very early in fetal life (from around 6 weeks post‐conception in the fetal liver and from around 11 weeks post‐conception in bone marrow) but are very rare in adult haemopoietic tissues.29 They are defined both by their immunophenotype (CD34+CD127+CD19−CD10−) and their ability to generate B, T and NK cells as well as a small number of myeloid cells.8,29 PreProB progenitors are one of two types of committed B progenitor cell in fetal life; they lack expression of the CD10 molecule and, like ELP, are very rare in adult bone marrow. By contrast, the second type of B progenitor, the ProB progenitor, is CD10+ and is the main, or sole, type of B progenitor found in adult bone marrow.29 It is likely that ProB progenitors lie downstream of PreProB in B lymphoid differentiation and, consistent with this, they have been shown to have undergone complete VH‐DH‐JH rearrangement of their immunoglobulin heavy chain (IgH) loci, in contrast to ELP and PreProB progenitors, which show only partial (DH‐JH) IgH rearrangement.8 The reasons for the existence of two types of B progenitor and a unique ELP cell in fetal life are unknown but it suggests that there are two pathways of fetal B cell production which may have different physiological roles.
Fig. 1.3 Immunophenotypically defined progenitor populations along the B cell differentiation trajectory in the human fetus. The cell surface markers used to define these populations are shown below each cell type. Based on reference 9.
Red blood cell production and development in the fetus and neonate
Normal erythropoiesis, the production of red blood cells, is crucial to early embryonic and fetal development. Most of our knowledge about the cells and genes involved in this process derives either from mouse models or from inherited anaemias, particularly in children. Almost all the characteristic features of red blood cells are different in the fetus and the newborn compared with their adult counterparts. These differences are even greater in preterm neonates and are directly relevant to our understanding of neonatal anaemias. The differences in erythropoiesis during fetal development are summarised in Table 1.1 and those that are important for our understanding of neonatal anaemias are discussed below.
Table 1.1 Features of fetal and neonatal red cells compared with adult red cells
| Haemoglobin production | Embryonic haemoglobins (globin chains) Gower 1 (ζ2ε2) Gower 2 (α2ε2) Portland (ζ2γ2) Fetal haemoglobin (globin chains) Fetal haemoglobin (α2γ2) Adult haemoglobins (globin chains) Haemoglobin A (α2β2) lower Haemoglobin A2 (α2δ2) considerably lower |
| Red cell membrane | Gives resistance to osmotic lysis Altered expression of receptors (e.g. insulin) Increased lipid content and altered phospholipid profile More prone to oxidative damage Altered glucose transport Weak expression of A, B and I blood group antigens Increased variation in red cell shape (poikilocytosis) Red cell ‘pocks’ due to hyposplenism |
| Red cell metabolism | Glycolytic pathway Increased glucose consumption Altered enzyme levels, e.g. low 2,3‐DPG and PFK Pentose phosphate pathway Increased susceptibility to oxidant‐induced injury Lower level of glutathione peroxidase Reduced ability to generate NADPH |
2,3‐DPG, 2,3‐diphosphoglycerate; NADPH, nicotinamide adenine dinucleotide phosphate; PFK, phosphofructokinase.
Erythropoietin production in the fetus and neonate
The principal cytokine responsible for regulating erythropoiesis in the fetus and newborn, as in adults, is erythropoietin (EPO).30 Since EPO does not cross the placenta, EPO‐mediated regulation of fetal erythropoiesis is predominantly under fetal control. The liver is the main site of EPO production in the fetus31 and the only stimulus to production under physiological conditions is hypoxia with or without anaemia (reviewed in reference 32). Little or no EPO is produced under normoxic conditions, but hypoxia very rapidly triggers expression by up to 200‐fold within 30 minutes, at least in hepatocyte cell lines.33 This explains the high EPO levels in fetuses of mothers with diabetes mellitus or hypertension and in those with intrauterine growth restriction (IUGR) or cyanotic congenital heart disease;34 EPO is also increased in fetal anaemia of any cause, including haemolytic disease of the fetus and newborn (HDFN). This, and the switch of EPO production from fetal liver to the neonatal kidney, may in part explain the physiological delay in triggering the production of new red blood cells, which is often not evident until the second month of life, even in healthy babies.
Haemoglobin synthesis and red blood cell production in the fetus and newborn
The rates of haemoglobin synthesis and red blood cell production fall dramatically immediately after birth and remain low for the first 2 weeks of life, probably in response to the sudden increase in tissue oxygenation at birth.35 In healthy neonates the physiological rise in red cell production starts several weeks later, so that by 3 months of age a healthy infant, whatever the period of gestation at birth, should be able to produce up to 2 ml of packed red blood cells every day.35 Studies in preterm neonates have estimated that over the first 2 months of life the maximal rate of red blood cell production may be closer to 1 ml/day. This is based on the observation that preterm babies receiving therapeutic EPO are unable to maintain their haemoglobin if more than 1 ml of blood per day is venesected for diagnostic purposes but can do so where sampling losses are less than this.36
The gestation‐related changes in globin chain synthesis in the human embryo, fetus and neonate have been studied in detail and are summarised in Fig. 1.4.37 The first haemoglobins, known as embryonic haemoglobins, are synthesised from approximately 2 or 3 weeks post‐conception, predominantly in the blood islands of the yolk sac, by the erythroblasts and red blood cells generated there. There are three embryonic haemoglobins (see Table 1.1). ζ or α globin, encoded by adjacent genes in the α globin locus on chromosome 16, combine with ε or γ globin, encoded by genes in the β globin locus on chromosome 11, to produce haemoglobin Gower 1 (ζ2ε2), haemoglobin Gower 2 (α2ε2) and haemoglobin Portland (ζ2γ2).
During normal human development, synthesis of embryonic haemoglobins is transient and largely restricted to yolk sac‐derived erythroblasts which are larger than those generated once definitive haemopoiesis starts in the AGM and fetal liver (Figs 1.5 and 1.6) and express different transcription factor and epigenetic programmes. From 4 or 5 weeks post‐conception, erythroblasts and red blood cells contain mainly haemoglobin F (α2γ2), which remains the principal haemoglobin throughout fetal life. The factors that control the switch from primitive to definitive erythropoiesis are not yet clear due to the difficulties in studying this process at such an early stage of development. Understanding more about the mechanisms which normally silence expression of ζ globin would potentially open up new ways of treating α thalassaemia major,38
