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INTRODUCTION

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SUMMARY

Blood cell production is an enormously complex process in which a small number of hematopoietic stem cells expand and differentiate into an excess of 1011 cells each day. Based on a number of strategies available to the experimental hematologist a hierarchy of hematopoietic stem, progenitor, and mature blood cells is emerging in which each successive developmental stage loses the potential to differentiate into a specific type or class of cells. The characteristics of the stem and progenitor cells that give rise to the cells of the blood are the subject of this chapter, including the roles played by transcription factors and external signals in lineage fate determination, the cytokines and cell adhesion molecules that support cell survival, self-renewal, expansion, and differentiation, and the cell surface properties that allow for their purification, and biochemical and genetic characterization. A thorough understanding of hematopoietic stem and progenitor cells and their supportive microenvironment can provide critical insights into developmental biology of multiple cell systems, favorably impact blood cell development for therapeutic benefit, impact genetic therapy for a number of blood and other human diseases, and potentially provide the tools necessary to allow the regeneration of multiple organs.

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Acronyms and Abbreviations:

AGM, aorta-gonad-mesonephros; BFU-E, burst-forming unit–erythroid; BFU-MK, burst-forming unit–megakaryocyte; CAFC, cobblestone area-forming cell; CAR, CXCL12–abundant reticular; CFC, colony-formingcell; CFU-E, colony-forming unit–erythroid; CFU-GM, colony-forming unit–granulocyte-macrophage; CFU-MK, colony-forming unit–megakaryocyte; CLP, common lymphoid progenitor; CMP, common myeloid progenitor; EBF, early B-cell factor; ECM, extracellular matrix; EGF, epidermal growth factor; EPO, erythropoietin; EPOR, erythropoietin receptor; FAK, focal adhesion kinase; FL, Flt-3 ligand; G-CSF, granulocyte colony-stimulating factor; G-CSF-R, granulocyte colony-stimulating factor receptor; GM-CSF, granulocyte-macrophage colony-stimulating factor; GM-CSF-R, granulocyte-monocyte colony-stimulating factor receptor; GMP, granulocyte-macrophage progenitor; HSC, hematopoietic stem cell; Ig, immunoglobulin; IL, interleukin; IRF4, interferon regulatory factor 4; LEF, lymphoid-enhancer binding factor; LR, laminin receptor; LTC, long-term culture; LTC-IC, long-term culture-initiating cell; MAPK, mitogen-activated protein kinase; M-CSF, macrophage colony-stimulating factor; MEP, megakaryocyte-erythroid progenitor; MK, megakaryocyte; MSC, mesenchymal stem cell; PI3K, phosphoinositol 3′-kinase; R, receptor; RAG, recombination activating gene; ROS, reactive oxygen species; SCF, stem cell factor; SCL, stem cell leukemia; SDF-1, stromal-derived factor-1; SLAM, signaling lymphocyte activation molecule; TCF, T-cell factor; TGF, transforming growth factor; TPO, thrombopoietin; VCAM, vascular cell adhesion molecule; VLA, very-late antigen.

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AN OVERVIEW OF HEMATOPOIESIS

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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 per microliter of blood, and their circulatory half-life, it can be calculated that each day an adult human produces 2 × 1011 erythrocytes, 1 × 1011 leukocytes, and 1 × 1011 platelets. These numbers can all increase 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 stem cells (HSCs) gradually lose one or more developmental potentials ...

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