Modeling hematopoietic development. (A) Hematopoietic differentiation of embryonic stem (ES) cells involves production of mesoderm-derived Brachyury+Flk1+ hemangioblasts, which are capable of generating endothelial and hematopoietic cells through an intermediate hematogenic endothelium stage. (B) Hemangioblasts have been observed transiently in the primitive streak in vivo and their differentiated progeny are thought to colonize the yolk sac. (C) At later stages, hematopoietic clusters appear in close association with the hematogenic endothelium within major vessels. Hematopoietic cells bud off and enter the vessel lumen. The question mark indicates that the origin of the hematogenic endothelium of the dorsal aorta in higher vertebrates is not entirely clear.