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. 1994 Dec 20;91(26):12368–12372. doi: 10.1073/pnas.91.26.12368

Adenovirus-mediated transfer of the HST-1 (FGF4) gene induces increased levels of platelet count in vivo.

H Sakamoto 1, T Ochiya 1, Y Sato 1, M Tsukamoto 1, H Konishi 1, I Saito 1, T Sugimura 1, M Terada 1
PMCID: PMC45439  PMID: 7809043

Abstract

The HST-1 (fibroblast growth factor 4, FGF4) protein is a potent mitogen for a variety of cell types of mesodermal and neuroectodermal origin, including fibroblasts, endothelial cells, and melanocytes in vitro. To identify the cells and tissue targets of HST-1 in vivo, adenovirus-mediated HST-1 gene transfer was performed. In nude mice, intraperitoneal injection of 3 x 10(9) plaque-forming units of adenoviruses carrying the HST-1 gene (Adex1HST-1L) caused an increase in the number of platelets in the peripheral blood. The number of platelets reached twice the pretreated level by 12 days after the virus injection and the increased level continued up to 20-30 days thereafter. Administration of recombinant HST-1 protein resulted in a transient increase in the platelet count. The number of megakaryocytes in the bone marrow and spleen of the animals with Adex1HST-1L was increased compared with the control animals. Other hematological changes attributed to HST-1 were not observed. Although the mechanisms involved in increased levels of platelet count by HST-1 protein remain to be elucidated, these findings also suggest that adenovirus with the HST-1 gene may be efficiently used for the treatment of thrombocytopenia in various diseases.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anderson K. J., Dam D., Lee S., Cotman C. W. Basic fibroblast growth factor prevents death of lesioned cholinergic neurons in vivo. Nature. 1988 Mar 24;332(6162):360–361. doi: 10.1038/332360a0. [DOI] [PubMed] [Google Scholar]
  2. Asano S., Okano A., Ozawa K., Nakahata T., Ishibashi T., Koike K., Kimura H., Tanioka Y., Shibuya A., Hirano T. In vivo effects of recombinant human interleukin-6 in primates: stimulated production of platelets. Blood. 1990 Apr 15;75(8):1602–1605. [PubMed] [Google Scholar]
  3. Bikfalvi A., Han Z. C., Fuhrmann G. Interaction of fibroblast growth factor (FGF) with megakaryocytopoiesis and demonstration of FGF receptor expression in megakaryocytes and megakaryocytic-like cells. Blood. 1992 Oct 15;80(8):1905–1913. [PubMed] [Google Scholar]
  4. Carrington P. A., Hill R. J., Stenberg P. E., Levin J., Corash L., Schreurs J., Baker G., Levin F. C. Multiple in vivo effects of interleukin-3 and interleukin-6 on murine megakaryocytopoiesis. Blood. 1991 Jan 1;77(1):34–41. [PubMed] [Google Scholar]
  5. Chomczynski P. A reagent for the single-step simultaneous isolation of RNA, DNA and proteins from cell and tissue samples. Biotechniques. 1993 Sep;15(3):532-4, 536-7. [PubMed] [Google Scholar]
  6. Folkman J., Klagsbrun M. Angiogenic factors. Science. 1987 Jan 23;235(4787):442–447. doi: 10.1126/science.2432664. [DOI] [PubMed] [Google Scholar]
  7. Fuller-Pace F., Peters G., Dickson C. Cell transformation by kFGF requires secretion but not glycosylation. J Cell Biol. 1991 Oct;115(2):547–555. doi: 10.1083/jcb.115.2.547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Han Z. C., Bikfalvi A., Shen Z. X., Bodevin E. Recombinant acidic human fibroblast growth factor (aFGF) stimulates murine megakaryocyte colony formation in vitro. Int J Hematol. 1992 Jun;55(3):281–286. [PubMed] [Google Scholar]
  9. Hill R. J., Warren M. K., Levin J. Stimulation of thrombopoiesis in mice by human recombinant interleukin 6. J Clin Invest. 1990 Apr;85(4):1242–1247. doi: 10.1172/JCI114559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hébert J. M., Basilico C., Goldfarb M., Haub O., Martin G. R. Isolation of cDNAs encoding four mouse FGF family members and characterization of their expression patterns during embryogenesis. Dev Biol. 1990 Apr;138(2):454–463. doi: 10.1016/0012-1606(90)90211-z. [DOI] [PubMed] [Google Scholar]
