Effects of erythropoietin, IL-3, IL-6 and LIF on a murine megakaryoblastic cell line: Growth enhancement and expression of receptor mRNAs

Sasaki, Hideki; Hirabayashi, Yoko; Ishibashi, Toshiyuki; Inoue, Tohru; Matsuda, Motoi; Kai, Satoru; Ikuta, Koichiro; Yokoyama, Keiko; Yokota, Takashi; Maruyama, Yukio; Matsuyama, Sho

doi:10.1016/0145-2126(94)00121-p

Cited by 12 publications

(10 citation statements)

References 26 publications

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“…Megakaryocytes have been shown to express constitutive 35 or inducible 36,37 high-affinity binding sites for Epo, resulting in enhanced growth in the presence of Epo. 38 In vitro studies in humans as well as in mice have demonstrated that Epo promotes megakaryocytic colony formation and increases the size, ploidy, and number of megakaryocytes, as well as their DNA and protein synthesis and cytoplasmic process formation. [38][39][40][41][42] Instead of directly stimulating megakaryocytes, Epo could also promote platelet production indirectly by enhancing global hematopoietic activity.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Recombinant Human Erythropoietin on Platelet Counts Is Strongly Modulated by the Adequacy of Iron Supply

Loo

Béguin

1999

Blood

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The effect of recombinant human erythropoietin (rHuEpo) on megakaryopoiesis remains controversial. Treatment with rHuEpo in renal failure patients has been associated with a slight elevation of platelet counts. In animal studies, high doses of rHuEpo produced an increase of platelet counts followed by a gradual return to normal after 7 to 15 days or even a substantial degree of thrombocytopenia. However, because iron deficiency is also known to be associated with thrombocytosis, (functional) iron deficiency during rHuEpo could be contributing to these observations. We investigated the impact of iron supply on changes in platelet counts induced by rHuEpo. Rats were either fed normal food (normal rats) or received 1% carbonyl iron for 2 weeks or 3 months, as well as during the experiment, to achieve iron supplementation or overload, respectively. Rats of all three categories then received daily intravenous injections of rHuEpo (10, 50, or 150 U) or normal saline (0 U) for 20 days. With 0 to 10 U rHuEpo, platelets remained stable. In normal rats receiving 50 to 150 U rHuEpo, platelets increased to 120% to 140% of baseline at 4 to 12 days to level off at 120% at 16 to 20 days. This response was less sustained in splenectomized animals. Iron-supplemented rats receiving 50 to 150 U rHuEpo also increased platelets initially, but the peak was at day 4, followed by a gradual return to baseline and even a moderate thrombocytopenia later on. Iron-overloaded rats receiving 50 to 150 U rHuEpo also had increased platelets at day 4, but the duration of platelet increase was shorter, and they experienced a more pronounced degree of thrombocytopenia in proportion to the dose of rHuEpo. Because the early elevation of platelets was of larger magnitude than hematocrit changes, it is unlikely that it could be accounted for by shrinkage of plasma volume. Because it was observed in all three iron conditions, there appears to be some direct positive effect of rHuEpo on platelet production. However, after this transient effect, expanded erythropoiesis appears to exert a negative impact upon platelet production. Secondary thrombocytopenia was not related to splenic pooling, and its very slow correction after cessation of rHuEpo therapy is not compatible with changes in platelet survival. Rather, it is consistent with stem cell competition between erythroid and megakaryocytic development. However, this secondary thrombocytopenia is masked by (functional) iron deficiency in rats not receiving an adequate iron supply from food or stores.

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Section: Discussionmentioning

confidence: 99%

The Effect of Recombinant Human Erythropoietin on Platelet Counts Is Strongly Modulated by the Adequacy of Iron Supply

Loo

Béguin

1999

Blood

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“…As reported previously, thrombocytopoiesis is regulated by a variety of haematopoietic cytokines, such as thrombopoietin (TPO), granulocyte–macrophage colony-stimulating factor (GM-CSF), interleukin family proteins (IL-1, IL-3, IL-6, and IL-11), and stromal cell-derived factor-1 (SDF-1). 9, 10, 11, 12, 13 However, the mechanisms underlying MK differentiation and platelet generation under physiological and pathological conditions have not been adequately elucidated.…”

Section: Open Questionsmentioning

confidence: 99%

ROS-mediated platelet generation: a microenvironment-dependent manner for megakaryocyte proliferation, differentiation, and maturation

