Mesenchymal stem cells over-expressing SDF-1 promote angiogenesis and improve heart function in experimental myocardial infarction in rats.
BACKGROUND
In addition to its multipotent capability, the mesenchymal stem cell (MSC) can secrete and supply a large amount of vascular endothelial growth factor (VEGF). The stromal-derived factor-1 alpha (SDF-1alpha) plays an important role in the homing of stem cells to the injured tissues of the heart. Therefore, the MSCs over-expressing SDF-1alpha could augment the angiogenesis pathway.


METHODS
In vitro, the differentiation of the MSCs into endothelial-like cells was induced by cultivation of cells in 10% foetal calf serum and 50 ngml(-1) SDF-1alpha or in specific inhibitors for endothelial nitrous oxide synthase (eNOS). In vivo, the rat model of myocardial infarction was established by occlusion of the left anterior descending coronary artery. Seven days following surgery, 5.0 x 10(9)pfu Ad-SDF-1alpha (adenoviral vector containing human SDF-1alpha gene under the control of the rous sarcoma virus (RSV) promoter), 5.0 x 10(6) Ad-LacZ-MSC or 5.0 x 10(6) Ad-SDF-MSC suspension in a 0.2-ml serum-free medium was injected into four sites in infarcted areas (0.05 ml per site). The rats receiving Ad-SDF-MSC also received the nitrous oxide (NO) synthesis inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME) in drinking water (1 mgkg(-1)). The rats in the control group received the same volume of cell-free medium. Four weeks following transplantation, the heart function was assessed, and histological and molecular analyses were conducted.


RESULTS
The MSCs could differentiate into endothelial cells in the presence of SDF-1alpha, and the effect could be inhibited by l-NAME in vitro and in vivo. Western Blotting revealed an increased expression of VEGF, Akt and eNOS. Four weeks following transplantation, a reduced infarct size and fibrosis, greater vascular density and thicker left ventricular wall were observed in the Ad-SDF-MSC group. The measurement of haemodynamic parameters showed an improvement in the left ventricular performance in the Ad-SDF-MSC group as compared with other groups.


CONCLUSIONS
The MSCs over-expressing the SDF-1alpha can produce effective angiogenesis, resulting in the prevention of progressive heart dysfunction after a myocardial infarction.
Tang
Junming
J
Institute of Clinical Medicine, Renmin Hospital, Yunyang Medical College, Shiyan, Hubei 442000, People's Republic of China. tangjm416@163.com
Wang
Jianing
J
Yang
Jianye
J
Kong
Xia
X
Zheng
Fei
F
Guo
Linyun
L
Zhang
Lei
L
Huang
Yongzhang
Y
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism*; D003326:Coronary Circulation / Q000502:physiology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D024510:Muscle Development / Q000502:physiology; D009203:Myocardial Infarction / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014161:Transduction, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D016277:Ventricular Function, Left / Q000502:physiology
D054377:Chemokine CXCL12; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat