It should be noted that, while studies using ESC-derived vascular cells do suggest some incorporation, to date there is a lack of detailed studies at single cell resolutions that rigorously quantify the extent to which transplanted cells directly contribute to the regenerative response. cells comes of age. which lies in the deleted region and has a major non-cell autonomous role in regulating neural crest migration . However, isolated functional mutations of have so far not been identified in patients with DiGeorge syndrome, suggesting that other genes and distal modifiers are important for the development of the full phenotype. Development of the mesoderm and its subtypes Vascular cells including endothelial cells and SMCs are predominantly derived from the mesoderm lineage. The primitive streak is a key structural component that discriminates the mesodermal precursors. Developmental studies in have shown that cells migrate from the epiblast through the primitive streak and organize into the mesodermal germ layer . The mesoderm subtypes, which include axial, paraxial, intermediate, and lateral plate mesoderm, are formed in order of their proximity to the primitive streak [42C44]. The patterning of mesoderm is influenced by multiple signaling gradients, growth factors, and transcriptional factors and is generally conserved across species . Early in vivo studies in and zebrafish embryos have shown that FGFs, Wnt, and members of the TGF- family, which include the BMPs, activin, and nodal molecules, play important roles in the induction and patterning of mesoderm [46, 47]. Marginal zone patterning experiments in embryos have also shown that a posterior to anterior BMP4 gradient gives rise to mesodermal subtypes. A higher concentration of BMP4 facilitates the formation of the lateral plate mesoderm while low concentrations WW298 give rise to paraxial mesoderm  (Fig.?1b). However, the WW298 precise functional relationship among these pathways in the induction and patterning of the mesoderm and its subtypes remains to be defined. Development of the proepicardium Coronary SMCs lining the walls of the coronary arteries are an important class of SMCs that originate from the proepicardium. The proepicardium is a transient mesothelial structure found in the wall of the pericardial cavity between the sinus venosus and the liver primordium during development of the heart tube. The proepicardium gives rise to epicardium, GLI1 the epithelial tissue covering the heart. Epicardial cells undergo EMT and invade the myocardium to become cells of the coronary vasculature [49, 50]. Although the importance of the proepicardium for heart development is clear, the signals that direct its formation are just beginning to be understood . The proepicardium is believed to have its origin from the lateral plate mesoderm progenitors that express and . Early in vivo experiments in chick showed that a distinct level of BMP2 signaling is required for inducing proepicardium-specific gene expression . Low levels of BMP2 induce/maintain proepicardium-specific gene expression WW298 whereas high levels promote myocardium formation. These findings also suggest that, although BMP is necessary, it is not sufficient for proepicardium induction and is likely to converge with other signaling molecules. In support of this, Kruithof and colleagues demonstrated that a cross-talk between FGF and BMP signaling is critical in determining a proepicardial fate . Other signaling pathways that regulate epicardium and coronary vessel development include retinoic acid, Wnt, notch, and sonic hedgehog (SHH) . What is not so well established is the cross-talk of various signaling pathways that direct epicardial differentiation to an endothelial, smooth muscle, or cardiomyocyte lineage. An alternative source of epicardial cells has also been described at the arterial pole, known as the arterial proepicardium, which gives rise to epicardial cells surrounding the intrapericardial segment of the great vessels . While these cells are also able to undergo EMT and contribute to epicardial-derived cells in the outer layers of aortic and pulmonary arteries, the mechanisms regulating their distinct migratory and functional properties are less well characterized than for the better studied sinus venosus-derived epicardial cells that surround the majority of the myocardium. Besides understanding how WW298 the epicardium is formed, it is also important to identify the developmental signals that initiate proepicardium formation. Recent studies suggest that tissues WW298 lying in close proximity of the developing proepicardium, such as liver buds, promote.