Combination Transplantation of Bone Marrow Mesenchymal Stem Cells and Hepatocyte Growth Factor Gene in the Treatment of Chronic Ischemic Heart Disease in Pigs_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

CHEN Anping , ZENG Zhiyong , YANG Shengsheng

1. Department of Cardiothoracic Surgery，Fuzong Clinical School of Fujian Medical University，Fuzhou 350025，P. R. China;;
2. Department of Cardiothoracic Surgery， Fuzhou General Hospital of Nanjing Military Command of PLA, Fuzhou 350025，P.R.China;;
3. Department of Cardiothoracic Surgery，Changhai Hospital，Second Military Medical University，Shanghai 200433，P. R. China;

Corresponding author：

Keywords：

Hepatocyte growth factor; Bone marrow mesenchymal stem cells; Chronic ischemic heart disease; Heart ischemia; Cell transplantation

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Abstract： Objective To investigate the effects of hepatocyte growth factor（HGF）gene transfected bone marrow mesenchymal stem cells （MSCs）transplantation in pigs with chronic ischemic heart disease. Methods MSCs were isolated from pig bone marrow by density gradient centrifugation and adherent cell culture, purified, and determined by cellsurface antigens（CD34, CD44, CD71, Ⅷ factor and desmin）. MSCs were transfected by adenovirus expressing hepatocyte growth factor（AdHGF）, and the influence of HGF on the biological characteristics of MSCs was tested. The pig model of chronic myocardial ischemia was established by placing Ameroid ring inside the left circumflex coronary artery via leftthoracotomy. A total of 40 pigs were randomly divided into 5 groups （n=8） and were injected 5×106/ml MSCs＋ 4×109 pfu 200 μl AdHGF （MSCs＋ AdHGF group）, 4×109 pfu 200 μl AdHGF （AdHGF group）, 5×106/ml MSCs 200 μl（MSCs group），4×109 pfu 200 μl AdNull （AdNull group）and 1 ml saline（control group） into the ischemic myocardiumrespectively. Echocardiogram, digital subtraction angiography （DSA） of coronary artery, single photon emission computed tomography（SPECT） myocardial perfusion imaging and cardiomyocyte apoptosis were examined after 4 weeks. Results Positive CD44 and CD71 and negative CD34, Ⅷ factorand desmin were detected in MSCs by flow cytometer. HGF had a b influence on stimulating the proliferation and differentiation of MSCs. Echocardiogram examination showed that left ventricular end-diastolic volume（LVEDV），left ventricular ejection fraction（LVEF），fractional shortening（FS）of MSCs＋ AdHGF group were significantly increased after treatment （P＜ 0.05）. DSA detection showed that ischemic neovascularization of MSCs＋ AdHGF group was significantly higher than those of AdHGF group and MSCs group （P＜ 0.05）. SPECT showed that the left ventricular myocardium of MSCs＋ AdHGF group appeared thickened,myocardial perfusion was significantly improved and the myocardial motion was significantly increased （P＜ 0.05）. Vascular density of MSCs＋ AdHGF group was significantly higher than those of AdHGF group and MSCs group by HE stain of myocardium ［（39.4±1.2）/ HPF vs. （36.5±1.4）/ HPF and（34.5±1.7）/ HPF，P＜ 0.05］. Cardiomyocyte apoptosis rate of MSCs＋ AdHGF group was significantly lower than those of AdHGF group and MSCs group by TUNEL stain （P＜ 0.05）. Conclusion Combination transplantation can promote the angiogenesis of chronic ischemic myocardium, inhibit cardiomyocyte apoptosis and improve heart function in pigs with chronic ischemic heart disease. The effect of HGF gene transfected MSCs transplantation is better than that of MSCs or HGF transplantation alone.

Citation： CHEN Anping,ZENG Zhiyong,YANG Shengsheng,et al .. Combination Transplantation of Bone Marrow Mesenchymal Stem Cells and Hepatocyte Growth Factor Gene in the Treatment of Chronic Ischemic Heart Disease in Pigs. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2012, 19(3): 286-292. doi: Copy

