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T M Dexter

Publications and source records attributed to T M Dexter.

At least 145 records · Page 8Linked to original sources
PubMed1990

The biochemistry and biology of the myeloid haemopoietic cell growth factors.

In the adult, blood cell production or haemopoiesis takes place mainly in the bone marrow. The blood cell types produced are a reflection of the needs of the organism at any moment, for example bacterial infection leads to a large increase in neutrophil production. The rate and scale of blood cell production in vivo are regulated, at least in part, by the synthesis and release of specific cytokines both within the bone marrow and also from other tissues. Here we detail the range of cytokines which act directly on haemopoietic stem cells and myeloid progenitor cells. Also cellular systems which will permit the elucidation of the specific interactions between these various cytokines which regulate stem cell self-renewal, differentiation and proliferation are described.

Animals↗
PubMed1990

The role of hemopoietic growth factors in self-renewal and differentiation of IL-3-dependent multipotential stem cells.

A multipotent hemopoietic cell line has been employed to assess the influence of the hemopoietic growth factors, IL-3, GM-CSF, G-CSF, and CSF-1 on the processes of self-renewal, the generation of lineage restricted progenitor cells and the production of mature neutrophils and macrophages. At a high concentration of IL-3, the cells undergo self-renewal and demonstrate little or no ability to undergo differentiation in the presence of the other growth factors. In the absence of IL-3, the cells show minimal (GM-CSF) or no (G-CSF or CSF-1) ability to respond to these other growth factors. When combined with a low concentration of IL-3, the ability of the cells to respond to GM-CSF, G-CSF, and CSF-1 is enhanced and a selective preference for the neutrophil or macrophage lineage is seen depending on the combination used, i.e., the presence of CSF-1 preferentially promotes macrophage development and G-CSF preferentially promotes neutrophil development. Conditions optimal for neutrophil development were seen using a combination of low IL-3 concentrations plus GM-CSF plus G-CSF. In such conditions, the cells undergo extensive proliferation and progressively lose their clonogenic potential (i.e., differentiation much greater than self-renewal) and acquire the biochemical markers characteristic of fully mature phagocytes.

Animals↗
PubMed1990

Hemopoietic effects of short-term in vivo treatment of mice with various doses of rhG-CSF.

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) was injected s.c., twice daily, into normal adult male BDF1 mice for a period of 4-5 days in doses ranging from 10 to 2500 micrograms/kg/day. The number of peripheral blood cells and their morphology was examined daily from the beginning of the experiment for 6 days. On the 5th day of treatment parameters such as spleen weight and cellularity, bone marrow morphology and cellularity, content of granulocyte-macrophage colony-forming cells (GM-CFC) or multipotential stem cells (CFU-S) in spleen and marrow, and also histology of lung and liver were examined. We observed a dose-dependent increase in the number of blood neutrophils, and an increase in weight, cellularity, and numbers of GM-CFC and CFU-S in the spleen. In the bone marrow, cellularity decreased to 40% of normal. Numbers of GM-CFC and CFU-S in marrow were also decreased, and examination of marrow morphology revealed an inhibition of erythropoiesis.

Animals↗
PubMed1990

Cell lineages in haemopoiesis: comments on their regulation.

The regulation of cell production and the determination of cell lineage in haemopoiesis are the result of multiple processes involving cell-cell interactions and the action of specific haemopoietic growth factors as well as other cytokines. Additive and synergistic interactions between these factors, and also with those involved in the regulation of lymphopoiesis have been described, which involve modulation of the growth and differentiation of haematopoietic precursors. However, the mechanisms which determine the self-renewal and the differentiation of the pluripotent lymphohaemopoietic stem cell remain largely undefined.

Animals↗
PubMed1990

Clinical application of hematopoietic growth factors.

Although many questions remain about the clinical use of hemopoietic growth factors, it is remarkable how much information has been gained in such a short time. There is enormous interest in these agents among physicians from a variety of specialties--all providing new ideas for potential studies. As the supplies increase, many new trials can be opened. It is important to design these studies with due regard to the results of in vitro and in vivo preclinical experiments--preferably after discussion with experimental hematologists--or vital information will be missed. There can have been few more exciting developments in clinical medicine in the recent past than the availability of the hemopoietic growth factors and, hopefully, it will not be long before the preliminary trials are completed and these agents are accepted for routine use to the benefit of a large number of patients.

Animals↗
PubMed1990

The use of cultured bone marrow cells in autologous transplantation.

The feasibility of ex vivo purging with long-term bone marrow cultures (LTBMC) for autologous transplantation in leukemia has been established. The procedure has been applied to patients with acute myeloid leukemia (in relapse or remission) and recently in one patient with chronic myeloid leukemia. The results in first remission AML are very encouraging with 4 out of 6 patients well and apparently disease free greater than 1 to 4 years post autograft. In patients transplanted with active disease, remissions of 6 to 8 months duration were seen in two patients transplanted in florid relapse. In a CML patient with 87% of his bone marrow cells Ph1 positive, there was a marked decline of karyotypically abnormal cells in culture. Reinfusion of the cultured cells into the patient resulted in engraftment with exclusively Ph1 negative cells. The therapeutic implications of LTBMC purging require further evaluation.

Bone Marrow Cells↗
PubMed1989

Metabolic properties of a homogeneous proteoglycan of a haemopoietic stem cell line, FDCP-mix.

