Enforced expression of KDR receptor promotes proliferation, survival and megakaryocytic differentiation of TF1 progenitor cell line

Coppola, Simona; Narciso, Laura; Feccia, Tiziana; Bonci, Desirée; Calabrò, Luana; Morsilli, Ornella; Gabbianelli, Marco; Maria, Ruggero De; Testa, Ugo; Peschle, Cesare

doi:10.1038/sj.cdd.4401698

Cited by 25 publications

(25 citation statements)

References 47 publications

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“…Previous assays of cell proliferation and cell cycle analysis of K562 cells also indicated that Nm23-H1 was a potential activator of K562 cell proliferation. Despite the appearance of 2-3 lobated nuclei in some of the shNm23 cells, one of the characterization of the megakaryocyte (Coppola et al 2006), analysis of DNA content and expression of CD41 (data not shown) indicated that knockdown of Nm23-H1 mRNA was not sufficient to induce differentiation of K562 cells. Therefore, we induced the differentiation of K562 cells with PMA, and unexpectedly found an accelerated appearance of polyploidy and expression of CD41 compared to K562 cells that overexpressed Nm23-H1 with the same treatment.…”

Section: Discussionmentioning

confidence: 73%

Nm23-H1 regulates the proliferation and differentiation of the human chronic myeloid leukemia K562 cell line: A functional proteomics study

Jin

Zhang

et al. 2009

Life Sciences

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Section: Discussionmentioning

confidence: 73%

Nm23-H1 regulates the proliferation and differentiation of the human chronic myeloid leukemia K562 cell line: A functional proteomics study

Jin

Zhang

et al. 2009

Life Sciences

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“…39 In brief, this retroviral vector contains the full-length Moloney LTRs, while the original cytomegalovirus (CMV)-GFP cassette was substituted by a viral IRES-GFP which is the most efficient tool for coexpressing two genes from a single provirus.…”

Section: Plasmidsmentioning

confidence: 99%

Overexpression of Ets-1 in human hematopoietic progenitor cells blocks erythroid and promotes megakaryocytic differentiation

et al. 2005

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Ets-1 is a widely expressed transcription factor implicated in development, tumorigenesis and hematopoiesis. We analyzed Ets-1 gene expression during human erythroid and megakaryocytic (MK) differentiation in unilineage cultures of CD34 þ progenitor cells. During erythroid maturation, Ets-1 is downmodulated and exported from the nucleus into the cytoplasm through an active mechanism mediated by a leucine-rich nuclear export signal. In contrast, during megakaryocytopoiesis Ets-1 increases and remains localized in the nucleus up to terminal maturation. Overexpression of Ets-1 in erythroid cells blocks maturation at the polychromatophilic stage, increases GATA-2 and decreases both GATA-1 and erythropoietin receptor expression. Conversely, Ets-1 overexpressing megakaryocytes are characterized by enhanced differentiation and maturation, coupled with upmodulation of GATA-2 and megakaryocyte-specific genes. We show that Ets-1 binds to and activates the GATA-2 promoter, in vitro and in vivo, indicating that one of the pathways through which Ets-1 blocks erythroid and promotes MK differentiation is via upmodulation of GATA-2 expression.

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“…20,26 In vitro VEGFR2 stimulation of cultured human MKs has been shown to promote MK proliferation (mitosis) and survival 21 while VEGFR1 activation potentiates maturation of hematopoietic progenitor cell-derived MKs as measured by increases in DNA ploidy content (endomitosis). 20 Therefore, we next examined the effect of VEGF on MK proliferation and maturation in vivo.…”

Section: Effect Of Vegfr1 and Vegfr2 On Mk Numbersmentioning

confidence: 99%

“…19 Interestingly, VEGFR1 and VEGFR2 expression has been demonstrated on cultured human MKs. 20,21 Moreover, under conditions of hypoxia, MKs have been shown to secrete VEGF-A, which acts in an autocrine fashion via VEGFR1 to accelerate MK maturation in vitro. 20 In addition, VEGFR2 stimulation of MK precursors has been demonstrated to control their survival and differentiation in vitro.…”

