Prostaglandin E2 regulates murine hematopoietic stem/progenitor cells directly via EP4 receptor and indirectly through mesenchymal progenitor cells

Ikushima, Yoshiko Matsumoto; Arai, Fumio; Hosokawa, Kentaro; Toyama, Hirofumi; Takubo, Keiyo; Furuyashiki, Tomoyuki; Narumiya, Shuh; Suda, Toshio

doi:10.1182/blood-2012-06-437889

Cited by 43 publications

(37 citation statements)

References 42 publications

(43 reference statements)

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“…NADPH oxidase, nicotinamide adenine dinucleotide phosphate-oxidase. that EP4 is the major receptor for PGE2-mediated regulation on HSC (32). When examined in vitro and in vivo, PGE2 was found to reduce ROS levels in stem cells, via reduction of AKT phosphorylation, maintaining the ROS low long-term repopulating stem cell pool (55).…”

Section: Cell Intrinsic Factors Mediating Ros Levels In Hscsmentioning

confidence: 99%

Reactive Oxygen Species Regulate Hematopoietic Stem Cell Self-Renewal, Migration and Development, As Well As Their Bone Marrow Microenvironment

Ludin

Gur-Cohen²,

Golan³

et al. 2014

Antioxidants & Redox Signaling

259

240

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Significance: Blood forming, hematopoietic stem cells (HSCs) mostly reside in the bone marrow in a quiescent, nonmotile state via adhesion interactions with stromal cells and macrophages. Quiescent, proliferating, and differentiating stem cells have different metabolism, and accordingly different amounts of intracellular reactive oxygen species (ROS). Importantly, ROS is not just a byproduct of metabolism, but also plays a role in stem cell state and function. Recent Advances: ROS levels are dynamic and reversibly dictate enhanced cycling and myeloid bias in ROS high short-term repopulating stem cells, and ROS low quiescent long-term repopulating stem cells. Low levels of ROS, regulated by intrinsic factors such as cell respiration or nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) activity, or extrinsic factors such as stem cell factor or prostaglandin E2 are required for maintaining stem cell self-renewal. High ROS levels, due to stress and inflammation, induce stem cell differentiation and enhanced motility. Critical Issues: Stem cells need to be protected from high ROS levels to avoid stem cell exhaustion, insufficient host immunity, and leukemic transformation that may occur during chronic inflammation. However, continuous low ROS production will lead to lack of stem cell function and opportunistic infections. Ultimately, balanced ROS levels are crucial for maintaining the small stem cell pool and host immunity, both in homeostasis and during stress situations. Future Directions: Deciphering the signaling pathway of ROS in HSC will provide a better understanding of ROS roles in switching HSC from quiescence to activation and vice versa, and will also shed light on the possible roles of ROS in leukemia initiation and development. Antioxid. Redox Signal. 21, 1605-1619.

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Section: Cell Intrinsic Factors Mediating Ros Levels In Hscsmentioning

confidence: 99%

Reactive Oxygen Species Regulate Hematopoietic Stem Cell Self-Renewal, Migration and Development, As Well As Their Bone Marrow Microenvironment

Ludin

Gur-Cohen²,

Golan³

et al. 2014

Antioxidants & Redox Signaling

259

240

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“…At end-product of the arachidonic acid pathway, PGE2 can reportedly expand HSCs in vitro and in vivo [45,46]. Moreover, neutrophil-derived PGE2 inhibits G-CSF-mediated HSPC mobilization [47].…”

