Preconditioning Human Cardiac Stem Cells with an HO‐1 Inducer Exerts Beneficial Effects After Cell Transplantation in the Infarcted Murine Heart

The regenerative potential of c‐kit(+) cardiac stem cells (CSCs) is severely limited by the poor survival of cells after transplantation in the infarcted heart. We have previously demonstrated that preconditioning human CSCs (hCSCs) with the heme oxygenase‐1 inducer, cobalt protoporphyrin (CoPP), has significant cytoprotective effects in vitro. Here, we examined whether preconditioning hCSCs with CoPP enhances CSC survival and improves cardiac function after transplantation in a model of myocardial infarction induced by a 45‐minute coronary occlusion and 35‐day reperfusion in immunodeficient mice. At 30 minutes of reperfusion, CoPP‐preconditioned hCSCs(GFP+), hCSCs(GFP+), or medium were injected into the border zone. Quantitative analysis with real‐time qPCR for the expression of the human‐specific gene HLA revealed that the number of survived hCSCs was significantly greater in the preconditioned‐hCSC group at 24 hours and 7 and 35 days compared with the hCSC group. Coimmunostaining of tissue sections for both green fluorescent protein (GFP) and human nuclear antigen further confirmed greater hCSC numbers at 35 days in the preconditioned‐hCSC group. At 35 days, compared with the hCSC group, the preconditioned‐hCSC group exhibited increased positive and negative left ventricular (LV) dP/dt, end‐systolic elastance, and anterior wall/apical strain rate (although ejection fraction was similar), reduced LV remodeling, and increased proliferation of transplanted cells and of cells apparently committed to cardiac lineage. In conclusion, CoPP‐preconditioning of hCSCs enhances their survival and/or proliferation, promotes greater proliferation of cells expressing cardiac markers, and results in greater improvement in LV remodeling and in indices of cardiac function after infarction. Stem Cells 2015;33:3596–3607