Reactive oxygen species generated by hematopoietic cytokines play roles in activation of receptor-mediated signaling and in cell cycle progression

Iiyama, Mitsuko; Kakihana, Kazuhiko; Kurosu, Tetsuya; Miura, Osamu

doi:10.1016/j.cellsig.2005.04.002

Cited by 90 publications

(98 citation statements)

References 32 publications

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“…ROS formation was very rapid, in agreement with previous reports 25 and was prevented by antioxidant treatment, which also hindered differentiation. The involvement of ROS was observed for both cell lines and primary cells studied, so it is also likely to occur in vivo.…”

Section: Discussionsupporting

confidence: 80%

“…The activation of different signalling pathways in response to ROS has been described previously, 25 but the molecular mechanism underlying this observation is not completely understood. ROS seem to activate signalling cascades depending on the context, that is, ROS production in response to G-CSF would be related to AKT activation but not to ERK activation, 23 whereas in our system, ROS were involved in the activation of both pathways.…”

Section: Discussionmentioning

confidence: 99%

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p22phox-dependent NADPH oxidase activity is required for megakaryocytic differentiation

et al. 2010

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Transient reactive oxygen species (ROS) production is currently proving to be an important mechanism in the regulation of intracellular signalling, but reports showing the involvement of ROS in important biological processes, such as cell differentiation, are scarce. In this study, we show for the first time that ROS production is required for megakaryocytic differentiation in K562 and HEL cell lines and also in human CD34 þ cells. ROS production is transiently activated during megakaryocytic differentiation, and such production is abolished by the addition of different antioxidants (such as N-acetyl cysteine, trolox, quercetin) or the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor diphenylene iodonium. The inhibition of ROS formation hinders differentiation. RNA interference experiments have shown that a p22 phoxdependent NADPH oxidase activity is responsible for ROS production. In addition, the activation of ERK, AKT and JAK2 is required for differentiation, but the activation of phosphatidylinositol 3-kinase and c-Jun N-terminal kinase seems to be less important. When ROS production is prevented, the activation of these signalling pathways is partly inhibited. Taken together, these results show that NADPH oxidase ROS production is essential for complete activation of the main signalling pathways involved in megakaryocytopoiesis to occur. We suggest that this might also be important for in vivo megakaryocytopoiesis.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

p22phox-dependent NADPH oxidase activity is required for megakaryocytic differentiation

et al. 2010

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“…ROS were shown to be generated in response to EPO (52,63), leading to the stimulation of the Ras/MAPK/ERK pathway (39).…”

Section: Discussionmentioning

confidence: 99%

“…ERK is activated by phosphorylation during the EPOdependent phase, and its activation is ROS-dependent (39,52). We first determined ERK expression and phosphorylation in WT bone marrow TER119…”

Section: Ucp2 Function In Erythropoiesismentioning

confidence: 99%

UCP2 Modulates Cell Proliferation through the MAPK/ERK Pathway during Erythropoiesis and Has No Effect on Heme Biosynthesis

Elorza

Hyde

Mikkola

et al. 2008

Journal of Biological Chemistry

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UCP2, an inner membrane mitochondrial protein, has been implicated in bioenergetics and reactive oxygen species (ROS) modulation. High levels of UCP2 mRNA were recently found in erythroid cells where UCP2 is hypothesized to function as a facilitator of heme synthesis and iron metabolism by reducing ROS production. We examined UCP2 protein expression and role in mice erythropoiesis in vivo. UCP2 was mainly expressed at early stages of erythroid maturation when cells are not fully committed in heme synthesis. Iron incorporation into heme was unaltered in reticulocytes from UCP2-deficient mice. Although heme synthesis was not influenced by UCP2 deficiency, mice lacking UCP2 had a delayed recovery from chemically induced hemolytic anemia. Analysis of progenitor cells from bone marrow and fetal liver both in vitro and in vivo revealed that UCP2 deficiency results in a significant decrease in cell proliferation at the erythropoietin-dependent phase of erythropoiesis. This was accompanied by reduction in the phosphorylated form of ERK, a ROS-dependent cytosolic regulator of cell proliferation. Analysis of ROS in UCP2 null erythroid cells revealed altered distribution of ROS, resulting in decreased cytosolic and increased mitochondrial ROS. Restoration of the cytosol oxidative state of erythroid progenitor cells by the pro-oxidant Paraquat reversed the effect of UCP2 deficiency on cell proliferation in in vitro differentiation assays. Together, these results indicate that UCP2 is a regulator of erythropoiesis and suggests that inhibition of UCP2 function may contribute to the development of anemia.

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“…The activation of p38 mitogen-activated protein kinase plays a role in HSC senescence [186,187]. A p38 specific inhibitor, SB203580, supports 3-fold of increase of SRCs after human cord blood CD133 + cells were cultured for 7 d, as determined by the NOD/SCID reconstitution analysis.…”

Section: P38 Inhibitormentioning

confidence: 99%

Ex vivo expansion of hematopoietic stem cells

Xie

Zhang

2015

Sci. China Life Sci.

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Ex vivo expansion of hematopoietic stem cells (HSCs) would benefit clinical applications in several aspects, to improve patient survival, utilize cord blood stem cells for adult applications, and selectively propagate stem cell populations after genetic manipulation. In this review we summarize and discuss recent advances in the culture systems of mouse and human HSCs, which include stroma/HSC co-culture, continuous perfusion and fed-batch cultures, and those supplemented with extrinsic ligands, membrane transportable transcription factors, complement components, protein modification enzymes, metabolites, or small molecule chemicals. Some of the expansion systems have been tested in clinical trials. The optimal condition for ex vivo expansion of the primitive and functional human HSCs is still under development. An improved understanding of the mechanisms for HSC cell fate determination and the HSC culture characteristics will guide development of new strategies to overcome difficulties. In the future, development of a combination treatment regimen with agents that enhance self-renewal, block differentiation, and improve homing will be critical. Methods to enhance yields and lower cost during collection and processing should be employed. The employment of an efficient system for ex vivo expansion of HSCs will facilitate the further development of novel strategies for cell and gene therapies including genome editing. ex vivo expansion, hematopoietic stem cells, niche, signal transduction, cord blood, transplantation, SCID-repopulating cell, genome editing, CRISPR/Cas9 Citation:Xie JJ, Zhang CC. Ex vivo expansion of hematopoietic stem cells.

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Reactive oxygen species generated by hematopoietic cytokines play roles in activation of receptor-mediated signaling and in cell cycle progression

Cited by 90 publications

References 32 publications

p22phox-dependent NADPH oxidase activity is required for megakaryocytic differentiation

p22phox-dependent NADPH oxidase activity is required for megakaryocytic differentiation

UCP2 Modulates Cell Proliferation through the MAPK/ERK Pathway during Erythropoiesis and Has No Effect on Heme Biosynthesis

Ex vivo expansion of hematopoietic stem cells

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