Effective prevention of thrombocytopenia using adenovirus-mediated transfer of HST-11FGF-4 gene: in vivo and in vitro studies.
A novel biological function of HST-1 protein (FGF-4) was investigated by constructing an adenovirus vector containing the HST-1 cDNA and applied for thrombocytopenia as a gene therapy. A single intraperitoneal injection of the replication-deficient adenovirus containing the HST-1 gene (Adex1HST-1) into mice caused a two-fold increase in peripheral platelet count for 30 days, and effectively prevented experimentally induced thrombocytopenia. Studies of Adex1HST-1-infected or HST-1 protein-treated megakaryocytic Dami cells suggested that HST-1 protein promotes megakaryocyte maturation, and increases cytokine secretion from megakaryocyte and adhesive interactions between megakaryocyte and endothelial cells. Colony assay revealed that HST-1 protein stimulated CFU-MK (colony-forming unit of megakaryocyte) not alone but synergistically with early-acting cytokines such as IL-3 or Tpo (c-mpl ligand) as a megakaryocyte potentiating factor. These results have important implications for clinical application of the Adex1HST-1 for thrombocytopenia.
Konishi
H
H
Genetics Division, National Cancer Center Research Institute, Tokyo, Japan.
Ochiya
T
T
Sakamoto
H
H
Tsukamoto
M
M
Yasuda
Y
Y
Muto
T
T
Sugimura
T
T
Terada
M
M
D000256:Adenoviridae; D000818:Animals; D004730:Endothelium, Vascular / Q000502:physiology; D051519:Fibroblast Growth Factor 4; D005346:Fibroblast Growth Factors / Q000096:biosynthesis / Q000235:genetics* / Q000494:pharmacology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D007377:Interleukin-3 / Q000494:pharmacology; D008533:Megakaryocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051379:Mice; D010973:Platelet Adhesiveness; D010976:Platelet Count; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000494:pharmacology; D013921:Thrombocytopenia / Q000517:prevention & control*; D013926:Thrombopoietin / Q000494:pharmacology
C496446:Fgf4 protein, mouse; D051519:Fibroblast Growth Factor 4; D007377:Interleukin-3; D011518:Proto-Oncogene Proteins; D005346:Fibroblast Growth Factors; D013926:Thrombopoietin