Repair of infarcted myocardium mediated by transplanted bone marrow-derived CD34+ stem cells in a nonhuman primate model.
Rodent and human clinical studies have shown that transplantation of bone marrow stem cells to the ischemic myocardium results in improved cardiac function. In this study, cynomolgus monkey acute myocardial infarction was generated by ligating the left anterior descending artery, and autologous CD34(+) cells were transplanted to the peri-ischemic zone. To track the in vivo fate of transplanted cells, CD34(+) cells were genetically marked with green fluorescent protein (GFP) using a lentivirus vector before transplantation (marking efficiency, 41% on average). The group receiving cells (n = 4) demonstrated improved regional blood flow and cardiac function compared with the saline-treated group (n =4) at 2 weeks after transplant. However, very few transplanted cell-derived, GFP-positive cells were found incorporated into the vascular structure, and GFP-positive cardiomyocytes were not detected in the repaired tissue. On the other hand, cultured CD34(+) cells were found to secrete vascular endothelial growth factor (VEGF), and the in vivo regional VEGF levels showed a significant increase after the transplantation. These results suggest that the improvement is not the result of generation of transplanted cell-derived endothelial cells or cardiomyocytes; and raise the possibility that angiogenic cytokines secreted from transplanted cells potentiate angiogenic activity of endogenous cells.
Yoshioka
Toru
T
Center for Molecular Medicine, Department of Internal Medicine, Jichi Medical School, Minamikawachi, Tochigi 329-0498, Japan.
Ageyama
Naohide
N
Shibata
Hiroaki
H
Yasu
Takanori
T
Misawa
Yoshio
Y
Takeuchi
Koichi
K
Matsui
Keiji
K
Yamamoto
Keiji
K
Terao
Keiji
K
Shimada
Kazuyuki
K
Ikeda
Uichi
U
Ozawa
Keiya
K
Hanazono
Yutaka
Y
D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis*; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D003331:Coronary Vessels / Q000601:surgery; D003402:Creatine Kinase / Q000097:blood; D004195:Disease Models, Animal; D004452:Echocardiography; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics; D006334:Heart Function Tests; D016086:Lentivirus / Q000235:genetics; D008026:Ligation; D008252:Macaca fascicularis; D008297:Male; D009203:Myocardial Infarction / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000502:physiology; D012039:Regional Blood Flow / Q000502:physiology; D013234:Stem Cells / Q000737:chemistry / Q000166:cytology / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D018952:Antigens, CD34; D042461:Vascular Endothelial Growth Factor A; D049452:Green Fluorescent Proteins; D003402:Creatine Kinase