  11. Ishibashi T., Kimura H., Shikama Y., Uchida T., Kariyone S., Hirano T., Kishimoto T., Takatsuki F., Akiyama Y. Interleukin-6 is a potent thrombopoietic factor in vivo in mice. Blood. 1989 Sep;74(4):1241–1244. [PubMed] [Google Scholar]
  12. Jaye M., Schlessinger J., Dionne C. A. Fibroblast growth factor receptor tyrosine kinases: molecular analysis and signal transduction. Biochim Biophys Acta. 1992 Jun 10;1135(2):185–199. doi: 10.1016/0167-4889(92)90136-y. [DOI] [PubMed] [Google Scholar]
  13. Johnson D. E., Williams L. T. Structural and functional diversity in the FGF receptor multigene family. Adv Cancer Res. 1993;60:1–41. doi: 10.1016/s0065-230x(08)60821-0. [DOI] [PubMed] [Google Scholar]
  14. Kanegae Y., Makimura M., Saito I. A simple and efficient method for purification of infectious recombinant adenovirus. Jpn J Med Sci Biol. 1994 Jun;47(3):157–166. doi: 10.7883/yoken1952.47.157. [DOI] [PubMed] [Google Scholar]
  15. Katoh O., Hattori Y., Sato T., Kimura A., Kuramoto A., Sugimura T., Terada M. Expression of the heparin-binding growth factor receptor genes in human megakaryocytic leukemia cells. Biochem Biophys Res Commun. 1992 Feb 28;183(1):83–92. doi: 10.1016/0006-291x(92)91612-t. [DOI] [PubMed] [Google Scholar]
  16. Kaushansky K., Lok S., Holly R. D., Broudy V. C., Lin N., Bailey M. C., Forstrom J. W., Buddle M. M., Oort P. J., Hagen F. S. Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietin. Nature. 1994 Jun 16;369(6481):568–571. doi: 10.1038/369568a0. [DOI] [PubMed] [Google Scholar]
  17. Kimura H., Ishibashi T., Shikama Y., Okano A., Akiyama Y., Uchida T., Maruyama Y. Interleukin-1 beta (IL-1 beta) induces thrombocytosis in mice: possible implication of IL-6. Blood. 1990 Dec 15;76(12):2493–2500. [PubMed] [Google Scholar]
  18. Lok S., Kaushansky K., Holly R. D., Kuijper J. L., Lofton-Day C. E., Oort P. J., Grant F. J., Heipel M. D., Burkhead S. K., Kramer J. M. Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production in vivo. Nature. 1994 Jun 16;369(6481):565–568. doi: 10.1038/369565a0. [DOI] [PubMed] [Google Scholar]
  19. Mulligan R. C. The basic science of gene therapy. Science. 1993 May 14;260(5110):926–932. doi: 10.1126/science.8493530. [DOI] [PubMed] [Google Scholar]
  20. Murakami A., Tanaka H., Matsuzawa A. Association of hst gene expression with metastatic phenotype in mouse mammary tumors. Cell Growth Differ. 1990 May;1(5):225–231. [PubMed] [Google Scholar]
  21. Neben T. Y., Loebelenz J., Hayes L., McCarthy K., Stoudemire J., Schaub R., Goldman S. J. Recombinant human interleukin-11 stimulates megakaryocytopoiesis and increases peripheral platelets in normal and splenectomized mice. Blood. 1993 Feb 15;81(4):901–908. [PubMed] [Google Scholar]
  22. Nishinaka-Kinoshita Y., Sasada R., Igarashi K., Ichimori Y., Terada M. Monoclonal antibodies against hst-1 gene product. Hybridoma. 1993 Dec;12(6):719–727. doi: 10.1089/hyb.1993.12.719. [DOI] [PubMed] [Google Scholar]
  23. Niswander L., Martin G. R. FGF-4 and BMP-2 have opposite effects on limb growth. Nature. 1993 Jan 7;361(6407):68–71. doi: 10.1038/361068a0. [DOI] [PubMed] [Google Scholar]
  24. Niswander L., Tickle C., Vogel A., Booth I., Martin G. R. FGF-4 replaces the apical ectodermal ridge and directs outgrowth and patterning of the limb. Cell. 1993 Nov 5;75(3):579–587. doi: 10.1016/0092-8674(93)90391-3. [DOI] [PubMed] [Google Scholar]
  25. Peters G., Brookes S., Smith R., Placzek M., Dickson C. The mouse homolog of the hst/k-FGF gene is adjacent to int-2 and is activated by proviral insertion in some virally induced mammary tumors. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5678–5682. doi: 10.1073/pnas.86.15.5678. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Saito I., Oya Y., Yamamoto K., Yuasa T., Shimojo H. Construction of nondefective adenovirus type 5 bearing a 2.8-kilobase hepatitis B virus DNA near the right end of its genome. J Virol. 1985 Jun;54(3):711–719. doi: 10.1128/jvi.54.3.711-719.