Date of Award

5-1-2001

Degree Type

Restricted Access Dissertation

Degree Name

Doctor of Philosophy

Field of Study

Microbiology and Immunology

Department

Graduate School of Biomedical Sciences

First Advisor

Lad Dory

Second Advisor

Richard Easom

Third Advisor

Stephen R. Grant

Abstract

The role of macrophage colony-stimulating factor (M-CSF) in hematopoiesis has been firmly established mainly by using bone marrow cell cultures. Semi-solid culture of bone marrow cells that were independently developed by Bradley and Metcalf in 1966 and Pluznik and Sachs in 1965, has been the standard method to study proliferation and differentiation of hematopoietic cells since the mid-1960s. It supports the clonal expansion of the hematopoietic colonies in vitro. Thus provides the means to functionally assay the hematopoietic colonies in vitro. Thus provides the means to functionally assay the hematopoietic progenitor cells and aides the discovery of growth factors regulating the progenitor cell differentiation. Macrophage colony-stimulating factor (M-CSF) was initially identified as a hematopoietic growth factor that stimulates the proliferation, differentiation and survival of monocytes, macrophages, and their progenitors (Robinson et al. 1969; Stanly et al. 1971). M-CSF is produced by a large variety of cells throughout the body. It can be purified from various body fluids as well as the conditioned media of several cell lines and tissues, such as leukocytes, placenta, lung, pancreatic cancer cells and spleen (Metcalf 1984; Stanley and Guilbert 1981; Yunis 1983). The sources of M-CSF recently have been extended to include liver parenchymal cells (Ezure et al. 1997) and thyrocytes (Kasai et al. 1997). It was also previously called colony-stimulating factor from human urine (CSF-HU) attributing the source of human urine growth factor that stimulated the formation of small aggregates consisting of granulocyte clusters in a soft agar culture system of human bone marrow cells (Metcalf 1974). At first without the knowledge about biochemical structures of CSFs, several colony-stimulating factors, later proven to be M-CSF, were recognized by their sources, i.e. mouse L-cell CSF, mouse uterus CSF, human lung-conditioned-medium CSF. Later, researchers in the field adopted the reclassification of CSF subtypes using the predominant colony types stimulated by the factor in semi-solid bone marrow cell cultures. M-CSF is for CSF that predominantly stimulates macrophage colony formation. Granulocyte colony-stimulating factor (G-CSF) refers to a granulocyte-active material, such as peritoneal cell-conditioned medium CSF (Horiuchi and Ichikawa 1977). CSF stimulating both types of colonies is called granulocyte-macrophage colony-stimulating factor, GM-CSF. M-CSF was also termed colony stimulating factor 1 (CSF-1), described as the first CSF to be purified (Stanley 1977). G-CSF was later called CSF-2. The existence of these two biochemically distinct CSFs was first identified in this lab (Wu et al. 1981). By the same virtue, GM-CSF sometimes was referred to as CSF-3. All of the three CSFs were later identified as distinct peptides encoded by different genes. Sachs and Pluznick group at Rehovot introduced alternative nomenclature for CSFs. The term macrophage granulocyte inducer-1M, MGI-1M, refers to M-CSF, MGI-1G is equivalent to G-CSF, and MGI-GM is used for GM-CSF. M-CSF stimulates differentiation of progenitor cells (colony-forming unit macrophage, CFU-M) to mature monocytes, and prolongs the survival of monocytes (Motoyoshi et al. 1997). It enhances expression of differentiation antigens (Hashimoto et al. 1997) and stimulates chemotactic, phagocytic and the killing activities of monocytes (Wang et al. 1988.) It also stimulates production of several cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF) and interleukin (IL)-6 by priming monocytes, and directly stimulates production and secretion of IL-8 and reactive nitrogen intermediates (Motoyoshi and Takaku 1991).

Comments

W 4 K15R 2001

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