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VEGFR1 stimulates a CXCR4-dependent translocation of megakaryocytes to the vascular niche, enhancing platelet production in mice

Pitchford

Lodie²,

Rankin

2012

Blood

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It has previously been reported that VEGF-A stimulates megakaryocyte (MK) maturation in vitro. Here we show that treatment of mice with the isoform VEGF-A 165 resulted in a significant increase in circulating numbers of platelets. Using specific VEGFR1 and VEGFR2 blocking mAbs and selective VEGFR1 and 2 agonists, PlGF-2 and VEGF-E, respectively, we show directly that stimulation of VEGFR1, but not VEGFR2, increases circulating platelet numbers in vivo. Using flow cytometric analysis of harvested MKs, we show that while PlGF does not change the absolute numbers of MKs present in the bone marrow and the spleen, it increases both their maturation and cell-surface expression of CXCR4 in the bone marrow. Histology of the bone marrow revealed a redistribution of MKs from the endosteal to the vascular niche in response to both VEGF-A 165 and PlGF-2 treatment in vivo. Antagonism of CXCR4 suppressed both the VEGFR1-stimulated redistribution of megakyocytes within the bone marrow compartment and the VEGF-A 165 -induced thrombocytosis. In conclusion, we define a novel proinflammatory VEGFR1-mediated pathway that stimulates the maturation and upregulation of CXCR4 on megakaryocytes, leading to their redistribution within the bone marrow environment, thereby enhancing platelet production in vivo. (Blood. 2012;120(14):2787-2795) IntroductionUnder homeostatic conditions, megakaryopoiesis is driven primarily by thrombopoietin (TPO) and stem cell factor (SCF). 1,2 Patients suffering from congenital amegakaryocytic thrombocytopenia (a mutation to the TPO receptor: cMPL), and mice with genetic deletions of SCF and TPO, therefore exhibit a profound thrombocytopenia. 3,4 Within the bone marrow endosteal niche, TPO acts synergistically with other hematopoietic cytokines to stimulate stem cell differentiation toward the megakaryocyte lineage to create promegakaryoblasts. 5 Promegakaryoblasts then begin to increase their ploidy content via the process of endomitosis. This process driven by TPO is essential for normal maturation into megakaryocytes (MKs). 6,7 Mature MKs then migrate to within close proximity of the bone marrow sinusoidal endothelium to form preplatelet buds, eventually releasing platelets. 8,9 Studies of megakaryopoiesis in vitro using CD34 ϩ cell unilineage differentiation cultures have shown that the upregulation of the chemokine receptor CXCR4 is associated with the maturation of megakaryocytes. 10 Although CXCL12 (the ligand for CXCR4) acting alone does not stimulate MK development, it has been reported to act synergistically with TPO to enhance megakaryopoiesis and platelet formation in vitro and in vivo. [11][12][13] The original studies describing the expression of CXCR4 on MKs demonstrated that CXCL12 stimulated their migration in vitro. 8,14 More recent studies have shown that adenoviral delivery of CXCL12, resulting in a sustained elevation in plasma CXCL12 over 10 days, increased circulating numbers of platelets in TPO-and MPL-deficient mice. It was shown that platelet production was enhanced, as a result o...

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Enforced expression of KDR receptor promotes proliferation, survival and megakaryocytic differentiation of TF1 progenitor cell line

Cited by 25 publications

References 47 publications

Nm23-H1 regulates the proliferation and differentiation of the human chronic myeloid leukemia K562 cell line: A functional proteomics study

Nm23-H1 regulates the proliferation and differentiation of the human chronic myeloid leukemia K562 cell line: A functional proteomics study

Overexpression of Ets-1 in human hematopoietic progenitor cells blocks erythroid and promotes megakaryocytic differentiation

VEGFR1 stimulates a CXCR4-dependent translocation of megakaryocytes to the vascular niche, enhancing platelet production in mice

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