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Background  Endogenous cardiac progenitor cells are a promising option for cell-therapy for myocardial infarction (MI). However, obtaining adequate numbers of cardiac progenitors after MI remains a challenge. Cardiospheres (CSs) have been proposed to have cardiac regenerative properties; however, their cellular composition and how they may be influenced by the tissue milieu remains unclear.    Methodology/Principal Finding  Using “middle aged” mice as CSs donors, we found that acute MI induced a dramatic increase in the number of CSs in a mouse model of MI, and this increase was attenuated back to baseline over time. We also observed that CSs from post-MI hearts engrafted in ischemic myocardium induced angiogenesis and restored cardiac function. To determine the role of Sca-1 + CD45 -  cells within CSs, we cloned these from single cell isolates. Expression of Islet-1 (Isl1) in Sca-1 + CD45 -  cells from CSs was 3-fold higher than in whole CSs. Cloned Sca-1 + CD45 -  cells had the ability to differentiate into cardiomyocytes, endothelial cells and smooth muscle cells  in vitro . We also observed that cloned cells engrafted in ischemic myocardium induced angiogenesis, differentiated into endothelial and smooth muscle cells and improved cardiac function in post-MI hearts.    Conclusions/Significance  These studies demonstrate that cloned Sca-1 + CD45 -  cells derived from CSs from infarcted “middle aged” hearts are enriched for second heart field (i.e., Isl-1 + ) precursors that give rise to both myocardial and vascular tissues, and may be an appropriate source of progenitor cells for autologous cell-therapy post-MI.

Sca-1+ Cardiosphere-Derived Cells Are Enriched for Isl1-Expressing Cardiac Precursors and Improve Cardiac Function after Myocardial Injury