Recombinant human c‐Mpl ligand is not a direct stimulator of proplatelet formation in mature human megakaryocytes

Ito, Toshiharu; Ishida, Yoshiteru; Kashiwagi, Rieko; Kuriya, S

doi:10.1046/j.1365-2141.1996.d01-1813.x

Cited by 49 publications

(32 citation statements)

References 11 publications

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“…Mpl was shown not only to be unnecessary for platelet formation but to favor endomitosis over platelet production in MK. 42,43 Increased endomitosis resulting from high Mpl expression might have induced the atypically large MK combined with low platelet counts. In some of the mice with high numbers of MK, we also found marrow fibrosis and bone neo-formation.…”

Section: Discussionmentioning

confidence: 99%

Lentiviral gene transfer regenerates hematopoietic stem cells in a mouse model for Mpl-deficient aplastic anemia

Heckl¹,

Wicke²,

Brugman³

et al. 2011

Blood

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Section: Discussionmentioning

confidence: 99%

Lentiviral gene transfer regenerates hematopoietic stem cells in a mouse model for Mpl-deficient aplastic anemia

Heckl¹,

Wicke²,

Brugman³

et al. 2011

Blood

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“…Nagahisa et al recently showed that TPO induces morphological changes in megakaryocytes resulting in the formation of lengthy, beaded cytoplasmic processes that are similar in appearance to the cytoplasmic projections of the proplatelet (6). Others, however, have shown that, although TPO is essential for megakaryocyte production and maturation, it plays only an indirect role in proplatelet formation (7,8). A secondary role of TPO in platelet formation has been supported by the phenotype of mice in which the gene for TPO has been deleted.…”

mentioning

confidence: 91%

Induction of platelet formation from megakaryocytoid cells by nitric oxide

Battinelli

Willoughby

Foxall

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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Although the growth factors that regulate megakaryocytopoiesis are well known, the molecular determinants of platelet formation from mature megakaryocytes remain poorly understood. Morphological changes in megakaryocytes associated with platelet formation and removal of senescent megakaryocytes are suggestive of an apoptotic process. Previously, we have established that nitric oxide (NO) can induce apoptosis in megakaryocytoid cell lines. To determine whether there is an association between NO-induced apoptosis and platelet production, we exposed Meg-01 cells to S-nitrosoglutathione (GSNO) with or without thrombopoeitin (TPO) pretreatment and used flow cytometry and electron microscopy to assess platelet-sized particle formation. Meg-01 cells treated with TPO alone produced few platelet-sized particles (<3% of total counts), whereas treatment with GSNO alone produced a significant percentage of platelet-sized particles (22 ؎ 4% of total counts); when combined with TPO pretreatment, however, GSNO led to a marked increase in platelet-sized particle production (48 ؎ 3% of total counts). Electron microscopy confirmed that Meg-01 cells treated with TPO and GSNO yielded platelet-sized particles with morphological features specific for platelet forms. The platelet-sized particle population appears to be functional, because addition of calcium, fibrinogen, and thrombin receptor-activating peptide led to aggregation. These results demonstrate that NO facilitates platelet production, thereby establishing the essential role of NO in megakaryocyte development and thrombopoiesis.thrombopoiesis ͉ apoptosis ͉ guanylyl cyclase T he mechanism by which platelets are produced from megakaryocytes (thrombocytopoiesis) is not well understood. Megakaryocytes differentiate from pluripotent hematopoietic stem cells in a process orchestrated by a series of growth factors that regulate distinct stages of megakaryocyte maturation. These stages include proliferation of progenitor cells, nuclear polyploidization (via endomitosis), cytoplasmic maturation, and, ultimately, proplatelet formation and platelet release (1). Cytoplasmic maturation is characterized by the formation of platelet-specific granules and the development of a demarcation membrane system that delineates the platelet fields in the cytoplasm. In recent years, a theory of proplatelet development has emerged in which long cytoplasmic exvaginations form from the mature megakaryocyte cytoplasm in the terminal phase of megakaryocyte development. These proplatelets insinuate between bone marrow sinusoidal cells to enter the circulation (2). Circulatory shear force within the marrow or possibly in the pulmonary circulation results in the fragmentation of these proplatelets, thereby releasing platelets into the circulation (3, 4). Moreover, Italiano and colleagues have recently demonstrated that the number of platelets released per megakaryocyte is enhanced by coordinated bending and bifurcation of proplatelet processes (5).The recently discovered growth factor thrombopoeitin (TPO) i...