1.	Dxionl M. Help from within:cardioprotective properties of hepatocyte growth factor. Cardiovasc Res, 2001, 51（1）：4-6.
2.	Morishita R, Moriguchi A, Higaki J, et al. Hepatocyte growth factor （HGF） as a potential index of severity of hypertension. Hypertens Res, 1999, 22（3）：161-167.
3.	Tomita S, Mickle DA, Weisel RD, et al. Improved heart function with myogenesis and angiogenesis after autologous porcine bone marrow stromal cell transplantation. J Thorac Cardiovasc Surg, 2002, 123（6）：1132-1140.
4.	姚康, 黄榕翀, 葛雷，等. 经冠状动脉自体骨髓单个核细胞移植治疗急性心肌梗死的安全性观察. 中华心血管病杂志, 2006, 34（7）：577-581.
5.	“WHO Disease and injury country estimates”. World Health Organization. 2009. Retrieved , Nov. 11, 2009.
6.	2011中国卫生统计提要. http：//www. moh. gov. cn/publicfiles/business/htmlfiles /mo hwsbwstjx xzx/s7967/201105/51862.htm.
7.	Jackson KA, Majka SM, Wang H, et al. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest, 2001, 107（11）：1395-1402.
8.	Itescu S, Kocher AA, Schuster MD. Myocardial neovascularization by adult bonemarrow. derived angioblasts:strategies for improvement of cardiomyocyte function.Heart Fail Rev, 2003, 8（3）：253-258.
9.	Deuse T, Peter C, Fedak PW, et al. Hepatocyte growth factor or vascular endothelial growth factor gene transfer maximizes mesenchymal stem cell-based myocardial salvage after acute myocardial infarction. Circulation , 2009, 15（120）：S247-S254.
10.	Sakakibara Y, Nishimura K, Tambara K, et al. Prevascularization with gelatin microspheres containing basic fibroblast growth factor enhances the benefits of cardiomyocyte transplantation. J Thorac Cardiovasc Surg, 2002, 124（1）：50-56.
11.	Ellison GM, Torella D, Dellegrottaglie S, et al. Endogenous cardiac stem cell activation by insulin-like growth factor-1/hepatocyte growth factor intracoronary injection fosters survival and regeneration of the infarcted pig heart. J Am Coll Cardiol, 2011, 58（9）：977-986.
12.	连锋, 朱洪生, 黄日太, 等. 骨髓间质干细胞移植梗死心肌后细胞因子分泌及对血管新生的影响. 中国胸心血管外科临床杂志, 2004, 11（1）：49-52.
13.	Ikonen TS, Pätilä T, Virtanen K, et al. Ligation of ameroid-stenosed coronary artery leads to reproducible myocardial infarction--a pilot study in a porcine model. J Surg Res, 2007, 142（1）：195-201.
14.	Radke PW, Heinl-Green A, Frass OM, et al. Evaluation of the porcine ameroid constrictor model of myocardial ischemia for therapeutic angiogenesis studies. Endothelium, 2006, 13（1）：25-33.
15.	Pätilä T, Ikonen T, Rutanen J, et al. Vascular endothelial growth factor C-induced collateral formation in a model of myocardial ischemia. J Heart Lung Transplant, 2006, 25（2）：206-213.

1. 　Dxionl M. Help from within:cardioprotective properties of hepatocyte growth factor. Cardiovasc Res, 2001, 51（1）：4-6.
2. 　Morishita R, Moriguchi A, Higaki J, et al. Hepatocyte growth factor （HGF） as a potential index of severity of hypertension. Hypertens Res, 1999, 22（3）：161-167.
3. 　Tomita S, Mickle DA, Weisel RD, et al. Improved heart function with myogenesis and angiogenesis after autologous porcine bone marrow stromal cell transplantation. J Thorac Cardiovasc Surg, 2002, 123（6）：1132-1140.
4. 　姚康, 黄榕翀, 葛雷，等. 经冠状动脉自体骨髓单个核细胞移植治疗急性心肌梗死的安全性观察. 中华心血管病杂志, 2006, 34（7）：577-581.
5. 　“WHO Disease and injury country estimates”. World Health Organization. 2009. Retrieved , Nov. 11, 2009.
6. 　2011中国卫生统计提要. http：//www. moh. gov. cn/publicfiles/business/htmlfiles /mo hwsbwstjx xzx/s7967/201105/51862.htm.
7. 　Jackson KA, Majka SM, Wang H, et al. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest, 2001, 107（11）：1395-1402.
8. 　Itescu S, Kocher AA, Schuster MD. Myocardial neovascularization by adult bonemarrow. derived angioblasts:strategies for improvement of cardiomyocyte function.Heart Fail Rev, 2003, 8（3）：253-258.
9. 　Deuse T, Peter C, Fedak PW, et al. Hepatocyte growth factor or vascular endothelial growth factor gene transfer maximizes mesenchymal stem cell-based myocardial salvage after acute myocardial infarction. Circulation , 2009, 15（120）：S247-S254.
10. 　Sakakibara Y, Nishimura K, Tambara K, et al. Prevascularization with gelatin microspheres containing basic fibroblast growth factor enhances the benefits of cardiomyocyte transplantation. J Thorac Cardiovasc Surg, 2002, 124（1）：50-56.
11. 　Ellison GM, Torella D, Dellegrottaglie S, et al. Endogenous cardiac stem cell activation by insulin-like growth factor-1/hepatocyte growth factor intracoronary injection fosters survival and regeneration of the infarcted pig heart. J Am Coll Cardiol, 2011, 58（9）：977-986.
12. 　连锋, 朱洪生, 黄日太, 等. 骨髓间质干细胞移植梗死心肌后细胞因子分泌及对血管新生的影响. 中国胸心血管外科临床杂志, 2004, 11（1）：49-52.
13. 　Ikonen TS, Pätilä T, Virtanen K, et al. Ligation of ameroid-stenosed coronary artery leads to reproducible myocardial infarction--a pilot study in a porcine model. J Surg Res, 2007, 142（1）：195-201.
14. 　Radke PW, Heinl-Green A, Frass OM, et al. Evaluation of the porcine ameroid constrictor model of myocardial ischemia for therapeutic angiogenesis studies. Endothelium, 2006, 13（1）：25-33.
15. 　Pätilä T, Ikonen T, Rutanen J, et al. Vascular endothelial growth factor C-induced collateral formation in a model of myocardial ischemia. J Heart Lung Transplant, 2006, 25（2）：206-213.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Combination Transplantation of Bone Marrow Mesenchymal Stem Cells and Hepatocyte Growth Factor Gene in the Treatment of Chronic Ischemic Heart Disease in Pigs

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