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.

Differential stem- and progenitor-cell trafficking by prostaglandin E2


To maintain lifelong production of blood cells, haematopoietic stem cells (HSCs) are tightly regulated by inherent programs and extrinsic regulatory signals received from their microenvironmental niche. Long-term repopulating HSCs reside in several, perhaps overlapping, niches that produce regulatory molecules and signals necessary for homeostasis and for increased output after stress or injury1,2,3,4,5. Despite considerable advances in the specific cellular or molecular mechanisms governing HSC–niche interactions, little is known about the regulatory function in the intact mammalian haematopoietic niche. Recently, we and others described a positive regulatory role for prostaglandin E2 (PGE2) on HSC function ex vivo6,7. Here we show that inhibition of endogenous PGE2 by non-steroidal anti-inflammatory drug (NSAID) treatment in mice results in modest HSC egress from the bone marrow. Surprisingly, this was independent of the SDF-1–CXCR4 axis implicated in stem-cell migration. Stem and progenitor cells were found to have differing mechanisms of egress, with HSC transit to the periphery dependent on niche attenuation and reduction in the retentive molecule osteopontin. Haematopoietic grafts mobilized with NSAIDs had superior repopulating ability and long-term engraftment. Treatment of non-human primates and healthy human volunteers confirmed NSAID-mediated egress in other species. PGE2 receptor knockout mice demonstrated that progenitor expansion and stem/progenitor egress resulted from reduced E-prostanoid 4 (EP4) receptor signalling. These results not only uncover unique regulatory roles for EP4 signalling in HSC retention in the niche, but also define a rapidly translatable strategy to enhance transplantation therapeutically.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

Figure 1: NSAIDs mobilize haematopoietic stem and progenitor cells.
Figure 2: Non-human primates and healthy human volunteers mobilize HSCs and HPCs in response to NSAID treatment.
Figure 3: PGE 2 EP4 receptor antagonism/knockout expands bone marrow HPCs and enhances mobilization.
Figure 4: NSAIDs attenuate haematopoietic supportive molecules and differentially mobilize HSCs and HPCs in Opn knockout and EP4 conditional knockout mice.


  1. Calvi, L. M. et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425, 841–846 (2003)

    Article  CAS  ADS  Google Scholar 

  2. Ding, L., Saunders, T. L., Enikolopov, G. & Morrison, S. J. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 481, 457–462 (2012)

    Article  CAS  ADS  Google Scholar 

  3. Méndez-Ferrer, S. et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466, 829–834 (2010)

    Article  ADS  Google Scholar 

  4. Raaijmakers, M. H. et al. Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature 464, 852–857 (2010)

    Article  CAS  ADS  Google Scholar 

  5. Zhang, J. et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425, 836–841 (2003)

    Article  CAS  ADS  Google Scholar 

  6. Hoggatt, J., Singh, P., Sampath, J. & Pelus, L. M. Prostaglandin E2 enhances hematopoietic stem cell homing, survival, and proliferation. Blood 113, 5444–5455 (2009)

    Article  CAS  Google Scholar 

  7. North, T. E. et al. Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature 447, 1007–1011 (2007)

    Article  CAS  ADS  Google Scholar 

  8. Ahmed, M., Khanna, D. & Furst, D. E. Meloxicam in rheumatoid arthritis. Expert Opin. Drug Metab. Toxicol. 1, 739–751 (2005)

    Article  CAS  Google Scholar 

  9. Rinder, H. M. et al. Effects of meloxicam on platelet function in healthy adults: a randomized, double-blind, placebo-controlled trial. J. Clin. Pharmacol. 42, 881–886 (2002)

    Article  CAS  Google Scholar 

  10. Breyer, R. M., Bagdassarian, C. K., Myers, S. A. & Breyer, M. D. Prostanoid receptors: subtypes and signaling. Annu. Rev. Pharmacol. Toxicol. 41, 661–690 (2001)

    Article  CAS  Google Scholar 

  11. Katayama, Y. et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 124, 407–421 (2006)

    Article  CAS  Google Scholar 

  12. Bethel, M., Srour, E. F. & Kacena, M. A. Hematopoietic cell regulation of osteoblast proliferation and differentiation. Curr. Osteoporos. Rep. 9, 96–102 (2011)