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“…Thrombopoietin (TPO) is the main humoral driver of megakaryopoiesis 5, 6. However, TPO does not regulate proplatelet formation,7 a process requiring complex remodelling of cytoskeletal elements, including actin and microtubules 8, 9…”

Section: Introductionmentioning

confidence: 99%

N‐methyl‐d‐aspartate receptor mediated calcium influx supports in vitro differentiation of normal mouse megakaryocytes but proliferation of leukemic cell lines

Kamal

Green

Hearn

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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Essentials Intracellular calcium pathways regulate megakaryopoiesis but details are unclear.We examined effects of NMDAR‐mediated calcium influx on normal and leukemic cells in culture.NMDARs facilitated differentiation of normal but proliferation of leukemic megakaryocytes.NMDAR inhibitors induced differentiation of leukemic Meg‐01 cells. Background N‐methyl‐d‐aspartate receptors (NMDARs) contribute calcium influx in megakaryocytic cells but their roles remain unclear; both pro‐ and anti‐differentiating effects have been shown in different contexts.ObjectivesThe aim of this study was to clarify NMDAR contribution to megakaryocytic differentiation in both normal and leukemic cells.MethodsMeg‐01, Set‐2, and K‐562 leukemic cell lines were differentiated using phorbol‐12‐myristate‐13‐acetate (PMA, 10 nmol L−1) or valproic acid (VPA, 500 μmol L−1). Normal megakaryocytes were grown from mouse marrow‐derived hematopoietic progenitors (lineage‐negative and CD41a‐enriched) in the presence of thrombopoietin (30‐40 nmol L−1). Marrow explants were used to monitor proplatelet formation in the native bone marrow milieu. In all culture systems, NMDARs were inhibited using memantine and MK‐801 (100 μmol L−1); their effects compared against appropriate controls.ResultsThe most striking observation from our studies was that NMDAR antagonists markedly inhibited proplatelet formation in all primary cultures employed. Proplatelets were either absent (in the presence of memantine) or short, broad and intertwined (with MK‐801). Earlier steps of megakaryocytic differentiation (acquisition of CD41a and nuclear ploidy) were maintained, albeit reduced. In contrast, in leukemic Meg‐01 cells, NMDAR antagonists inhibited differentiation in the presence of PMA and VPA but induced differentiation when applied by themselves.Conclusions NMDAR‐mediated calcium influx is required for normal megakaryocytic differentiation, in particular proplatelet formation. However, in leukemic cells, the main NMDAR role is to inhibit differentiation, suggesting diversion of NMDAR activity to support leukemia growth. Further elucidation of the NMDAR and calcium pathways in megakaryocytic cells may suggest novel ways to modulate abnormal megakaryopoiesis.

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Recombinant human c‐Mpl ligand is not a direct stimulator of proplatelet formation in mature human megakaryocytes

Cited by 49 publications

References 11 publications

Lentiviral gene transfer regenerates hematopoietic stem cells in a mouse model for Mpl-deficient aplastic anemia

Lentiviral gene transfer regenerates hematopoietic stem cells in a mouse model for Mpl-deficient aplastic anemia

Induction of platelet formation from megakaryocytoid cells by nitric oxide

N‐methyl‐d‐aspartate receptor mediated calcium influx supports in vitro differentiation of normal mouse megakaryocytes but proliferation of leukemic cell lines

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