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Figure 1.1 Stages in haemopoietic cell development.

The lifelong production of blood cells occurs in haemopoietic tissue. This involves a very high level of cell turnover, demanded by the need to replace mature circulating blood cells at a rapid rate, and is necessitated by the limited lifespan of the mature cells. Granulocytes survive for only a few hours and erythrocytes for a few months, so that some 1013 new cells must be replaced each day to maintain steady-state blood counts. This is equivalent to an annual number of cells approximating the total body weight, but the total bone marrow of an adult human contains around 1012 cells, 10-fold less than daily needs. From these estimates it is clear that the blood cells required for lifelong haemopoiesis cannot be preformed in the body.

The bone marrow, which is the major site of haemopoiesis in adult humans, contains cells that represent the stages in the development of the different types of blood cells (Figure 1.1). The later stages are recognizable as belonging to the major lineages of haemopoiesis (granulocytes, erythrocytes, monocyte/ macrophages, megakaryocytes, eosinophils, basophils, and T and B lymphocytes). They are the myelocytes, metamyelocytes, erythroblasts, reticulocytes, etc. Earlier stages of development become progressively less morphologically distinct in their lineage affiliation and fewer in number, whereas the least frequent cells, which cannot be discriminated morphologically, are the committed progenitor cell populations and the stem cells.

The stem cells are the most important cells in haemopoietic cell production. They are ultimately responsible for regenerating haemopoiesis following damage to the haemopoietic system by myelotoxic chemotherapy or after stem cell transplantation. This is accomplished by stem cell division, producing new stem cells to maintain the stem cell pool (stem cell renewal) and differentiating cells that are the progenitor cells of each of the blood cell lineages. Estimates of stem cell frequency in human bone marrow are about one stem cell per 20 million nucleated cells.

They are very difficult to measure, although various assays for candidate human stem cells have been developed. These include both in vitro and in vivo assays such as long-term bone marrow culture (LT-BMC), cobblestone-area colony (CAFC) formation and the NOD/SCID mouse repopulating assay.

Haemopoiesis is regulated by soluble factors that were discovered when immobilization ofbone marrow cells in a semisolid matrix containing medium 'conditioned' by the growth of a cell line in culture resulted in the growth of clonal colonies of granulocytes and macrophages. Identification of the active factors in the conditioned medium led eventually to cloning, production of recombinant protein and clinical use of cytokines in the therapy of haematological disease.

In addition to the haemopoietic system, the bone marrow contains stromal stem cells (mesenchymal stem cells), which are important for constructing the haemopoietic microenvironment. The microenvironment provides more than simply mechanical support and has been shown to be an essential component of the long-term bone marrow culture system. Moreover, damage to the microenvironment, for example by chemotherapy, has been implicated in haemopoietic insufficiency after treatment.

Studies in haemopoietic stem cell biology have now expanded to embrace the concepts of stem cell plasticity. This term refers to the ability of haemopoietic and stromal (mesenchymal) stem cells to produce cells associated with other tissues, such as liver, lung and muscle. Although this area remains highly controversial, the therapeutic applications of haemopoietic stem cell plasticity are obvious as it would provide an easily accessible source of cells that could be redirected to repair a variety of damaged tissues.

The development of the haemopoietic system is associated with the development of suitable microenvironments, which are colonized by migrating stem cells. The migration of stem cells from site to site must require mechanisms for their entry, transit and exit. These processes probably involve specific recognition and adhesive interactions between the stem cells and cells of the various microenvironments. Extracellular matrix-degrading enzymes such as the metalloproteinases have been implicated in the reversal of adhesion and exit from tissues.

There has been a long-accepted dogma that the adult haemopoietic system originates in the embryonic yolk sac. The mesenchyme of the yolk sac differentiates into endothelial cells, on the one hand, and haemopoietic stem cells on the other. At this stage, haemopoiesis consists of blood islands, consisting of primitive primordial cells (haemocytoblasts) and erythro-blastoid cells surrounded by endothelial cells. The observation that endothelial and haemopoietic cell development occur in close proximity led to the hypothesis that these two cell types are derived from a common precursor, the haemangioblast, which represents the origin of the circulatory system as well as the blood cells. Following the development of the circulation, stem cells can migrate into the embryo where they sequentially seed the liver, spleen and bone marrow.

Challenging the yolk sac origin of adult haemopoiesis, embryo-grafting experiments in birds revealed that adult haemopoiesis is derived from an intraembryonic source. This is the aorta-gonad-mesonephros (AGM) region, located in the para-aortic splanchnopleure. It is not overtly erythropoietic, unlike yolk sac haemopoiesis, but contains a spectrum of lymphoid and myeloid stem and progenitor cells. Similarly, active haemopoiesis is found in the AGM region of embryo mice. It is thought that a second wave of fetal liver colonization, originating in the AGM region, supplies stem cells for the eventual development of the adult haemopoietic system, in contrast with the primitive and temporary haemopoiesis derived from the yolk sac.

Primitive erythropoiesis persists as the major visible haemo-poietic activity in the fetal blood vessels, liver and spleen but large numbers of granulocytes can be found in the connective tissue, outside the organs, for most of intrauterine life. Granulocytic cells are not produced in large numbers until haemopoiesis is established in the bone marrow. This occurs at different times in different bones and coincides with the process of ossification. Large numbers of stem cells are found in umbilical cord blood as well as in the fetal circulation, and this has led to the use of cord blood as an alternative to bone marrow as a source of cells for transplantation. At birth, haemopoietic activity is distributed throughout the human skeleton but it gradually recedes with time so that in normal adult life haemopoiesis is found mainly in the sternum and pelvis, with small amounts in other bones like the ribs, skull and vertebrae.

A small number of stem cells are present in the circulation of normal adult humans. This number increases physiologically in some circumstances, such as following exercise and during infections, and may be increased pharmacologically by administration of haemopoietic growth factors and/or cytotoxic chemotherapy. This phenomenon has been exploited to provide large numbers of circulating stem cells, which can then be collected by leuca-pheresis and used as a source of cells for stem cell transplantation.

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