Document Detail

Tissue inhibitor of matrix metalloproteinase-3 or vascular endothelial growth factor transfection of aged human mesenchymal stem cells enhances cell therapy after myocardial infarction.
MedLine Citation:
PMID:  22950427     Owner:  NLM     Status:  MEDLINE    
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.
Jie Yao; Shu-Lin Jiang; Wei Liu; Cheng Liu; Wei Chen; Lu Sun; Kai-Yu Liu; Zhi-Bo Jia; Ren-Ke Li; Hai Tian
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-09-24
Journal Detail:
Title:  Rejuvenation research     Volume:  15     ISSN:  1557-8577     ISO Abbreviation:  Rejuvenation Res     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-26     Completed Date:  2013-07-12     Revised Date:  2013-10-09    
Medline Journal Info:
Nlm Unique ID:  101213381     Medline TA:  Rejuvenation Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  495-506     Citation Subset:  IM    
Department of Cardiovascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
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MeSH Terms
Cell Differentiation
Mesenchymal Stem Cell Transplantation*
Mesenchymal Stromal Cells / cytology*,  metabolism
Myocardial Infarction / metabolism,  therapy*
Neovascularization, Physiologic / genetics
Rats, Wistar
Tissue Inhibitor of Metalloproteinase-3 / genetics*,  metabolism
Vascular Endothelial Growth Factor A / genetics*,  metabolism
Grant Support
MOP102535//Canadian Institutes of Health Research
Reg. No./Substance:
0/Tissue Inhibitor of Metalloproteinase-3; 0/Vascular Endothelial Growth Factor A

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