Chen

Wang

2013

Cell Death Dis

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Platelets have an important role in the body because of their manifold functions in haemostasis, thrombosis, and inflammation. Platelets are produced by megakaryocytes (MKs) that are differentiated from haematopoietic stem cells via several consecutive stages, including MK lineage commitment, MK progenitor proliferation, MK differentiation and maturation, cell apoptosis, and platelet release. During differentiation, the cells migrate from the osteoblastic niche to the vascular niche in the bone marrow, which is accompanied by reactive oxygen species (ROS)-dependent oxidation state changes in the microenvironment, suggesting that ROS can distinctly influence platelet generation and function in a microenvironment-dependent manner. The objective of this review is to reveal the role of ROS in regulating MK proliferation, differentiation, maturation, and platelet activation, thereby providing new insight into the mechanism of platelet generation, which may lead to the development of new therapeutic agents for thrombocytopenia and/or thrombosis.

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“…[3][4][5] Nevertheless, the fact that some Megs and platelets are still present in these animals even in the total absence of TPO suggests that some other factors can compensate for TPO deficiency and the cytokines that signal through gp130 such as interleukin-6 (IL-6), IL-11, leukemia inhibitory factor, cilliary neurotropic factor and oncostatin M have been suggested to be such factors. [6][7][8][9] However, recent data show that IL-6 and IL-11 do not induce platelet production in thrombocytopenic, TPO-deficient (Tpo À/À ) and TPO-receptor-deficient (Mpl À/À ) mice. 10 Thus, it is unlikely that gp130 signaling cytokines are significantly involved in platelet production in these animals.…”

Section: Introductionmentioning

confidence: 99%

“…10 Thus, it is unlikely that gp130 signaling cytokines are significantly involved in platelet production in these animals. [4][5][6][7][8][9][10] The a-chemokine stromal-derived factor-1 (SDF-1) has been proposed as a new regulator of Megs maturation and platelet formation. [11][12][13][14][15][16] A recently published study clearly demonstrated that SDF-1, together with fibroblast growth factor-4 (FGF-4), restored thrombopoiesis in Tpo À/À and Mpl À/À mice by directing trans-localization of megakaryocytic progenitors positive for CXCR4, the receptor for SDF-1, from the endostial to the vascular niche, thereby promoting survival, maturation to megakaryocytes and platelet production.…”

Section: Introductionmentioning

confidence: 99%

Cleavage fragments of the third complement component (C3) enhance stromal derived factor-1 (SDF-1)-mediated platelet production during reactive postbleeding thrombocytosis

et al. 2007

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We hypothesized that the third complement component (C3) cleavage fragments (C3a and des-Arg C3a) are involved in stress/ inflammation-related thrombocytosis, and investigated their potential role in reactive thrombocytosis induced by bleeding. We found that platelet counts are lower in C3-deficient mice in response to excessive bleeding as compared to normal littermates and that C3a and des-Arg C3a enhance stromalderived factor-1 (SDF-1)-dependent megakaryocyte (Megs) migration, adhesion and platelet shedding. At the molecular level, C3a stimulates in Megs MAPKp42/44 phosphorylation, and enhances incorporation of CXCR4 into membrane lipid rafts increasing the responsiveness of Megs to SDF-1. We found that perturbation of lipid raft formation by statins decreases SDF-1/C3a-dependent platelet production in vitro and in an in vivo model statins ameliorated post-bleeding thrombocytosis. Thus, inhibition of lipid raft formation could find potential clinical application as a means of ameliorating some forms of thrombocytosis. Leukemia (2007) 21, 973-982.

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Effects of erythropoietin, IL-3, IL-6 and LIF on a murine megakaryoblastic cell line: Growth enhancement and expression of receptor mRNAs

Cited by 12 publications

References 26 publications

The Effect of Recombinant Human Erythropoietin on Platelet Counts Is Strongly Modulated by the Adequacy of Iron Supply

The Effect of Recombinant Human Erythropoietin on Platelet Counts Is Strongly Modulated by the Adequacy of Iron Supply

ROS-mediated platelet generation: a microenvironment-dependent manner for megakaryocyte proliferation, differentiation, and maturation

Cleavage fragments of the third complement component (C3) enhance stromal derived factor-1 (SDF-1)-mediated platelet production during reactive postbleeding thrombocytosis

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