Blood consists of red and white cells which, along with platelets, are all suspended in plasma. All peripheral blood cells are derived from a single cell type, i.e. the stem cell (also known as a pluripotential, pluripotent or haemopoietic stem cell; see also Chapter 14). These stem cells reside in the bone marrow, alongside additional cell types, including (marrow) stromal cells. Pluripotential stem cells have the capacity to undergo prolonged or indefinite self-renewal. They also have the potential to differentiate, thereby yielding the range of cells normally found in blood (Table 10.4). This process, by which a fraction of stem cells is continually 'deciding' to differentiate (thus continually producing new blood cells and platelets to replace aged cells), is known as haemopoiesis.
Pharmaceutical biotechnology: concepts and applications Gary Walsh © 2007 John Wiley & Sons, Ltd ISBN 978 0 470 01244 4 (HB) 978 0 470 01245 1 (PB)
Table 10.1 Overview of some polypeptide growth factors. Many can be grouped into families on the basis of amino acid sequence homology, or the cell types affected. Most growth factors are produced by more than one cell type and display endocrine, paracrine or autocrine effects on target cells by interacting with specific cell surface receptors
Growth factor Major target cells
Interleukins Various, mainly cells mediating immunity and inflammation ifn-y Mainly lymphocytes and additional cells mediating immunity
CSFs Mainly haemopoietic cells
EPO Erythroid precursor cells
TPO Mainly megakaryocytes
Neurotrophic factors Several, but mainly neuronal cell populations
IGFs A very wide range of cells found in various tissue types
EGF Various, including epithelial and endothelial cells and fibroblasts
PDGF Various, including fibroblasts, glial cells and smooth muscle cells
FGFs Various, including fibroblasts, osteoblasts and vascular endothelial cells
LIF Mainly various haemopoietic cells
Table 10.2 Growth factors approved for general medical use
Neupogen (filgrastim; G-CSF) Leukine (sargramostim, GM-CSF)
Neulasta (PEGylated filgrastim, see above)
Epogen (epoetin alfa, rEPO)
Procrit (epoetin alfa, rEPO)
Neorecormon (epoetin beta, rEPO)
Aranesp (darbepoetin alfa, a rEPO
analogue) Nespo (darbepoetin alfa, a rEPO
analogue Regranex (becaplermin, rPDGF) Kepivance (palifermin, rKGF) Increlex (mecasermin, rh IGF-1) Iplex (mecasermin rinfabate, complex of rhIGF-1 and IGFBP-3) GEM 21S (implantable product containing rhPDGF-BB)
Neutropenia caused by chemotherapy
Bone marrow transplants Autologous bone marrow transplantation Neutrophil recovery after bone marrow transplantation Neutropenia
Anaemia associated with various medical conditions Anaemia associated with various medical conditions Anaemia associated with various medical conditions Anaemia associated with various medical conditions Anaemia associated with various medical conditions Neuropathic diabetic ulcers Severe oral mucositis Growth failure in children Growth failure in children
Periodontally related defects
Company Amgen Inc.
Janssen & Ortho-McNeil Amgen
Luitpold Pharmaceuticals and Biomimetic Pharmaceuticals aIGFBP: insulin like growth factor binding protein.
Table 10.3 Some growth factors that may have significant future therapeutic application, and the conditions they aim to treat
Growth factor Possible medical indication
EGF Wound healing, skin ulcers
TGF-P Bone healing, skin ulcers, detached retinas
FGFs Soft tissue ulcers, wound healing
Neurotrophic factors Mainly conditions caused by/associated with neurodegeneration, including peripheral neuropathies, amyotrophic lateral sclerosis and neurodegenerative diseases of the brain
The study of the process of haemopoiesis is rendered difficult by the fact that it is extremely difficult to distinguish or separate individual stem cells from their products during the earlier stages of differentiation. However, a picture of the process of differentiation is now beginning to emerge (Figure 10.1). During the haemopoietic process, the stem cells differentiate, producing cells that become progressively more restricted in their choice of developmental options.
The production of many mature blood cells begins when a fraction of the stem cells differentiates, forming a specific cell type termed CFU-S (where CFU refers to colony-forming unit). These cells, in turn, differentiate to yield CFU-GEMM cells, a mixed CFU that has the potential to differentiate into a range of mature blood cell types, including granulocytes, monocytes, erythrocytes, platelets, eosinophils and basophils. Note that lymphocytes are not derived from the CFU-GEMM pathway, but differentiate via an alternative pathway from stem cells (Figure 10.1).
The details of haemopoiesis presented thus far prompt two very important questions: (1) How is the correct balance between stem cell self-renewal and differentiation maintained? (2) What forces exist that regulate the process of differentiation? The answer to both questions, in particular the latter, is beginning to emerge in the form of a group of cytokines termed 'haemopoietic growth factors'. This group includes:
• several interleukins, which primarily affect production and differentiation of lymphocytes;
• CSFs, which play a major role in the differentiation of stem-derived cells into neutrophils, macrophages, megakaryocytes (from which platelets are derived), eosinophils and basophils;
• EPO, which is essential in the production of red blood cells;
• TPO, which is essential in the production of platelets.
Table 10.4 The range of blood cells that are ultimately produced upon the differentiation of pluripotential stem cells (see text for details). (Note that osteoclasts are multinucleated cells often associated with small depressions on the surface of bone. They function to reabsorb calcified bone)
Neutrophils T- and B-lymphocytes
Most of these haemopoietic growth factors are glycoproteins, displaying a molecular mass in the region of 14-24 kDa. Most are produced by more than one cell type, and several such regulators can stimulate proliferation of any one haemopoietic cell lineage. This is due to the presence of receptors for several such factors on their surface. Receptor numbers for any one growth factor are low (less than 500 per cell), and proliferation can be stimulated even when only a small proportion of these are occupied.
During normal haemopoiesis, only a small fraction of stem cells undergo differentiation at any given time. The remainder continue to self-renew. The molecular detail underpinning self-renewal is poorly understood. However, it has been shown that certain transformed stem cells can be induced to undergo continuous proliferation in vitro under the influence of IL-3. The concentration of IL-3 is critical, with differentiation occurring below certain threshold concentrations of this cytokine. The delicate balance between stem cell renewal and differentiation is likely affected not only by the range of growth factors experienced, but also by the concentration of each growth factor.
Was this article helpful?