HEMOPOIETIC STEM CELL DIFFERENTIATION TO MACROPHAGES

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The overall aim of this project is to investigate the mechanisms by which pluripotent hemopoietic stem cells give rise to macrophages to characterize the growth factors involved in this process. Three factors implicated in this pathway have been studied. They are the colony stimulating factor-1 (CSF-1), hemopoietin-1, and hemopoietin-2. The mononuclear phagocyte lineage specific growth factor, CSF-1, has been shown to consist of two disulfide-bonded, 14,000 Mr polypeptide chains that are possibly identical. The dimeric protein core is heavily glycosylated with N-linked oligosaccharides of the acidic "complex" type. More than 85% of the carbohydrate can be removed without loss of biological, receptor-binding, or antibody-binding activities. However, mild reduction in the absence of dissociating agents results in loss of these activities. These properties of CSF-1 are shared by both murine and human forms of the molecule. In collaboration with others, the sequence of the first 39 amino acids at the N-terminal end of murine CSF-1 has been determined, together with an internal sequence of 23 additional residues. There is a high degree of homology between the human and murine CSF-1 sequences. The hemopoietins have been identified as growth factors that regulate the production of macrophage progenitor cells from developmentally earlier cells. Hemopoietin-2 is active, by itself, on developmentally later cells than those responsive to hemopoietin-1. It has been highly purified from the serum-free medium conditioned by a murine cell line and is similar in properties to the factor posseasing erythroid burst promoting activity and to interleukin 3. Hemopoietin-1 requires CSF-1 in order to generate macrophage progenitor cells. It has been purified from the serum-free medium conditioned by a human cell line. Both hemopoietins appear to be multilineage, rather than lineage specific, hemopoietic growth factors. (MB)