Cardiomyocyte differentiation has also been demonstrated in hES cell differentiation cultures (Nir et al. 2003). As observed with the mouse system, the cells differentiate over time in culture, following a maturation process similar to that reported in vivo (Kehat et al. 2001; Nir et al. 2003; Snir et al. 2003). Although the hES-cell-derived cardiomyocytes do not undergo maturation to the stage of adult cardiomyocytes, cells with electrical properties of nodal, atrial, and ventricular cells have been identified (He et al. 2003). The induction events for cardiac development in the hES cell cultures have not been defined in any detail, and in most studies the populations are generated following serum stimulation. As observed with mouse ES cells, coculture of hES cells with END-2 endoderm cells enhanced the development of cardiac cells in these differentiation cultures (Mummery et al. 2003).
Recently, hES-cell-derived cardiomyocytes have been used in xenogeneic transplantation as "biologic pacemakers" for the treatment of bradycardia (Kehat et al. 2004). To demonstrate this potential, clusters of contracting cardiomyocytes isolated from the differentiation cultures were transplanted into the left ventricle of pigs that had their atrioventricular node ablated. The recipient hearts had spontaneous rhythms that appeared to originate from the transplanted cells as assessed by high-resolution electroanatomical mapping. Though promising, these results also raise the concern that transplanted cells could serve as a nidus for arrhythmia.
Other mesoderm-derived lineages
While the hematopoietic, vascular, and cardiac lineages have been studied in most detail, the ES cell system does offer the potential to develop many other mesoderm lineages. To date, cell populations representing the skeletal muscle (Rohwedel et al. 1994), the osteogenic (Buttery et al. 2001; zur Nieden et al. 2003), the chrondrogenic (Kramer et al. 2000), and adipogenic (Dani et al. 1997) lineages have been generated from ES cells differentiated in culture. Where analyzed in detail, the development of the lineage in vitro recapitulated its development in vivo, indicating that these populations progressed through normal differentiation programs. As with the other lineages discussed in this review, access to these cell types from ES cells offer unprecedented opportunities to establish model systems to study lineage commitment and to provide a source of cells for transplantation.