title: Tissue inhibitor of matrix metalloproteinase-3 or vascular endothelial growth factor transfection of aged human mesenchymal stem cells enhances cell therapy after myocardial infarction.
abstract: Mesenchymal stem cell (MSC) transplantation has been proposed as a potential therapeutic approach for ischemic heart disease, but the regenerative capacity of these cells decreases with age. In this study, we genetically engineered old human MSCs (O-hMSCs) with tissue inhibitor of matrix metalloproteinase-3 (TIMP3) and vascular endothelial growth factor (VEGF) and evaluated the effects on the efficacy of cell-based gene therapy in a rat myocardial infarction (MI) model. Cultured O-hMSCs were transfected with TIMP3 (O-TIMP3) or VEGF (O-VEGF) and compared with young hMSCs (Y-hMSCs) and non-transfected O-hMSCs for growth, clonogenic capacity, and differentiation potential. In vivo, rats were subjected to left coronary artery ligation with subsequent injection of Y-hMSCs, O-hMSCs, O-TIMP3, O-VEGF, or medium. Echocardiography was performed prior to and at 1, 2, and 4 weeks after MI. Myocardial levels of matrix metalloproteinase-2 (MMP2), MMP9, TIMP3, and VEGF were assessed at 1 week. Hemodynamics, morphology, and histology were measured at 4 weeks. In vitro, genetically modified O-hMSCs showed no changes in growth, colony formation, or multi-differentiation capacity. In vivo, transplantation with O-TIMP3, O-VEGF, or Y-hMSCs increased capillary density, preserved cardiac function, and reduced infarct size compared to O-hMSCs and medium control. O-TIMP3 and O-VEGF transplantation enhanced TIMP3 and VEGF expression, respectively, in the treated animals. O-hMSCs genetically modified with TIMP3 or VEGF can increase angiogenesis, prevent adverse matrix remodeling, and restore cardiac function to a degree similar to Y-hMSCs. This gene-modified cell therapy strategy may be a promising clinical treatment to rejuvenate stem cells in elderly patients.
authors.affiliation: Department of Cardiovascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yao
authors.forename: Shu-Lin
authors.initials: SL
authors.lastname: Jiang
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Cheng
authors.initials: C
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Lu
authors.initials: L
authors.lastname: Sun
authors.forename: Kai-Yu
authors.initials: KY
authors.lastname: Liu
authors.forename: Zhi-Bo
authors.initials: ZB
authors.lastname: Jia
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
authors.forename: Hai
authors.initials: H
authors.lastname: Tian
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D009203:Myocardial Infarction / Q000378:metabolism / Q000628:therapy*; D018919:Neovascularization, Physiologic / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
chemical_list: D019717:Tissue Inhibitor of Metalloproteinase-3; D042461:Vascular Endothelial Growth Factor A