Mesenchymal stem cells with overexpression of midkine enhance cell survival and attenuate cardiac dysfunction in a rat model of myocardial infarction

Abstract

IntroductionElevated midkine (MK) expression may contribute to ventricular remodeling and ameliorate cardiac dysfunction after myocardial infarction (MI). Ex vivo modification of signaling mechanisms in mesenchymal stem cells (MSCs) with MK overexpression may improve the efficacy of cell-based therapy. This study sought to assess the safety and efficacy of MSCs with MK overexpression transplantation in a rat model of MI.MethodsA pLenO-DCE vector lentivirus encoding MK was constructed and infected in MSCs. MSC migration activity and cytoprotection was examined in hypoxia-induced H9C2 cells using transwell insert in vitro. Rats were randomized into five groups: sham, MI plus injection of phosphate buffered saline (PBS), MSCs, MSCs-green fluorescent protein (MSCs-GFP) and MSCs-MK, respectively. Survival rates were compared among groups using log-rank test and left ventricular function was measured by echocardiography at baseline, 4, 8 and 12 weeks.ResultsOverexpression of MK partially prevented hypoxia-induced MSC apoptosis and exerted MSC cytoprotection to anoxia induced H9C2 cells. The underlying mechanisms may be associated with the increased mRNA and protein levels of vascular endothelial growth factor (VEGF), transformation growth factor-β (TGF-β), insulin-like growth factor 1 (IGF-1) and stromal cell-derived factor 1 (SDF-1a) in MSCs-MK compared with isolated MSCs and MSCs-GFP. Consistent with the qPCR results, the culture supernatant of MSCs-MK had more SDF-1a (9.23 ng/ml), VEGF (8.34 ng/ml) and TGF-β1 (17.88 ng/ml) expression. In vivo, a greater proportion of cell survival was observed in the MSCs-MK group than in the MSCs-GFP group. Moreover, MSCs-MK administration was related to a significant improvement of cardiac function compared with other control groups at 12 weeks.ConclusionsTherapies employing MSCs with MK overexpression may represent an effective treatment for improving cardiac dysfunction and survival rate after MI.

Mesenchymal Stem/Stromal Cells in Regenerative Medicine: Can Preconditioning Strategies Improve Therapeutic Efficacy

“…The cellular responses are complex, and, in most cases, the pretreatment procedure affects a great number of factors, and not only a single, specific molecule or protein. In contrast, it should be mentioned that another approach to enhance the release of a specific regenerative factor is to overexpress a single factor in MSCs [70,71,72,73,74]. Nevertheless, these genetically engineered MSCs are not reviewed in this article.…”

The effect of midkine on growth factors and oxidative status in an experimental wound model in diabetic and healthy rats

“…), and can be protective against hypoxia. This mechanism explains the increase in angiogenesis and oxygenation because MK improves the expression of VEGF, TGF-β and insulin-like growth factor-1 (Zhao et al 2014). MK may improve angiogenesis and wound healing because it increases levels of VEGF and TGF-β in the HM group.…”

Myocardin-related transcription factor-A-overexpressing bone marrow stem cells protect cardiomyocytes and alleviate cardiac damage in a rat model of acute myocardial infarction

“…The chest was then closed with a silk suture to minimize heart displacement, taking care to leave the ends of the coronary suture threads emerging from the surgical wound (11,22). Immediately after ligation, a 31-gauge needle was used to inject 6x10 6 MRTF-A-BMSCs [injected at six sites (23)] into the anterior and lateral aspects of the viable myocardium bordering the infarction. Twelve AMI model rats were administered an equal volume of Dulbecco's modified Eagle's medium (DMEM; Sigma-Aldrich, St. Louis, MO, USA) via the same route served as medium controls.…”