It has been proposed that during embryonic development haematopoietic cells arise from a mesodermal progenitor with both endothelial and haematopoietic potential called the haemangioblast1,2. A conflicting theory instead associates the first haematopoietic cells with a phenotypically differentiated endothelial cell that has haematopoietic potential (that is, a haemogenic endothelium)3,4,5. Support for the haemangioblast concept was initially provided by the identification during mouse embryonic stem cell differentiation of a clonal precursor, the blast colony-forming cell (BL-CFC), which gives rise to blast colonies with both endothelial and haematopoietic components6,7. Although recent studies have now provided evidence for the presence of this bipotential precursor in vivo8,9, the precise mechanism for 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 mouse embryos and generates haematopoietic cells on further culture. At the molecular level, we demonstrate that the transcription factor Tal1 (also known as Scl; ref. 10) is indispensable for the establishment of this haemogenic endothelium population whereas the core binding factor Runx1 (also known as AML1; ref. 11) is critical for generation of definitive haematopoietic cells from haemogenic endothelium. Together our results merge the two a priori conflicting theories on the origin of haematopoietic development into a single linear developmental process.
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We thank K. Labib, C. Miller and T. Somervaille for critical reading of the manuscript, J. Barry and M. Hughes for cell sorting, S. Bagley for help with the time-lapse photography, G. Ashton for help with preparation of sections, and L. Gautreau for advice with the OP9 cultures. Cancer Research UK supported this work.
Author Contributions P.S. designed and performed experiments, and analysed the data. C.S. performed experiments. T.A. designed research. C.L., V.K. and G.L. designed the research, performed experiments, analysed the data and wrote the paper.
This file contains Supplementary Figures 1-11 with Legends (PDF 4489 kb)
Supplementary Video 1 shows the generation of non-adherent cells from tight adherent structures observed during blast cultures established with Flk1+ wild type cells. (MOV 5810 kb)
Supplementary Video 2 shows in the circle the generation of a blast colony from one Flk1+ cell through an intermediate stage corresponding to a cluster of tightly associated cells. Generation of blast colonies following aggregation of cells of different origins is also observed. (MOV 4873 kb)
Supplementary Video 3 shows the absence of generation of non adherent cells from tight adherent structures observed during blast cultures established with Flk1+ Runx1-/- cells. (MOV 3746 kb)
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Lancrin, C., Sroczynska, P., Stephenson, C. et al. The haemangioblast generates haematopoietic cells through a haemogenic endothelium stage. Nature 457, 892–895 (2009). https://doi.org/10.1038/nature07679
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