A biochemical analysis has been carried out of metabolically labelled proteoglycans and glycosaminoglycans synthesized by a haemopoietic multipotential stem cell line, FDCP-mix. The only proteoglycan identified in these multipotential cells was a homogeneous component that contained chondroitin 4-sulphate chains (Mr approximately 10,000) arranged in close proximity in a proteinase-resistant domain of the protein core. Small quantities of free chondroitin 4-sulphate were also detected. Following a 48 h incubation with Na2 35SO4 the majority of the 35S-radiolabelled proteoglycans (approximately 80%) were associated with the cells, mainly in an intracellular compartment, and the remaining 20% were in the culture medium. Pulse-chase studies demonstrated two turnover pathways for the newly synthesized cellular proteoglycans. In the minor pathway, the proteoglycans were secreted rapidly into the medium without any discernable structural modification. In the major pathway the proteoglycans seemed to be transferred into a storage compartment from which the intact macromolecules were not secreted. Eventually, these proteoglycans were degraded to yield free polysaccharide chains and these chains were then released into the medium, but only at a relatively slow rate. There was very little intracellular degradation of chondroitin sulphate chains. The pathway to polysaccharide secretion was a slow stepwise process with a time-lag of about 5 h between proteoglycan synthesis and the appearance of free chondroitin sulphate and a second time-lag, also of about 5 h, before these chains began to be secreted. The existence of separate secretory pathways for proteoglycans and chondroitin sulphate chains is an interesting characteristic that seems to distinguish proteoglycan metabolism in primitive multipotent stem cells from related metabolic processes in mature haemopoietic cells.

Animals↗
PubMed1989

Identification of a common signal associated with cellular proliferation stimulated by four haemopoietic growth factors in a highly enriched population of granulocyte/macrophage colony-forming cells.

We have prepared a population of bone marrow cells that is highly enriched in neutrophil/macrophage progenitor cells (GM-CFC). Four distinct haemopoietic growth factors can stimulate the formation of mature cells from this population, although the proportions of neutrophils and/or macrophages produced varied depending on the growth factor employed: interleukin 3 (IL-3) and granulocyte/macrophage colony-stimulating factor (GM-CSF) stimulated the formation of colonies containing both neutrophils and macrophages; macrophage colony-stimulating factor (M-CSF) produced predominantly macrophage colonies; and granulocyte colony-stimulating factor (G-CSF) promoted neutrophil colony formation. Combinations of these four growth factors did not lead to any additive or synergistic effect on the number of colonies produced in clonal soft agar assays, indicating the presence of a common set of cells responsive to all four haemopoietic growth factors. These enriched progenitor cells therefore represent an ideal population to study myeloid growth-factor-stimulated survival, proliferation and development. Using this population we have examined the molecular signalling mechanisms associated with progenitor cell proliferation. We have shown that modulation of cyclic AMP levels has no apparent role in GM-CFC proliferation, whereas phorbol esters and/or Ca2+ ionophore can stimulate DNA synthesis, indicating a possible role for protein kinase C activation and increased cytosolic Ca2+ levels in the proliferation of these cells. The lack of ability of all four myeloid growth factors to mobilize intracellular Ca2+ infers that these effects are not achieved via inositol lipid hydrolysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiloride↗
PubMed1989

Cellular interactions between 3T3 cells and interleukin-3-dependent multipotent haemopoietic cells: a model system for stromal-cell-mediated haemopoiesis.

With the aid of a multipotent stem cell line (FDCP-mix cells) co-cultured with either normal or irradiated Swiss 3T3, cellular interactions between stromal cells and haemopoietic stem cells were studied by electron microscopy and time-lapse video microscopy. When cultured in the presence of interleukin 3 (IL-3) but in the absence of stromal cells, the FDCP-mix cells have a characteristic blast morphology. In the absence of IL-3, the cells die unless they are co-cultured with marrow stromal cells or 3T3 cells. In the latter case, they attach, proliferate, and differentiate on both normal and irradiated Swiss 3T3 cell layers without the addition of extrinsic growth factor (IL-3). At the initial attachment sites of these two cell lines, cellular recognition seemed to be mediated by the formation of microvillus cytoplasmic projections and extracellular matrix. These areas may well be the sites of plasma-membrane-bound signalling/adhesional molecules between the interacting cells.

Animals↗
PubMed1989

Growth and development of haemopoietic cells: a deterministic process?

The in vitro methods used to study haemopoiesis fall into two distinct categories. Short-term colony forming assays have identified a number of potent soluble factors capable of maintaining survival, proliferation and differentiation of haemopoietic cells but not their self-renewal. In contrast, in long-term bone marrow culture, extensive self-renewal occurs in the absence of exogenous factors and direct physical contact between haemopoietic cells and cells of the adherent stromal layer seems to be important. Obviously, LTBMC more closely resembles the situation in haemopoietic tissues but the potency of growth factors imply that they too play a role. Our data suggest that this may be at an earlier stage of haemopoietic development than previously appreciated. Primitive multipotent cells have the potential to respond to CSFs which were previously thought to stimulate only committed progenitor cells. This response is only seen, however, when the cells are exposed to a combination of factors which include either IL-1 or G-CSF. Thus, a combination of factors is able to recruit cells which are not already committed and determine the lineage along which they will differentiate. While it remains to be conclusively demonstrated that growth factors regulate normal "steady state" haemopoiesis in vivo it is clear that contact with stromal cells is important. The mechanisms by which the adherent layer influences haemopoietic development, however, are less obvious. We have shown that a component of stroma, heparan sulphate, is able to bind growth factors and present them to haemopoietic cells in a way that stimulates haemopoiesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