Haemopoiesis PDF

~HAPTER1 1 aemopoiesis Site of haemopoiesis, 1 Growth factor receptors and signal h'ansduction, 6 Haemopoietic stem and progenitor cells, 1 The...

~HAPTER1 1 aemopoiesis Site of haemopoiesis, 1 Growth factor receptors and signal h'ansduction, 6 Haemopoietic stem and progenitor cells, 1 The cell cycle, 7 Bone marrow stroma, 3 Apoptosis,9 Stem cell plasticity, 4 Transcription factors, 10 The regulation of haemopoiesis, 5 Adhesion molecules, 11 Haemopoietic growth factors, 5 Bibliography, 11 This first chapter is concerned with the general the major haemopoietic organs and continue to pro- aspects of blood cell formation (haemopoiesis). The duce blood cells until about 2 weeks after birth processes that regulate haemopoiesis and the early (Table 1.1) (see Fig. 6.1b). The bone marrow is the stages of formation of red cells (erythropoiesis), most important site from 6 to 7 months of fetal life. granulocytes and monocytes (myelopoiesis) and During normal childhood and adult life the marrow platelets (thrombopoiesis) are also discussed. is the only source of new blood cells. The develop- ing cells are situated outside the bone marrow sinuses and mature cells are released into the sinus Site of haemopoiesis spaces, the marrow microcirculation and so into the In the first few weeks of gestation the yolk sac is the general circulation. main site of haemopoiesis. However, definitive In infancy all the bone marrow is haemopoietic haemopoiesis derives from a population of stem but during childhood there is progressive fatty cells first observed on the dorsal aorta termed the replacement of marrow tlu-oughout the long bones AGM (aorta-gonads-mesonephros) region. These so that in adult life haemopoietic marrow is con- common precursors of endothelial and haemopoi- fined to the central skeleton and proximal ends of etic cells (haemangioblasts) are believed to seed the the femurs and humeri (Table 1.1). Even in these liver, spleen and bone marrow and from 6 weeks haemopoietic areas, approximately 50% of the lUltil6-7 months of fetal life the liver and spleen are marrow consists of fat (Fig. 1.1). The remaining fatty marrow is capable of reversion to haemopoiesis Table 1.1 Sites ofhaemopoiesis. and in many diseases there is also expansion of haemopoiesis down the long bones. Moreover, the Fetus 0-2 months (yolk sac) liver and spleen can resume their fetal haemopoietic 2-7 months (liver, spleen) role ('extramedullary haemopoiesis'). 5-9 months (bone marrow) Infants Bone marrow (practically all bones) Haemopoietic stem and progenitor cells Adults Vertebrae, ribs, sternum, skull, sacrum and pelvis, proximal ends of femur Haemopoiesis starts with a pluripotential stem cell that can give rise to the separate cell lineages.  2 CHAPTER 1 This haemopoietic stem cell is rare, perhaps 1 in every 20 million nucleated cells in bone marrow. Although its exact phenotype is unknown, on immlUlological testing it is CD34+ CD3S- and has the appearance of a small or medium-sized lympho- cyte (Fig. 21.3). Cell differentiation occurs from the stem cell via the committed haemopoietic pro- genitol's which are restricted in their developmental potential (Fig. 1.2). The existence of the separate progenitor cells can be demonstrated by in vitro cul- ture tecluuques. Very early progelutors are assayed by culture on bone marrow stroma as long-term Fig. 1.1 A normal bone marrow trephine biopsy culture initiating cells whereas late progenitors are (posterior iliac crest). Haematoxylin and eosin stain; generally assayed in semi-solid media. An example approximately 50% of the intertrabecular tissue is is the earliest detectable mixed myeloid precursor haemopoietic tissue and 50% is fat. which gives rise to granulocytes, erytluocytes, monocytes and megakaryocytes and is termed Erythroid progenitors CFUMeg CFUE Megakary- Thymus ocyte progenitor o Red cells b.00 Platelets Mono- Neutro- Eosino- Baso- Lymphocytes NK cell cytes phils phils phils Fig.1.2 Diagrammatic representation of the bone marrow pluripotent stem cell and the cell lines that arise from it. Various progenitor cells can be identified by culture in semi-solid medilUl1 by the type of colony they form. Baso, basophil; BFU, burst-forming tmit; CFU, colony-forming ttnit; E, erythroid; Eo, eosinophil; GEMM, granulocyte, erytlu'oid, monocyte and megakaryocyte; GM, granulocyte, monocyte; Meg, megakaryocyte; NK, natural killer.  "tf:..