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Epoxyeicosatrienoic Acids Enhance Haematopoietic Stem and Progenitor Cell Specification and Engraftment

ABSTRACT: Haematopoietic stem and progenitor cell (HSPC) transplant is a widely used treatment for life-threatening conditions including leukemia; however, the molecular mechanisms regulating HSPC engraftment of the recipient niche remain incompletely understood. Here, we developed a competitive HSPC transplant method in adult zebrafish, using in vivo imaging as a non-invasive readout. We used this system to conduct a chemical screen and identified epoxyeicosatrienoic acids (EET) as a family of lipids that enhance HSPC engraftment. EETs’ pro-haematopoietic effects are conserved in the developing zebrafish, where this molecule promotes HSPC specification through activating a unique AP-1/runx1 transcription program autonomous to the haemogenic endothelium. This effect requires the activation of PI3K pathway, specifically PI3Kg. In adult HSPCs, EETs induce transcriptional programs including AP-1 activation, modulating multiple cellular processes, such as migration, to promote engraftment. Finally, we demonstrated that the EET effects on enhancing HSPC homing and engraftment are conserved in mammals. Our study established a novel method to explore the molecular mechanisms of HSPC engraftment, and discovered a previously unrecognized, evolutionarily conserved pathway regulating multiple haematopoietic generation and regeneration processes. EETs may have clinical application in marrow or cord blood transplantation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE66767 | GEO | 2015/07/13

SECONDARY ACCESSION(S): PRJNA277940

REPOSITORIES: GEO

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Specific Oxylipins Enhance Vertebrate Hematopoiesis via the Receptor GPR132

Project description:Epoxyeicosatrienoic acids (EETs) are endogenous lipid signaling molecules with cardioprotective and vasodilatory actions. We recently showed that exogenous addition of 11,12-EET enhances hematopoietic induction and engraftment in mice and zebrafish. EETs are known to signal via a G-protein coupled receptor(s), but no specific EET receptor has been identified. Identification of an EET receptor would enable genetic interrogation of the EET signaling pathway and perhaps clinical use of this molecule. We developed a bioinformatic approach to identify the EET receptor based on the expression of GPCRs in cell lines with differential responses to EETs. We found 10 candidate EET receptors that are commonly expressed in three EET-responsive human cell lines, but not expressed in an EET-unresponsive line. Of these candidates, only GPR132 showed EET-responsiveness in vitro using a luminescence-based assay for β-arrestin recruitment. Knockdown of zebrafish gpr132b prevented EET-induced hematopoiesis, and marrow from GPR132 knockout mice showed decreased long-term engraftment capability. GPR132 has affinity for certain fatty acids in vitro, and we found that these same fatty acids enhance hematopoietic stem cell specification in the zebrafish. We conducted structure-activity relationship analyses using both in vitro and in vivo assays on diverse medium chain fatty acids. Certain oxygenated, unsaturated free fatty acids showed high activation of GPR132, while unoxygenated or saturated fatty acids had lower activity. Absence of the carboxylic acid moiety prevented activity, suggesting that this moiety is required for receptor activation. GPR132 responds to a select panel of polyunsaturated, oxygenated fatty acids to enhance both embryonic and adult hematopoiesis.

2018-08-10 | GSE113550 | GEO

Time-resolved Phosphoproteomic Analysis Elucidates Hepatic 11,12-Epoxyeicosatrienoic Acid Signaling Pathways

Project description:Epoxyeicosatrienoic acids (EETs) are potent lipid mediators with well-established effects in vascular tissues. Recent studies indicated an emerging role of these eicosanoids in metabolic diseases and the EET signaling pathway was shown to be involved in hepatic insulin sensitivity. However, compared to vascular tissues, there is only limited knowledge about the underlying signaling pathways in the liver. Therefore, we employed an LC-MS/MS-based time-resolved phosphoproteomics approach to characterize 11,12-EET-mediated signaling events in the liver cell line Hepa 1-6. 11,12-EET treatment resulted in the time-dependent regulation of phosphopeptides involved in processes as yet unknown to be affected by EETs, including RNA processing, splicing and translation regulation. Pathway analysis combined with western blot-based validation revealed enhanced AKT/mTOR/p70S6K signaling as demonstrated by increased acute phosphorylation of AKT (Ser473) and p70S6K (Thr389). In addition, 11,12-EET treatment led to differential regulation of phosphopeptides including important mediators of the DNA damage response and we observed a prolonged induction of the etoposide-induced DNA damage marker γH2AX in response to 11,12-EET. In summary, our findings extend current knowledge of 11,12-EET signaling events and emphasize the importance of the AKT/mTOR/p70S6K pathway in hepatic 11,12-EET signaling. Based on the results presented in this study, we furthermore propose a novel role of EET signaling in the regulation of the DNA damage response.

