After studying this chapter, you should know:
The developmental origins of the blood-forming tissues.
The properties and functions that define hematopoietic stem cells.
The role of growth factors and transcription factors in the regulation of hematopoiesis.
The therapeutic impact of growth factors and hematopoietic stem cell transplantation.
In Chapter 1, we introduced the morphologically recognizable marrow progenitors and their progeny, the red cells, white cells, and platelets that make up the formed elements of the blood. Here we turn to the topic of hematopoiesis (from the Greek “to make blood”), the process by which these elements are created. Hematopoiesis depends on rare, morphologically inconspicuous progenitor cells that have remarkable functional properties. Unraveling how hematopoiesis is maintained and regulated has provided a paradigm for understanding the biology of tissue stem cells and has resulted in the development of effective therapies for certain cancers and genetic disorders as well as a variety of conditions in which bone marrow output is inadequate to maintain normal blood cell counts.
DEVELOPMENT OF BLOOD-FORMING TISSUES
The developmental origins of hematopoietic cells are complex and incompletely understood. Cells with the properties of hematopoietic stem cells (HSCs) arise several times in different tissues during prenatal development, producing successive waves of hematopoiesis (Figure 2-1). Hematopoiesis first appears around day 16 of gestation in the embryonic yolk sac; at this site, it is limited to the production of platelets and red cells, which are needed for oxygen transport in the newly developed circulatory system, and monocytes, some of which mature into long-lived resident immune cells in organs such as the brain (where they become microglial cells) and the liver (where they become Kupffer cells). Hematopoietic cells arise anew around 3 to 4 weeks of gestation in a portion of the ventral mesoderm referred to as the aorta-gonad-mesonephros region. HSCs derived from this region (and possibly the yolk sac as well) are believed to migrate through the blood and take up residence in the liver, which becomes a hematopoietic organ at around 6 weeks of gestation and serves as the major source of hematopoietic cells throughout much of fetal development. HSCs and some hematopoietic progenitors also appear by around 6 weeks of gestation in the placenta and umbilical cord blood and persist in these sites until birth. By 7 to 8 weeks of gestation, lymphoid progenitors derived from the liver begin to seed the newly developed thymus, which is the major site of T-lymphocyte development. At about 5 months of gestation, HSCs derived from the liver (and possibly other sites) home to the bone marrow, which, by the time of birth, replaces the liver as the dominant site of hematopoiesis.
Ontogeny of human hematopoiesis. The dotted line signifies that yolk sac hematopoiesis is not thought to contribute to definitive hematopoiesis, which arises later in embryonic development in the indicated tissues.