Читать книгу Neonatal Haematology - Barbara J. Bain, Irene Roberts - Страница 14

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 cells^20,21 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