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E G Wright

Publications and source records attributed to E G Wright.

At least 91 records · Page 5Linked to original sources
PubMed1984

Spatial organisation of CFU-S proliferation regulators in the mouse femur.

CFU-S proliferation can be regulated by an inhibitor and a stimulator which are produced locally in the bone marrow. The spatial distribution of cells elaborating these factors has been studied by separating marrow, zonally, into axial, marginal and bone-associated fractions and further separating the inhibitor and stimulator producing cells from these fractions by means of density cuts in bovine serum albumin. The inhibitor- and stimulator-producing cells are found respectively in bands of density less than 1.064 g/cm3 and 1.064-1.072 g/cm2. Factors synthesised by these individual fractions were assayed for their ability to inhibit or stimulate CFU-S proliferation by thymidine suicide measurements. Axial cells contain a high concentration of inhibitor-producing cells but the marginal and bone fractions contain relatively few. Stimulator-producing cells have a very sharp gradient in the opposite direction with an extremely high concentration in the vicinity of the bone surface. These distributions fit with those of CFU-S proliferation and of fibroblastoid-CFC suggesting that the inhibitor-producing cell is an integral part of the micro-environment which maintains the stem cell's capacities while the stimulator-producing cell may be more closely associated with the differentiation processes which take place closer to the bone surface.

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PubMed1982

Stimulation of haemopoietic stem cell proliferation: characteristics of the stimulator-producing cells.

Media conditioned by regenerating murine bone marrow cells contain a stimulator of haemopoietic stem cell proliferation. Fractionated cell populations have been examined for production of this stimulatory activity in order to characterize its cellular source. The stimulator is produced by adherent, phagocytic, radioresistant, Thy 1.2-, Fc+ cells in a population concentrated in a density range of 1.064-1.072 g/ml. The results indicate that the producer cells reside in the heterogenous mononuclear phagocytic population of the bone marrow.

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PubMed1982

Interaction of inhibitor and stimulator in the regulation of CFU-S proliferation.

An inhibitor and stimulator of CFU-S proliferation can be obtained from haemopoietic tissue containing, respectively, relatively quiescent CFU-S (e.g. normal bone marrow) and proliferating CFU-S (e.g. regenerating bone marrow). In this paper we explore the capacity for inhibitor and stimulator production in relation to changes in the proliferative status of the CFU-S and their mode of interaction. The increase in proliferative activity of CFU-S following a concentrated regime of phenylhydrazine injections is paralleled by an increase in the capacity for stimulator production and a decrease in the capacity for inhibitor production. These processes are reversed as the normal low proliferative activity returns. Using density fractionated marrow populations, dose-response measurements show that while inhibitor- and stimulator-producing cells persist throughout the changes in CFU-S proliferation, their magnitude of factor production moderates in relation to those changes. The inhibitor and stimulator are not mutually destructive: the two factors retain their activities after co-incubation and re-separation. On the other hand, the presence of either factor blocks the synthesis of the other by the appropriate producer cells. A model for the regulation of CFU-S proliferation by the inhibitor and stimulator is thus suggested in which the relative spatial distributions of CFU-S in a microenvironment containing inhibitor- and stimulator-producing cells are an important feature. It also implies the existence of a signal from the CFU-S compartment which determines the appropriate inhibitor or stimulator production.

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PubMed1982

Production of presumptive humoral haematopoietic regulators in canine cyclic haematopoiesis.

Conditioned media (CM) were prepared according to previously published techniques from the bone marrow of dogs with cyclic haematopoiesis (CH). CM prepared from day 9 marrows inhibited mouse bone marrow CFU-s proliferation rate while CM from day 10 marrows were stimulatory and also contained an erythroid stimulating factor which appeared to be erythropoietin. In addition a highly significant trend from CM containing CFU-s inhibitory materials to media with CFU-s stimulatory activity was observed through cycles day 1 to 8. These studies further support the concept that CH is due to a defect in factors controlling stem cell proliferation and suggest that a major event occurs in CH dog marrow on days 9 and/or 10 of the cycle.

