Abstract
Objectives. Low survival rate of mesenchymal stem cells (MSCs) severely limited the therapeutic efficacy of cell therapy in the treatment of myocardial infarction (MI). Bcl-xL genetic modification might enhance MSC survival after transplantation. Methods. Adult rat bone marrow MSCs were modified with human Bcl-xL gene (hBcl-xL-MSCs) or empty vector (vector-MSCs). MSC apoptosis and paracrine secretions were characterized using flow cytometry, TUNEL, and ELISA in vitro. In vivo, randomized adult rats with MI received myocardial injections of one of the three reagents: hBcl-xL-MSCs, vector-MSCs, or culture medium. Histochemistry, TUNEL, and echocardiography were carried out to evaluate cell engraftment, apoptosis, angiogenesis, scar formation, and cardiac functional recovery. Results. In vitro, cell apoptosis decreased 43%, and vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1), and plate-derived growth factor (PDGF) increased 1.5-, 0.7-, and 1.2-fold, respectively, in hBcl-xL-MSCs versus wild type and vector-MSCs. In vivo, cell apoptosis decreased 40% and 26% in hBcl-xL-MSC group versus medium and vector-MSC group, respectively. Similar results were observed in cell engraftment, angiogenesis, scar formation, and cardiac functional recovery. Conclusions. Genetic modification of MSCs with hBcl-xL gene could be an intriguing strategy to improve the therapeutic efficacy of cell therapy in the treatment of heart infarction.
Highlights
Cell transplantation has emerged as a promising therapeutic approach for the restoration of heart function after myocardial infarction
Our results showed that both hBcl-xLMSCs and vector-mesenchymal stem cells (MSCs) were successfully marked with enhanced green fluorescent protein (EGFP), and human Bcl-xL (hBcl-xL)-MSCs were successfully modified with hBcl-xL
The low survival rate of the grafted MSCs severely holds back the therapeutic efficacy of cell transplantation aiming at cardiomyocytes restoration
Summary
Cell transplantation has emerged as a promising therapeutic approach for the restoration of heart function after myocardial infarction. Bone marrow mesenchymal stem cells (MSCs) are self-renewing, multipotent precursors of nonhematopoietic stromal tissues. MSCs were demonstrated to be able to promote angiogenesis and the survival of ischemic cardiomyocytes through the paracrine production of various cytokines [6, 7]. It was shown that MSCs are immunosuppressive favoring the inhibition of inflammatory responses and the future fibrosis of the injured heart tissue [8, 9]. MSCs can be isolated from the bone marrow or adipose tissue and expanded in vitro based on their ability to adhere to culture dishes. MSCs appear to be an appealing cell source for transplantation therapy in myocardial infarction
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