Powered in part by the discovery of iPS cells (12
), CPCs or cardiomyocytes derived from pluripotent cells have provided a potential avenue for cardiac regenerative approaches. In particular, the plasticity and cardiogenic differentiation potential of SSEA-1+
CPCs make them attractive sources for cells to replace damaged myocytes in an infarcted heart.
A true test of the value of these cells is to determine whether they functionally incorporate themselves into heart tissue. Before moving to animal graft experiments, Blin and colleagues examined the maturation of cardiomyocytes derived from BMP2-induced SSEA-1+
CPCs ex vivo (11
). A large proportion of differentiated cells (60%–80%) displayed organized sarcomeres and expressed cardiac α-actinin, ventricular myosin light chain, and the adult β-myosin heavy chain isoform. Importantly, the gap junction protein connexin 43 (Cx43) was phosphorylated in these cells, indicating the potential for cell-cell coupling. However, whether these cardiomyocytes are in fact electrophysiologically functional will have to be established by standard patch-clamp single-cell recordings.
As a proof of concept, Blin and colleagues transplanted Rhesus ES cell–derived SSEA-1+
CPCs into a Rhesus monkey model of myocardial infarction (11
). Previous studies used human ESC-derived cardiomyocytes or CPCs in a rodent myocardial infarction model (16
), but the human cardiomyocytes failed to couple to rodent host myocardium, possibly due to differences in their intrinsic beating frequency. The unsuccessful coupling might explain the absence of long-term (i.e., up to 12 weeks) functional benefits (16
). The Rhesus SSEA-1+
CPCs engrafted in the infarcted monkey hearts, without forming teratomas, and differentiated into morphologically matured cardiomyocytes that were positive for myosin light chain 2 and myosin light chain kinase.
However, a major goal of cardiac repair is to restore long-term function in an effort to prevent or treat heart failure. Newly formed muscle must provide passive mechanical support and, more importantly, couple and contract in synchrony with the host myocardium. Using immunohistochemistry, Blin et al. reported activation of Cx43 expression within and surrounding the graft. Although this indicates electrical coupling between the graft and the surrounding myocardium, additional electrophysiological studies (e.g., intracellular calcium imaging) will be needed to unequivocally show successful coupling. Since incomplete coupling can cause ectopic electrical activity and increase the risk of arrhythmia, more functional analyses are needed to prove the procedure is safe and effective. Moreover, the functional benefit of cells engrafted into nonhuman primate hearts remains to be determined.
Despite these issues, the pioneering studies of Blin et al. are very encouraging. Their imaginative work using a nonhuman primate model of myocardial infarction to test the capacity of SSEA-1+ CPCs to engraft and differentiate into matured cardiomyocytes represents an important milestone. Future studies on the long-term survival, functional integration, physiological compatibility of engrafted cells, and beneficial effects on cardiac function will provide new insights into the potential use of SSEA-1+ CPCs for cardiovascular regenerative medicine. Most importantly, the ability to isolate nonhuman primate CPCs using a cell surface marker brings us one step closer to the ultimate dream of cell-based therapies for some of the most devastating forms of heart disease.