Irene Roberts - Neonatal Haematology

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Neonatal Haematology

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Fetal haemopoietic stem cells

Studies in mice, and more recently in humans, indicate that fetal HSC are markedly different from those in adult bone marrow. 913–16Elucidating the nature of the differences between fetal and adult HSC, and the molecular mechanisms that underpin these differences, is likely to help our understanding of many of the haematological problems that affect neonates and potentially open up new approaches to treatment. For example, the need for rapid expansion of haemopoietic cells to meet the needs of the growing fetus means that the numbers of fetal HSC have to increase more rapidly than at any other time of life. Furthermore, since HSC are responsible for life‐long haemopoiesis, this process of HSC expansion needs to be precisely regulated to prevent either uncontrolled proliferation (and the risk of haematological malignancy) on the one hand or HSC ‘exhaustion’ (and the risk of bone marrow failure) on the other. These properties are thought to underlie the particular prevalence of certain haematological diseases in fetal and neonatal life, including Diamond–Blackfan anaemia and juvenile myelomonocytic leukaemia. 17

Fig 12 A simplified scheme of the fetal haemopoietic stem and progenitor cell - фото 3

Fig. 1.2 A simplified scheme of the fetal haemopoietic stem and progenitor cell hierarchy showing the differentiation of multipotent and committed progenitor cells from haemopoietic stem cells. Details of the fetal‐specific pathway of B lineage progenitor differentiation are shown in Fig. 1.3. Based on reference 9.

There are differences both in the intrinsic properties of the HSC and in the regulatory signals produced by the haemopoietic microenvironment during fetal life. 16One of the characteristic intrinsic differences in fetal HSC is the increased proportion of HSC that are actively cycling and undergoing a process of ‘self‐renewal’ that results in expansion of the pool of long‐lived HSC in fetal life. 18This behaviour of fetal HSC contrasts dramatically with adult HSC which are largely quiescent cells that enter the cell cycle infrequently. 9,16,18The amplification in fetal HSC numbers probably takes place mainly in fetal liver rather than in the bone marrow, 16,19which may explain why so many haematological disorders in neonates are accompanied by hepatomegaly. A second characteristic of fetal HSC is that they are primed to give rise to a higher proportion of erythroid and megakaryocytic progenitors compared with adult HSC, reflecting the requirement of the fetus for large numbers of red blood cells and the importance of adequate numbers of platelets to maintain vascular integrity. 9,17Finally, fetal HSC exhibit different sensitivity to and dependence upon haemopoietic growth factors, such as insulin‐like growth factors, compared with adult cells 20,21and a different pattern of mature cell output. 9,16,18Reflecting this, fetal HSC also have unique gene expression programmes, 1315–17,22–26which have recently been shown to be important in the leukaemic transformation events that lead to infant acute lymphoblastic leukaemia (ALL). 27

Fetal haemopoietic progenitor cells

The different types of haemopoietic progenitor cell present in fetal life are shown in Figs 1.2and 1.3. The overall scheme of differentiation of HSC is similar in fetal and adult life. However, recent studies have identified fetal‐specific lymphoid progenitors, including early lymphoid progenitors (ELP) and PreProB progenitors that may be important not only to rapidly boost B cell production during the second trimester, but also to act as targets of leukaemic transformation in infant and childhood ALL. 927–29ELP are found 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. 29They 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. 8,29PreProB 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. 29It 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 V H‐D H‐J Hrearrangement of their immunoglobulin heavy chain (IgH) loci, in contrast to ELP and PreProB progenitors, which show only partial (D H‐J H) IgH rearrangement. 8The 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 13 Immunophenotypically defined progenitor populations along the B cell - фото 4

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 1.1and 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 (ζ 2ε 2) Gower 2 (α 2ε 2) Portland (ζ 2γ 2) Fetal haemoglobin (globin chains) Fetal haemoglobin (α 2γ 2) Adult haemoglobins (globin chains) Haemoglobin A (α 2β 2) lower Haemoglobin A 2(α 2δ 2) 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). 30Since 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 fetus 31and 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. 33This 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; 34EPO 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.

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