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The haemangioblast generates haematopoietic cells through a haemogenic endothelium stage

Nature volume 457, pages 892–895 (2009)Cite this article

Abstract

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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Figure 1: Analysis of blast colony development.
Figure 2: Tie2 hi c-Kit + CD41 - cells can generate haematopoietic progenitors.
Figure 3: Runx1 requirement in blast colony development.
Figure 4: Scl requirement during blast colony development.

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References

  1. Sabin, F. R. Studies on the origin of blood vessels and of red corpuscules as seen in the living blastoderm of the chick during the second day of incubation: contributions to embryology. Contrib. Embryol. 9, 213–262 (1920)

    Google Scholar 

  2. Murray, P. D. F. The development in vitro of the blood of the early chick embryo. Proc. R. Soc. Lond. 11, 497–521 (1932)

    ADS  Google Scholar 

  3. Jaffredo, T., Gautier, R., Eichmann, A. & Dieterlen-Lievre, F. Intraaortic hemopoietic cells are derived from endothelial cells during ontogeny. Development 125, 4575–4583 (1998)

    Article  CAS  Google Scholar 

  4. Nishikawa, S. I. et al. In vitro generation of lymphohematopoietic cells from endothelial cells purified from murine embryos. Immunity 8, 761–769 (1998)

    Article  CAS  Google Scholar 

  5. North, T. E. et al. Runx1 expression marks long-term repopulating hematopoietic stem cells in the midgestation mouse embryo. Immunity 16, 661–672 (2002)

    Article  CAS  Google Scholar 

  6. Kennedy, M. et al. A common precursor for primitive erythropoiesis and definitive haematopoiesis. Nature 386, 488–493 (1997)

    Article  ADS  CAS  Google Scholar 

  7. Choi, K., Kennedy, M., Kazarov, A., Papadimitriou, J. C. & Keller, G. A common precursor for hematopoietic and endothelial cells. Development 125, 725–732 (1998)

    Article  CAS  Google Scholar 

  8. Huber, T. L., Kouskoff, V., Fehling, H. J., Palis, J. & Keller, G. Haemangioblast commitment is initiated in the primitive streak of the mouse embryo. Nature 432, 625–630 (2004)

    Article  ADS  CAS  Google Scholar 

  9. Vogeli, K. M., Jin, S. W., Martin, G. R. & Stainier, D. Y. A common progenitor for haematopoietic and endothelial lineages in the zebrafish gastrula. Nature 443, 337–339 (2006)

    Article  ADS  CAS  Google Scholar 

  10. Porcher, C. et al. The T cell leukemia oncoprotein SCL/tal-1 is essential for development of all hematopoietic lineages. Cell 86, 47–57 (1996)

    Article  CAS  Google Scholar 

  11. Okuda, T., van Deursen, J., Hiebert, S. W., Grosveld, G. & Downing, J. R. AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell 84, 321–330 (1996)

    Article  CAS  Google Scholar 

  12. Faloon, P. et al. Basic fibroblast growth factor positively regulates hematopoietic development. Development 127, 1931–1941 (2000)

    Article  CAS  Google Scholar 

  13. Dumont, D. J., Yamaguchi, T. P., Conlon, R. A., Rossant, J. & Breitman, M. L. tek, a novel tyrosine kinase gene located on mouse chromosome 4, is expressed in endothelial cells and their presumptive precursors. Oncogene 7, 1471–1480 (1992)

    CAS  PubMed  Google Scholar 

  14. Ferkowicz, M. J. et al. CD41 expression defines the onset of primitive and definitive hematopoiesis in the murine embryo. Development 130, 4393–4403 (2003)

    Article  CAS  Google Scholar 

  15. Mikkola, H. K., Fujiwara, Y., Schlaeger, T. M., Traver, D. & Orkin, S. H. Expression of CD41 marks the initiation of definitive hematopoiesis in the mouse embryo. Blood 101, 508–516 (2003)

    Article  CAS  Google Scholar 

  16. Li, W., Ferkowicz, M. J., Johnson, S. A., Shelley, W. C. & Yoder, M. C. Endothelial cells in the early murine yolk sac give rise to CD41-expressing hematopoietic cells. Stem Cells Dev. 14, 44–54 (2005)