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PubMed1980

Bone marrow lipids in normal and anemic mice.

The lipids in the bone marrow of six strains of normal mice, and mice with genetically determined anemias (W/Wv and S1/S1d) and experimentally induced anemia were analyzed. Cholesterol and phospholipid accounted for 60-75% of total lipid; the remainder was triglyceride and neutral glyceryl ether lipids. In mice with phenylhydrazine (PHZ)-induced hemolytic anemia there was a threefold increase in neutral glyceryl ether lipids immediately preceding a twofold increase in recognizable erythroid precursors. Comparisons were made between the femoral bone marrow and the cells maintained in the adherent populations of long-term bone marrow cultures. In cultures of B6D2F1 bone marrow (which support long-term proliferation and differentiation of hemopoietic stem cells) the adherent layers contained the same lipids as freshly aspirated bone marrow. In W/Wv and S1/S1d cultures (which duplicate, respectively, the stem cell and environmental defect found in vivo) the lipid content of the adherent layers differed from bone marrow, particularly in the absence of ether-containing lipids. The results are consistent with the hypothesis that marrow lipids have an active (as opposed to passive) role in murine hemopoiesis and indicate that long-term bone marrow culture may prove useful in further biochemical studies of the hemopoietic inductive microenvironment.

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PubMed1980

The regulation of hemopoiesis in long-term bone marrow cultures. II. Stimulation and inhibition of stem cell proliferation.

The isolation of a DNA synthesis inhibitor (NBME fraction IV) and stimulator (RBME fraction III) specific for the hemopoietic stem cell (CFU-s) from freshly isolated normal adult and regenerating murine bone marrow, respectively, has been well documented. We have utilized long-term liquid bone marrow cultures in a further analysis of the role of these factors in the regulation of CFU-s proliferation. Our results show that shortly after feeding, at a time when the cultured CFU-s are actively proliferating, high levels of the hemopoietic stem cell proliferation stimulator fraction III can be isolated from the culture medium. In contrast, the presence of essentially noncycling CFU-s found in cultures fed 8-10 days previously correlates with high levels of the hemopoietic stem cell inhibitor fraction IV. These results suggest that a certain balance between these factors determines CFU-s proliferation in the long-term cultures. In support of this, DNA synthesis in actively cycling CFU-s in the long-term cultures is inhibited for at least 3 days by the addition of excess NBME fraction IV (inhibitor). Furthermore, DNA synthesis in noncycling cultured CFU-s is stimulated for at least 5 days by the addition of RBME fraction III (stimulator).

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PubMed1980

Sources of haemopoietic stem cell proliferation: stimulators and inhibitors.

Based on earlier findings that haemopoietic tissue contains extractable factors which are capable of specifically inhibiting or stimulating the movement of CFU-S into DNA synthesis, a series of preliminary experiments has now been carried out to investigate their cellular source(s), their activity in vivo, and their applicability to human problems. In vivo treatment of mice, in which femoral CFU-S are proliferating rapidly, with the inhibitory factor reduces the proportion of CFU-S in DNA synthesis to non-significant proportions. In addition, the inhibitor is capable of reducing the number of CFU-S induced to enter S following treatment with hydroxyurea, thus protecting CFU-S from the lethal effects of S-phase cytotoxic agents. Removal of specific types of marrow cells shows that both inhibitor and stimulator are adherent, phagocytic and, in the case of inhibitor, Thy--1-. These results suggest that the producer cells probably reside somewhere in the heterogeneous macrophage complex though their different densities suggest they are probably different cell types. Fresh human bone marrow is found to contain a very similar inhibitor and long-term cultures are also found to produce it continuously. The isolation of the producer cells may thus contribute to the understanding of normal physiological stem cell regulation and, by in vivo application, its eventual manipulation and protection.

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PubMed1979

Mechanisms of haemopoietic stem cell proliferation control.

