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

Abstract

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 ...

Connexin-43 prevents hematopoietic stem cell senescence through transfer of reactive oxygen species to bone marrow stromal cells

“…At physiological levels, low and moderate levels of ROS appear to be required for HSC activity (41)(42)(43), including early hematopoietic reconstitution after transplantation (44). However, a sustained, abnormal increase in ROS production occurs under aging (24) and genotoxic stress (45), including 5-FU chemotherapy (46), which can inhibit HSC self-renewal and induce HSC senescence and hematopoietic dysfunction (24).…”

Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions

“…Hydroxyeicosatetraenoic acids (HETEs), such as 12-HETE and 15-HETE, are produced by 12/15-LOX and function as signal transducers in various situations, including inflammatory settings [38]. Loss of 12/15-LOX in HSCs induces defective hematopoiesis in a homeostatic context and repopulation deficits following transplantation, suggesting a critical role for 12/15-LOX in normal hematopoiesis and in maintaining HSC capacity [39]. In pathological settings, 12/15-LOX activity suppresses myeloproliferative disorder [40].…”

Scd1 Plays a Tumor-Suppressive Role in Survival of Leukemia Stem Cells and the Development of Chronic Myeloid Leukemia

“…Another study shows that the level of Scd1 expression correlates with predisposition to liver carcinogenesis (6). However, the role of Scd1 in leukemogenesis and hematopoiesis remains unknown, although it has been suggested that fatty acid metabolism plays a role in leukemogenesis and hematopoiesis (14,20). In the present study, using the BCR-ABL induced CML mouse model, we found that the expression of the Scd1 gene was downregulated in LSCs and the deletion of Scd1 accelerated CML development through affecting the function of LSCs but not normal HSCs, suggesting that Scd1 plays a tumor-suppressive role in BCR-ABL leukemogenesis.…”

“…(B-ALL) by BCR-ABL had been described previously (8,9,14,16,20,22). Briefly, in order to induce CML, donor mice were primed by intravenous injection with 5-fluorouracil (5-FU; 200 mg/kg) 4 days before collecting bone marrow cells.…”