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


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.
Nagaya
Noritoshi
N
Department of Internal Medicine, National Cardiovascular Center, Osaka, Japan. nagayann@hsp.ncvc.go.jp
Kangawa
Kenji
K
Kanda
Munetake
M
Uematsu
Masaaki
M
Horio
Takeshi
T
Fukuyama
Naoto
N
Hino
Jun
J
Harada-Shiba
Mariko
M
Okumura
Hiroyuki
H
Tabata
Yasuhiko
Y
Mochizuki
Naoki
N
Chiba
Yoshihide
Y
Nishioka
Keisuke
K
Miyatake
Kunio
K
Asahara
Takayuki
T
Hara
Hiroshi
H
Mori
Hidezo
H
D053607:Adrenomedullin; D000818:Animals; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004195:Disease Models, Animal; D004337:Drug Carriers; D004730:Endothelium, Vascular / Q000166:cytology*; D005312:Fetal Blood / Q000166:cytology; D005780:Gelatin; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins; D006801:Humans; D006822:Hybrid Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000628:therapy*; D008164:Luminescent Proteins / Q000235:genetics; D008297:Male; D016686:Monocrotaline; D010455:Peptides / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D010587:Phagocytosis; D011652:Pulmonary Circulation / Q000187:drug effects; D051381:Rats; D011923:Rats, Nude; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000166:cytology; D015996:Survival Rate; D014655:Vascular Resistance / Q000187:drug effects
D004337:Drug Carriers; D008164:Luminescent Proteins; D010455:Peptides; D049452:Green Fluorescent Proteins; D053607:Adrenomedullin; D016686:Monocrotaline; D005780:Gelatin; D004247:DNA