The haemangioblast generates haematopoietic cells through a haemogenic endothelium stage

Abstract

It has been proposed that during embryonic development haematopoietic cells arise from a mesodermal progenitor with both endothelial and haematopoietic potential called the haemangioblast 1, 2. A conflicting theory associates instead the first haematopoietic cells with a phenotypically differentiated endothelial cell with haematopoietic potential, i.e. a haemogenic endothelium 3- 5. Support for the haemangioblast concept was initially provided by the identification during embryonic stem (ES) cells differentiation of a clonal precursor, the blast colony-forming cell (BL-CFC), which gives rise to blast colonies with both endothelial and haematopoietic components 6, 7. Although recent studies have now provided evidence for the presence of this bipotential precursor in vivo 8, 9, the precise mechanism of generation of haematopoietic cells from the haemangioblast still remains completely unknown. Here we demonstrate that the haemangioblast generates haematopoietic cells through the formation of a haemogenic endothelium intermediate, providing the first direct link between these two precursor populations. The cell population containing the haemogenic endothelium is transiently generated during BL-CFC development. This cell population is also present in gastrulating embryos and generates haematopoietic cells upon further culture. At the molecular level, we demonstrate that the transcription factor Scl/Tal1 10 is indispensable for the establishment of this haemogenic endothelium population whereas the core binding factor Runx1/AML1 11 is critical for generation of definitive haematopoietic cells from haemogenic endothelium. Together our results merge into a single linear developmental process the two a priori conflicting theories on the origin of haematopoietic development.