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Results for “ERYTHROPOIESIS”

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PubMed1985

Immunohistochemical and ultrastructural study on erythropoiesis in hepatoblastoma.

Eighteen cases of hepatocellular carcinoma in children were examined, and it was found that erythropoiesis exclusively appeared in the well differentiated type of hepatoblastoma. In such foci large immature erythroblasts were found among the tumor cells, whereas mature forms tended to gather in the subendothelial spaces or within sinusoids. Desmosome-like attachments were frequently found between immature erythroblasts and tumor cells. The tumor cells were well differentiated and had a distinct polarity. The erythropoietic foci were never found in lymph nodes, spleens and in the non-neoplastic hepatic tissues obtained by surgery or autopsy. Erythroblastic cells did not show an increase in number in the bone marrows. These findings indicate that hepatoblastoma cells in certain stages of differentiation have the capacity to induce the differentiation of pluripotent hemopoietic stem cells into the cells of erythrocytic series, or that the microenvironment composed of one or more tumor cells offer good soil for the differentiation of erythroblastic cells. There seems to be no intimate relationship between the production of alpha-fetoprotein by tumor cells and the appearance of erythropoiesis.

Carcinoma, Hepatocellular↗

PubMed1982

Erythropoiesis in hairy cell leukaemia: a true erythroid failure.

A quantitative evaluation of erythropoiesis was carried out in 12 patients with hairy cell leukaemia (HCL). The results were compared with those obtained in eight patients with aplastic anaemia (AA) in order to define the characteristics of erythroid failure in HCL. Discriminant analysis was applied to both haematological and erythrokinetic parameters of the two disease groups. Plasma iron concentration and MCV were significantly higher in AA, and allowed a perfect separation of the patients. As regards erythrokinetics, values of ineffective erythropoiesis and peripheral haemolysis were able to separate completely the two disease groups, being significantly lower in HCL than in AA. A true erythroid failure was the peculiar erythrokinetic pattern of HCL. This conclusion allows one to speculate on the nature of the stem cell damage in this disease.

Adult↗

PubMed1997

Clinical results of recombinant erythropoietin in transfusion-dependent patients with refractory multiple myeloma: role of cytokines and monitoring of erythropoiesis.

Recombinant erythropoietin (r-EPO) was administered to 37 patients with advanced, transfusion-dependent and chemo-resistant multiple myeloma (MM), at the fixed dose of 10,000/U s.c., 3 times a week, for 2 months. Thirteen patients (35.1%) achieved a significant response in terms of complete abolition of red cell transfusions. Factors significantly predictive of response were: a) inappropriate production of endogenous EPO, as expressed by a reduced observed/predicted ratio; b) presence of a consistent number of circulating erythroid precursors BFU-E; c) low serum levels of tumor necrosis factor (TNF) and interleukin-1 (IL-1), cytokines with inhibitory activity on erythropoiesis; d) a single line of previously received chemotherapy. Renal failure, bone marrow plasma cell infiltration, serum levels of IL-6 and other main clinical and laboratory parameters did not affect significantly the response to r-EPO. High fluorescence reticulocytes (HFR) and soluble transferrin receptor (sTfR) values were useful to detect an early stimulation of erythropoiesis in responders, while a high percentage of circulating hypochromic erythrocytes (HE), as assessed by an automated counter, identified those patients developing functional iron deficiency during r-EPO treatment. We conclude that about one-third of severely anemic patients with advanced MM, unresponsive to chemotherapy, may benefit by r-EPO therapy. The clinical management of these patients can be accomplished using non-invasive parameters, such as sTfR, HFR and HE.

Adult↗

PubMed1982

Humoral regulation of erythropoiesis and thrombopoiesis in appropriate and small for gestational age infants.

