2007 George E. Brown Memorial Lecture—Use of Very Small Embryonic-Like (VSEL) Stem Cells and Cardiac Stem Cells for Repair of Myocardial Infarction
Although bone marrow (BM)–derived cells have been shown to improve left ventricular (LV) function and attenuate adverse LV remodeling after myocardial infarction (MI), the cell type or types responsible for these beneficial effects are uncertain. Recent studies have identified in adult BM a rare population of pluripotent SSEA-1+/Oct-4+/ Sca-1+/lin−/CD45−, very small embryonic-like stem cells (VSELs) that differentiate into cardiac lineage in vitro. Using a murine model of MI, we found that VSELs were barely detectable in peripheral blood at baseline but increased significantly after MI, peaking at 48 hours (flow cytometry), concomitant with increased levels of mRNA for markers of pluripotency (Oct-4, Nanog, Rex-1, Dppa1, and Rif1) in peripheral blood cells (RQ-PCR analysis), indicating that VSELs are mobilized into the blood shortly after MI. Importantly, direct intramyocardial injection of VSELs in mice improved LV function and attenuated LV remodeling, suggesting that these pluripotent cells could be used therapeutically for repair of MI. Another promising approach to cell therapy is the use of c-kit+ cardiac stem cells (CSCs) present in adult myocardium. We found that intracoronary administration of CSCs exerts beneficial effects both in a model of acute MI in rats and in 2 models of old, healed MI (rats and pigs); in all cases, CSC administration resulted in improved systolic function, reduced LV dilatation, and regeneration of myocytes and coronary vessels. These data support the therapeutic utility of CSCs for repair of both acute and old MI and provide the basis for upcoming clinical trials of CSCs.