Effect of Erythropoietin on Proliferation of Erythroid Stem Cells in the Absence of Transplantable Colony-forming Units

Reißmann, Kurt R.; Samorapoompichit, Sommart

doi:10.1182/blood.v36.3.287.287

Cited by 61 publications

(13 citation statements)

References 15 publications

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“…Although BFU-e can form erythroid colonies in the absence of erythropoietin, both in vivo and in vitro studies indicate that they are responsive to it even at an early stage in their development. Thus, in mice treated with cytotoxic drugs which suppress both blood production and the self-renewal and differentiation of CFU-s, multiple in vivo injections of erythropoietin accelerated the recovery of erythropoiesis [22,49], suggesting that the hormone can recruit cells capable of differentiating in response to it [66]. In vitro studies by Dessypris and Krantz also demonstrated that erythropoietin is a mitogen for early marrow BFU-e, albeit in the presence of serum .…”

Section: Erythropoietin-responsive Cellsmentioning

confidence: 95%

“…This was not true for CFU-s and colony-forming units granulocytelmacrophage spivak 144 (CFU-gm), suggesting that CFU-s and CFU-e are separated by a number of cell divisions and do not share a direct precursor-progeny relationship [47]. CFU-s and CFUe also have different physical characteristics as demonstrated by sedimentation at unit gravity [48], and agents which suppress the proliferation of CFU-s do not prevent expansion of the erythroid progenitor cell pool by erythropoietin [49]. Taken together with the substantial evidence provided by Oguwu and colleagues for the stochastic behavior of pluripotent and multipotent stem cells [50], it is likely that the effects of erythropoietin are limited to specific types of committed progenitor cells not involved in self-renewal.…”

Section: Il3mentioning

confidence: 99%

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The mechanism of action of erythropoietin

Spivak

1986

The International Journal of Cell Cloning

171

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The proliferation and differentiation of committed erythroid progenitor cells is regulated by the glycoprotein hormone erythropoietin. Erythropoietin increases the number of developing erythroid precursors and accelerates the release of reticulocytes from the marrow without markedly altering the cell cycle length or number of mitotic divisions involved in the differentiation process. Although the hormone has been purified, molecularly cloned and sequenced, its secondary and tertiary structure and active site have not been defined. Erythropoietin has both mitogenic and differentiation functions, and whether an erythroid progenitor cell responds to the hormone by proliferating or differentiating appears to depend on its level of maturation. Erythroid progenitor cells are responsive to a variety of growth and developmental agents but only erythropoietin appears obligatory in vivo for terminal differentiation. Erythropoietin interacts with its target cells through specific high-affinity receptors and Ca*+ may be involved in the receptor-ligand interaction. Caz+ may also be involved in the induction of differentiation by erythropoietin. An increase in RNA synthesis due to activation of transcription is one of the earliest recognized effects of the hormone and appears not to require protein or DNA synthesis but the initial sequence of biochemical events triggered by erythropoietin is still undefined.are not freely accessible in the native state. Given the limited studies to date on the hormone's physical and chemical properties, it is clear that much remains to be learned about the erythropoietin molecule, particularly with respect to its structure and active site. With the availability of abundant quantities of hormone, substantial progress in this area can now be expected. m e Physiology of ErythropoiesisThe principal function of the red cell is to transport oxygen from the lungs to the tissues, and tissue oxygen demands are linked to red cell production through the action of erythropoietin. By unknown mechanisms, hypoxia stimulates erythropoietin production while a surfeit of oxygen suppresses it. Although fluctuations thus occur in the plasma erythropoietin concentration, it is worth emphasizing that such fluctuations are usually temporary and that production of the hormone is not an intermittent process. For example, while hypoxia evokes an increase in the plasma erythropoietin concentration, this soon subsides to normal even if the hypoxia persists [18, 191. Furthermore, erythrocytosis, either endogenous as in polycythemia Vera or induced by hypertransfusion, does not entirely suppress erythropoietin production [20], a phenomenon not recognized before the development of a sensitive radioimmunoassay for the hormone.Whole animal studies indicate that erythropoietin increases the number of developing erythroid precursors and accelerates the release of reticulocytes from the marrow without markedly altering the cell-cycle length or the number of mitotic divisions involved in the differentiation process [21]. In addit...

