Accéder au contenu
Merck

Hybrid cell-gene therapy for pulmonary hypertension based on phagocytosing action of endothelial progenitor cells.

Circulation (2003-07-02)
Noritoshi Nagaya, Kenji Kangawa, Munetake Kanda, Masaaki Uematsu, Takeshi Horio, Naoto Fukuyama, Jun Hino, Mariko Harada-Shiba, Hiroyuki Okumura, Yasuhiko Tabata, Naoki Mochizuki, Yoshihide Chiba, Keisuke Nishioka, Kunio Miyatake, Takayuki Asahara, Hiroshi Hara, Hidezo Mori
RÉSUMÉ

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. 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. 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.

MATÉRIAUX
Référence du produit
Marque
Description du produit

Sigma-Aldrich
Anticorps anti-VE-cadhérine, clone BV6, clone BV6, from mouse
Sigma-Aldrich
Monoclonal Anti-Vascular Endothelial Growth Factor Receptor-2 antibody produced in mouse, clone KDR-1, ascites fluid