Hematopoietic Growth Factors: Focus on Erythropoiesis-Stimulating Agents
Hematopoiesis is an intricate, well-regulated, and homeostatic multistep process that allows immature precursor cells in the bone marrow to proliferate, differentiate, mature, and become functional blood cells that transport oxygen and carbon dioxide; con
- PDF / 317,623 Bytes
- 14 Pages / 595.28 x 790.87 pts Page_size
- 85 Downloads / 185 Views
Hematopoietic Growth Factors: Focus on Erythropoiesis-Stimulating Agents Juan Jose Pérez-Ruixo and Andrew T. Chow
INTRODUCTION Hematopoiesis is an intricate, well-regulated, and homeostatic multistep process that allows immature precursor cells in the bone marrow to proliferate, differentiate, mature, and become functional blood cells that transport oxygen and carbon dioxide; contribute to host immunity; and facilitate blood clotting. In the early 1900s, scientists recognized the presence of circulating factors that regulate hematopoiesis. It took approximately 50 years to develop in vitro cell culture systems in order to definitively prove that the growth and survival of early blood cells require the presence of specific circulating factors, called hematopoietic growth factors (HGF). The presence of many HGF with different targets at extremely small amounts in blood, bone marrow, and urine confounded the search for a single HGF with a specific activity. Scientific progress was slow until it became possible to purify sufficient quantities to evaluate the characteristics and biologic potential of the isolated materials. The introduction of recombinant DNA technology triggered a flurry of studies and an information explosion, which confirmed hematopoiesis is mediated by a series of HGF that acts individually and in various combinations involving complex feedback mechanisms. Today, many HGF have been isolated; some have been studied extensively, and a few have been manufactured for clinical use. Different mature blood cells have been identified, each derived from primitive hematopoietic stem cells in the bone marrow. The most primitive pool of pluripotent stem cells comprises approximately 0.1 % of the nucleated cells of the bone marrow, and 5 % of these cells may be actively cycling at a given time. The stem cell pool maintains itself, seemingly without extensive depletion, by asymmetrical cell division. J.J. Pérez-Ruixo, Ph.D. (*) • A.T. Chow, Ph.D. Department of Quantitative Pharmacology, Pharmacokinetics and Drug Metabolism, Amgen Inc, Thousand Oaks, CA, USA e-mail: [email protected]
When a stem cell divides, one daughter cell remains in the stem cell pool and the other becomes a committed colony-forming unit (CFU). CFU proliferates at a greater rate than the other stem cells and are more limited in self-renewal than pluripotent hematopoietic stem cells. Proliferation and differentiation are regulated by different mechanisms that necessarily involve HGF, which eventually convert the dividing cells into a population of terminally differentiated functional cells committed to the myeloid or the lymphoid pathway. Functional hematopoietic-derived blood cells from the myeloid pathway are red blood cells (erythrocytes), granulocytes (neutrophils, eosinophils, and basophils), monocytes and macrophages, tissue mast cells, and platelets (thrombocytes). Cells committed to the lymphoid pathway give rise to B- or T-lymphocytes and plasma cells. Most HGF are glycosylated single-chain polypeptides encoded by a specific gene
Data Loading...
