Hematopoiesis in the yolk sac: more than meets the eye

The first blood cells observed in the embryo are large nucleated erythroblasts generated in blood islands of the extraembryonic yolk sac. These unique red cells have been termed primitive because of their resemblance to nucleated erythroblasts of nonmammalian species. It is now widely assumed that hematopoiesis in the yolk sac is “primitive” and that “definitive” hematopoiesis has its origins in the aorta/gonad/mesonephros (AGM) region. Recent studies of yolk sac hematopoiesis have challenged several aspects of this paradigm. First, primitive erythropoiesis in mammals shares many features with definitive erythropoiesis, including progressive erythroblast maturation leading to the circulation of enucleated erythrocytes. Second, the emergence of primitive erythroid progenitors in the yolk sac prior to somitogenesis may be associated with the macrophage and megakaryocyte lineages, raising the possibility that “primitive” hematopoiesis may be multilineage in nature. Third, a second wave of hematopoietic progenitors emerge from the yolk sac during early somitogenesis that consists of multiple myeloid lineages that are temporally and spatially associated with definitive erythroid progenitors. These “definitive” hematopoietic progenitors expand in numbers in the yolk sac and are thought to seed the fetal liver and generate the first definitive blood cells that rapidly emerge from the liver. Recent findings support a model of hematopoietic ontogeny in which the conceptusʹ first maturing blood cells and committed progenitors are provided by the yolk sac, allowing survival until AGM-derived hematopoietic stem cells can emerge, seed the liver and differentiate into mature blood cells.