    Article  Google Scholar 

  13. Hoggatt, J. & Pelus, L. M. Many mechanisms mediating mobilization: an alliterative review. Curr. Opin. Hematol. 18, 231–238 (2011)

    Article  CAS  Google Scholar 

  14. Mundy, G. R., Yoneda, T. & Hiraga, T. Preclinical studies with zoledronic acid and other bisphosphonates: impact on the bone microenvironment. Semin. Oncol. 28, 35–44 (2001)

    Article  CAS  Google Scholar 

  15. Winkler, I. G. et al. Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSCs. Blood 116, 4815–4828 (2010)

    Article  CAS  Google Scholar 

  16. Chow, A. et al. Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. J. Exp. Med. 208, 261–271 (2011)

    Article  CAS  Google Scholar 

  17. Christopher, M. J., Rao, M., Liu, F., Woloszynek, J. R. & Link, D. C. Expression of the G-CSF receptor in monocytic cells is sufficient to mediate hematopoietic progenitor mobilization by G-CSF in mice. J. Exp. Med. 208, 251–260 (2011)

    Article  CAS  Google Scholar 

  18. Heissig, B. et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of Kit-ligand. Cell 109, 625–637 (2002)

    Article  CAS  Google Scholar 

  19. Chitteti, B. R. et al. Impact of interactions of cellular components of the bone marrow microenvironment on hematopoietic stem and progenitor cell function. Blood 115, 3239–3248 (2010)

    Article  CAS  Google Scholar 

  20. Nakamura, Y. et al. Isolation and characterization of endosteal niche cell populations that regulate hematopoietic stem cells. Blood 116, 1422–1432 (2010)

    Article  CAS  Google Scholar 

  21. Stier, S. et al. Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size. J. Exp. Med. 201, 1781–1791 (2005)

    Article  CAS  Google Scholar 

  22. Grassinger, J. et al. Thrombin-cleaved osteopontin regulates hemopoietic stem and progenitor cell functions through interactions with α9β1 and α4β1 integrins. Blood 114, 49–59 (2009)

    Article  CAS  Google Scholar 

  23. Nie, Y. et al. The role of CXCR4 in maintaining peripheral B cell compartments and humoral immunity. J. Exp. Med. 200, 1145–1156 (2004)

    Article  CAS  Google Scholar 

  24. Kennedy, C. R. et al. Salt-sensitive hypertension and reduced fertility in mice lacking the prostaglandin EP2 receptor. Nature Med. 5, 217–220 (1999)

    Article  CAS  Google Scholar 

  25. Guan, Y. et al. Antihypertensive effects of selective prostaglandin E2 receptor subtype 1 targeting. J. Clin. Invest. 117, 2496–2505 (2007)

    Article  CAS  Google Scholar 

  26. Schneider, A. et al. Generation of a conditional allele of the mouse prostaglandin EP4 receptor. Genesis 40, 7–14 (2004)

    Article  CAS  Google Scholar 

  27. Mignone, J. L., Kukekov, V., Chiang, A. S., Steindler, D. & Enikolopov, G. Neural stem and progenitor cells in nestin-GFP transgenic mice. J. Comp. Neurol. 469, 311–324 (2004)

    Article  CAS  Google Scholar 

  28. Kalajzic, Z. et al. Directing the expression of a green fluorescent protein transgene in differentiated osteoblasts: comparison between rat type I collagen and rat osteocalcin promoters. Bone 31, 654–660 (2002)

    Article  CAS  Google Scholar 

  29. Chen, X. S., Sheller, J. R., Johnson, E. N. & Funk, C. D. Role of leukotrienes revealed by targeted disruption of the 5-lipoxygenase gene. Nature 372, 179–182 (1994)

    Article  CAS  ADS  Google Scholar 

  30. King, A. G. et al. Rapid mobilization of murine hematopoietic stem cells with enhanced engraftment properties and evaluation of hematopoietic progenitor cell mobilization in rhesus monkeys by a single injection of SB-251353, a specific truncated form of the human CXC chemokine GROβ. Blood 97, 1534–1542 (2001)

