon bone marrow transplantation in the treatment of blood malignancies. Unfortunately, shortages of bone marrow donors or lack of compatible donors result in patients remaining for too long on transplant waiting lists. An alternative source of blood stem cells usable for transplantation in the clinic relies on the in vitro differentiation of pluripotent stem cells. However, this therapeutical aim will only be achieved with a full understanding of the differentiation processes and the thorough characterization of clinically useful cell populations. To date, this remains one of the principal limitations and most difficult challenge of the regenerative medicine field.During embryonic life, all blood cells including adult blood stem cells are generated from precursor cells termed haemogenic endothelium. However, despite the fundamental importance of the haemogenic endothelium in establishing the blood system, we still know very little about this cell population. In this project, we propose to explore the molecular and cellular characteristics of this progenitor population derived from the in vitro differentiation of human pluripotent stem cells. First, we will investigate the level of heterogeneity of the haemogenic endothelium population generated during the course of in vitro differentiation. Next, we will explore whether the cell fate specification of the haemogenic endothelium can be modulated by culture conditions. Finally, we will dissect at the molecular level the progressive changes involved in the transition from endothelium to blood cells. The successful completion of this project will lead to a better characterisation of haemogenic endothelium generated upon the differentiation of pluripotent stem cells. Findings from this project will advance our understanding of early human haematopoiesis and inform the design and optimization of differentiation protocols for the generation of haematopoietic cell populations usable in the clinic for regenerative medicine purposes.