Alchemy and the New Age of Cardiac Muscle Cell Biology

A growing number of studies are reporting the isolation of cardiac stem cells from a variety of tissue sources and examining their effects on promoting the repair of the injured heart. In the current issue of PLoS Biology, the storyline takes an unexpected, interesting twist, as Neal Epstein and his colleagues report the isolation of a novel cell type from skeletal muscle that can adopt a highly differentiated cardiac muscle cell phenotype in vitro and in vivo [1]. In this study, the authors use a differential isolation procedure to remove the skeletal muscle cells and myoblasts (immature muscle cells), and then collect the cells that are negative for a cell-surface marker called Sca-1. Under defi ned in vitro conditions, these cells adopt a cardiomyocyte phenotype that goes beyond the simple expression of cardiacrestricted biochemical and molecular markers, extending to the types of single-cell physiological functions that are hallmarks of authentic cardiomyocytes, including action potentials, calcium transients, and contractile activity. They call the cells Spoc cells, an acronym for “skeletal-based precursor of cardiomyocytes.” The study goes on to show that these cells can adopt this phenotype without the addition of cytokines or agents such as azacytidine that are known to activate the muscle gene program in nonmuscle cells. The cells also adopt the cardiac phenotype following their in vivo implantation into the ischemic heart following myocardial infarction, suggesting a potential therapeutic utility for these cells. Since Spoc cells were isolated from murine skeletal muscle, they may eventually allow the use of sophisticated conditional genetic tracking techniques to monitor the migration, maturation, and differentiation of the cells in the in vivo context. Of course, a study with results this unexpected also raises a number of intriguing questions. Identifying the native location of Spoc cells, as well as the in vivo niche that insulates them from entering the differentiated cardiac program, will be valuable. A rigorous exploration of their developmental origin and their relationship to the other wellknown cell types in skeletal muscle should be forthcoming. In this regard, a set of skeletal muscle stem cells, distinct from myoblasts, has also been found [2], and the question arises as to whether Spoc cells are related to these other skeletal muscle progenitors.