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CHAPTER 18 AN OVERVIEW OF HEMATOPOIESIS

HEMATOPOIETIC STEM Blood cell production is an enormous and complex process. Based on
the adult blood volume (5 L), the number of each of the blood cell types
CELLS, PROGENITORS, per microliter of blood, and their circulatory half-life, it can be calcu-
lated that each day an adult human produces 2 × 10 erythrocytes, 1 ×
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10 leukocytes, and 1 × 10 platelets. These numbers can all increase
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AND CYTOKINES approximately 10-fold in states of blood cell destruction or enhanced
need. Over the past four decades experimental hematologists have
developed a model of blood cell production in which a hierarchical
developmental progression of primitive, multipotential hematopoietic
Kenneth Kaushansky stem cells (HSCs) gradually lose one or more developmental poten-
tials and ultimately become committed to a single cell lineage, which
matures into the corresponding blood cell type. Perhaps one of the
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SUMMARY most compelling arguments supporting this model of hematopoiesis is
derived from extensive purification schemes using cell surface mark-
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Blood cell production is an enormously complex process in which a small num- ers that yield cells at each predicted developmental stage (Fig. 18–1).
ber of hematopoietic stem cells expand and differentiate into an excess of 10 Although hematopoietic development is considered by most investiga-
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cells each day. Based on a number of strategies available to the experimen- tors as an irreversible stepwise and progressive loss of developmental
potentials, studies now suggest that cells undergoing apparent differen-
tal hematologist a hierarchy of hematopoietic stem, progenitor, and mature tiation steps might oscillate between different stages depending on their
blood cells is emerging in which each successive developmental stage loses position in the cell cycle. But regardless of the precise relationships
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the potential to differentiate into a specific type or class of cells. The charac- between different stages of hematopoietic development, the availability
teristics of the stem and progenitor cells that give rise to the cells of the blood of this model and the data leading to its construction have provided
are the subject of this chapter, including the roles played by transcription fac- important insights into the biology and clinical uses of hematopoietic
tors and external signals in lineage fate determination, the cytokines and cell stem and progenitor cells. This chapter focuses on our understanding of
adhesion molecules that support cell survival, self-renewal, expansion, and the molecular basis for blood cell development, beginning with the HSC
differentiation, and the cell surface properties that allow for their purification, and its offspring, the lineage-committed progenitor cells.
and biochemical and genetic characterization. A thorough understanding of
hematopoietic stem and progenitor cells and their supportive microenviron- DEVELOPMENTAL BIOLOGY
ment can provide critical insights into developmental biology of multiple cell OF HEMATOPOIESIS
systems, favorably impact blood cell development for therapeutic benefit,
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impact genetic therapy for a number of blood and other human diseases, and Blood cell production begins in the yolk sac, where extraembryonic
potentially provide the tools necessary to allow the regeneration of multiple mesoderm develops into angioblasts and primitive erythroid precur-
sors at day 7 postcoitum of the mouse; cells of the outer layer of the
organs.
undifferentiated mesoderm at this time flatten and become endothe-
lial cells, and the inner cells round up to become clusters of erythroid
precursors, termed blood islands(Chap. 7). Like in the embryo proper,
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there is much evidence to suggest that these two cells are derived from
a common precursor (the hemangioblast). Once adjacent blood islands
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Acronyms and Abbreviations: AGM, aorta-gonad-mesonephros; BFU-E, burst- begin to coalesce on day 8, the endothelial cells form vascular channels,
forming unit–erythroid; BFU-MK, burst-forming unit–megakaryocyte; CAFC, which by day 8.5 connect with the embryonic vasculature, allowing yolk
cobblestone area-forming cell; CAR, CXCL12–abundant reticular; CFC, colony-forming sac blood cells to exit the blood islands, complete their maturation, and
cell; CFU-E, colony-forming unit–erythroid; CFU-GM, colony-forming unit– enucleate in the embryonic bloodstream. In both mouse and man there
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granulocyte-macrophage; CFU-MK, colony-forming unit–megakaryocyte; CLP, com- is a stage of embryonic development where both primitive erythro-
mon lymphoid progenitor; CMP, common myeloid progenitor; EBF, early B-cell factor; cytes (as characterized by ζ globin phenotype) and definitive red cells
ECM, extracellular matrix; EGF, epidermal growth factor; EPO, erythropoietin; EPOR, are produced in the yolk sac, although the former appears only very
erythropoietin receptor; FAK, focal adhesion kinase; FL, Flt-3 ligand; G-CSF, granu- transiently. Although not as well characterized, yolk sac myelopoiesis
locyte colony-stimulating factor; G-CSF-R, granulocyte colony-stimulating factor and thrombopoiesis also occur, perhaps as part of the development of
receptor; GM-CSF, granulocyte-macrophage colony-stimulating factor; GM-CSF-R, multipotent progenitors that appear by day 8.5 postcoitum. Cells capa-
granulocyte-monocyte colony-stimulating factor receptor; GMP, granulocyte- ble of differentiating into multiple cell lineages become recognizable
macrophage progenitor; HSC, hematopoietic stem cell; Ig, immunoglobulin; IL, inter- early during yolk sac hematopoiesis. However, such cells reproducibly
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leukin; IRF4, interferon regulatory factor 4; LEF, lymphoid-enhancer binding factor; engraft only in the marrow of myeloablated embryonic animals and not
LR, laminin receptor; LTC, long-term culture; LTC-IC, long-term culture-initiating cell; in adults, making it unlikely that such cells are true HSCs, although this
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MAPK, mitogen-activated protein kinase; M-CSF, macrophage colony-stimulating topic remains controversial. By day 11 postcoitum repopulating HSCs
factor; MEP, megakaryocyte-erythroid progenitor; MK, megakaryocyte; MSC, mes- are clearly present in the yolk sac, but the relationship of these cells and
enchymal stem cell; PI3K, phosphoinositol 3′-kinase; R, receptor; RAG, recombina- the HSCs that are clearly demonstrable a day earlier in a region of the
tion activating gene; ROS, reactive oxygen species; SCF, stem cell factor; SCL, stem cell embryonic paraaortic splanchnopleure known as the aorta-gonad-me-
leukemia; SDF-1, stromal-derived factor-1; SLAM, signaling lymphocyte activation sonephros (AGM) is not certain. By day 12.5, postcoitum hematopoiesis
molecule; TCF, T-cell factor; TGF, transforming growth factor; TPO, thrombopoietin; in the murine yolk sac is eliminated.
VCAM, vascular cell adhesion molecule; VLA, very-late antigen. Although it was long believed that the developmental origin of the
adult mammalian hematopoietic system was the yolk sac, subsequent

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