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Proc Natl Acad Sci U S A. 2018 Sep 11;115(37):9252-9257. doi: 10.1073/pnas.1806077115. Epub 2018 Aug 23.

Specific oxylipins enhance vertebrate hematopoiesis via the receptor GPR132.

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Stem Cell Program, Boston Children's Hospital, Boston, MA 02115.
Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115.
Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138.
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138.
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115.
Stem Cell Program, Boston Children's Hospital, Boston, MA 02115;
Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115.


Epoxyeicosatrienoic acids (EETs) are lipid-derived signaling molecules with cardioprotective and vasodilatory actions. We recently showed that 11,12-EET enhances hematopoietic induction and engraftment in mice and zebrafish. EETs are known to signal via G protein-coupled receptors, with evidence supporting the existence of a specific high-affinity receptor. Identification of a hematopoietic-specific EET receptor would enable genetic interrogation of EET signaling pathways, and perhaps clinical use of this molecule. We developed a bioinformatic approach to identify an EET receptor based on the expression of G protein-coupled receptors in cell lines with differential responses to EETs. We found 10 candidate EET receptors that are expressed in three EET-responsive cell lines, but not expressed in an EET-unresponsive line. Of these, only recombinant GPR132 showed EET-responsiveness in vitro, using a luminescence-based β-arrestin recruitment assay. Knockdown of zebrafish gpr132b prevented EET-induced hematopoiesis, and marrow from GPR132 knockout mice showed decreased long-term engraftment capability. In contrast to high-affinity EET receptors, GPR132 is reported to respond to additional hydroxy-fatty acids in vitro, and we found that these same hydroxy-fatty acids enhance hematopoiesis in the zebrafish. We conducted structure-activity relationship analyses using both cell culture and zebrafish assays on diverse medium-chain fatty acids. Certain oxygenated, unsaturated free fatty acids showed high activation of GPR132, whereas unoxygenated or saturated fatty acids had lower activity. Absence of the carbon-1 position carboxylic acid prevented activity, suggesting that this moiety is required for receptor activation. GPR132 responds to a select panel of oxygenated polyunsaturated fatty acids to enhance both embryonic and adult hematopoiesis.


GPCR; free fatty acid; hematopoiesis; zebrafish

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