Effects of Lipoxygenase Metabolites of Arachidonic Acid on the Growth of Human Blood CD34+ Progenitors

Desplat, Vanessa; Ivanović, Zoran; Dupuis, F.; Faucher, Jean‐Luc; Denizot, Yves; Perreten, Vincent

doi:10.1006/bcmd.2000.0321

Cited by 15 publications

(11 citation statements)

References 23 publications

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“…Differential gene expression analysis in Gli1 1 cells in bone marrow fibrosis demonstrated that megakaryocyte-associated genes were significantly upregulated, in particular the chemokine C-X-C motif ligand 4 (CXCL4) and the arachidonate lipoxygenase enzyme ALOX12, which have been implicated as playing a role in fibrosis [73][74][75][76] and HSC regulation 77 and are linked to megakaryocyte, platelet, and stromal cell biology. 78,79 Future studies will focus on dissecting the interaction between megakaryocytes derived from the MPN clone and fibrosis-driving cells. An important question to be answered is whether the interaction between dysplastic megakaryocytes and fibrosis-driving stromal cells functions mainly via cytokines and growth factors or whether there is heterocellular transfer of material (eg, through mitochondrial transfer or microvesicles).…”

Section: Mechanisms In the Transcriptional And Functional Reprogrammimentioning

confidence: 99%

The identification of fibrosis-driving myofibroblast precursors reveals new therapeutic avenues in myelofibrosis

Kramann

Schneider

2018

Blood

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Myofibroblasts are fibrosis-driving cells and are well characterized in solid organ fibrosis, but their role and cellular origin in bone marrow fibrosis remains obscure. Recent work has demonstrated that Gli1 and LepR mesenchymal stromal cells (MSCs) are progenitors of fibrosis-causing myofibroblasts in the bone marrow. Genetic ablation of Gli1 MSCs or pharmacologic targeting of hedgehog (Hh)-Gli signaling ameliorated fibrosis in mouse models of myelofibrosis (MF). Moreover, pharmacologic or genetic intervention in platelet-derived growth factor receptor α () signaling in stromal cells suppressed their expansion and ameliorated MF. Improved understanding of cellular and molecular mechanisms in the hematopoietic stem cell niche that govern the transition of MSCs to myofibroblasts and myofibroblast expansion in MF has led to new paradigms in the pathogenesis and treatment of MF. Here, we highlight the central role of malignant hematopoietic clone-derived megakaryocytes in reprogramming the hematopoietic stem cell niche in MF with potential detrimental consequences for hematopoietic reconstitution after allogenic stem cell transplantation, so far the only therapeutic approach in MF considered to be curative. We and others have reported that targeting Hh-Gli signaling is a therapeutic strategy in solid organ fibrosis. Data indicate that targeting Gli proteins directly inhibits Gli1 cell proliferation and myofibroblast differentiation, which results in reduced fibrosis severity and improved organ function. Although canonical Hh inhibition (eg, smoothened [Smo] inhibition) failed to improve pulmonary fibrosis, kidney fibrosis, or MF, the direct inhibition of Gli proteins ameliorated fibrosis. Therefore, targeting Gli proteins directly might be an interesting and novel therapeutic approach in MF.

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Section: Mechanisms In the Transcriptional And Functional Reprogrammimentioning

confidence: 99%

The identification of fibrosis-driving myofibroblast precursors reveals new therapeutic avenues in myelofibrosis

Kramann

Schneider

2018

Blood

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“…16,17 These lipid mediators have pleiotropic affects on myriad cell types, 18 but our knowledge of their role in HSCs is limited. 19,20 Notably, in leukemia that results from abnormal hematopoiesis, lipid mediators are reduced. [21][22][23] Previously, we showed that 12/15-LOX is a novel suppressor of myeloproliferative disease (MPD).…”

Section: (S)-hydroxyeicosatetraenoic Acid (12(s)-hete) 15(s)-hydroxymentioning

confidence: 99%

“…26 Moreover, 12(S)-HETE and 15(S)-HETE can affect development of human CD34 ϩ hematopoietic progenitors in culture. 19 However, a role for 12/15-LOX per se has not been established in hematopoietic development and HSC function.…”

Section: (S)-hydroxyeicosatetraenoic Acid (12(s)-hete) 15(s)-hydroxymentioning

confidence: 99%

Hematopoietic stem cell function requires 12/15-lipoxygenase–dependent fatty acid metabolism

