Sphingosine kinase-1 protects transplanted mesenchymal stem cells and improves the performance of the infarcted heart Research Article

In this study we investigated whether sphingosine kinase-1 (SPK1) modification could offer cytoprotective effects on mesenchymal stem cells (MSCs) in vitro and in vivo in a myocardial infarction rat model. MSCs carrying green fluorescent protein (MSCs/GFP), SPK1 (MSCs/SPK1) or with firefly luciferase genes (MSCs/GFP/luc and MSCs/SPK1/luc) were obtained and functionally identified. The in vitro protective effects of SPK1 on MSCs were evaluated after exposure to serum-deprivation and hypoxia stimuli. Cells (1 x 106) were injected intramyocardially around the infarcted zone and the fate of the transplanted cells was traced by SPK1 and luciferase assessment in the ischemic myocardium. The survival of the remaining myocardiocytes was evaluated by in situ TUNEL assay 72hours after cell transplantation. The morphological and functional features of the injured heart were observed with echocardiography, hemodynamic and histological examinations. The results showed that SPK1 protected MSCs both in vitro and in vivo. MSCs/SPK1/luc implantation elevated SPK1 activities in the ischemic myocardium, which peaked on day 3 and reduced to the baseline on day 7. Compared with MSCs/GFP/luc, luciferase activity was significantly higher in MSCs/SPK1/luc-injected myocardium (p<0.01 on days 3 and 5 post-injection). The percentage of TUNEL-positive cells in the ischemic area was significantly lower in MSCs/SPK1 (%, 15.5 +/- 2.3 vs. MSCs/GFP 23.1 +/- 4.9, p<0.05). Concordantly, the parameters including fractional shortening (%, 29.33 +/- 2.94 vs. MSCs/GFP 23.29 +/- 2.86, p<0.05), ejection fraction (%, 60.35 +/- 4.96 vs. 51.99 +/- 5.16, p<0.05), left ventricular end-diastolic pressure (15.3 +/- 3.6 vs. 18.2 +/- 3.3 mmHg, p<0.05) and blood vessel density (number per field: 33.82 +/- 5.45 vs. 23.06 +/- 4.01, p<0.01) were greatly improved in MSCs/SPK1, though those of the infarct size, collagen deposition in non-infracted area and the spherical indexes of the hearts were comparable between two cell treatment groups. In conclusion, MSCs/SPK1 improve the performance of the infarcted hearts by providing prosurvival signals to the transplanted MSCs and myocardiocytes.