Intravenous injection of phagocytes transfected ex vivo with FGF4 DNA/biodegradable gelatin complex promotes angiogenesis in a rat myocardial ischemia/reperfusion injury model

  • N. Fukuyama
  • E. Tanaka
  • Y. Tabata
  • H. Fujikura
  • M. Hagihara
  • H. Sakamoto
  • K. Ando
  • H. Nakazawa
  • H. Mori


Conventional gene therapies still present difficulties due to poor tissue-targeting, invasiveness of delivery, method, or the use of viral vectors. To establish the feasibility of using non-virally ex vivo transfected phagocytes to promote angiogenesis in ischemic myocardium, gene-transfection into isolated phagocytes was performed by culture with positively charged gelatin impregnated with plasmid DNA. A high rate of gene transfection was achieved in rat macrophages and human monocytes, but not in mouse fibroblasts. The efficiency was 68 ± 11% in rat macrophages and 78 ± 8% in human monocytes. Intravenously injected phagocytes accumulated predominantly in ischemic tissue (13 ± 8%) and spleen (84 ± 6%), but negligibly in other organs in rodents. The efficiency of accumulation in the target ischemic tissue reached more than 86% on direct local tissue injection. In a rat model of myocardial ischemia-reperfusion, intravenous injection of fibroblast growth factor 4 (FGF4)-gene-transfected macrophages significantly increased regional blood flow in the ischemic myocardium (78 ± 7.1 % in terms of flow ratio of ischemic/non-ischemic myocardium) compared with intravenous administration of saline (36 ± 11%) or nontransfected macrophages (42 ± 12 %), or intramuscular administration of naked DNA encoding FGF4 (75 ± 18 %). Enhanced angiogenesis in the ischemic tissue we confirmed histologically. Similarly, intravenous injection of FGF4-gene-transfected monocytes enhanced regional blood flow in an ischemic hindlimb model in mice (93 ± 22 %), being superior to the three other treatments described above (38 ± 12, 39 ± 15, and 55 ± 12%, respectively).

Phagocytes transfected ex vivo with FGF4 DNA/gelatin promoted angiogenesis. This approach might have potential for non-viral angiogenic gene therapy.

Key words

angiogenesis cells gene therapy growth substances ischemia 

Abbreviations and acronyms


= analysis of variance


= fibroblast growth factor-4


= green fluorescent protein


= isoelectric point


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Copyright information

© Steinkopff-Verlag 2006

Authors and Affiliations

  • N. Fukuyama
    • 1
  • E. Tanaka
    • 2
  • Y. Tabata
    • 3
  • H. Fujikura
    • 1
  • M. Hagihara
    • 1
  • H. Sakamoto
    • 4
  • K. Ando
    • 1
  • H. Nakazawa
    • 1
  • H. Mori
    • 5
  1. 1.Depts. of Physiology, Internal Medicine and Center for Regenerative MedicineTokai University School of MedicineIseharaJapan
  2. 2.Dept. of Nutritional SciencesTokyo University of AgricultureTokyoJapan
  3. 3.Research Center for Biomedical EngineeringKyoto UniversityKyotoJapan
  4. 4.Genetics DivisionNational Cancer Center Research InstituteTokyoJapan
  5. 5.National Cardiovascular Center Research InstituteSuitaJapan

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