Autologous Transplantation of Endothelial Progenitor Cells Genetically Modified by Adeno-Associated Viral Vector Delivering Insulin-Like Growth Factor-1 Gene After Myocardial Infarction

Abstract

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.

Transplantation of bone marrow-derived endothelial progenitor cells attenuates myocardial interstitial fibrosis and cardiac dysfunction in streptozotocin-induced diabetic rats

“…These results are consistent with previous ones demonstrating that several cytokines, released by peripheral blood or bone marrow-derived EPC, are potent inhibitors of apoptosis (39)(40). Furthermore, a recent study by Sen et al (41) showed that autologous transplantation of the genetic modification of EPCs also inhibited cardiac apoptosis in a rat model of myocardial infarction. Collectively, results in the current study confirmed previous findings demonstrating that cardiomyocytes apoptosis is associated with the progression of DCM, and that EPC implantation has the potential to prevent cardiomyocytes apoptosis in diabetic conditions.…”

Therapeutic Angiogenesis: Foundations and Practical Application

“…This method has been tested in animal models of ischemia using exogenous delivery of VEGF165 [98], insulin-like growth factor-1 [99], HO-1 [100], or other genes to diferent types of cells: AD-MSC, EC, BM-MSC, etc. In majority of reports, modiication resulted in improvement of response after delivery to ischemic tissue.…”

Genetic Modification of Stem Cells in Diabetes and Obesity

“…We have previously demonstrated the use of genetically modified rat EPCs to treat myocardial infarction (MI)-related complications in Sprague-Dawley rats. Adeno-associated virus (AAV) mediated IGF-1 expression reportedly increased cardiac function by increasing cardiomyocyte proliferation and capillary density in the myocardium and by decreasing cardiomyocyte apoptosis in a myocardial infarction rat model [7]. Both adenovirus and recombinant AAV are DNA virus which, remains as an episomal character without integrating with host genome.…”