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Nature. 2015 Jul 23;523(7561):468-71. doi: 10.1038/nature14569.

Epoxyeicosatrienoic acids enhance embryonic haematopoiesis and adult marrow engraftment.

Author information

1
1] Stem Cell Program and Division of Haematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachuestts 02115, USA [2] Chemical Biology Program, Harvard University, Cambridge, Massachusetts 02138, USA.
2
Stem Cell Program and Division of Haematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachuestts 02115, USA.
3
1] Stem Cell Program and Division of Haematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachuestts 02115, USA [2] Department of Hematology and Oncology, Dr. von Hauner Children's Hospital, Ludwig-Maximilians University, 80337 Munich, Germany.
4
Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
5
Department of Haematology, St Jude Children's Research Hospital, Memphis, Tennessee 38105-3678, USA.
6
Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.

Abstract

Haematopoietic stem and progenitor cell (HSPC) transplant is a widely used treatment for life-threatening conditions such as leukaemia; however, the molecular mechanisms regulating HSPC engraftment of the recipient niche remain incompletely understood. Here we develop a competitive HSPC transplant method in adult zebrafish, using in vivo imaging as a non-invasive readout. We use this system to conduct a chemical screen, and identify epoxyeicosatrienoic acids (EETs) as a family of lipids that enhance HSPC engraftment. The pro-haematopoietic effects of EETs were conserved in the developing zebrafish embryo, where 11,12-EET promoted HSPC specification by activating a unique activator protein 1 (AP-1) and runx1 transcription program autonomous to the haemogenic endothelium. This effect required the activation of the phosphatidylinositol-3-OH kinase (PI(3)K) pathway, specifically PI(3)Kγ. In adult HSPCs, 11,12-EET induced transcriptional programs, including AP-1 activation, which modulate several cellular processes, such as migration, to promote engraftment. Furthermore, we demonstrate that the EET effects on enhancing HSPC homing and engraftment are conserved in mammals. Our study establishes a new method to explore the molecular mechanisms of HSPC engraftment, and discovers a previously unrecognized, evolutionarily conserved pathway regulating multiple haematopoietic generation and regeneration processes. EETs may have clinical application in marrow or cord blood transplantation.

PMID:
26201599
PMCID:
PMC4754787
DOI:
10.1038/nature14569
[Indexed for MEDLINE]
Free PMC Article

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