Cell-based therapy in humans raises tremendous hopes for the treatment of myocardial infarction and heart failure. Several cell types have shown promising results in animal studies. A number of clinical trials have been initiated, mainly using bone marrow-derived stem cells. However, the significant long-term improvement of cardiac function has not been observed. The primary goal of this project is to achieve significant improvement of heart function in humans using clinically relevant cell-based strategies. We isolated therefore a subpopulation of multipotent clonogenic cardiac precursor cells from human atrial appendages. Cardiac precursor cells express uniformly CD73, CD90, and CD105, which characterize these cells as multipotent mesenchymal stromal cells. Importantly, human adult CPCs expressed NKX2.5, GATA4, and MEF2C, indicating they are specified to the cardiogenic lineage. Nevertheless, adult cardiac precursor cells preferentially produce smooth muscle cells and not cardiomyocytes. Therefore, reprogramming toward the cardiomyocyte fate is needed to reveal the full potential of these cells in vivo. We have shown recently that this can be achieved via sequential activation and inhibition of NOTCH signaling, which is sufficient to redirect human cardiac precursor cells from a default smooth muscle commitment to a differentiation into cardiomyocytes. One target of NOTCH signaling in adult cardiac precursor cells is the locus encoding MIR-143/145, two miRNAs that are known to promote smooth muscle differentiation. In the MIR-143/145 locus, NOTCH activates a proximal enhancer element that is associated with different isoforms of an enhancer-associated lncRNA. We recently named this enhancer-associated lncRNA CARMEN, and demonstrated its importance as a regulator of cardiac differentiation.