Novel vascular endothelial growth factor gene delivery system-manipulated mesenchymal stem cells repair infarcted myocardium.
Transplantation of vascular endothelial growth factor (VEGF) gene-manipulated mesenchymal stem cells (MSCs) has been proposed as a promising therapy strategy for cardiac repair after myocardium infarction. However, the gene delivery system, including targeted VEGF gene and delivery vehicle, still needs to be optimized. In this study, a novel, hyperbranched poly(amidoamine) (hPAMAM), polymer-based, hypoxia-regulated VEGF(165) plasmid (pHRE-VEGF(165)) delivery system was constructed for effective, biocompatible and controllable gene expression. The hPAMAM demonstrated high transfection efficiency (38.98 ± 1.95%) with minor cytotoxicity (cell viability = 92.38 ± 1.09%) in primary MSCs under optimal conditions. Under hypoxia, hPAMAM-pHRE-hVEGF(165)-transfected MSCs could over-express hVEGF(165) stably for 14 days, with a peak expression at day 2, which promoted endothelial cell proliferation in vitro. The transplantation of hPAMAM-pHRE-hVEGF(165) gene delivery system-manipulated MSCs could enhance ischemic myocardium VEGF concentration obviously, which improved the graft MSC survival, increased neovascularization, and ultimately preserved cardiac function to a significantly greater degree than untreated MSC transplantation. This work demonstrated that hPAMAM-based pHRE-hVEGF(165) gene delivery combined with MSC transplantation is an economical, feasible and biocompatible strategy for cardiac repair.
Department of Cardiac Surgery, Zhongshan Hospital, Fudan University & Shanghai Institute of Cardiovascular Diseases, No. 180, Fenglin Road, Xuhui District, Shanghai 200032,  PR China.
Kai
K
Zhu
Hao
H
Lai
Changfa
C
Guo
Demin
D
Xu
Chunsheng
C
Wang
D000818:Animals; D049109:Cell Proliferation; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D018014:Gene Transfer Techniques; D006321:Heart / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D018919:Neovascularization, Physiologic / Q000502:physiology; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
D042461:Vascular Endothelial Growth Factor A