The mammalian heart lacks the capacity to replace the large numbers of cardiomyocytes lost due to cardiac injury. and Embryonic Cardiac Progenitors Myocardial cells are lineage descendents of the developing the mesoderm, which emerges from the primitive streak during gastrulation (Rawles, 1943). From the anterior primitive streak, cardiac precursors migrate under the head folds and divide into two populations, one on either side of the midline. Cells then extend toward the midline, forming the cardiac crescent, where committed cardiovascular cells are first observed. The cardiac crescent then fuses along the midline, forming the linear heart tube, which undergoes rightward looping, the first asymmetric event during organogenesis. Finally, with further hypertrophy of the left and right ventricles and atria, the four heart chambers undergo several phases of remodeling 604-80-8 and septation before assuming their fully mature structure. At the primitive streak stage, cardiac precursors are not yet irreversibly committed to a cardiac lineage and can also contribute to the paraxial mesoderm forming the skeletal muscle in the head 604-80-8 and neck (Saga et al., 1999). Markers such as Mesp1 and Mesp2 have been used to identify these earliest cardiac and skeletal precursors (Lindsley et al., 2008; Wu et al., 2008). When mesodermal precursors restrict their fate to cardiovascular and hematopoietic lineages, they begin to express Mesp1 and Flk1 (Wu, 2008). Flk1 is used to denote primitive precursors for cardiovascular cells (Kattman et al., 2006) and has been detected in undifferentiated embryonic stem cells (Kouskoff et al., 2005). Mesp1 and Mesp2 are expressed transiently during the primitive streak stage and their expression is turned off as cardiac precursors migrate away from the primitive streak (Kitajima et al., 2000). Moreover, descendants of Mesp1+ and Mesp2+ cells colonize the entire myocardium (Saga et al., 2000), enabling Mesp1 and Mesp2 to be reliably used as cardiac progenitor markers. Mesp1 is not only a useful marker of cardiac precursors, but plays an important role in cardiac lineage commitment. Inducible Mesp1 overexpression during embryonic stem cell differentiation results in induces myocardial expansion in a Wnt-independent fashion (Lindsley et al., 2008). In zebrafish, ubiquitous Mesp1 overexpression leads to the formation of ectopic cardiac cells that show a beating phenotype (David et al., 2008). Mesp1 drives commitment of mesodermal precursors to the cardiac lineage by promoting the stable expression of cardiomyogenic transcription factors, including Nkx2.5, Gata4, Isl1, and myocardin, in a cell-autonomous manner (Bondue et al., 2008). At the cardiac crescent stage, cardiac precursors irreversibly commit to cardiovascular lineages and begin to express transcription factors such as Nkx2.5, Gata4 and Isl1 (Moretti et al., 2006; Wu et al., 2006). These cardiac progenitors undergo rapid expansion to provide the necessary cells for the increase in size concomitant with heart tube formation, looping, and chamber formation. The expression of Nkx2.5 is cardiac-selective (Komuro and Izumo, 1993) and has been used as a marker of cardiac progenitor cells during embryonic development. While Isl1 is not strictly cardiac-specific, its expression is often used for the identification of cardiac progenitor cells because it is Rabbit Polyclonal to B3GALTL transiently expressed in cardiac mesoderm but is then turned off during cardiomyocyte maturation (Cai et al., 2003). Cardiogenic Nkx2.5+ and Isl1+ cells are tri-potent and contribute cardiomyocytes, endothelial cells, and vascular smooth muscle cells to the developing heart (Kattman et al., 2006; Moretti et al., 2006; Wu et al., 2006). These multipotent cardiac progenitor cells contribute to the formation of a functional heart by making lineage choice decisions at a single-cell level (Wu et al., 2006). In addition to myocardial expansion within the heart tube, two 604-80-8 heart fields contribute cardiac progenitor cells at the anterior and venous poles of the heart tube. The first heart field is located bilaterally in the anterior splanchnic mesoderm and gives rise to cells that contribute to the left ventricle and both atria (Meilhac et al., 2004). Reliable molecular markers of the first heart field are lacking, though Tbx5 is associated with the first heart field (Takeuchi et al., 2003). The second heart field is pharyngeal mesoderm-derived and is marked by Isl1 expression (Cai et al., 2003)..