The process of erythropoiesis includes all steps of haemopoiesis, starting with the initial specification of haemopoietic stem cells (HSCs) from mesoderm during embryogenesis. This continues with the decisions of these cells to undergo self-renewal or differentiation, through the process of lineage specification and proliferation to form committed erythroid progenitors. Finally, erythroblasts undergo terminal differentiation and post-mitotic maturation as they develop into red blood cells.
In a normal adult, the numbers of circulating red blood cells and their precursors remain more or less constant with a balance between the continuous loss of mature cells by senescence and new red cell production in the marrow. This balance is maintained by an oxygen-sensing system that is affected by the red cell mass and responds via the production of erythropoietin (Epo), which, in turn, controls red cell production by binding and signalling to committed erythroid progenitors. Many other cytokines, growth factors and hormones also influence ery-throid proliferation, differentiation and maturation.
Over the past 10 years, key transcription factors controlling the internal programmes of erythroid progenitors have been identified and some insights into their roles in lineage specification and erythroid differentiation have been discovered. Understanding the basic biology of erythropoiesis provides a logical basis for the diagnosis and treatment of the inherited and acquired anaemias that are so frequently encountered in clinical practice.
Primitive haemopoiesis in man (predominantly erythropoiesis) first appears in the blood islands of the extraembryonic yolk sac at around day 21 of gestation. About 1 week later (days 28-40), definitive haemopoietic stem cells emerge from the vitelline artery and the ventral wall of the embryonic aorta within the aorta-gonad-mesonephros (AGM) region. Both primitive (embryonic) and definitive (fetal/adult) haemopoietic stem cells arise in close association with endothelial cells. Several lines of evidence now suggest that haemopoietic and endothelial cells may emerge from a common progenitor, the haemangioblast, giving rise to both blood cells and blood vessels (see Chapter 1). At about 30-40 days, definitive haemopoiesis starts to occur in the fetal liver and definitive erythroid cells are released into the circulation at about 60 days. By 10-12 weeks, haemopoiesis starts to migrate to the bone marrow, where eventually erythropoiesis is established during the last 3 months of fetal life (Figure 2.1).
Primitive and definitive erythropoietic cells are distinguished by their cellular morphology, cell-surface markers, cytokine responsiveness, growth kinetics, transcription factor programmes and more general patterns of gene expression. In particular, the types of haemoglobin produced are quite distinct in embryonic (Hb Gower I Ç2e2, Gower II a2e2 and Hb Portland Ç2y2), fetal (HbF a2y2) and adult (HbA a2P2 and HbA2 a2S2) erythroid cells. These specific patterns of globin expression have provided critical markers for identifying the developmental stages of erythropoiesis. Nevertheless, it is still not clear whether primitive and definitive haemopoiesis in mammals have entirely separate origins or if they are both derived from common stem cells that arise during early development. Accurately defining the embryological origins of these cells continues be of considerable importance for understanding the normal mechanisms that establish and maintain haemopoietic stem cells and how these programmes are subverted in common haematological disorders.
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