Fourteen infants with birth weight appropriate for gestational age (AGA) and 16 small for gestational age (SGA) infants were investigated for haemoglobin concentration, haematocrit level and thrombocyte count on the first day of life. Cord serum was tested for erythropoietin (ESF) and thrombopoietin (TSF) activity. The same investigations were performed on venous blood and serum from 18 healthy adult individuals. SGA infants had higher haemoglobin concentration and haematocrit level (p less than 0.05), and lower platelet count (p less than 0.001) than AGA infants. Significant ESF activity was present in cord serum, but was not detectable in serum from adults. Significant TSF activity was present in cord serum as well as in serum from adults, with higher levels in the newborn infants (p less than 0.05). An inverse relationship was found between serum TSF activity and the number of platelets in adults, which was not demonstrable in newborn infants. Long-term intrauterine hypoxia because of placental dysfunction may be the reason for polycythemia and thrombocytopenia in SGA infants. Thrombocytopenia may be caused by competitive mechanisms on common stem cells for erythropoiesis and thrombopoiesis, shunting stem cells in direction of erythropoiesis during hypoxic exposure. Normal serum TSF activity in SGA infants indicates that lack of the humoral factor for platelet production is not the reason for the thrombocytopenia in these infants. A negative feed-back mechanism may exist between platelet number and TSF production.

Adult↗

PubMed1985

Hb F production in stressed erythropoiesis: observations and kinetic models.

The mechanism of stimulation of Hb F in stressed erythropoiesis is examined. Conditions known to produce a transient elevation of F-cells (acute anemia; acute expansion; treatment with cytotoxic compounds) have a common element, the acute kinetic perturbations of erythroid differentiation/maturation they trigger. Cell cycling must be shortened and the total time of differentiation (from BFUe to erythroblast) must be shortened. We propose that F-cells are formed either because of the shortening of erythroid differentiation time or because of shortening of cell cycle of erythroid cells. With the model of shortened differentiation time F-cell formation is attributed to "premature commitment" of progenitors. gamma-gene expression occurs either because chromatin changes that normally inactivate the gamma genes are not completed or because critical divisions in which the gamma genes are normally inactivated are skipped. The model of faster cycling explains F-cell formation by assuming that gamma-gene transcription is activated when the cycle (and especially the duration of G0/G1) of progenitors or erythroblasts falls below a critical time. The proposed models can readily explain the F-cells of the normal adult as the products of random deviation from normal erythroid kinetics. The two models can also explain F-cell formation in chronic erythropoietic stress (chronic hemolytic anemias, patients with hemoglobinopathies). Differences in the degree of F-cell elevation in such patients may reflect differences in the intensity of kinetic perturbation of their erythropoiesis.

Anemia↗

PubMed1994

Detection of functional and dimeric activin A in human marrow microenvironment. Implications for the modulation of erythropoiesis.

Activin A, which was initially recognized as a gonadal protein, was implicated in the modulation of erythropoiesis through a paracrine control in the bone marrow microenvironment. Present studies demonstrate that, in contrast to T lymphocytes and cultured skin fibroblasts, human marrow stromal cells produce a functional and dimeric beta A beta A molecule (i.e., activin A). RT-PCR further indicates that both alpha and beta A mRNAs of inhibin A/activin A are produced in human stromal cells. The level of beta A subunit mRNAs, however, is in large excess over that of alpha subunit mRNAs, suggesting the predominant production of beta A beta A dimers, as well as some inhibin A (alpha beta A). It should be noted, however, that the beta A subunit can form dimeric proteins other than activin A, such as activin AB (beta A beta B) and inhibin A (alpha beta A). Hence, the presence of the beta A subunit may not necessarily indicate the production of the activin A molecule in any tissue. Therefore, a special quantitative sandwich ELISA assay specific for the dimeric beta A beta A molecule was developed for the measurement of activin A. With this assay, production of activin A in marrow stromal cells is found to be greatly enhanced by cytokines and inflammatory mediators such as TNF-alpha, IL-1 alpha, and lipopolysaccharide. These studies thus suggest that inflammatory cytokines are the inducers for activin A, probably serving a role of up-regulating activin A production locally in bone marrow microenvironment. At present, activin A is not known to play any role in inflammatory reaction; this study may thus raise the possibility that activin A performs more functions than are currently recognized. Alternatively, the enhanced production of this molecule in the bone marrow microenvironment may be regarded as a compensatory mechanism in host defenses, countering inflammatory mediators that are known to suppress erythropoiesis.

Activins↗

PubMed2003

Design and chemical synthesis of a homogeneous polymer-modified erythropoiesis protein.

