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The expression of Sox17 identifies and regulates haemogenic endothelium

Abstract

Although it is well recognized that haematopoietic stem cells (HSCs) develop from a specialized population of endothelial cells known as haemogenic endothelium, the regulatory pathways that control this transition are not well defined. Here we identify Sox17 as a key regulator of haemogenic endothelial development. Analysis of Sox17–GFP reporter mice revealed that Sox17 is expressed in haemogenic endothelium and emerging HSCs and that it is required for HSC development. Using the mouse embryonic stem cell differentiation model, we show that Sox17 is also expressed in haemogenic endothelium generated in vitro and that it plays a pivotal role in the development and/or expansion of haemogenic endothelium through the Notch signalling pathway. Taken together, these findings position Sox17 as a key regulator of haemogenic endothelial and haematopoietic development.

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Figure 1: Expression of Sox17 identifies the emergence of haemogenic endothelial and haematopoietic progenitors in vitro.
Figure 2: Sox17 expression marks haemogenic endothelium in vivo and is required for the generation of long-term repopulating HSCs.
Figure 3: Expression of Sox17 is required for the EHT and definitive haematopoiesis in mESC differentiation cultures.
Figure 4: Effects of enforced Sox17 expression on haemogenic endothelial and haematopoietic development.
Figure 5: The effects of enforced Sox17 expression are mediated through Notch signalling.

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References

  1. 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).

    CAS  Google Scholar 

  2. Cumano, A., Dieterlen-Lievre, F. & Godin, I. Lymphoid potential, probed before circulation in mouse, is restricted to caudal intraembryonic splanchnopleura. Cell 86, 907–916 (1996).

    Article  CAS  Google Scholar 

  3. Medvinsky, A. & Dzierzak, E. Definitive hematopoiesis is autonomously initiated by the AGM region. Cell 86, 897–906 (1996).

    Article  CAS  Google Scholar 

  4. Jaffredo, T. et al. From hemangioblast to hematopoietic stem cell: an endothelial connection? Exp. Hematol. 33, 1029–1040 (2005).

    Article  Google Scholar 

  5. Kissa, K. & Herbomel, P. Blood stem cells emerge from aortic endothelium by a novel type of cell transition. Nature 464, 112–115 (2010).

    Article  CAS  Google Scholar 

  6. Bertrand, J. Y. et al. Haematopoietic stem cells derive directly from aortic endothelium during development. Nature 464, 108–111 (2010).

    Article  CAS  Google Scholar 

  7. Boisset, J. C. et al. In vivo imaging of haematopoietic cells emerging from the mouse aortic endothelium. Nature 464, 116–120 (2010).

    Article  CAS  Google Scholar 

  8. Eilken, H. M., Nishikawa, S. & Schroeder, T. Continuous single-cell imaging of blood generation from haemogenic endothelium. Nature 457, 896–900 (2009).

    Article  CAS  Google Scholar 

  9. Iacovino, M. et al. HoxA3 is an apical regulator of haemogenic endothelium. Nature Cell Biol. 13, 72–78 (2011).

    Article  CAS  Google Scholar 

  10. Kumano, K. et al. Notch1 but not Notch2 is essential for generating hematopoietic stem cells from endothelial cells. Immunity 18, 699–711 (2003).

    Article  CAS  Google Scholar 

  11. Chen, M. J., Yokomizo, T., Zeigler, B. M., Dzierzak, E. & Speck, N. A. Runx1 is required for the endothelial to haematopoietic cell transition but not thereafter. Nature 457, 887–891 (2009).

    Article  CAS  Google Scholar 

  12. Serrano, A. G., Gandillet, A., Pearson, S., Lacaud, G. & Kouskoff, V. Contrasting effects of Sox17- and Sox18-sustained expression at the onset of blood specification. Blood 115, 3895–3898 (2010).

    Article  CAS  Google Scholar 

  13. Costa, G. et al. SOX7 regulates the expression of VE-cadherin in the haemogenic endothelium at the onset of haematopoietic development. Development 139, 1587–1598 (2012).

    Article  CAS  Google Scholar 

  14. Gandillet, A. et al. Sox7-sustained expression alters the balance between proliferation and differentiation of hematopoietic progenitors at the onset of blood specification. Blood 114, 4813–4822 (2009).

    Article  CAS  Google Scholar 

  15. Sakamoto, Y. et al. Redundant roles of Sox17 and Sox18 in early cardiovascular development of mouse embryos. Biochem. Biophys. Res. Commun. 360, 539–544 (2007).

