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 several strategies, experimental hematologists began to construct a hierarchical model of hematopoietic stem, progenitor, and mature blood cell development, in which each successive developmental stage loses the potential to differentiate into a specific type or class of cells, creating a series of progenitors of more and more restricted developmental fate. However, with the availability of single-cell transcriptome sequencing, this model of hematopoiesis is being reexamined and refined. 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.
Acronyms and Abbreviations
AGM, aorta-gonad-mesonephros; ANGPTL, angiopoietin-like molecules; BFU-E, burst-forming unit–erythroid; BFU-MK, burst-forming unit–megakaryocyte; CAFC, cobblestone area-forming cell; CAR, CXCL12–abundant reticular; CFC, colony-forming cell; 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; GFI, growth factor independence; GM-CSF, granulocyte-macrophage colony-stimulating factor; GM-CSF-R, granulocyte-monocyte colony-stimulating factor receptor; GMP, granulocyte-macrophage progenitor; HIF, hypoxia-inducible factor; HSC, hematopoietic stem cell; Ig, immunoglobulin; IL, interleukin; IRF4, interferon regulatory factor 4; LEF, lymphoid-enhancer binding factor; LMPP, lymphoid primed multipotent progenitors; 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; NOD, non-obese diabetes; PI3K, phosphoinositol 3¢-kinase; R, receptor; RAG, recombination activating gene; ROS, reactive oxygen species; SCF, stem cell factor; SCID, severe combined immunodeficiency; 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.
AN OVERVIEW OF HEMATOPOIESIS
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 liter 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. ...