Experimental study of bone marrow-derived mesenchymal stem cells combined with hepatocyte growth factor transplantation via noninfarct-relative artery in acute myocardial infarction.
We investigated the impact of bone marrow-derived mesenchymal stem cells (BM-MSCs) alone or in combination with hepatocyte growth factor (HGF) transplantation via noninfarct-relative artery in a swine myocardial infarction (MI) model. Donor BM-MSCs were derived in vitro from swine auto-bone marrow cultures labeled by bromodeoxyuridine (BrdU) incorporation. Host MI swine model was created by ligating the distal left anterior descending artery. After 4 weeks, age-matched male MI swines were used for the transplantation. Male MI swines were transfused via noninfarct-relative artery with vehicle (control, n=6) or BrdU-labeled BM-MSCs (5 x 10(6)) alone (MSCs, n=6) or BrdU-labeled BM-MSCs (5 x 10(6)) combined with HGF (4 x 10(9) PFU) (MSCs+HGF, n=6). To evaluate the collateral artery growth (Rentrop) and cardiac perfusion in these animals, gate cardiac perfusion imaging and coronary angiography were performed before and 4 weeks after transplantation, respectively. To assess the contribution of donor-originated cells in stimulation of cardiomyocyte regeneration and angiogenesis, immunohistochemistry for BrdU and alpha-smooth muscle actin (alpha-SMA) and quantitative image analysis were performed at 4 weeks after transplantation. The results are as follows: (1) BrdU-positive cells were detected in host myocardium in both MSCs and MSCs+HGF groups, but not in the vehicle group. Most BrdU-positive cells expressed myosin heavy chain beta. (2) alpha-SMA(-)positive arteriole densities in the infarcted border area and infarcted area were increased significantly in both transplantation groups compared with the vehicle group. (3) Gate cardiac perfusion imaging demonstrated that the cardiac perfusion was significantly improved in transplantation groups compared with the vehicle group. (4) Ejection fraction and alpha-SMA-positive arteriole densities were increased significantly in both transplantation groups compared with the vehicle group. However, there was no difference in ejection fraction and alpha-SMA-positive arteriole densities between the MSCs group and the MSCs+HGF group. Growth of collateral arteries was not detected by coronary angiography in all three groups. In conclusion, the current study indicates that BM-MSCs transplantation via noninfarct-relative artery stimulates cardiomyocyte regeneration and angiogenesis and improves cardiac function, but does not stimulate collateral artery growth. BM-MSCs transplantation combined with HGF therapy is not superior to BM-MSCs alone transplantation. BM-MSCs transplantation via noninfarct-relative artery may be an alternative for those patients who cannot be transplanted via infarct-relative artery in clinical practice.
Yang
Z-J
ZJ
Department of cardiovascular medicine, the first affiliated hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China. derek6585@sina.com
Ma
D-C
DC
Wang
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W
Xu
S-L
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Zhang
Y-Q
YQ
Chen
B
B
Zhou
F
F
Zhu
T-B
TB
Wang
L-S
LS
Xu
Z-Q
ZQ
Zhang
F-M
FM
Cao
K-J
KJ
Ma
W-Z
WZ
D000818:Animals; D001158:Arteries; D003097:Collateral Circulation; D003131:Combined Modality Therapy; D003326:Coronary Circulation; D015316:Genetic Therapy / Q000379:methods*; D017228:Hepatocyte Growth Factor / Q000008:administration & dosage* / Q000502:physiology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D023421:Models, Animal; D009203:Myocardial Infarction / Q000473:pathology / Q000628:therapy*; D018919:Neovascularization, Physiologic; D011897:Random Allocation; D013552:Swine; D016896:Treatment Outcome
D017228:Hepatocyte Growth Factor