HST-1/FGF-4 stimulates proliferation of megakaryocyte progenitors synergistically and promotes megakaryocyte maturation.
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.
Konishi
H
H
Genetics Division, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
Ochiya
T
T
Yasuda
Y
Y
Sakamoto
H
H
Muto
T
T
Sugimura
T
T
Terada
M
M
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
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