We report the design and total chemical synthesis of "synthetic erythropoiesis protein" (SEP), a 51-kilodalton protein-polymer construct consisting of a 166-amino-acid polypeptide chain and two covalently attached, branched, and monodisperse polymer moieties that are negatively charged. The ability to control the chemistry allowed us to synthesize a macromolecule of precisely defined covalent structure. SEP was homogeneous as shown by high-resolution analytical techniques, with a mass of 50,825 +/-10 daltons by electrospray mass spectrometry, and with a pI of 5.0. In cell and animal assays for erythropoiesis, SEP displayed potent biological activity and had significantly prolonged duration of action in vivo. These chemical methods are a powerful tool in the rational design of protein constructs with potential therapeutic applications.

Amino Acid Sequence↗

PubMed1967

Virus-induced erythropoiesis in hypertransfused-polycythemic mice.

Friend, Rauscher, and polycythemic viruses produce a marked erythrocytopoiesis in the spleens of infected mice. The erythrocytopoiesis induced by the Friend and Rauscher viruses can be inhibited in a hypertransfused polycythemic state. Like erythropoietin, the polycythemic virus can initiate erythropoiesis in this state. However, the mechanism by which the polycythemic virus initiates erythropoiesis in this state is not understood. These studies also show similarity of the Friend and Rauscher viruses in their erythropoietic response.

Animals↗

PubMed2001

Requirement of DNase II for definitive erythropoiesis in the mouse fetal liver.

Mature erythrocytes in mammals have no nuclei, although they differentiate from nucleated precursor cells. The mechanism by which enucleation occurs is not well understood. Here we show that deoxyribonuclease II (DNase II) is indispensable for definitive erythropoiesis in mouse fetal liver. No live DNase II-null mice were born, owing to severe anemia. When mutant fetal liver cells were transferred into lethally irradiated wild-type mice, mature red blood cells were generated from the mutant cells, suggesting that DNase II functions in a non-cell-autonomous manner. Histochemical analyses indicated that the critical cellular sources of DNase II are macrophages present at the site of definitive erythropoiesis in the fetal liver. Thus, DNase II in macrophages appears to be responsible for destroying the nuclear DNA expelled from erythroid precursor cells.

Animals↗

PubMed2024

Retrotransposons are co-opted to activate hematopoietic stem cells and erythropoiesis.

Hematopoietic stem cells (HSCs) and erythropoiesis are activated during pregnancy and after bleeding by the derepression of retrotransposons, including endogenous retroviruses and long interspersed nuclear elements. Retrotransposon transcription activates the innate immune sensors cyclic guanosine 3',5'-monophosphate-adenosine 5'-monophosphate synthase (cGAS) and stimulator of interferon (IFN) genes (STING), which induce IFN and IFN-regulated genes in HSCs, increasing HSC division and erythropoiesis. Inhibition of reverse transcriptase or deficiency for cGAS or STING had little or no effect on hematopoiesis in nonpregnant mice but depleted HSCs and erythroid progenitors in pregnant mice, reducing red blood cell counts. Retrotransposons and IFN-regulated genes were also induced in mouse HSCs after serial bleeding and, in human HSCs, during pregnancy. Reverse transcriptase inhibitor use was associated with anemia in pregnant but not in nonpregnant people, suggesting conservation of these mechanisms from mice to humans.

Animals↗

PubMed1994

Inhibition of in vitro erythropoiesis by soluble mediators in Plasmodium chabaudi AS malaria: lack of a major role for interleukin 1, tumor necrosis factor alpha, and gamma interferon.