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Section: Erythropoietin-responsive Cellsmentioning

confidence: 95%

Section: Il3mentioning

confidence: 99%

The mechanism of action of erythropoietin

Spivak

1986

The International Journal of Cell Cloning

171

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“…In the present study, further information is presented on this regulation, and the question is examined whether a cytokinetic balance exists between the two processes stimulated by erythropoietin. As in our previous study (Reissmann & Samorapoompichit, 1970) Myleran was used to suppress in mice their CFU to such low levels that no significant inflow of CFU into the ERC compartment could take place. Polycythemic mice were employed and the erythropoietin test (Gurney, Lajtha & Oliver, 1962) was used to assess the ERC population present at various days after Myleran administration.…”

Section: Introductionmentioning

confidence: 93%

Effect of Erythropoietin on Proliferation of Erythropoietin‐responsive Cells

Reißmann

Udupa

1972

Cell Proliferation

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A B S T R A C TA single dose of Myleran suppressed CFU in polycythemic mice to around 1 % of normal for a period of 2 weeks and permitted the study of effects of erythropoietin on unipotential, erythroid stem cells (erythropoietin-responsive cells, ERC) in the absence of cell inflow from the CFU compartment. Without erythropoietin no ERC were detectable for 12 days after Myleran. Injections of erythropoietin had no effect on CFU but restored ERC populations in proportion to the dose of erythropoietin. Hydroxyurea given after erythropoietin markedly inhibited ERC repopulation and the latter is attributed to a stimulation of ERC proliferation by erythropoietin. Evidence in support of an age structure in the ERC population is presented. Daily erythropoietin injection resulted in stable ERC populations, indicating that ERC loss through differentiation and ERC self-replication were in balance. I N T R O D U C T I O NErythropoietin (Ep) regulates erythropoiesis by governing the rate of differentiation of erythropoietin-responsive cells (ERC) into proerythroblasts (PE), the earliest erythroblasts that can be recognized morphologically. Evidence is mounting to indicate that ERC are not identical with the pluripotential transplantable stem cells (CFU). It now appears likely that the CFU first undergo a partial differentiation into unipotential erythroid stem cells or ERC and these are then induced by erythropoietin to differentiate into PE (Lajtha et al., 1969). During accelerated erythropoiesis, a greater number of ERC is forced into differentiation, and if the ERC population is to be sustained, the greater cell outflow must be balanced either by an increased inflow from the CFU compartment or by increased self-replication of ERC. The exact mechanism and the regulation of this important step in erythropoiesis remain to be elucidated. We have presented evidence of a marked proliferative capability of ERC and have shown that erythropoietin stimulates this process (Reissmann & Samorapoompichit,

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“…Emphasis has been placed on erythropoietin which promotes the differentiation of the erythropoietic stem cells to normoblasts [23] . Erythropoietin has been reported to stimulate vasoproliferation [24] and the production of stem cells [24,25] . Whether erythropoietin is the sole humoral factor or whether other humoral or local marrow factors are necessary for the marrow erythroid hyperplasia is unknown.…”

Section: At the Marrow Level Major Attention Has Been Paid To The Dismentioning

confidence: 99%

Marrow adipose tissue: Response to erythropoiesis

1978

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A group of rabbits was treated chronically with phenylhydrazine t o induce hemolysis and stimulate erythropoiesis. The mean volume of the marrow fat cell of a control group of hematologically normal rabbits was 54.8 pl; the mean volume of the perinephric fat cell was 549.5 pl, a volume ratio, perinephric/marrow of 10: 1. In the experimental animals the mean volume of the marrow fat cell fell t o 25.9 pl; the volume of the perinephric fat cell was unchanged and the volume ratio, perinephric/marrow was 18: l . Fat cell volume studies performed on rabbits subjected t o chronic bleeding yielded comparable data. The l-C14 palmitate uptake (esterification capacity) calculated on a cell basis was the same for both marrow and perinephric fat cells and was unaffected by phenylhydrazine treatment. The fatty acid composition shows higher content of unsaturated fatty acids in the marrow fat than in the perinephric fat of the control animal. In the experimental animal there appears t o be a preferential release of the unsaturated fatty acid. The findings of the study suggest that increased hematopoiesis stimulates lipolysis of marrow fat cells, probably through the local release of a chemical substance. Marrow fat appears to be functionally related t o hematopoiesis rather than t o systemic fat storage. Marrow fat may be involved in the metabolic support of hematopoiesis.

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Effect of Erythropoietin on Proliferation of Erythroid Stem Cells in the Absence of Transplantable Colony-forming Units

Cited by 61 publications

References 15 publications

The mechanism of action of erythropoietin

The mechanism of action of erythropoietin

Effect of Erythropoietin on Proliferation of Erythropoietin‐responsive Cells

Marrow adipose tissue: Response to erythropoiesis

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