on June 30, 2003
Published online before print June 30, 2003, doi: 10.1161/01.CIR.0000079161.56080.22
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Submitted on December 3, 2002
From the Departments of Internal Medicine (N.N., T.H., K.M.) and Perinatology (Y.C.), National Cardiovascular Center, Osaka, Japan; Departments of Biochemistry (K.K., J.H., M.H.-S., H.O.), Cardiac Physiology (M.K., H.M.), and Structural Analysis (N.M.), National Cardiovascular Center Research Institute, Osaka, Japan; Cardiovascular Division (M.U.), Kansai Rosai Hospital, Hyogo, Japan; Department of Physiology (N.F.), Tokai University School of Medicine, Kanagawa, Japan; Department of Biomaterials (Y.T.), Field of Tissue Engineering, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan; Department of Transfusion Medicine (K.N., H.H.), Hyogo College of Medicine, Hyogo, Japan; and Department of Regenerative Medicine (T.A.), Institute of Biomedical Research and Innovation, Kobe, Japan. * To whom correspondence should be addressed. E-mail: nagayann{at}hsp.ncvc.go.jp.
Background--Circulating endothelial progenitor cells (EPCs) migrate to injured vascular endothelium and differentiate into mature endothelial cells. We investigated whether transplantation of vasodilator gene-transduced EPCs ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats. Methods and Results--We obtained EPCs from cultured human umbilical cord blood mononuclear cells and constructed plasmid DNA of adrenomedullin (AM), a potent vasodilator peptide. We used cationic gelatin to produce ionically linked DNA-gelatin complexes. Interestingly, EPCs phagocytosed plasmid DNA-gelatin complexes, which allowed nonviral, highly efficient gene transfer into EPCs. Intravenously administered EPCs were incorporated into the pulmonary vasculature of immunodeficient nude rats given MCT. Transplantation of EPCs alone modestly attenuated MCT-induced pulmonary hypertension (16% decrease in pulmonary vascular resistance). Furthermore, transplantation of AM DNA-transduced EPCs markedly ameliorated pulmonary hypertension in MCT rats (39% decrease in pulmonary vascular resistance). MCT rats transplanted with AM-expressing EPCs had a significantly higher survival rate than those given culture medium or EPCs alone. Conclusions--Umbilical cord blood-derived EPCs had a phagocytosing action that allowed nonviral, highly efficient gene transfer into EPCs. Transplantation of AM gene-transduced EPCs caused significantly greater improvement in pulmonary hypertension in MCT rats than transplantation of EPCs alone. Thus, a novel hybrid cell-gene therapy based on the phagocytosing action of EPCs may be a new therapeutic strategy for the treatment of pulmonary hypertension.
Revised on April 17, 2003
Accepted on April 18, 2003
Hybrid Cell-Gene Therapy for Pulmonary Hypertension Based on Phagocytosing Action of Endothelial Progenitor Cells
Noritoshi Nagaya MD*,
Key words: pulmonary heart disease • natriuretic peptides • gene therapy • endothelium
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