The control of stem cell (CFU-S) proliferation is mediated by short-range acting factors which can be detected by the proliferation modifying activities present in media conditioned by haemopoietic cells. A specific inhibitor of stem cell proliferation is obtained from haemopoietic tissue containing minimally proliferating CFU-S, whilst stimulatory material is obtained from cell suspensions containing rapidly proliferating CFU-S. Used competitively, these factors, which are detected in different molecular weight range fractions, manipulate the rate of CFU-S proliferation in a manner compatible with a physiological control mechanism. In addition, a long-term bone marrow culture system has been shown to provide an in vitro model of stem cell control. Fractionation of cell populations from haemopoietic tissues reveals marked concentration differences of the CFU-S proliferation modifying activities depending on the proliferative state of the CFU-S. However, irrespective of whether the tissue contains stem cells that are actively or minimally proliferating, both stimulatory and inhibitory activities are detected. From dose-response studies it is concluded that stem cell proliferation is controlled by an appropriate balance of stimulatory and inhibitory factors which, however, are not produced by the stem cells themselves.

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PubMed1977

Regulation of CFU-S proliferation by locally produced endogenous factors.

The presence of proliferating and non-proliferating CFU-S in, respectively, the bone marrow and spleens of phenylhydrazine (PHZ) treated mice has afforded the opportunity to investigate the presence and role of local factors responsible for the control of CFU-S proliferation. When bone marrow cells from PHZ treated mice are incubated with irradiated spleen cells taken from the same mice, there is a marked fall in the proportion of femoral CFU-S in DNA synthesis. In the converse experiments rapid triggering of splenic CFU-S is achieved. Changes in CFU-S proliferation have also been demonstrated in other situations where cell populations containing proliferating and minimally proliferating CFU-S are mixed.

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PubMed1977

A stimulator of stem cell proliferation in regenerating bone marrow.

A factor, capable of stimulating resting haemopoietic stem cells into DNA-synthesis has been extracted from regenerating bone marrow. It has a molecular weight in the range of 30.000-50.000 daltons and is not detectable in normal bone marrow. Used in combination with a stem cell proliferation inhibitor, previously described, it will restimulate proliferation in stem cells initially stopped by the inhibitor. Conversely, stimulation produced by this factor can be reversed by the addition of inhibitor. It is concluded that stem cell proliferation is controlled by an appropriate balance of endogenously produced stimulatory and inhibitory factors.

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PubMed1977

Regulation of haemopoietic stem cell proliferation in long term bone marrow cultures.

The development of a suitable bone marrow derived adherent cell population appears to be essential for the prolonged maintenance of haemopoietic stem cells in vitro. When established adherent layers are inoculated with freshly isolated bone marrow cells, proliferation of stem cells (CFU-S) regularly occurs both in the adherent layer and amongst the non-adherent cells. Furthermore, CFU-S present within the adherent layer are able to regenerate both themselves and the "non-adherent" CFU-S. One day after re-feeding the cultures (by removal of half the growth medium and addition of fresh medium) both the "non-adherent" and the "adherent" CFU-S are in a high cycling state (greater than 40% kill with 3HTdR). This proportion decreases with time of re-feeding and 5-7 days later the majority of "adherent" and "non-adherent" CFU-S are in a low cycling state ( less than 10% 3HTdR kill). Following a further re-feeding, CFU-S again enter a high cycling state.

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PubMed1977

Lack of effect of a granulocyte proliferation inhibitor or their committed precursor cells.

Using the agar culture technique, we have measured the effect of granulocyte extracts GCE (and of erythrocyte-RCE and lymph node extracts-LNE) on the growth and proliferation of the committed granulocytic precursor cells, CFU-C. In addition we have determined their effects on the proliferation of the developing colony cells and on the ultimate cell production in the colonies. The results show that GCE has no effect on the growth or proliferative activity on the CFU-C. It does, however, reduce both the autoradiographic labelling indices of the developing colony cells and the net colony cellularities, acting as a cell cycle modulator. These are effects specific to the GCE since at the dose levels used, neither RCE nor LNE affected these measurements.

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