Editors' ChoiceImmunology

Eicosanoids enhance transplant success

Sci. Signal.  28 Jul 2015:
Vol. 8, Issue 387, pp. ec202
DOI: 10.1126/scisignal.aad0883

Efficient engraftment of donor cells is critical for the clinical success of hematopoietic stem and progenitor cell (HSPC) transplant in treating patients with blood cancers such as leukemia. Li et al. developed an in vivo system for identifying compounds that enhanced engraftment of donor HSPCs in zebrafish. When cotransplanted into the same irradiated recipient, HSPCs from two transgenic donor fish—one ubiquitously expressing green fluorescent protein (GFP) and one ubiquitously expressing DsRed—engrafted into the region of the kidney where hematopoiesis occurs in a 1:1 ratio. The authors used this assay to screen a library of bioactive molecules for compounds that, when applied to the GFP+ HSPCs prior to transplantation, increased the ratio of engrafted GFP+:DsRed+ HSPCs. Among the compounds that enhanced engraftment of HSPCs were 11,12-EET (epoxyeicosatrienoic acid) and 14,15-EET, which are eicosanoid lipids that are derived from arachidonic acid. 11,12-EET also stimulated hematopoiesis in zebrafish embryos. Treatment with 11,12-EET increased the number of cells expressing HSPC markers in the tissue that is the source of HSPCs in the zebrafish embryo, and these extra HSPCs homed to their proper niche. EET-mediated induction of HSPC markers required signaling through phosphatidylinositol 3-kinase γ (PI3Kγ). Transcriptomic analysis indicated that 11,12- EET also promoted the activation of cell migratory pathways in human umbilical cord HSPCs and in a human myeloid cell line. In mice, donor HSPCs treated with 11,12-EET engrafted more successfully than untreated HSPCs. Addition of a chemical inhibitor of PI3K signaling diminished the ability of 11,12-EET to enhance engraftment. These results indicate that EETs promote specification and homing of HSPCs and suggest that eicosanoids like EETs and prostaglandin E2 (PGE2), which has previously been shown to promote hemoatopoiesis and homing, could have clinical benefit.

P. Li, J. L. Lahvic, V. Binder, E. K. Pugach, E. B. Riley, O. J. Tamplin, D. Panigrahy, T. V. Bowman, F. G. Barrett, G. C. Heffner, S. McKinney-Freeman, T. M. Schlaeger, G. Q. Daley, D. C. Zeldin, L. I. Zon, Epoxyeicosatrienoic acids enhance embryonic haematopoiesis and adult marrow engraftment. Nature 523, 468–471 (2015). [PubMed]