Magnetic resonance evaluation of transplanted mesenchymal stem cells after myocardial infarction in swine

Objectives To trace and evaluate intracoronary transplanted mesenchymal stem cells(MSCs) labeled with superparamagnetic iron oxide(SPIO) by using magnetic resonance imaging(MRI) in a swine model of myocardial infarction (MI).Methods MSCs were transfected with a lentiviral vector carrying the gene encoding green fluorescent protein (GFP) and labeled in vitro with SPIO.Two weeks after MI, swine were randomized to intracoronary transplantation of dual -labeled MSCs(n = 10),MSCs-GFP(n = 10) and saline(n = 5).MRI examination was performed with a 1.5T clinical scanner at 24 hours,3 weeks and 8 weeks after cells transplantation. Signal intensity(SI) changes,cardiac function and MI size were measured using MRI.Correlation between MR findings and histomorphologic findings was also investigated. Results The labeling efficiency at a combination of 25μg Fe/ml SPIO and 0.8 pi/ml Lipofectamine 2000 reached 100%.SPIO labeling did not affect GFP fluorescence and dual-labeling did not affect cell proliferation(P】0.05). Multipotentiality was not affected especially for cardiomyocyte-like cells differentiation.Cardiac cell marker of a-MHC and actinin were positively expressed by immunofluorescence staining after induction.SI on T2 * WI decreased substantial- ly in the interventricular septum 24 hours after injection of MSCs.The intensity of hypo-intense signals appeared to increase throughout the later time points.Changes in SI at 24 hours,3 weeks and 8 weeks were 52.98%±10.74%,21.53%±5.40%and 6.23%±2.01%,respectively(P【0.01).DE-MRI demonstrated both dual-labeled MSCSs and MSCs-GFP could dramatically reduce the size of MI and improve cardiac function. Histological data revealed that prussian blue stain-positive cells were found mainly in the border zone which also showed green fluorescence but negative for macrophage marker(CD68).Gross pathologic examination revealed that engrafted MSCs dramatically reduce the extent of necrotic myocardium and promote the regeneration of new,contractile myocardium along the subendocardial surface of the MI. Conclusions MSCs could be efficiently and safely labeled with SPIO and GFP,and could be detected reproducibly and noninvasively in vivo using cardiac MRI.Intracoronary transplantation of dual-labeled MSCs could increase cardiac function and reduce the size of MI.

VEGF-expressing Bone Marrow Mesenchymal Stem Cells Transplantation Improved Heart Function of Myocardial Infarct Rabbits

Objectives To treat myocardial infarction with MSCs transplantation combined with VEGF gene therapy in rabbits and to study its mechanisms. Methods Forty-eight rabbits were randomly divided into MI group （n=12）, MSCs group （n=12）, VEGF group （n=12）, MSCs＋VEGF group （M＋V group, n=12）. Rabbit myocardial infarction models were founded by the ligation of left anterior descending artery. 107 MSCs were injected into the infarct-zone in four sites 2 weeks later in MSCs and M＋ V group, phVEGF gene were injected in infarct-zone in VEGF group and MSCs transfected with phVEGF gene were injected in M＋V group. Heart function including LVEDP, LVSP, LVDP, -dp/dtmax, ＋dp/dtmax, were measured in vivo. The hearts were harvested at 4 weeks after transplantation and sectioned for HE stain, immunohistochemical stain of BrdU and VIII factor antigen. Results The left ventricular hemodynamics parameters showed that heart function were improved more in M＋V group than MSCs group, MI group and VEGF group. The numbers of BrdU positive cells in M＋ V group（61±8）were more than in MSCs group （44±8, P 〈 0.01）. The numbers of vessels in infarcted zone were more in M＋V group （49±8） than in MSCs group （33±6, P 〈 0.01）,VEGF group（30±8, P 〈 0.01）and Mlgroup （18±4, P〈0.01）. Conclusions VEGF-expressing MSCs transplantation could improve heart function after myocardial infarction, and they were more effective than sole MSCs transplantation. Keeping more MSCs survival and ameliorating the blood supply of infarct-zone might be involved in the mechanisms.

Hypoxia Enhances the Therapeutic Potential of Superparamagnetic Iron Oxide-labeled Adipose-derived Stem Cells for Myocardial Infarction

Adipose-derived stem cells（ASCs） induce therapeutic angiogenesis due to pro-angiogenic cytokines secretion. Superparamagnetic iron oxide（SPIO） nanoparticles are critical for magnetic resonance（MR） tracking of implanted cells. Hypoxia is a powerful stimulus for angiogenic activity of ASCs. In this study, we investigated whether therapeutic potency could be enhanced by implantation of hypoxia-preconditioned SPIO-labeled ASCs（SPIOASCs） into the infarcted myocardium. ASCs and SPIOASCs were cultured under 2% O_2（hypoxia） or 95% air（normoxia）. Cells were intramyocardially injected into the infarcted myocardium after 48-h culture. We found that hypoxia culture increased the m RNA expression of hypoxia-inducible factor-1 alpha（HIF-1α） and vascular endothelial growth factor（VEGF） in ASCs and SPIOASCs. The VEGF protein in the conditioned medium was significantly higher in hypoxic ASCs and SPIOASCs than in normoxic ASCs and SPIOASCs. The capillary density and left ventricular contractile function in the infarcted myocardium were significantly higher 4 weeks after implantation with hypoxic ASCs and SPIOASCs than with normoxic ASCs and SPIOASCs. Improvement in the capillary density and left ventricle function didn＇t differ between hypoxic ASCs-transplanted rats and hypoxic SPIOASCs-transplanted rats. Hypoxic culture enhanced the angiogenic efficiency of ASCs. It was concluded that implantation of hypoxic ASCs or SPIOASCs promotes therapeutic angiogenesis and cardiac function recovery in the infarcted myocardium. SPIO labeling does not impact the beneficial effect of hypoxic ASCs.

When is The Best Time of Stem Cell Transplantation for Treating Acute Myocardial Infarction──A Brief Meta-analysis of Current Clinic Trials

The best time of stem cells transplantation for treating acute myocardial infarction (AMI) is still to be followed with interest and a focus issue for clinical cardiologist. A brief meta-analysis of clinical trials about timing-window and therapeutic effects of stem cell transplantation for treating AMI will be made out in this article.