Kinder

Wei

Shelat

et al. 2010

Blood

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IntroductionHematopoiesis is the process whereby the blood cell lineages are generated from a multipotent hematopoietic stem cell (HSC). HSCs possess the unique ability to self-renew but also differentiate to give rise to mature blood cells. Long-term HSCs (LT-HSCs) are the most primitive HSCs and can fully reconstitute the hematopoietic compartment of lethally irradiated animals. They reside in a hypoxic niche and are generally quiescent. 1,2 In comparison, short-term HSCs (ST-HSCs) are temporally limited in their ability to reconstitute lethally irradiated animals and more actively cycle. HSCs are regulated through their environmental niche, cytokine signaling, and the orchestrated activities of various transcription factors. 3 However, there is a relative paucity of information about the signal transduction events that regulate HSC function. In particular, the effects of fatty acid (FA) metabolism and lipid mediators on HSC function are not well understood.The function of HSCs is dependent on their unique capacity to both differentiate and self-renew, which is related to their proliferative capacity. 4,5 Highly proliferative HSCs are less efficient at reconstituting lethally irradiated mice. 6 Thus, HSCs that lack cell-cycle inhibitors required to maintain quiescence, such as p21cip/WAF, are defective. 7 HSC function is also regulated by transcription factors including Gfi-1, Bmi, Hox4b, and PU.1. [8][9][10][11] Furthermore, canonical Wnt signaling was shown to regulate HSC function by maintaining quiescence and initiating a self-renewal program of gene transcription. [12][13][14] 12/15-Lipoxygenase (12/15-LOX) is a lipid-peroxidizing enzyme that mediates unsaturated FA metabolism. 12/15-LOX introduces molecular oxygen into arachidonic acid (AA) and linoleic acid to produce bioactive labile lipid intermediates such as 12(S)-hydroperoxyeicosatetraenoic acid, 15(S)-hydroperoxyeicosatetraenoic acid, and 13(S)-hydroperoxyoctadecadienoic acid. These intermediates are rapidly reduced by glutathione reductase, which releases reactive oxygen species (ROS) and produces additional bioactive lipid metabolites, including 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE), 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE), 13(S)-hydroxyoctadecadienoic (13(S)-HODE), lipoxins, and hepoxilins. 15 Eicosanoid products activate multiple signaling pathways and transcription factors such as peroxisome proliferator-activated receptor-␥, interferon consensus sequencebinding protein/interferon regulatory factor-8 (ICSBP/IRF-8), and nuclear factor-B to modulate gene transcription. 16,17 These lipid mediators have pleiotropic affects on myriad cell types, 18 but our knowledge of their role in HSCs is limited. 19,20 Notably, in leukemia that results from abnormal hematopoiesis, lipid mediators are reduced. [21][22][23] Previously, we showed that 12/15-LOX is a novel suppressor of myeloproliferative disease (MPD). 24 Although less than 15% of 12/15-LOX-deficient mice (Alox15 mice) develop a severe MPD over the course of a year, the majority ...

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“…Recently, it has been shown that the niche regulates self-renewal of HSPCs via retinoic acid signaling [ 17 ]. Furthermore, there are studies indicating that HSPC quiescence is tightly regulated by the metabolic microenvironment [ 18 , 19 ]. Chemotherapy induces metabolic changes such as down-regulation of extracellular glutathione peroxidase and up-regulation of gamma-tocopherol concentration in patient serum [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

MicroRNAs and Metabolites in Serum Change after Chemotherapy: Impact on Hematopoietic Stem and Progenitor Cells

et al. 2015

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Hematopoietic regeneration after high dose chemotherapy necessitates activation of the stem cell pool. There is evidence that serum taken after chemotherapy comprises factors stimulating proliferation and self-renewal of CD34+ hematopoietic stem and progenitor cells (HSPCs) – however, the nature of these feedback signals is yet unclear. Here, we addressed the question if specific microRNAs (miRNAs) or metabolites are affected after high dose chemotherapy. Serum taken from the same patients before and after chemotherapy was supplemented for in vitro cultivation of HSPCs. Serum taken after chemotherapy significantly enhanced HSPC proliferation, better maintained a CD34+ immunophenotype, and stimulated colony forming units. Microarray analysis revealed that 23 miRNAs changed in serum after chemotherapy – particularly, miRNA-320c and miRNA-1275 were down-regulated whereas miRNA-3663-3p was up-regulated. miRNA-320c was exemplarily inhibited by an antagomiR, which seemed to increase proliferation. Metabolomic profiling demonstrated that 44 metabolites were less abundant, whereas three (including 2-hydroxybutyrate and taurocholenate sulphate) increased in serum upon chemotherapy. Nine of these metabolites were subsequently tested for effects on HSPCs in vitro, but none of them exerted a clear concentration dependent effect on proliferation, immunophenotype and colony forming unit formation. Taken together, serum profiles of miRNAs and metabolites changed after chemotherapy. Rather than individually, these factors may act in concert to recruit HSPCs into action for hematopoietic regeneration.

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Effects of Lipoxygenase Metabolites of Arachidonic Acid on the Growth of Human Blood CD34+ Progenitors

Cited by 15 publications

References 23 publications

The identification of fibrosis-driving myofibroblast precursors reveals new therapeutic avenues in myelofibrosis

The identification of fibrosis-driving myofibroblast precursors reveals new therapeutic avenues in myelofibrosis

Hematopoietic stem cell function requires 12/15-lipoxygenase–dependent fatty acid metabolism

MicroRNAs and Metabolites in Serum Change after Chemotherapy: Impact on Hematopoietic Stem and Progenitor Cells

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