TY - JOUR
T1 - Epoxyeicosatrienoic acids enhance embryonic haematopoiesis and adult marrow engraftment
AU - Li, Pulin
AU - Lahvic, Jamie L.
AU - Binder, Vera
AU - Pugach, Emily K.
AU - Riley, Elizabeth B.
AU - Tamplin, Owen J.
AU - Panigrahy, Dipak
AU - Bowman, Teresa V.
AU - Barrett, Francesca G.
AU - Heffner, Garrett C.
AU - McKinney-Freeman, Shannon
AU - Schlaeger, Thorsten M.
AU - Daley, George Q.
AU - Zeldin, Darryl C.
AU - Zon, Leonard I.
N1 - Funding Information:
Acknowledgements We thank C. R. Lee, M. L. Edin and N. Gray for providing reagents; Y. Zhou, A. Dibiase, S. Yang, S. Datta, P. Manos, R. Mathieu and M. Ammerman for technicalassistance; H. Huangfor providing graphic illustration; R.M. White, T. E. North and C. Mosimann for discussion. Microarray studies were performed by the Molecular Genetics Core Facility at Boston Children’s Hospital, supported by NIH-P50-NS40828 and NIH-P30-HD18655. S. Li in Y. Zhang’s laboratory at the Longwood HHMI joint core facility helped with RNA-seq. L.I.Z. and G.Q.D. are Howard Hughes Medical Institute (HHMI) investigators. This work was supported by HHMI and National Institutes of Health (NIH) grants R01 HL04880, P015PO1HL32262-32, 5P30 DK49216, 5R01 DK53298, 5U01 HL10001-05, R24 DK092760, and 1R01HL097794-04 (to L.I.Z.). This work was also funded, in part, by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES025034 to D.C.Z.), the National Cancer Institute grant ROCA148633-01A5 (D.P.), and DFG and Care-for-Rare Foundation (V.B.).
Publisher Copyright:
© 2015 Macmillan Publishers Limited.
PY - 2015/7/22
Y1 - 2015/7/22
N2 - 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.
AB - 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.
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U2 - 10.1038/nature14569
DO - 10.1038/nature14569
M3 - Article
C2 - 26201599
AN - SCOPUS:84937820643
SN - 0028-0836
VL - 523
SP - 468
EP - 471
JO - Nature
JF - Nature
IS - 7561
ER -