Nature 447, 1007-1011 (21 June 2007) | doi:10.1038/nature05883; Received 4 December 2006; Accepted 30 April 2007

Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis

Trista E. North1,2, Wolfram Goessling1,2, Carl R. Walkley1,3, Claudia Lengerke1, Kamden R. Kopani1,2, Allegra M. Lord1,2, Gerhard J. Weber1,2, Teresa V. Bowman1,2, Il-Ho Jang1, Tilo Grosser4, Garret A. FitzGerald4, George Q. Daley1, Stuart H. Orkin1,2,3 & Leonard I. Zon1,2

  1. Stem Cell Program and Division of Hematology/Oncology, Children's Hospital, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
  2. Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA
  3. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA
  4. Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA

Correspondence to: Leonard I. Zon1,2 Correspondence and requests for materials should be addressed to L.I.Z. (Email: zon@enders.tch.harvard.edu).

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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