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: Jie Yao, Shu-Lin Jiang, Wei Liu, Cheng Liu, Wei Chen, Lu Sun, Kai-Yu Liu, Zhi-Bo Jia, Ren-Ke Li, Hai Tian
• Journal: Rejuvenation research (Rejuvenation Res) Vol. 15 Issue 5 Pg. 495-506 (Oct 2012) ISSN: 1557-8577 [Electronic] United States
• PMID: 22950427 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Tissue Inhibitor of Metalloproteinase-3
• Vascular Endothelial Growth Factor A

Topics

• Animals
• Cell Differentiation
• Humans
• Male
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells (cytology, metabolism)
• Myocardial Infarction (metabolism, therapy)
• Neovascularization, Physiologic (genetics)
• Rats
• Rats, Wistar
• Tissue Inhibitor of Metalloproteinase-3 (genetics, metabolism)
• Transfection
• Vascular Endothelial Growth Factor A (genetics, metabolism)