The hematopoietic system, which comprises all the cellular components of the blood, is one of the earliest organ systems to evolve during embryo development. Hematopoietic stem cells (HSCs), which are rare blood cells residing in the bone marrow of the adult organism, are the founder cells that give rise to the entire hematopoietic system. HSCs are primarily characterized by their ability to self-renew, as well as their potential to mature and differentiate into all blood cell lineages, including erythroid, myeloid, and lymphoid cells. Considering the short lifespan of mature blood cells (around 120 days in humans), the self-renewing and multi-potent nature of HSCs provides a way to continuously replenish the mother blood cell population that can give rise to more differentiated lineages throughout life .
During early development, the various cell types of the hematopoietic system are formed at distinct anatomical niches within the embryo, in a spatially and temporally controlled manner, until this function is completely taken over by the bone marrow and thymus (for T-lymphoid cell generation) just prior to birth. A number of studies have now confirmed that the development of the hematopoietic system, in humans and other mammals, occurs in two phases: a primitive hematopoietic phase that gives rise to transitory, bi-potent HSCs, and a definitive hematopoietic phase that generates long-lived, multipotent HSCs .
Primitive hematopoiesis: The primitive phase of hematopoiesis starts very early, at around the third week of mammalian embryo development, in an extraembryonic tissue called the yolk sac. Within this yolk sac, mesodermal cells start forming cell aggregates at around day 16 of embryo development . Soon after, the peripheral cells of the aggregate acquire endothelial characteristics, while the inner cells disappear to form the lumen of the primitive blood vessels. At around day 19, distinct blood islands are formed by mesodermal cells that remain attached to the endothelial walls, and cells of these blood islands give rise to progenitors of the erythroid and myeloid lineage . Upon the separation of yolk sac from the embryo at the 19-day stage, when the blood circulation between the extra- and intra-embryonic compartments is still not established, only erythroid and myeloid cells were identified in the yolk sac. This study confirmed that the primitive hematopoietic cells generated in the yolk sac lack the potential to differentiate into a lymphoid lineage . The simultaneous emergence of both endothelial and hematopoietic cells, as well as the expression of common molecular markers and transcription factors  by both of these cell types confirmed that they arose from a common mesodermal ancestor called the hemangioblast, whose existence was initially proposed in the first half of the twentieth century [Murray PDF, 1932].
Definitive hematopoiesis: The earliest evidence for intraembryonic hematopoietic activity came from experiments in birds, in which blood cell progenitors were identified in and around the region neighboring the dorsal aorta . In human and other vertebrate embryos, a homologous region called the aorta-gonad-mesonephros (AGM) as well as the earlier stage precursor tissue, the Para-aortic Splanchnopleura (P-Sp), were identified as the primary sites for definitive hematopoiesis during early embryogenesis. HSCs could be detected in the P-Sp and AGM regions as early as day 19 of gestation; these HSCs showed the potential to form progenitors of both myeloid and lymphoid lineages, unlike the yolk sac HSCs, whose differentiation potential was restricted to erythroid and myeloid lineages . The central role of the AGM region in establishing autonomous hematopoietic activity within the embryo was further analyzed through immunohistochemical analyses of human embryos, which revealed a high concentration of CD34 (a molecular marker that identifies undifferentiated, immature progenitor cells) expressing cells in the AGM region as well as in the ventral endothelium of the aorta . The results were followed up with in vitro colony assays using a subset of CD34+ expressing cells, which demonstrated that these AGM region cells could generate high clone numbers of hematopoietic progenitors . More recent studies have employed three-dimensional culture techniques, which enable the development of organ rudiments isolated from whole embryos, to further confirm the hematopoietic potential within the human embryo .
Following their emergence from the AGM region, the definitive HSCs enter the primitive blood circulation and migrate to the other major embryonic hematopoietic sites, including the fetal liver, thymus, and spleen. The HSCs form colonies in the fetal liver by rapidly proliferating and expanding their populations, and thereafter, differentiate into erythroid and myeloid progenitors. The spleen and the thymus, both of which develop later during gestation, also function as sites for differentiation into highly differentiated lineages. During the later stages of gestation, the HSCs eventually move on to colonize the bone marrow, which then functions as the major hematopoietic site for the entirety of the adult life .
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