~:;'·,~'· HAEMOPOIESIS 3 ISelf-renewal I Differentiation and development (al - - - - - - - - - - - - - - - - - - - ~ - - - - - - > Q Stem cells I I III I I Progenitor cells recognized by II Recognizable proliferating Mature cells 'culture techniques marrow (bl precursors Fig.1.3 (al Bone marrow cells are increasingly differentiated and lose the capacity for self-renewal as they mature. (bl A Single stem cell gives rise, after multiple cell divisions (shown by vertical lines), to >106 mature cells. CFU (colony-forming lmit)-GEMM (Fig. 1.2). The other cell line when the need arises. The development bone marrow is also the primary site of origin of of the mature cells (red cells, granulocytes, mono- lymphocytes (Chapter 8) which differentiate from cytes, megakaryocytes and lymphocytes) is consid- a conUl10n lymphOid precursor. ered further in other sections of this book. The stem cell has the capability for self-renewal (Fig. 1.3) so that marrow cellularity remains constant Bone marrow stroma in a normal healthy steady state. There is consider- able amplification in the system: one stem cell is The bone marrow forms a suitable envirOlilllent capable of producing about 106 mature blood cells for stem cell survival, growth and development. It is after 20 cell divisions (Fig. 1.3). The precursor cells composed of stromal cells and a microvascular net- are, however, capable of responding to haemopoietic work (Fig. 1.4). The stromal cells include adipocytes, growth factors with increased production of one or fibroblasts, endothelial cells and macrophages and Fig. 1.4 Haemopoiesis occurs in a suitable microenvironment provided by a stromal matrix on which stem cells grow and divide. There are Endothelial cell Fibroblast probably specific recognition and adhesion sites (p. 11); extracellular - 0 Adhesion molecule ) - - - Ligand glycoproteins and other compotmds are involved in the binding. ----0 Growth factor >---- Growth factor receptor they secrete eXh'aceliular molecules such as collagen, interactions maintain stem cell viability and pro- glycoproteins (fibronectin and thrombospondin) duction in the stroma including stem cell factor and glycosaminoglycans (hyaluronic acid and (SCF) and Jagged proteins expressed on stroma and chondroitin derivatives) to form an extracellular their respective receptors c-Kit and Notch expressed matrix. In addition, stromal cells secrete several on stem cell. growth factors necessary for stem cell survival. Mesenchymal stem ceUs are thought to be critical Stem cell plasticity in stromal cell formation. Stem cells are able to traffic around the body and There is some evidence that adult stem cells in are found in peripheral blood in low numbers. different organs are pluripotent and can generate In order to exit the bone marrow, cells must cross various types of tissue (Fig. 1.5). Studies in patients the blood vessel endothelium and this process of and animals who have received haemopoietic stem mobilization is enhanced by administration of cell transplants (Chapter 21) have suggested that cytokines such as granulocyte colony-stimulatiTtg donor cells may contribute to tissues such as neu- factor (G-CSF) or granulocyte-macrophage colony- rons, liver and muscle. The contribution of adult stimulating factor (GM-CSF) (p. 97). The reverse donor bone marrow cells to non-haemopoietic tis- process of stem cell homing appears to depend on sues is at most small. The persistence of pluripoten- a chemokine gradient in which the stromal- tial stem cells in postnatal life, organ-specific stem derived factor (SDF-l) is critical. Several critical cells and fusion of transplanted cells with host cells Totipotent cell (a) Embryonic stem cells Myeloid and lymphoid cells _ Liver, etc. " Epithelial stem cell Haemopoietic stem cell Fig. 1.5 (a) Cells in the early embryo are able to generate all the _ Neural ~ tissues of the body and are known tissues Muscle, _ _ tendon, cartilage, Z-o/ Neural as totipotent. (b) Specialized adult stem cells of the bone marrow, etc. Mesenchymal nervous tissue, epithelial and stem cell stem cell other tissues give rise to differentiated cells of the same (b) Adult stem cells tissue and possibly to other tissues (see text).  · ;-·"~;'~c HAEMOPOIESIS 5 have all been proposed, however, to explain many of lineage whereas GATA-l has an essential role in the findings suggesting stem cell plasticity. erytlu·opoietic and megakaryocytic differentiation. The regulation of haemopoiesis Haemopoietic growth factors Haemopoiesis starts with stem cell division in The haemopoietic growth factors are glycoprotein which one cell replaces the stem cell (self-renewal) hormones that. regulate the proliferation and differ- and the other is committed to differentiation. These entiation of haemopoietic progenitor cells and the early committed progenitors express low levels of ftU1ction of mature blood cells. They may act locally transcription factors that may commit them to dis- at the site where they are produced by cell-cell con- crete cell lineages. Which cell lineage is selected for tact or circulate in plasma. They also bind to the differentiation may depend both on chance and on eXh"acellular matrix to form niches to which stem the external signals received by progenitor cells. and progenitor cells adhere. The growth factors Several transcription factors have beeri isolated that may cause cell proliferation but can also stimulate regulate differentiation along the major cell lineages. differentiation, maturation, prevent apoptosis and For instance, PD.l commits cells to the myeloid affect the ftU1ction of mature cells (Fig. 1.6).. Proliferation €J) Early cell G-CSF < e @ Mooo,>,,' ~ Differentiation €J)