Molecular Imaging of Mesenchymal Stem Cell Mechanistic Insight Into Cardiac Repair After Experimental Myocardial Infarction

Background-Mesenchymal stem cells (MSCs) can differentiate into endothelial cells in vivo. However, it is unknown if the differentiated MSCs persist in vivo and if this potential persistence contributes to functional improvement after experimental myocardial infarction. Methods and Results-We generated a lentivector encoding 2 distinct reporter genes, one driven by a constitutive murine stem cell virus promoter and the other driven by an endothelial-specific Tie-2 promoter. The endothelial specificity of the lentivector was validated by its expression in endothelial cells but not in human MSCs (hMSCs). The lentivirus-transduced hMSCs were injected into peri-infarct areas of the hearts of severe combined immune-deficient mice. Persistence of injected cells was tracked by bioluminescence imaging (BLI) and verified by immunohistochemical staining. The BLI signal from the endothelial-specific reporter revealed that hMSCs differentiated into endothelial cells 48 hours after injection. However, both the constitutive and endothelial-specific BLI signals disappeared by day 50. Nonetheless, the improvement in left ventricle ejection fraction with hMSC therapy persisted for up to 6 months. Immunohistochemical staining showed that hMSC-derived endothelial cells integrated into endogenous CD31(+) vessels. Furthermore, hMSC-transplanted hearts had more CD31(+) vessels and a lesser degree of cardiac fibrosis compared with the controls at 6 months. Conclusions-hMSCs differentiated into endothelial cells and integrated into blood vessels after experimental myocardial infarction. The differentiated hMSCs only lasted for up to 50 days in vivo, but improvement in cardiac function persisted for up to 6 months. Increased angiogenesis and decreased fibrosis were associated with cardiac functional improvement after hMSC transplantation. (Circ Cardiovasc Imaging. 2012;5:94-101.)