By using erythropoietin-dependent proliferation of splenic erythroid cells as an in vitro erythropoiesis model system, we demonstrate that spleen cells from Plasmodium chabaudi AS-infected C57BL/6 mice potently inhibited erythroid cell proliferation. Inhibitory activity was detected in spleen cell conditioned media (SPCM) prepared from infected mice but not from uninfected mice. The inhibitory activity in SPCM was characterized as being heat sensitive, macromolecular, and host derived. The inhibitory activity was not reversed by increasing the erythropoietin concentration and was found to be specific for the late erythroid lineage. Mouse strains, which differ in their resistance to P. chabaudi AS infection, produced and responded to the inhibitory activity to a similar extent. Putative immune mediators, interleukin 1 alpha, interleukin 1 beta, and gamma interferon, were found to be potent inhibitors of erythroid cell proliferation. However, antibody neutralization experiments failed to demonstrate a major role for these cytokines in the inhibitory activity of SPCM. Our results suggest that the elaboration of inhibitor(s) of erythropoiesis in hemopoietic organs of Plasmodium-infected mice may impair erythroid regeneration. The identity of the inhibitory mediator(s) is presently unknown but is distinct from interleukin 1, tumor necrosis factor alpha, and gamma interferon.

Anemia↗

PubMed1999

Severe leukopenia and dysregulated erythropoiesis in SCID mice persistently infected with the parvovirus minute virus of mice.

Parvovirus minute virus of mice strain i (MVMi) infects committed granulocyte-macrophage CFU and erythroid burst-forming unit (CFU-GM and BFU-E, respectively) and pluripotent (CFU-S) mouse hematopoietic progenitors in vitro. To study the effects of MVMi infection on mouse hemopoiesis in the absence of a specific immune response, adult SCID mice were inoculated by the natural intranasal route of infection and monitored for hematopoietic and viral multiplication parameters. Infected animals developed a very severe viral-dose-dependent leukopenia by 30 days postinfection (d.p.i.) that led to death within 100 days, even though the number of circulating platelets and erythrocytes remained unaltered throughout the disease. In the bone marrow of every lethally inoculated mouse, a deep suppression of CFU-GM and BFU-E clonogenic progenitors occurring during the 20- to 35-d.p.i. interval corresponded with the maximal MVMi production, as determined by the accumulation of virus DNA replicative intermediates and the yield of infectious virus. Viral productive infection was limited to a small subset of primitive cells expressing the major replicative viral antigen (NS-1 protein), the numbers of which declined with the disease. However, the infection induced a sharp and lasting unbalance of the marrow hemopoiesis, denoted by a marked depletion of granulomacrophagic cells (GR-1(+) and MAC-1(+)) concomitant with a twofold absolute increase in erythroid cells (TER-119(+)). A stimulated definitive erythropoiesis in the infected mice was further evidenced by a 12-fold increase per femur of recognizable proerythroblasts, a quantitative apoptosis confined to uninfected TER-119(+) cells, as well as by a 4-fold elevation in the number of circulating reticulocytes. Therefore, MVMi targets and suppresses primitive hemopoietic progenitors leading to a very severe leukopenia, but compensatory mechanisms are mounted specifically by the erythroid lineage that maintain an effective erythropoiesis. The results show that infection of SCID mice with the parvovirus MVMi causes a novel dysregulation of murine hemopoiesis in vivo.

Animals↗

PubMed1982

In-vitro studies of ineffective erythropoiesis in rheumatoid arthritis.

Ineffective erythropoiesis was assessed in a series of 32 patients with rheumatoid arthritis by means of a new in-vitro method which measures the release of haem from a labelled cohort of erythroblasts in culture. Haem release was significantly increased in patients with the anaemia of chronic disorders but was normal in those who were not anaemic or who had an iron-deficiency anaemia. In 2 patients with anaemia of chronic disorders haem release returned to normal after successful antirheumatic therapy. The increased ineffective erythropoiesis in patients with rheumatoid arthritis and anaemia of chronic disorders appeared to be unrelated to functional iron deficiency and was not attributable to a serum factor.

Adolescent↗

PubMed1988

Mechanism of anaemia in rheumatoid arthritis: demonstration of raised interleukin 1 beta concentrations in anaemic patients and of interleukin 1 mediated suppression of normal erythropoiesis and proliferation of human erythroleukaemia (HEL) cells in vitro.

