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      The haemangioblast generates haematopoietic cells through a haemogenic endothelium stage

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          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.

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          Most cited references 28

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          Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium.

          The vascular endothelial growth factor (VEGF) and its high-affinity binding receptors, the tyrosine kinases Flt-1 and Flk-1, are thought to be important for the development of embryonic vasculature. Here we report that Flt-1 is essential for the organization of embryonic vasculature, but is not essential for endothelial cell differentiation. Mouse embryos homozygous for a targeted mutation in the flt-1 locus, flt-1lcz, formed endothelial cells in both embryonic and extra-embryonic regions, but assembled these cells into abnormal vascular channels and died in utero at mid-somite stages. At earlier stages, the blood islands of flt-1lcz homozygotes were abnormal, with angioblasts in the interior as well as on the periphery. We suggest that the Flt-1 signalling pathway may regulate normal endothelial cell-cell or cell-matrix interactions during vascular development.
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            Development of erythroid and myeloid progenitors in the yolk sac and embryo proper of the mouse.

            In this study, we have mapped the onset of hematopoietic development in the mouse embryo using colony-forming progenitor assays and PCR-based gene expression analysis. With this approach, we demonstrate that commitment of embryonic cells to hematopoietic fates begins in proximal regions of the egg cylinder at the mid-primitive streak stage (E7.0) with the simultaneous appearance of primitive erythroid and macrophage progenitors. Development of these progenitors was associated with the expression of SCL/tal-1 and GATA-1, genes known to be involved in the development and maturation of the hematopoietic system. Kinetic analysis revealed the transient nature of the primitive erythroid lineage, as progenitors increased in number in the developing yolk sac until early somite-pair stages of development (E8.25) and then declined sharply to undetectable levels by 20 somite pairs (E9.0). Primitive erythroid progenitors were not detected in any other tissue at any stage of embryonic development. The early wave of primitive erythropoiesis was followed by the appearance of definitive erythroid progenitors (BFU-E) that were first detectable at 1-7 somite pairs (E8.25) exclusively within the yolk sac. The appearance of BFU-E was followed by the development of later stage definitive erythroid (CFU-E), mast cell and bipotential granulocyte/macrophage progenitors in the yolk sac. C-myb, a gene essential for definitive hematopoiesis, was expressed at low levels in the yolk sac just prior to and during the early development of these definitive erythroid progenitors. All hematopoietic activity was localized to the yolk sac until circulation was established (E8.5) at which time progenitors from all lineages were detected in the bloodstream and subsequently in the fetal liver following its development. This pattern of development suggests that definitive hematopoietic progenitors arise in the yolk sac, migrate through the bloodstream and seed the fetal liver to rapidly initiate the first phase of intraembryonic hematopoiesis. Together, these findings demonstrate that commitment to hematopoietic fates begins in early gastrulation, that the yolk sac is the only site of primitive erythropoiesis and that the yolk sac serves as the first source of definitive hematopoietic progenitors during embryonic development.
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              Defective angiogenesis in mice lacking endoglin.

              Endoglin is a transforming growth factor-beta (TGF-beta) binding protein expressed on the surface of endothelial cells. Loss-of-function mutations in the human endoglin gene ENG cause hereditary hemorrhagic telangiectasia (HHT1), a disease characterized by vascular malformations. Here it is shown that by gestational day 11.5, mice lacking endoglin die from defective vascular development. However, in contrast to mice lacking TGF-beta, vasculogenesis was unaffected. Loss of endoglin caused poor vascular smooth muscle development and arrested endothelial remodeling. These results demonstrate that endoglin is essential for angiogenesis and suggest a pathogenic mechanism for HHT1.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                13 March 2009
                28 January 2009
                12 February 2009
                12 August 2009
                : 457
                : 7231
                : 892-895
                Affiliations
                [1 ]Cancer Research UK Stem Cell Biology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow road, Manchester M20 4BX, United Kingdom
                [2 ]Cancer Research UK Structural Cell Biology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow road, Manchester M20 4BX, United Kingdom
                [3 ]Cancer Research UK Stem Cell Haematopoiesis Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow road, Manchester M20 4BX, United Kingdom
                Author notes
                Correspondence and requests for materials should be addressed to G.L. ( glacaud@ 123456picr.man.ac.uk ).

                Author Contributions P.S. designed, 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.

                Article
                UKMS4235
                10.1038/nature07679
                2661201
                19182774
                Funding
                Funded by: Cancer Research UK :
                Award ID: A5297 || CRUK_
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