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Differential stem- and progenitor-cell trafficking by prostaglandin E2

Abstract

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.

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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.

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Acknowledgements

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.

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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.

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

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Hoggatt, J., Mohammad, K., Singh, P. et al. Differential stem- and progenitor-cell trafficking by prostaglandin E2. Nature 495, 365–369 (2013). https://doi.org/10.1038/nature11929

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