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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
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).
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).
Medvinsky, A. & Dzierzak, E. Definitive hematopoiesis is autonomously initiated by the AGM region. Cell 86, 897–906 (1996).
Jaffredo, T. et al. From hemangioblast to hematopoietic stem cell: an endothelial connection? Exp. Hematol. 33, 1029–1040 (2005).
Kissa, K. & Herbomel, P. Blood stem cells emerge from aortic endothelium by a novel type of cell transition. Nature 464, 112–115 (2010).
Bertrand, J. Y. et al. Haematopoietic stem cells derive directly from aortic endothelium during development. Nature 464, 108–111 (2010).
Boisset, J. C. et al. In vivo imaging of haematopoietic cells emerging from the mouse aortic endothelium. Nature 464, 116–120 (2010).
Eilken, H. M., Nishikawa, S. & Schroeder, T. Continuous single-cell imaging of blood generation from haemogenic endothelium. Nature 457, 896–900 (2009).
Iacovino, M. et al. HoxA3 is an apical regulator of haemogenic endothelium. Nature Cell Biol. 13, 72–78 (2011).
Kumano, K. et al. Notch1 but not Notch2 is essential for generating hematopoietic stem cells from endothelial cells. Immunity 18, 699–711 (2003).
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).
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).
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).
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).
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).
Liao, W. et al. Generation of a mouse line expressing Sox17-driven cre recombinase with specific activity in arteries. Genesis 47, 476–483 (2009).
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).
Choi, E. et al. Dual lineage-specific expression of Sox17 during mouse embryogenesis. Stem cells 30, 2297–2308 (2012).
Irion, S. et al. Temporal specification of blood progenitors from mouse embryonic stem cells and induced pluripotent stem cells. Development 137, 2829–2839 (2010).
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).
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).
Yoshimoto, M. et al. Autonomous murine T-cell progenitor production inthe extra-embryonic yolk sac before HSC emergence. Blood 119, 5706–5714 (2012).
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).
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).
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).
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).
Nakajima-Takagi, Y. et al. Role of SOX17 in hematopoietic development from human embryonic stem cells. Blood 121, 447–458 (2013).
Pendeville, H. et al. Zebrafish Sox7 and Sox18 function together to control arterial-venous identity. Dev. Biol. 317, 405–416 (2008).
Yokomizo, T. et al. Whole-mount three-dimensional imaging of internally localized immunostained cells within mouse embryos. Nat. Protocol. 7, 421–431 (2012).
Ying, Q. L. et al. The ground state of embryonic stem cell self-renewal. Nature 453, 519–523 (2008).
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).
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)
Author information
Authors and Affiliations
Contributions
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.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Information
Supplementary Information (PDF 1265 kb)
Supplementary Information
Supplementary Table 1 (XLSX 51 kb)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ncb2724
This article is cited by
-
A Sox17 downstream gene Rasip1 is involved in the hematopoietic activity of intra-aortic hematopoietic clusters in the midgestation mouse embryo
Inflammation and Regeneration (2023)
-
The construction of a testis transcriptional cell atlas from embryo to adult reveals various somatic cells and their molecular roles
Journal of Translational Medicine (2023)
-
Ferric citrate and apo-transferrin enable erythroblast maturation with β-globin from hemogenic endothelium
npj Regenerative Medicine (2023)
-
A genome-wide relay of signalling-responsive enhancers drives hematopoietic specification
Nature Communications (2023)
-
Integrative epigenomic and transcriptomic analysis reveals the requirement of JUNB for hematopoietic fate induction
Nature Communications (2022)