healthy term and preterm neonates
Introduction
Haemopoiesis is the process that ensures life‐long production of haemopoietic cells. In newborn infants the process has many distinct features that differ from those in older children and adults. These differences reflect both the ontogeny of haemopoiesis during fetal development and the unique interaction between the fetus and mother, as well as the effects of birth itself. The sequential changes in the sites and regulation of haemopoiesis during development also help to explain the natural history of many neonatal haematological problems.
Brief outline of the ontogeny of haemopoiesis
Haemopoiesis in humans begins in the yolk sac between 2 and 3 weeks post‐conception (Fig. 1.1).1,2 This is known as primitive haemopoiesis. Studies in other species, particularly in mice, indicate that the predominant cell types produced in the yolk sac are erythroid cells and macrophages.2,3 While megakaryocytes and lymphoid cells may also be yolk sac‐derived, the current consensus of opinion is that true, long‐lived haemopoietic stem cells (HSC) arise from a region of specialised endothelium (‘haemogenic’ endothelium), which is localised to the ventral wall of the dorsal aorta in a region known as the aorto‐gonado‐mesonephros (AGM).4–6 In humans, haemopoiesis begins in the AGM at around 5 weeks post‐conception and is known as definitive haemopoiesis.6–8 Haemopoiesis in the aortic wall is only transient, presumably because this region lacks the necessary physical space and specialised microenvironment to support expansion and differentiation of the HSC and progenitor populations required to meet the needs of the growing fetus.
By 6 weeks post‐conception, HSC and progenitor cells have migrated to the fetal liver,8,9 which remains the main site of blood cell production throughout fetal life10,11 and AGM haemopoiesis ceases. The first signs of haemopoiesis in the bone marrow are evident from around 11 weeks post‐conception.8,12 Although fetal bone marrow is able to give rise to cells of all lineages, it is becoming clear that the predominant cell types produced in the bone marrow are B lymphocytes and their progenitor cells together with granulocytes, monocytes and their progenitors. Although erythropoiesis and megakaryopoiesis take place in the fetal bone marrow from the end of the first trimester, most red blood cell and megakaryocyte production takes place in the fetal liver until shortly before term.8 Thus, for preterm infants, the liver is the main haemopoietic organ at and shortly after birth; this is likely to be a contributory factor in a number of disorders, including the haematological abnormalities seen in neonates with Down syndrome (see pages 154–160 and 206).
Fig. 1.1 Ontogeny of human haemopoiesis in embryonic and fetal life. AGM, aorto‐gonado‐mesonephros; pcw, post‐conceptional week. Based on references 1 and 2.
Properties of fetal haemopoietic stem and progenitor cells
Major advances in the immunological and molecular tools available to analyse haemopoietic stem and progenitor cells have allowed us to build up a much clearer picture of the process of haemopoiesis in fetal life and how this differs from adult life. Fetal HSC, like adult HSC, are the cells at the top of the haemopoietic hierarchy (Fig. 1.2). When HSC divide, they do so either through a process of ‘self‐renewal’, where they generate more HSC (sometimes referred to ‘symmetric cell division’), or through asymmetric division during which one of the two daughter cells differentiates into progenitor cells, which in turn generate the mature cells of all the haemopoietic lineages (Fig. 1.2).9
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.913–16 Elucidating 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. 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.16 One 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.18 This behaviour of fetal HSC contrasts dramatically with adult HSC which are largely quiescent cells that enter the cell cycle infrequently.9,16,18 The amplification in fetal HSC numbers probably takes place mainly in fetal liver rather than in the bone marrow,16,19 which 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.9,17 Finally, fetal HSC exhibit different sensitivity to and dependence upon haemopoietic growth factors, such as insulin‐like growth factors, compared with adult cells20,21 and a different pattern of mature cell output.9,16,18 Reflecting this, fetal HSC also have unique gene expression programmes,1315–17,22–26 which 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 1.2 and 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