Section: Adipocytes Fatty Acid Metabolism and Hematopoiesismentioning

confidence: 99%

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

Karigane

Takubo

2017

Int J Hematol

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organisms. HSPCs are composed of hematopoietic stem cells (HSCs) and several types of lineage-biased, but not fully committed, hematopoietic progenitor cells (HPCs). HSC capacities such as self-renewal and multilineage differentiation maintain the whole hematopoietic system over an organism's lifetime [1], and contribute to blood regeneration under stress condition, whereas HPCs reportedly function to maintain the supply of blood cells at steady state [2,3]. The surrounding BM microenvironment or "niche" determines HSC fate, namely its quiescence, symmetric/asymmetric division, differentiation, or migration potential, in both steady state and during stress. It is now evident that metabolic programs operating in HSCs play critical roles in maintaining hematopoietic homeostasis [4], often in response to BM niche signals [5]. Cellular pathways generate various metabolites through enzymatic activity that supplies material used as fuel, building blocks for other factors, or modulators of intra-or intercellular activities (Fig. 1). Despite the fact that numerous biochemical studies have addressed HSC metabolic regulation, numerous gaps in our knowledge of that regulation remain.Recently, novel means to fractionate metabolites using highly sensitive mass spectrometric technology [6] have dramatically facilitated metabolome analysis. These technologies reduce the need for high cell numbers and increase sensitivity of metabolite selection. As a result, metabolome analysis is feasible in rare cell populations such as HSCs. These analyses have revealed that metabolic programs play critical roles in maintaining stem cell "stemness" (Fig. 2). Here we review recent advances in the field of how metabolic changes regulate HSC dynamics under quiescence, proliferation, and differentiation from the viewpoint of each pathway. In addition to the normal HSC system, we also review activity of leukemia-related metabolic pathways, tumor-associated metabolites (oncometabolites), and Abstract Hematopoietic stem cells (HSCs) exhibit multilineage differentiation and self-renewal activities that maintain the entire hematopoietic system during an organism's lifetime. These abilities are sustained by intrinsic transcriptional programs and extrinsic cues from the microenvironment or niche. Recent studies using metabolomics technologies reveal that metabolic regulation plays an essential role in HSC maintenance. Metabolic pathways provide energy and building blocks for other factors functioning at steady state and in stress. Here we review recent advances in our understanding of metabolic regulation in HSCs relevant to cell cycle quiescence, symmetric/asymmetric division, and proliferation following stress and lineage commitment, and discuss the therapeutic potential of targeting metabolic factors or pathways to treat hematological malignancies.

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“…For example, pretreatment of mesenchymal stem cells with dimethyl-PGE2 enhances their ability to support HSPC colony formation in vitro. 93 PGE2 rapidly increases in the marrow microenvironment after radiation, and treatment of mice with dimethyl-PGE2 after sublethal radiation injury suppresses apoptotic gene expression in HSPCs and stimulates cyclooxygenase-2 activity in the marrow, specifically in a population of a-smooth muscle actin 1 macrophages that participate in HSC support. 94,95 Moreover, the PGE2 receptor EP4 (PGE receptor 4) regulates trafficking of HSCs in the bone marrow through modulation of mesenchymal/osteolineage populations.…”

Section: Prostaglandin E2mentioning

confidence: 99%

The hematopoietic stem cell niche in homeostasis and disease

Calvi

Link

2015

Blood

190

151

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The bone marrow microenvironment contains a heterogeneous population of stromal cells organized into niches that support hematopoietic stem cells (HSCs) and other lineage-committed hematopoietic progenitors. The stem cell niche generates signals that regulate HSC self-renewal, quiescence, and differentiation. Here, we review recent studies that highlight the heterogeneity of the stromal cells that comprise stem cell niches and the complexity of the signals that they generate. We highlight emerging data that stem cell niches in the bone marrow are not static but instead are responsive to environmental stimuli. Finally, we review recent data showing that hematopoietic niches are altered in certain hematopoietic malignancies, and we discuss how these alterations might contribute to disease pathogenesis.

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Prostaglandin E2 regulates murine hematopoietic stem/progenitor cells directly via EP4 receptor and indirectly through mesenchymal progenitor cells

Cited by 43 publications

References 42 publications

Reactive Oxygen Species Regulate Hematopoietic Stem Cell Self-Renewal, Migration and Development, As Well As Their Bone Marrow Microenvironment

Reactive Oxygen Species Regulate Hematopoietic Stem Cell Self-Renewal, Migration and Development, As Well As Their Bone Marrow Microenvironment

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

The hematopoietic stem cell niche in homeostasis and disease

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