Figure 1. Cardiovascular lineages during embryonic development and embryonic stem cell differentiation.

Cardiac differentiation from ESCs closely mimics cardiac development in the embryo. In either case, the specification of the cardiovascular lineages involves a transition through a sequence of increasingly restricted progenitors, proceeding from a pluripotent state to mesoderm and then to cells committed to cardiovascular fates. Growth factors that regulate fate choices are listed at branch points, and key transcription factors and surface markers for each cell state are listed under the cell types. These growth factors are useful for directing the differentiation of ESCs, while the markers are useful for purifying cells at defined developmental states. Primitive cardiomyocytes in the embryonic heart tube and nodal/pacemaker cells exhibit slow electrical propagation and a small cell size. In contrast, the eventual specification of working atrial and ventricular cardiomyocytes is accompanied by more rapid conduction, ion channel remodeling and increased cell size. While the field has made considerable progress toward the elucidation of early events during cardiogenesis, a better understanding of how pacemaker vs. chamber-specific cardiac subtypes are formed is required for clinical applications.