Abstract
Megakaryocyte (MK) development is dependent on the complex interaction of MK progenitors, various cytokines and stromal elements. We previously reported that an injection of replication-deficient adenovirus containing HST-1/FGF-4 cDNA (Adex1HST-1) into mice caused a twofold increase in peripheral platelet count for 30 days without any other hematological or histological abnormality. In the present study using Adex1HST-1-infected human megakaryocytic Dami cells, we demonstrated for the first time that HST-1/FGF-4 promoted MK maturation, inducing increases in DNA ploidy, cytoplasmic and membrane maturation, and platelet-like particle release. Moreover, HST-1/FGF-4 acted on megakaryocytic cells to induce secretion of IL-6 and TNF-alpha, and increased adhesion of megakaryocytic cells to human endothelial cells primarily via VLA-4 and LFA-1 molecules; both mechanisms have been shown to lead to MK maturation. We also showed that HST-1/FGF-4 stimulates the proliferation of MK progenitors not alone but synergistically with IL-3 via IL-6 and with c-mpl ligand (thrombopoietin) not via IL-6. This result supports the hypothesis of the presence of two distinct populations of MK progenitors: IL-3-dependent and Tpo-dependent. All these results suggest that HST-1/FGF-4 can regulate MK development not only as an MK potentiating factor, but also as an inducer of cytokine secretion from MK, and as a modulator of adhesive interactions with endothelial cells.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenoviruses, Human / genetics
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Amino Acid Sequence
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Animals
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Cell Adhesion / drug effects
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Cell Differentiation / drug effects
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Cell Division / drug effects
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Cell Line
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DNA Replication
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Drug Synergism
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Endothelium, Vascular / cytology
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Fibroblast Growth Factor 4
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Fibroblast Growth Factors / genetics
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Fibroblast Growth Factors / pharmacology
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Fibroblast Growth Factors / physiology*
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Genetic Vectors / genetics
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Humans
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Integrin alpha4beta1
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Integrins / metabolism
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Interleukin-3 / pharmacology
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Interleukin-6 / pharmacology
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Interleukin-6 / physiology
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Lymphocyte Function-Associated Antigen-1 / metabolism
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Male
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Megakaryocytes / cytology*
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Mice
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Mice, Inbred BALB C
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Molecular Sequence Data
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Ploidies
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / pharmacology
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Proto-Oncogene Proteins / physiology*
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Receptors, Lymphocyte Homing / metabolism
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Recombinant Fusion Proteins / metabolism
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Recombinant Fusion Proteins / pharmacology
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Thrombopoietin / pharmacology
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Tumor Necrosis Factor-alpha / metabolism
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Tumor Necrosis Factor-alpha / pharmacology
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Umbilical Veins
Substances
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FGF4 protein, human
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Fgf4 protein, mouse
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Fibroblast Growth Factor 4
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Integrin alpha4beta1
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Integrins
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Interleukin-3
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Interleukin-6
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Lymphocyte Function-Associated Antigen-1
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Proto-Oncogene Proteins
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Receptors, Lymphocyte Homing
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Recombinant Fusion Proteins
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Tumor Necrosis Factor-alpha
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Fibroblast Growth Factors
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Thrombopoietin