    Article  CAS  Google Scholar 

  16. Liao, W. et al. Generation of a mouse line expressing Sox17-driven cre recombinase with specific activity in arteries. Genesis 47, 476–483 (2009).

    Article  CAS  Google Scholar 

  17. Kim, I., Saunders, T.L. & Morrison, S.J. Sox17 dependence distinguishes the transcriptional regulation of fetal from adult hematopoietic stem cells. Cell 130, 470–483 (2007).

    Article  CAS  Google Scholar 

  18. Choi, E. et al. Dual lineage-specific expression of Sox17 during mouse embryogenesis. Stem cells 30, 2297–2308 (2012).

    Article  CAS  Google Scholar 

  19. Irion, S. et al. Temporal specification of blood progenitors from mouse embryonic stem cells and induced pluripotent stem cells. Development 137, 2829–2839 (2010).

    Article  CAS  Google Scholar 

  20. Burtscher, I., Barkey, W., Schwarzfischer, M. & Theis, F.J. Lickert, H. The Sox17-mCherry fusion mouse line allows visualization of endoderm and vascular endothelial development. Genesis 50, 496–505 (2012).

    Article  CAS  Google Scholar 

  21. Taoudi, S. et al. Extensive hematopoietic stem cell generation in the AGM region via maturation of VE-cadherin+CD45+ pre-definitive HSCs. Cell Stem Cell 3, 99–108 (2008).

    Article  CAS  Google Scholar 

  22. Yoshimoto, M. et al. Autonomous murine T-cell progenitor production inthe extra-embryonic yolk sac before HSC emergence. Blood 119, 5706–5714 (2012).

    Article  CAS  Google Scholar 

  23. Yurugi-Kobayashi, T. et al. Adrenomedullin/cyclic AMP pathway induces Notch activation and differentiation of arterial endothelial cells from vascular progenitors. Arterioscler. Thromb. Vasc. Biol. 26, 1977–1984 (2006).

    Article  CAS  Google Scholar 

  24. 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 

  25. Bryne, J. C. et al. JASPAR, the open access database of transcription factor-binding profiles: new content and tools in the 2008 update. Nucleic Acids Res. 36, D102–D106 (2008).

    Article  CAS  Google Scholar 

  26. Chen, M. J. et al. Erythroid/myeloid progenitors and hematopoietic stem cells originate from distinct populations of endothelial cells. Cell Stem Cell 9, 541–552 (2011).

    Article  CAS  Google Scholar 

  27. Nakajima-Takagi, Y. et al. Role of SOX17 in hematopoietic development from human embryonic stem cells. Blood 121, 447–458 (2013).

    Article  CAS  Google Scholar 

  28. Pendeville, H. et al. Zebrafish Sox7 and Sox18 function together to control arterial-venous identity. Dev. Biol. 317, 405–416 (2008).

    Article  CAS  Google Scholar 

  29. Yokomizo, T. et al. Whole-mount three-dimensional imaging of internally localized immunostained cells within mouse embryos. Nat. Protocol. 7, 421–431 (2012).

    Article  CAS  Google Scholar 

  30. Ying, Q. L. et al. The ground state of embryonic stem cell self-renewal. Nature 453, 519–523 (2008).

    Article  CAS  Google Scholar 

  31. Gadue, P., Huber, T. L., Paddison, P. J. & Keller, G. M. Wnt and TGF-beta signalling are required for the induction of an in vitro model of primitive streak formation using embryonic stem cells. Proc. Natl Acad. Sci. USA 103, 16806–16811 (2006).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank S. Morrison and H. Lickert for sharing of mice and mESC lines. We thank C. Sturgeon, A. Ditadi and B. Chanda for advice and technical support with the studies and comments on the manuscript. This work was supported by the Canadian Institutes of Health Research (CIHR MOP-95369) and the National Institutes of Health (NIH 5U01 HL100395)

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R.C. and G.K. designed experiments and wrote the manuscript. G.K. supervised the project. R.C. performed all mESC and transplantation experiments. A.Y. performed confocal imaging. Y.Y. performed JASPER analysis and luciferase assays. A.B. and C.B. generated the doxycycline-inducible mESC line.

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Correspondence to Gordon Keller.

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The authors declare no competing financial interests.

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Clarke, R., Yzaguirre, A., Yashiro-Ohtani, Y. et al. The expression of Sox17 identifies and regulates haemogenic endothelium. Nat Cell Biol 15, 502–510 (2013). https://doi.org/10.1038/ncb2724

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