    Article  Google Scholar 

  17. Newman, P. J. et al. PECAM-1 (CD31) cloning and relation to adhesion molecules of the immunoglobulin gene superfamily. Science 247, 1219–1222 (1990)

    Article  ADS  CAS  Google Scholar 

  18. Hirai, H. et al. Hemogenic and nonhemogenic endothelium can be distinguished by the activity of fetal liver kinase (Flk)-1 promoter/enhancer during mouse embryogenesis. Blood 101, 886–893 (2003)

    Article  CAS  Google Scholar 

  19. Hallmann, R., Mayer, D. N., Berg, E. L., Broermann, R. & Butcher, E. C. Novel mouse endothelial cell surface marker is suppressed during differentiation of the blood brain barrier. Dev. Dyn. 202, 325–332 (1995)

    Article  CAS  Google Scholar 

  20. Young, P. E., Baumhueter, S. & Lasky, L. A. The sialomucin CD34 is expressed on hematopoietic cells and blood vessels during murine development. Blood 85, 96–105 (1995)

    Article  CAS  Google Scholar 

  21. Li, D. Y. et al. Defective angiogenesis in mice lacking endoglin. Science 284, 1534–1537 (1999)

    Article  ADS  CAS  Google Scholar 

  22. Fong, G. H., Rossant, J., Gertsenstein, M. & Breitman, M. L. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376, 66–70 (1995)

    Article  ADS  CAS  Google Scholar 

  23. Breier, G. et al. Molecular cloning and expression of murine vascular endothelial-cadherin in early stage development of cardiovascular system. Blood 87, 630–641 (1996)

    Article  CAS  Google Scholar 

  24. Mukouyama, Y. et al. The AML1 transcription factor functions to develop and maintain hematogenic precursor cells in the embryonic aorta–gonad–mesonephros region. Dev. Biol. 220, 27–36 (2000)

    Article  CAS  Google Scholar 

  25. Fehling, H. J. et al. Tracking mesoderm induction and its specification to the hemangioblast during embryonic stem cell differentiation. Development 130, 4217–4227 (2003)

    Article  CAS  Google Scholar 

  26. Palis, J., Robertson, S., Kennedy, M., Wall, C. & Keller, G. Development of erythroid and myeloid progenitors in the yolk sac and embryo proper of the mouse. Development 126, 5073–5084 (1999)

    Article  CAS  Google Scholar 

  27. Lacaud, G. et al. Runx1 is essential for hematopoietic commitment at the hemangioblast stage of development in vitro . Blood 100, 458–466 (2002)

    Article  CAS  Google Scholar 

  28. Voyta, J. C., Via, D. P., Butterfield, C. E. & Zetter, B. R. Identification and isolation of endothelial cells based on their increased uptake of acetylated-low density lipoprotein. J. Cell Biol. 99, 2034–2040 (1984)

    Article  CAS  Google Scholar 

  29. D’Souza, S. L., Elefanty, A. G. & Keller, G. SCL/Tal-1 is essential for hematopoietic commitment of the hemangioblast but not for its development. Blood 105, 3862–3870 (2005)

    Article  Google Scholar 

  30. Kyba, M., Perlingeiro, R. C. & Daley, G. Q. HoxB4 confers definitive lymphoid–myeloid engraftment potential on embryonic stem cell and yolk sac hematopoietic progenitors. Cell 109, 29–37 (2002)

    Article  CAS  Google Scholar 

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Acknowledgements

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.

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Authors and Affiliations

  1. Cancer Research UK Stem Cell Biology Group,,

    Christophe Lancrin, Patrycja Sroczynska, Catherine Stephenson & Georges Lacaud

  2. Cancer Research UK Structural Cell Biology Group,,

    Terry Allen

  3. Cancer Research UK Stem Cell Haematopoiesis Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow road, Manchester M20 4BX, UK ,

    Valerie Kouskoff

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  1. Christophe Lancrin
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  6. Georges Lacaud
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Corresponding author

Correspondence to Georges Lacaud.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-11 with Legends (PDF 4489 kb)

Supplementary Video 1

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

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

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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