The pathogenesis of the anaemia associated with rheumatoid disease is unclear. It has previously been shown that the degree of the anaemia correlates with the severity of the inflammatory disease and that serum from patients with arthritis inhibits erythropoiesis. This study was designed to examine whether interleukin 1 could be a mediator of the anaemia in rheumatoid arthritis. Radioimmunoassay of interleukin 1 beta in serum showed that patients with rheumatoid arthritis and associated anaemia had significantly higher interleukin 1 beta concentrations than patients with rheumatoid arthritis without anaemia. Pure recombinant human interleukin 1 alpha and interleukin 1 beta, in concentration ranges similar to those found in the arthritic patients, markedly suppressed the colony formation of the erythroid, but not the granulocyte-macrophage progenitor cells in cultures of normal bone marrow. Natural human interleukin 1 and recombinant interleukin 1 beta, but not interleukin 1 alpha, suppressed in a dose dependent manner the proliferation of the human erythroleukaemia cell line (HEL) in cultures, suggesting that the interleukin 1 effect is a direct one. The results show that interleukin 1 is a humoral inhibitor of erythropoiesis and suggests that interleukin 1 is involved in the development of anaemia in association with rheumatoid arthritis.

Adult↗

PubMed1975

Megaloblastic erythropoiesis and macrocytosis in patients on anticonvulsants.

The results of deoxyuridine suppression tests on the bone marrow cells of 14 patients on anticonvulsant drugs, 11 of whom had evidence of megaloblastic erythropoiesis, indicated that the megaloblastic changes and macrocytosis encountered in treated epileptics are often not caused either by folate deficiency or by drug-induced impairment of the 5, 10-methylenetetrahydrofolate-dependent methylation of deoxyuridylate to thymidylate. A folate-related abnormality in the methylation of deoxyuridylate was found in only two of the 11 patients with megaloblastic erythropoiesis.

Adult↗

PubMed2004

Delayed hepcidin response explains the lag period in iron absorption following a stimulus to increase erythropoiesis.

INTRODUCTION: The delay of several days between an erythropoietic stimulus and the subsequent increase in intestinal iron absorption is commonly believed to represent the time required for body signals to programme the immature crypt enterocytes and for these cells to migrate to the villus. Recent data however suggest that signals from the body to alter absorption are mediated by circulating hepcidin and that this peptide exerts its effect on mature villus enterocytes. METHODS: We have examined the delay in the absorptive response following stimulated erythropoiesis using phenylhydrazine induced haemolysis and correlated this with expression of hepcidin in the liver and iron transporters in the duodenum. RESULTS: There was a delay of four days following haemolysis before a significant increase in iron absorption was observed. Hepatic hepcidin expression did not decrease until day 3, reaching almost undetectable levels by days 4 and 5. This coincided with the increase in duodenal expression of divalent metal transporter 1, duodenal cytochrome b, and Ireg1. CONCLUSION: These results suggest that the delayed increase in iron absorption following stimulated erythropoiesis is attributable to a lag in the hepcidin response rather than crypt programming, and are consistent with a direct effect of the hepcidin pathway on mature villus enterocytes.

Analysis of Variance↗

PubMed1989

Primary acquired sideroblastic erythropoiesis in non-anaemic and minimally anaemic subjects.

Six patients had primary sideroblastic erythropoiesis together with a haemoglobin concentration of 12.0 g/dl or higher. In four cases this was associated with macrocytosis. Other abnormalities included failure of erythroid progenitor growth from peripheral blood in three cases and occasional dysplastic appearances in neutrophils and megakaryocytes. Sideroblastic erythropoiesis seems to be an early manifestation of the myelodysplastic syndrome and may present clinically at a pre-anaemic stage.

Aged↗

PubMed1997

Developmental regulation of erythropoietin and erythropoiesis.

It is well established that erythropoiesis occurs first in the yolk sac, then in the liver, subsequently moving to the bone marrow and, in rodents, the spleen during development. The origin of the erythropoietic precursors and some factors suggested to be important for the changing location of erythropoiesis are discussed in this review. Until recently, the major site of erythropoietin (Epo) production in the fetus was thought to be the liver, but studies have shown now that the Epo gene is expressed strongly in the fetal kidney, even in the temporary mesonephros. The metanephric Epo mRNA is upregulated by anemia, downregulated by glucocorticoids, and contributes substantially to circulating hormone levels in hemorrhaged ovine fetuses. Other sites of Epo and Epo receptor production, likely to have important actions during development, are the placenta and the brain.

Aging↗