    Article  CAS  Google Scholar 

  31. Pelus, L. M., Broxmeyer, H. E., Kurland, J. I. & Moore, M. A. Regulation of macrophage and granulocyte proliferation. Specificities of prostaglandin E and lactoferrin. J. Exp. Med. 150, 277–292 (1979)

    Article  CAS  Google Scholar 

  32. Broxmeyer, H. E. et al. SDF-1/CXCL12 enhances in vitro replating capacity of murine and human multipotential and macrophage progenitor cells. Stem Cells Dev. 16, 589–596 (2007)

    Article  CAS  Google Scholar 

  33. Fukuda, S., Bian, H., King, A. G. & Pelus, L. M. The chemokine GROβ mobilizes early hematopoietic stem cells characterized by enhanced homing and engraftment. Blood 110, 860–869 (2007)

    Article  CAS  Google Scholar 

  34. Hoggatt, A. F., Hoggatt, J., Honerlaw, M. & Pelus, L. M. A spoonful of sugar helps the medicine go down: a novel technique to improve oral gavage in mice. J. Am. Assoc. Lab. Anim. Sci. 49, 329–334 (2010)

    PubMed  PubMed Central  Google Scholar 

  35. Sutherland, D. R., Anderson, L., Keeney, M., Nayar, R. & Chin-Yee, I. The ISHAGE guidelines for CD34+ cell determination by flow cytometry. J. Hematother. 5, 213–226 (1996)

    Article  CAS  Google Scholar 

  36. Mohammad, K. S. et al. Pharmacologic inhibition of the TGF-β type I receptor kinase has anabolic and anti-catabolic effects on bone. PLoS ONE 4, e5275 (2009)

    Article  ADS  Google Scholar 

  37. Rowe, P. S. et al. Correction of the mineralization defect in hyp mice treated with protease inhibitors CA074 and pepstatin. Bone 39, 773–786 (2006)

    Article  CAS  Google Scholar 

  38. Parfitt, A. M. et al. Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J. Bone Miner. Res. 2, 595–610 (1987)

    Article  CAS  Google Scholar 

  39. Murali, G. et al. Fish oil and indomethacin in combination potently reduce dyslipidemia and hepatic steatosis in LDLR−/− mice. J. Lipid Res. 53, 2186–2197 (2012)

    Article  CAS  Google Scholar 

  40. Liu, T. et al. Prostaglandin E2 deficiency uncovers a dominant role for thromboxane A2 in house dust mite-induced allergic pulmonary inflammation. Proc. Natl Acad. Sci. USA 109, 12692–12697 (2012)

    Article  CAS  ADS  Google Scholar 

Download references


These studies were supported by National Institutes of Health (NIH) grants HL096305 (L.M.P.), CA143057, CA069158 (T.A.G., K.S.M.), HL100402 (D.T.S.) and DK37097 (R.M.B.). J.H. was supported by NIH training grants DK07519, HL07910 and HL087735. Flow cytometry was performed in the Flow Cytometry Resource Facility of the Indiana University Simon Cancer Center (NCI P30 CA082709). Additional core support was provided by a Center of Excellence in Hematology grant P01 DK090948. The authors would like to thank H. E. Broxmeyer and B. Saez for critically reading the manuscript.

Author information

Authors and Affiliations



All authors assisted in writing of the manuscript. J.H. analysed data, wrote the manuscript, designed all experiments and implemented all experiments with assistance from P.S., A.F.H., B.R.C., J.M.S., P.H., B.A.P., K.N.S., F.F., L.S. and F.K.W. K.S.M., M.C. and T.A.G. performed histological analyses and assisted with corresponding study designs. G.L.M. and R.M.B. performed eicosanoid analysis and generated E-prostanoid receptor knockout mice, and C.H.S. assisted with Alox5 mice and experiments. D.T.S. and E.F.S. assisted with experimental design and data analyses. L.M.P. designed and performed experiments, analysed and evaluated all data, and wrote the manuscript.

Corresponding author

Correspondence to Louis M. Pelus.

Ethics declarations

Competing interests

J.H. and L.M.P. have filed patent applications based on these findings.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-23. (PDF 1587 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hoggatt, J., Mohammad, K., Singh, P. et al. Differential stem- and progenitor-cell trafficking by prostaglandin E2. Nature 495, 365–369 (2013).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


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