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Sakamoto H., Mori M., Taira M., Yoshida T., Matsukawa S., Shimizu K., Sekiguchi M., Terada M., Sugimura T. Transforming gene from human stomach cancers and a noncancerous portion of stomach mucosa. Proc Natl Acad Sci U S A. 1986 Jun;83(11):3997–4001. doi: 10.1073/pnas.83.11.3997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. San H., Yang Z. Y., Pompili V. J., Jaffe M. L., Plautz G. E., Xu L., Felgner J. H., Wheeler C. J., Felgner P. L., Gao X. Safety and short-term toxicity of a novel cationic lipid formulation for human gene therapy. Hum Gene Ther. 1993 Dec;4(6):781–788. doi: 10.1089/hum.1993.4.6-781. [DOI] [PubMed] [Google Scholar]
  29. Sanes J. R., Rubenstein J. L., Nicolas J. F. Use of a recombinant retrovirus to study post-implantation cell lineage in mouse embryos. EMBO J. 1986 Dec 1;5(12):3133–3142. doi: 10.1002/j.1460-2075.1986.tb04620.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Simon R. H., Engelhardt J. F., Yang Y., Zepeda M., Weber-Pendleton S., Grossman M., Wilson J. M. Adenovirus-mediated transfer of the CFTR gene to lung of nonhuman primates: toxicity study. Hum Gene Ther. 1993 Dec;4(6):771–780. doi: 10.1089/hum.1993.4.6-771. [DOI] [PubMed] [Google Scholar]
  31. Suzuki H. R., Sakamoto H., Yoshida T., Sugimura T., Terada M., Solursh M. Localization of HstI transcripts to the apical ectodermal ridge in the mouse embryo. Dev Biol. 1992 Mar;150(1):219–222. doi: 10.1016/0012-1606(92)90020-h. [DOI] [PubMed] [Google Scholar]
  32. Taira M., Yoshida T., Miyagawa K., Sakamoto H., Terada M., Sugimura T. cDNA sequence of human transforming gene hst and identification of the coding sequence required for transforming activity. Proc Natl Acad Sci U S A. 1987 May;84(9):2980–2984. doi: 10.1073/pnas.84.9.2980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Talarico D., Ittmann M. M., Bronson R., Basilico C. A retrovirus carrying the K-fgf oncogene induces diffuse meningeal tumors and soft-tissue fibrosarcomas. Mol Cell Biol. 1993 Apr;13(4):1998–2010. doi: 10.1128/mcb.13.4.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Theillet C., Le Roy X., De Lapeyrière O., Grosgeorges J., Adnane J., Raynaud S. D., Simony-Lafontaine J., Goldfarb M., Escot C., Birnbaum D. Amplification of FGF-related genes in human tumors: possible involvement of HST in breast carcinomas. Oncogene. 1989 Jul;4(7):915–922. [PubMed] [Google Scholar]
  35. Tsuda H., Hirohashi S., Shimosato Y., Hirota T., Tsugane S., Yamamoto H., Miyajima N., Toyoshima K., Yamamoto T., Yokota J. Correlation between long-term survival in breast cancer patients and amplification of two putative oncogene-coamplification units: hst-1/int-2 and c-erbB-2/ear-1. Cancer Res. 1989 Jun 1;49(11):3104–3108. [PubMed] [Google Scholar]
  36. Wendling F., Maraskovsky E., Debili N., Florindo C., Teepe M., Titeux M., Methia N., Breton-Gorius J., Cosman D., Vainchenker W. cMpl ligand is a humoral regulator of megakaryocytopoiesis. Nature. 1994 Jun 16;369(6481):571–574. doi: 10.1038/369571a0. [DOI] [PubMed] [Google Scholar]
  37. Yoshida T., Miyagawa K., Odagiri H., Sakamoto H., Little P. F., Terada M., Sugimura T. Genomic sequence of hst, a transforming gene encoding a protein homologous to fibroblast growth factors and the int-2-encoded protein. Proc Natl Acad Sci U S A. 1987 Oct;84(20):7305–7309. doi: 10.1073/pnas.84.20.7305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Yoshida T., Tsutsumi M., Sakamoto H., Miyagawa K., Teshima S., Sugimura T., Terada M. Expression of the HST1 oncogene in human germ cell tumors. Biochem Biophys Res Commun. 1988 Sep 30;155(3):1324–1329. doi: 10.1016/s0006-291x(88)81286-5. [DOI] [PubMed] [Google Scholar]
  39. de Sauvage F. J., Hass P. E., Spencer S. D., Malloy B. E., Gurney A. L., Spencer S. A., Darbonne W. C., Henzel W. J., Wong S. C., Kuang W. J. Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand. Nature. 1994 Jun 16;369(6481):533–538. doi: 10.1038/369533a0. [DOI] [PubMed] [Google Scholar]

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