2019-11-06 | PXD015245 | Pride

Zebrafish whole embryos at 36 hpf treated with DMSO or 5uM 11,12-EET

Project description:In our previous study, we found zebrafish embryos treated with 5uM 11,12-EET (epoxyeicosatrienoic acid) had increased stem cell marker, runx1, expression in the AGM. EET also induced ectopic runx1 expression in the tail. To systematically study how EET regulates gene expression, we performed microarray analysis on EET-treated embryos. Zebrafish whole embryos were synchronized at fertilization. Embryos were grown at 28 degree overnight. 25 embryos per group were treated with DMSO or 5uM 11,12-EET starting from 24 hpf (hour post fertilization) until 36 hpf at 28 degree. The triplicates were from three different clutches of embryos, and split into DMSO v.s. EET for each clutch. EET vs. DMSO

2012-07-27 | E-GEOD-39707 | biostudies-arrayexpress

Zebrafish whole embryos at 36 hpf treated with DMSO or 5uM 11,12-EET

2012-07-28 | GSE39707 | GEO

Homo sapiens

Project description:Epoxyeicosatrienoic Acids Enhance Haematopoietic Stem and Progenitor Cell Specification and Engraftment

| PRJNA277940 | ENA

Macrophage epoxygenase determines a pro-fibrotic transcriptomesignature

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2015-02-10 | E-GEOD-65715 | biostudies-arrayexpress

CXCL8 and CXCR1 Remodel the Vascular Niche to Promote Hematopoietic Stem and Progenitor Cell Colonization and Engraftment [wt vs kdrl:cxcr1]

Project description:The microenvironment is an important regulator of hematopoietic stem and progenitor cell (HSPC) biology. Interactions between the niche and stem cells have been difficult to track, but recent advances marking fluorescent HSPCs have allowed exquisite visualization in the caudal hematopoietic tissue (CHT) of the developing zebrafish. Sinusoidal endothelial cells interact closely with HSPCs as they colonize this niche. Here we show that the chemokine cxcl8 and its receptor, cxcr1, are abundantly expressed by zebrafish endothelial cells and we identify cxcl8/cxcr1 signaling as a positive regulator of HSPC colonization using genetic gain- and loss-of-function techniques. Single-cell tracking experiments demonstrated that this effect is due to an increase in HSPC “cuddling” by endothelial cells, thereby increasing CHT residency time and allowing more HSPC cell divisions to occur. Enhanced cxcl8/cxcr1 signaling was associated with an increase in the volume of the CHT and induction of cxcl12a expression, favoring HSPC colonization. Finally, using parabiotic zebrafish, we show that cxcr1 acts stem cell non-autonomously to improve the efficiency of donor HSPC engraftment. This work identifies a mechanism by which the hematopoietic niche remodels to promote HSPC engraftment and suggests that cxcl8/cxcr1 signaling is a potential therapeutic target in patients undergoing hematopoietic stem cell transplantation.

2017-03-24 | GSE92542 | GEO

CXCL8 and CXCR1 Remodel the Vascular Niche to Promote Hematopoietic Stem and Progenitor Cell Colonization and Engraftment [huvec CXCL8 vs control]

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Differential Multigenomic Effect of Soluble Epoxide Hydrolase Inhibition on the Hippocampal Brain Microvasculature of FeFemale Mice on Low and High Glycemic Diets.

Project description:Microvascular dysfunction is central to the development of dementia. The effect of high glycemic diet (HGD), independent from dietary fat, on brain microvasculature is crucial, yet an understudied research topic, especially in feFemales. Our study aimed to determine the transcriptomic changes in feFemale brain hippocampal microvasculature induced by a HGD and characterize the response to soluble epoxide hydrolase inhibitor (sEHI). We demonstrated for the first time in feFemales that the HGD had an opposite gene expression profile compared to the LGD and differentially expressed 506 genes, primarily downregulated, with functions related to cell signaling, cell adhesion, cellular metabolism, and neurodegenerative diseases. Surprisingly, the sEHI modified the transcriptome of feFemale mice consuming the LGD more than the HGD, by modulating genes involved in metabolic pathways that synthesize neuroprotective epoxyeicosatrienoic acids (EETs) and associated with a higher EETs/ dihydroxyeicosatrienoic acids (DHETs) ratio.

2022-11-16 | GSE195975 | GEO

Macrophage epoxygenase determines a pro-fibrotic transcriptomesignature

Project description:Epoxygenases belong to the cytochrome P450 family and they generate epoxyeicosatrienoic acids (EETs) known to have anti-inflammatory effects but little is known about their role in macrophage function. By high-throughput sequencing of RNA (RNA-seq) in primary macrophages derived fromrodents and humans, we establish the relative expression of epoxygenases in these cells. Zinc-finger nuclease-mediated targeted gene deletion of the major ratmacrophage epoxygenaseCyp2j4 (orthologue of human CYP2J2),resulted inreduced EET synthesis. Cyp2j4-/-macrophages have relatively increased PPARγ levels and show a pro-fibrotic transcriptome,displayingover-expression of a specific subset of genes (260 transcripts) primarily involved in extracellular matrix, with fibronectin being the most abundantly expressed transcript.Fibronectin expression is under the control of epoxygenase activity in human and rat primary macrophages. In keeping with the invitro findings, Cyp2j4-/- rats show up-regulation of type I collagen following unilateral ureter obstruction (UUO) of the kidney and quantitative proteomics analysis (LC-MS/MS) showed increased renal type I collagen and fibronectin protein abundance resulting from experimentally induced crescentic glomerulonephritis in these rats. Taken together, these results identify the rat epoxygenase Cyp2j4 as a determinant of a pro-fibrotic macrophage transcriptome that could have implications in various inflammatory conditions depending on macrophage function.

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