title: HST-1/FGF-4 stimulates proliferation of megakaryocyte progenitors synergistically and promotes megakaryocyte maturation.
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.
authors.affiliation: Genetics Division, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Konishi
authors.forename: T
authors.initials: T
authors.lastname: Ochiya
authors.forename: Y
authors.initials: Y
authors.lastname: Yasuda
authors.forename: H
authors.initials: H
authors.lastname: Sakamoto
authors.forename: T
authors.initials: T
authors.lastname: Muto
authors.forename: T
authors.initials: T
authors.lastname: Sugimura
authors.forename: M
authors.initials: M
authors.lastname: Terada
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004261:DNA Replication; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000166:cytology; D051519:Fibroblast Growth Factor 4; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D039041:Integrin alpha4beta1; D016023:Integrins / Q000378:metabolism; D007377:Interleukin-3 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology / Q000502:physiology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D008297:Male; D008533:Megakaryocytes / Q000166:cytology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D011003:Ploidies; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology; D013926:Thrombopoietin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D014471:Umbilical Veins
chemical_list: C496445:FGF4 protein, human; C496446:Fgf4 protein, mouse; D051519:Fibroblast Growth Factor 4; D039041:Integrin alpha4beta1; D016023:Integrins; D007377:Interleukin-3; D015850:Interleukin-6; D016169:Lymphocyte Function-Associated Antigen-1; D011518:Proto-Oncogene Proteins; D016201:Receptors, Lymphocyte Homing; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D005346:Fibroblast Growth Factors; D013926:Thrombopoietin