Normal Hematopoiesis and Blood Cell Maturation

Hematopoietic Development

Hematopoiesis is the process by which the various cellular components of the blood are formed. The short-term need for these components can be highly variable, but evidence has accumulated that hematopoietic stem cells (HSCs) are capable of meeting even drastic changes in demand through a variety of differentiation paths.

The development of this capacity is complex. It begins in the embryo with a series of transient hematopoietic waves that occur across several discrete anatomic sites that shift as the embryo evolves . A clear description of how this development occurs is of fundamental importance to our understanding of basic biology and medical science, but our knowledge of embryonic hematopoiesis is still limited compared with what we know of adult HSCs and their microenvironment. This is particularly true for human hematopoiesis, and is reflected in our current difficulties in recapitulating in vitro the development of HSCs from pluripotent stem cells.

In humans, as in other vertebrates, the initial wave of hematopoiesis occurs outside the embryo, in the yolk sac blood islands. These islands are formed by tight groups of mesenchymal cells that originate in the mesoderm but are adjacent to the endoderm; they first differentiate into hematopoietic cells surrounded by endothelial cells in a simple structure that is eventually remodeled to form the branched structure of the yolk sac vascular plexus. The yolk sac primarily produces primitive erythroid cells that express embryonic globins that deliver oxygen to the tissues of the rapidly growing embryo. Large primitive nucleated erythrocytes, with the occasional presence of primitive macrophages and megakaryocytes, represent the major hematopoietic output of the yolk sac from embryonic day 7 to 7.5 in the mouse and 18 days postconception (dpc) in humans. ^{, ,} This phase of primitive erythropoiesis is transient; it is eventually replaced by adult or definitive hematopoiesis that sustains blood production throughout development and postnatal life.

Hematopoietic activity is first detected within the embryo in a region around the ventral wall of the dorsal aorta called the aorta-gonad mesonephros (AGM). Definitive HSCs, which are marked by serially transplantable activity together with long-term engraftment capacity, emerge alongside non–self-renewing hematopoietic progenitor cells in the AGM region at embryonic day 10.5 in mice and after 5 to 6 weeks of gestation in humans. They are organized in intraaortic hematopoietic clusters (IAHCs) that bud predominantly from the endothelial floor of the dorsal aorta, and accordingly coexpress both endothelial and hematopoietic markers. ^, As early blood cells develop in close connection with vascular structures (both in the yolk sac and the dorsal aorta), it is believed that a common precursor cell population exists called the hemogenic endothelium (originally referred to as the hemangioblast) that gives rise to both blood and blood vessel cells, which emerge from hemogenic endothelial–expressing cells through an endothelial-to-hematopoietic transition, although definitive proof of this is still awaited. ^,

It has yet to be determined whether all hematopoietic stem and progenitor cell (HSPC) subsets and differentiation trajectories are present in the same proportions in each of the embryonic organs, and it is unclear whether HSCs arise in the embryo proper from the AGM or arrive by colonization from the yolk sac. Soon after HSCs emerge, however, hematopoiesis is detected in the fetal liver, followed by the spleen, thymus, and ultimately bone marrow ; it is therefore believed that AGM HSCs (or possibly yolk sac HSCs) first migrate to the liver. The liver rudiment emerges as a diverticulum from the floor of the embryonic gut at early 21 dpc, and from late 22 dpc it contains primitive yolk sac–derived erythrocytes and CD45 ⁺ cells, which are likely of monocytic/macrophage lineage. ^, From 27 to 29 dpc, the liver is seeded by growing numbers of CD34 ⁺ /CD45 ⁺ cells. In the fetal liver, expansion and differentiation of HSCs enable the development of definitive red blood cells, myeloid cells, and lymphoid cells (including T cells in the thymus and B cells in the marrow), and this organ remains an important niche for hematopoietic differentiation and HSC expansion until birth. Additional hematopoietic activity by HSCs has been found in other tissues, including the placenta, allantois, and umbilical arteries. ^{, ,} Bone marrow also contains multipotential cells and mesenchymal stem cells (MSCs) that can produce a variety of mesenchymal cell types: osteoblasts (to make bone), chondrocytes (to make cartilage), connective and synovial tissue (to make tendon), and possibly skeletal muscle ( Fig. 1.1 ). There is active research into these and other mesoendodermal bone marrow cell populations, because they suggest that bone marrow could be used to purify and expand these populations for therapeutic benefit in the spleens of mice transplanted with bone marrow cells. ^,

Thus the composition and location of the HSPC compartment changes during the developmental stage. Given the importance of environmental signals in eliciting responses to the changing requirements for different blood cell types throughout the growth of the embryo, it seems likely that the activities of HSCs (and their differentiating progeny) are influenced by the dramatic changes in their locations that occur during this period. ^, Although the role of such extrinsic factors has been difficult to delineate, evidence of intrinsic changes have been easier to infer from comparisons of their behavior when assessed in the same environment either in vitro or in vivo.