The origins of blood during development

Ectoderm

Primitive red cells

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Dorsal aortae

Embryo (20 days)

Fetal liver (30 days)

Endothelium Developing haematopoietic cells

Neural tube Somite Dorsal aorta Hindgut

Neural tube Somite Dorsal aorta Hindgut

Mesonephros Genital ridge/ gonad

Mesonephros Genital ridge/ gonad

Bone marrow (70 days)

Embryo (20 days)

Fetal liver (30 days)

Bone marrow (70 days)

Blood islands

Dorsal aortae

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Figure 2.1 An outline of the origin and development of erythropoiesis during embryogenesis. Although both primitive (blood islands) and definitive (AGM, liver and bone marrow) haemopoiesis are derived from mesoderm, probably via a haemangioblast, the true origin of these early cells is not yet clear. The figure shows the formation of embryonic blood islands in the extraembryonic yolk sac and the formation of definitive haemopoiesis initially in the aorta-gonad-mesonephros region,

At all stages of development there is a continuous need to renew senescent blood cells that are ultimately lost from the peripheral blood days, weeks or months after undergoing terminal differentiation. For example, throughout adult life approximately 1011 senescent red cells must be replaced every day, and there are similar requirements for other mature blood cells (e.g. granulocytes). To prevent depletion of the haemopoietic cells requires a system that not only maintains a self-renewing stem cell pool, but also has the potential to differentiate into all types of highly specialized mature blood cells through a process referred to as lineage specification.

At present, the mechanisms underlying self-renewal and the early events committing multipotential haemopoietic stem cells (HSCs) to an increasingly restricted repertoire of lineage(s) are not fully understood. A popular interpretation is that commitment of multipotential haemopoietic cells to one or another lineage is a stochastic process. The probability of commitment to any particular lineage may be influenced by a complex with subsequent migration to the liver and bone marrow. 'A' denotes a magnified image of the early embryonic aortic region. Ma denotes a macrophage. The specific types of haemoglobin formed at each stage of erythropoiesis are indicated. The approximate times at which CD34+ cells first appear at each site are given in days of gestation (adapted from Dzierzak etal. (1998) Immunology Today 19:228-36).

interplay between the internal transcriptional programmes and epigenetic patterns (e.g. changes in nuclear position, replication timing, chromatin modification, DNA methylation) with external signals from the microenvironment (e.g. cytokines, growth factors and cell-cell interactions).

It is of interest that microarray analyses of haemopoietic stem cells and their progeny consistently show a very wide range of gene expression in the earliest cell populations. Furthermore, many of the genes that are specific to individual lineages (e.g. erythroid, myeloid or lymphoid) are already transcribed, albeit at low levels, in HSCs. In other words, HSCs appear to show 'multilineage priming' and, as their progeny become committed to one pathway of differentiation, that lineage-specific gene expression programme becomes reinforced, whereas those of other lineages are suppressed.

In human adult bone marrow, approximately 1 per 104-106 nucleated cells are long-lived, multipotential HSCs that can be enriched on the basis of their cell-surface markers (e.g. CD33+ and CD34+ and lack of lineage-specific markers; see Figures 2.2 and 2.3), but such markers do not exclusively select stem cells (see Chapter 1). The only rigorous assay for bona fide HSCs is to

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