Epoxyeicosatrienoic acids enhance embryonic haematopoiesis and adult marrow engraftment
- Li, P., Lahvic, J.L., Binder, V., Pugach, E.K., Riley, E.B., Tamplin, O.J., Panigrahy, D., Bowman, T.V., Barrett, F.G., Heffner, G.C., McKinney-Freeman, S., Schlaeger, T.M., Daley, G.Q., Zeldin, D.C., Zon, L.I.
- Nature 523: 468-71 (Journal)
- Registered Authors
- Bowman, Teresa, Schlaeger, Thorsten, Tamplin, Owen, Zon, Leonard I.
- Haematopoietic stem cells, Haematopoiesis, Haematological diseases
- MeSH Terms
- 8,11,14-Eicosatrienoic Acid/analogs & derivatives*
- 8,11,14-Eicosatrienoic Acid/metabolism
- Cell Line
- Cell Movement
- Core Binding Factor Alpha 2 Subunit/metabolism
- Gene Expression Regulation
- Hematopoietic Stem Cell Transplantation*
- Hematopoietic Stem Cells/cytology*
- Human Umbilical Vein Endothelial Cells
- Phosphatidylinositol 3-Kinases
- Transcription Factor AP-1/metabolism
- Transcription, Genetic
- 26201599 Full text @ Nature
Li, P., Lahvic, J.L., Binder, V., Pugach, E.K., Riley, E.B., Tamplin, O.J., Panigrahy, D., Bowman, T.V., Barrett, F.G., Heffner, G.C., McKinney-Freeman, S., Schlaeger, T.M., Daley, G.Q., Zeldin, D.C., Zon, L.I. (2015) Epoxyeicosatrienoic acids enhance embryonic haematopoiesis and adult marrow engraftment. Nature. 523:468-71.
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.
Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and NotesThis article is corrected by ZDB-PUB-220906-167 .