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Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis

Abstract

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.

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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.

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Acknowledgements

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.

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North, T., Goessling, W., Walkley, C. et al. Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature 447, 1007–1011 (2007). https://doi.org/10.1038/nature05883

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