title: Coronary vein infusion of multipotent stromal cells from bone marrow preserves cardiac function in swine ischemic cardiomyopathy via enhanced neovascularization.
abstract: Few reports have examined the effects of adult bone marrow multipotent stromal cells (MSCs) on large animals, and no useful method has been established for MSC implantation. In this study, we investigate the effects of MSC infusion from the coronary vein in a swine model of chronic myocardial infarction (MI). MI was induced in domestic swine by placing beads in the left coronary artery. Bone marrow cells were aspirated and then cultured to isolate the MSCs. At 4 weeks after MI, MSCs labeled with dye (n=8) or vehicle (n=5) were infused retrogradely from the anterior interventricular vein without any complications. Left ventriculography (LVG) was performed just before and at 4 weeks after cell infusion. The ejection fraction (EF) assessed by LVG significantly decreased from baseline up to a follow-up at 4 weeks in the control group (P<0.05), whereas the cardiac function was preserved in the MSC group. The difference in the EF between baseline and follow-up was significantly greater in the MSC group than in the control group (P<0.05). The MSC administration significantly promoted neovascularization in the border areas compared with the controls (P<0.0005), though it had no affect on cardiac fibrosis. A few MSCs expressed von Willebrand factor in a differentiation assay, but none of them expressed troponin T. In quantitative gene expression analysis, basic fibroblast growth factor and vascular endothelial growth factor (VEGF) levels were significantly higher in the MSC-treated hearts than in the controls (P<0.05, respectively). Immunohistochemical staining revealed VEGF production in the engrafted MSCs. In vitro experiment demonstrated that MSCs significantly stimulated endothelial capillary network formation compared with the VEGF protein (P<0.0001). MSC infusion via the coronary vein prevented the progression of cardiac dysfunction in chronic MI. This favorable effect appeared to derive not from cell differentiation, but from enhanced neovascularization by angiogenic factors secreted from the MSCs.
authors.affiliation: Division of Cardiology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Sato
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Iso
authors.forename: Taro
authors.initials: T
authors.lastname: Uyama
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kawachi
authors.forename: Kohei
authors.initials: K
authors.lastname: Wakabayashi
authors.forename: Yasutoshi
authors.initials: Y
authors.lastname: Omori
authors.forename: Teruko
authors.initials: T
authors.lastname: Soda
authors.forename: Makoto
authors.initials: M
authors.lastname: Shoji
authors.forename: Shinji
authors.initials: S
authors.lastname: Koba
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Noboru
authors.initials: N
authors.lastname: Fukuda
authors.forename: Satoshi
authors.initials: S
authors.lastname: Saito
authors.forename: Takashi
authors.initials: T
authors.lastname: Katagiri
authors.forename: Youichi
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Youichi
authors.initials: Y
authors.lastname: Takeyama
authors.forename: Akihiro
authors.initials: A
authors.lastname: Umezawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods*; D002454:Cell Differentiation; D002908:Chronic Disease; D003331:Coronary Vessels; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005355:Fibrosis; D006321:Heart / Q000503:physiopathology*; D007262:Infusions, Intravenous; D039902:Multipotent Stem Cells / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D009203:Myocardial Infarction / Q000150:complications; D017202:Myocardial Ischemia / Q000209:etiology / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery*; D009206:Myocardium / Q000473:pathology; D018919:Neovascularization, Physiologic; D010641:Phenotype; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D013552:Swine; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2