Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis


Haematopoietic stem cell (HSC) homeostasis is tightly controlled by growth factors, signalling molecules and transcription factors. Definitive HSCs derived during embryogenesis in the aorta–gonad–mesonephros region subsequently colonize fetal and adult haematopoietic organs1,2. To identify new modulators of HSC formation and homeostasis, a panel of biologically active compounds was screened for effects on stem cell induction in the zebrafish aorta–gonad–mesonephros region. Here, we show that chemicals that enhance prostaglandin (PG) E2 synthesis increased HSC numbers, and those that block prostaglandin synthesis decreased stem cell numbers. The cyclooxygenases responsible for PGE2 synthesis were required for HSC formation. A stable derivative of PGE2 improved kidney marrow recovery following irradiation injury in the adult zebrafish. In murine embryonic stem cell differentiation assays, PGE2 caused amplification of multipotent progenitors. Furthermore, ex vivo exposure to stabilized PGE2 enhanced spleen colony forming units at day 12 post transplant and increased the frequency of long-term repopulating HSCs present in murine bone marrow after limiting dilution competitive transplantation. The conserved role for PGE2 in the regulation of vertebrate HSC homeostasis indicates that modulation of the prostaglandin pathway may facilitate expansion of HSC number for therapeutic purposes.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Prostaglandin agonists and antagonists alter runx1/cmyb expression without affecting vascular development.
Figure 2: Treatment with dmPGE2 enhances haematopoietic recovery in sublethally irradiated adult zebrafish.
Figure 3: dmPGE2 modulates colony number and haematopoietic differentiation in mouse embryonic stem cells.
Figure 4: Exposure of murine bone marrow to dmPGE2 increases the number of CFU-S and repopulating HSCs.


  1. Dzierzak, E. The emergence of definitive hematopoietic stem cells in the mammal. Curr. Opin. Hematol. 12, 197–202 (2005)

    Article  Google Scholar 

  2. Galloway, J. L. & Zon, L. I. Ontogeny of hematopoiesis: examining the emergence of hematopoietic cells in the vertebrate embryo. Curr. Top. Dev. Biol. 53, 139–158 (2003)

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  4. Mukouyama, Y. et al. Hematopoietic cells in cultures of the murine embryonic aorta-gonad-mesonephros region are induced by c-Myb. Curr. Biol. 9, 833–836 (1999)

    CAS  Article  Google Scholar 

  5. Kalev-Zylinska, M. L. et al. Runx1 is required for zebrafish blood and vessel development and expression of a human RUNX1–CBF2T1 transgene advances a model for studies of leukemogenesis. Development 129, 2015–2030 (2002)

    CAS  PubMed  Google Scholar 

  6. Grosser, T., Yusuff, S., Cheskis, E., Pack, M. A. & FitzGerald, G. A. Developmental expression of functional cyclooxygenases in zebrafish. Proc. Natl Acad. Sci. USA 99, 8418–8423 (2002)

    CAS  Article  ADS  Google Scholar 

  7. Cha, Y. I., Kim, S. H., Solnica-Krezel, L. & Dubois, R. N. Cyclooxygenase-1 signaling is required for vascular tube formation during development. Dev. Biol. 282, 274–283 (2005)

    CAS  Article  Google Scholar 

  8. Cha, Y. I. et al. Cyclooxygenase-1-derived PGE2 promotes cell motility via the G-protein-coupled EP4 receptor during vertebrate gastrulation. Genes Dev. 20, 77–86 (2006)

    CAS  Article  Google Scholar 

  9. Burns, C. E., Traver, D., Mayhall, E., Shepard, J. L. & Zon, L. I. Hematopoietic stem cell fate is established by the Notch-Runx pathway. Genes Dev. 19, 2331–2342 (2005)

    CAS  Article  Google Scholar 

  10. Nakano, T., Kodama, H. & Honjo, T. In vitro development of primitive and definitive erythrocytes from different precursors. Science 272, 722–724 (1996)

    CAS  Article  ADS  Google Scholar 

  11. Ivanova, N. B. et al. A stem cell molecular signature. Science 298, 601–604 (2002)

    CAS  Article  ADS  Google Scholar 

  12. Akashi, K. et al. Transcriptional accessibility for genes of multiple tissues and hematopoietic lineages is hierarchically controlled during early hematopoiesis. Blood 101, 383–389 (2003)

    CAS  Article  Google Scholar 

  13. Venezia, T. A. et al. Molecular signatures of proliferation and quiescence in hematopoietic stem cells. PLoS Biol. 2, e301 (2004)

    Article  Google Scholar 

  14. Zhang, C. C. & Lodish, H. F. Insulin-like growth factor 2 expressed in a novel fetal liver cell population is a growth factor for hematopoietic stem cells. Blood 103, 2513–2521 (2004)

    CAS  Article  Google Scholar 

  15. Boer, A. K., Drayer, A. L., Rui, H. & Vellenga, E. Prostaglandin-E2 enhances EPO-mediated STAT5 transcriptional activity by serine phosphorylation of CREB. Blood 100, 467–473 (2002)

