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Mesenchymal stem cells over-expressing SDF-1 promote angiogenesis and improve heart function in experimental myocardial infarction in rats

^a Institute of Clinical Medicine, Renmin Hospital, Yunyang Medical College, Shiyan, Hubei 442000, People's Republic of China
^b Department of Cardiology, Renmin Hospital, Yunyang Medical College, Shiyan, Hubei 442000, People's Republic of China
^c Department of Physiology, Yunyang Medical College, Shiyan, Hubei 442000, People's Republic of China
^d Key Lab of Human Embryonic Stem Cell of Hubei Province, Yunyang Medical College, Shiyan, Hubei 442000, People's Republic of China

Received 24 November 2008; received in revised form 13 April 2009; accepted 27 April 2009.

^_* Corresponding author. Address: Institute of Clinical Medicine, Renmin Hospital, Yunyang Medical College, Shiyan, Hubei 442000, People's Republic of China. Tel.: +86 719 8637170; fax: +86 719 8637011. (Email: tangjm416{at}163.com; rywjn{at}vip.163.com).

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-1) plays an important role in the homing of stem cells to the injured tissues of the heart. Therefore, the MSCs over-expressing SDF-1 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 ng ml^–1 SDF-1 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 10⁹ pfu Ad-SDF-1 (adenoviral vector containing human SDF-1 gene under the control of the rous sarcoma virus (RSV) promoter), 5.0 x 10⁶ Ad-LacZ-MSC or 5.0 x 10⁶ 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 mg kg^–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-1, 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. Conclusion: The MSCs over-expressing the SDF-1 can produce effective angiogenesis, resulting in the prevention of progressive heart dysfunction after a myocardial infarction.

Key Words: Angiogenesis • Myocardial infarction • SDF-1 • Stem cell • VEGF • eNOS