The hematopoietic system is one of the first complex tissues to develop in the mammalian conceptus. Of particular interest within the field of developmental hematopoiesis is the origin of adult bone marrow hematopoietic stem cells. Tracing their origin is complicated because blood is a mobile tissue, and because hematopoietic cells emerge from multiple embryonic sites. The origin of the adult mammalian blood system remains a topic of lively discussion and intense research. Interest is also focused on developmental signals that induce the adult hematopoietic stem cell program, as these may prove useful for generating and expanding these clinically important cells ex vivo. This review presents a historical overview of, and the most recent data on the developmental origins of hematopoiesis.Defining the embryonic origins of specific cell lineages is important for understanding how tissues of the adult organism develop. The signaling events that induce the molecular programs governing lineage-specific fate decisions in embryonic cells provide insight into the complexity of lineage relationships, cell diversity, and ultimately tissue function in the adult. The process of blood cell development in the mammalian conceptus is particularly complex, as it occurs in multiple sites that are separated both temporarily and spatially. Furthermore, unlike stationary tissues, cells of the hematopoietic system circulate, and thus their ancestry and the distinct characteristics associated with their site of origin are confounded by the natural mobility of the system. Recent studies have begun to reveal the lineage relationships between, and molecular programs controlling hematopoietic cell emergence in the conceptus and the legacy of the cells emerging from distinct anatomic sites. This review focuses on the embryonic origins of the hematopoietic system, and the environments and molecules affecting the development of adult mammalian hematopoietic stem cells.
Sites and cells: Where does it start?The conceptus consists of embryonic tissues that will ultimately become part of the fetus, and extra-embryonic tissues that support fetal development. It has been long recognized that the first blood cells in the vertebrate conceptus appear in the extra-embryonic yolk sac concomitant with the developing vasculature. The yolk sac of early chick embryos was shown by histological studies to harbor the first visible hematopoietic cells, primitive erythrocytes 1 . The close physical association of primitive erythrocytes and their synchronous appearance with endothelial cells led to the postulate of a common mesodermal precursor for these two lineages coined the hemangioblast 2 . Studies utilizing the in vitro differentiation of totipotent mouse Correspondence should be addressed to: E-mail: e.dzierzak@erasmusmc.nl Phone: 31-10-704-3172 and E-mail: Nancy.A.Speck@dartmouth. embryonic stem cells (ES) produced the first functional evidence for mammalian hemangioblasts 3, 4 , and later analyses of early stage mouse conceptuses revealed presump...