    CAS  Article  Google Scholar 

  16. Rocca, B. et al. Cyclooxygenase-2 expression is induced during human megakaryopoiesis and characterizes newly formed platelets. Proc. Natl Acad. Sci. USA 99, 7634–7639 (2002)

    CAS  Article  ADS  Google Scholar 

  17. Feher, I. & Gidali, J. Prostaglandin E2 as stimulator of haemopoietic stem cell proliferation. Nature 247, 550–551 (1974)

    CAS  Article  ADS  Google Scholar 

  18. Langenbach, R., Loftin, C., Lee, C. & Tiano, H. Cyclooxygenase knockout mice: models for elucidating isoform-specific functions. Biochem. Pharmacol. 58, 1237–1246 (1999)

    CAS  Article  Google Scholar 

  19. Langenbach, R. et al. Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration. Cell 83, 483–492 (1995)

    CAS  Article  Google Scholar 

  20. Lorenz, M. et al. Cyclooxygenase-2 is essential for normal recovery from 5-fluorouracil-induced myelotoxicity in mice. Exp. Hematol. 27, 1494–1502 (1999)

    CAS  Article  Google Scholar 

  21. Cayeux, S. J., Beverley, P. C., Schulz, R. & Dorken, B. Elevated plasma prostaglandin E2 levels found in 14 patients undergoing autologous bone marrow or stem cell transplantation. Bone Marrow Transplant. 12, 603–608 (1993)

    CAS  PubMed  Google Scholar 

  22. Talosi, G. et al. Prostaglandin E1 treatment in patent ductus arteriosus dependent congenital heart defects. J. Perinat. Med. 32, 368–374 (2004)

    CAS  Article  Google Scholar 

  23. Thanopoulos, B. D., Andreou, A. & Frimas, C. Prostaglandin E2 administration in infants with ductus-dependent cyanotic congenital heart disease. Eur. J. Pediatr. 146, 279–282 (1987)

    CAS  Article  Google Scholar 

  24. Hertelendy, F., Woods, R. & Jaffe, B. M. Prostaglandin E levels in peripheral blood during labor. Prostaglandins 3, 223–227 (1973)

    CAS  Article  Google Scholar 

  25. Zhu, H. et al. Regulation of the lmo2 promoter during hematopoietic and vascular development in zebrafish. Dev. Biol. 281, 256–269 (2005)

    CAS  Article  Google Scholar 

  26. Weber, G. J. et al. Mutant-specific gene programs in the zebrafish. Blood 106, 521–530 (2005)

    CAS  Article  Google Scholar 

  27. Pini, B. et al. Prostaglandin E synthases in zebrafish. Arterioscler. Thromb. Vasc. Biol. 25, 315–320 (2005)

    CAS  Article  Google Scholar 

  28. Traver, D. et al. Effects of lethal irradiation in zebrafish and rescue by hematopoietic cell transplantation. Blood 104, 1298–1305 (2004)

    CAS  Article  Google Scholar 

  29. Kyba, M. et al. Enhanced hematopoietic differentiation of embryonic stem cells conditionally expressing Stat5. Proc. Natl Acad. Sci. USA 100 (Suppl 1). 11904–11910 (2003)

    CAS  Article  ADS  Google Scholar 

  30. Wang, Y., Yates, F., Naveiras, O., Ernst, P. & Daley, G. Q. Embryonic stem cell-derived hematopoietic stem cells. Proc. Natl Acad. Sci. USA 102, 19081–19086 (2005)

    CAS  Article  ADS  Google Scholar 

Download references


We thank the Institute of Chemical and Cellular Biology at Harvard Medical School for access to the chemical libraries used in the screen. We thank: A. Flint, E. Mayhall and C.E. Burns for technical assistance and advice on the kidney marrow analysis; C. Thisse and B. Thisse for information and plasmids for PTGER2; and A. Meyers and J. Ojeda for technical help with the zebrafish chemical screen. This work was supported by grants from the National Institutes of Health (T.E.N., W.G., G.Q.D., S.H.O., G.A.F. and L.I.Z), the American Cancer Socitey (T.E.N.), the American Gastroenterological Association (W.G.), the Leukemia and Lymphoma Society (C.R.W.), the American Heart Association (T.G.) and the Dr. Mildred Scheel Foundation for Cancer Research (C.L.). S.H.O. and L.I.Z. are Howard Hughes Medical Institute investigators.

Author Contributions T.E.N. and K.R.K. conducted the chemical screen. T.E.N., W.G. and A.M.L. performed the zebrafish prostaglandin studies. T.E.N. and C.R.W. conducted the murine experiments. G.J.W. completed the microarray analysis. T.E.N., W.G. and T.V.B. performed 5-FU treatment. T.G. provided cox1 and cox2 probes and completed the mass spectroscopy analysis. C.L. and I.H.J. performed the embryonic stem cell assays. T.E.N., W.G. and L.I.Z. wrote the manuscript. All authors discussed results and commented on the manuscript.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Leonard I. Zon.

Ethics declarations

Competing interests

Reprints and permissions information is available at The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-5 with Legends and Supplementary Tables 1-10. (PDF 2101 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

North, T., Goessling, W., Walkley, C. et al. Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature 447, 1007–1011 (2007).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing