Autologous transplantation of endothelial progenitor cells genetically modified by adeno-associated viral vector delivering insulin-like growth factor-1 gene after myocardial infarction.
The regenerative potential of bone marrow-derived endothelial progenitor cells (EPCs) has been adapted for the treatment of myocardial and limb ischemia via ex vivo expansion. We sought to enhance EPC function by the efficient genetic modification of EPCs in a rat model of myocardial infarction. Peripheral blood EPCs were expanded and transduced, using adeno-associated virus (AAV). AAV-mediated EPC transduction efficacy was 23 ± 1.2%, which was improved by 4.0- to 7.2-fold after pretreatment with the tyrosine kinase inhibitor genistein. Adult rats (n = 7 in each group) underwent myocardial infarction by left anterior descending coronary artery occlusion, and received autologous EPCs transduced by AAV-IGF-1 or AAV-lacZ into the periinfarct area. Echocardiography demonstrated that cardiac function in the IGF-1-EPC group was significantly improved compared with the lacZ-EPC control group 12 weeks after myocardial infarction. In addition, IGF-1-expressing EPCs led to reduced cardiac apoptosis, increased cardiomyocyte proliferation, and increased numbers of capillaries in the periinfarct area. AAV expression was limited to the targeted heart region only. Pretreatment with genistein markedly improved AAV transduction of EPCs. IGF-1-expressing EPCs exhibit favorable cell-protective effects with tissue-limited expression in rat heart postinfarction.
Sen
Sabyasachi
S
Cardiovascular Research, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA.
Merchan
Juan
J
Dean
Jarrod
J
Ii
Masaaki
M
Gavin
Mary
M
Silver
Marcy
M
Tkebuchava
Tengiz
T
Yoon
Young-sup
YS
Rasko
John E J
JE
Aikawa
Ryuichi
R
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002196:Capillaries; D003331:Coronary Vessels / Q000473:pathology; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D004452:Echocardiography; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D019833:Genistein / Q000494:pharmacology; D006334:Heart Function Tests; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D051381:Rats; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000378:metabolism*; D014161:Transduction, Genetic; D014182:Transplantation, Autologous
D007334:Insulin-Like Growth Factor I; D019833:Genistein