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PubMed2003

Regulated expression of MUC1 epithelial antigen in erythropoiesis.

MUC1 is a large surface glycoprotein expressed by epithelial cells, which is overexpressed and aberrantly glycosylated in carcinomas. MUC1 is involved in epithelial cell interactions and appears to function as a signal-transducing molecule. The finding that MUC1 can also be expressed in the haematopoietic lineages prompted us to further investigate the possible function(s) of this molecule in haematopoietic cells. In bone marrow differentiating cells, MUC1 was strongly and selectively expressed during erythropoiesis; it was also weakly expressed during megakaryocytopoiesis and granulomonocytopoiesis; however, no correlation between MUC1 and differentiation marker expression was observed in these lineages. In vitro CD34+ cells, induced towards erythroid differentiation, acquired MUC1 transiently, while expressing increasing levels of the lineage marker glycophorin A. MUC1 was absent in the circulating erythrocytes. During erythropoiesis, MUC1 expression was transcriptionally regulated and the molecule underwent phosphorylation. To investigate the possible role of MUC1 during erythropoiesis, we studied the ability of MUC1 to act as ligand for cell-cell interaction. The sialylated MUC1 glycoforms selectively expressed on erythroid cells were able to bind the macrophage-restricted molecule sialoadhesin. These results suggest that MUC1 can function as a cross-talk molecule between the erythroblasts and the surrounding cells during erythropoiesis.

Antigens, CD34↗

PubMed2003

cAMP/PKA-mediated regulation of erythropoiesis.

The role of cyclic AMP (cAMP) as second messenger in erythropoiesis has been suggested in the early 1980s. However, careful analysis showed that cAMP is not generated in direct response to the main erythropoiesis-controlling cytokines such as erythropoietin (Epo). As a result, cAMP disappeared from the central stage in research of erythropoiesis. Instead, other signal transduction pathways, including the Ras/extracellular regulated kinase (ERK)-pathway, the phosphatidylinositol 3-kinase (P13K) and the signal transducer and activator of transcription (STAT5)-pathways, have been found and explored. In concert, these signaling pathways control the transcriptional machinery of erythroid cells. Although cAMP is not directly generated in response to Epo stimulation, it has recently been demonstrated that increased cAMP-levels and in particular the cAMP-dependent protein kinase A (PKA) can modulate erythroid signal transduction pathways. In some cases, like the ERK-signaling pathway, PKA affects signal transduction by regulating the balance between specific phosphatases and kinases. In other cases, such as the STAT5 pathway, PKA enhances Epo signaling by inducing recruitment of additional co-regulators of transcription. In addition to STAT5, PKA also activates other transcription factors that are required for erythroid gene expression. This review discusses the impact of cAMP/PKA on Epo-mediated signaling pathways and summarizes the role of cAMP in malignant erythropoiesis.

Animals↗

PubMed2003

Enhanced hypoxia-stimulated erythropoietin production in mice with depression of erythropoiesis induced by hyperoxia.

Current evidence suggests that a modulatory action on O(2)-dependent EPO secretion is exerted by the erythroid/precursor cell population in the erythropoietic organs through a negative feedback system. The hypothesis is based on studies of stimulated-EPO secretion performed in mice in whom the erythropoietic rates were either enhanced or depressed in the presence of normal plasma EPO half-lives. Since erythropoietic depression was elicited by cyclophosphamide administration, which could have altered EPO production directly, the aim of the present investigation was to estimate hypoxia-stimulated EPO secretion in a mouse model of functional depressed erythropoiesis induced by exposure to normobaric hyperoxia. Females CF#1 mice aged 70 d were divided into control (C) and experimental (E) groups. The former was maintained in plastic cages in a normal environment, while the latter was placed in an environment of 60% O(2)/40% N(2) in an 85-dm(3) atmospheric chamber with air flow of 1 L/min. Erythropoiesis was evaluated by either 24-h RBC-(59)Fe uptake or iron kinetics performed 3 h after IV injection of a tracer dose of (59)Fe. Both indexes of the red cell production rate were significantly depressed in E mice. Plasma disappearance of exogenous EPO in C mice, as well as in E mice exposed to hyperoxia for 4 d, was estimated by injecting (125)I-rHuEPO intravenously. Linear regression analysis indicated that neither the differences between the slopes of both curves nor the Y-intercepts were significant. Hypobaric hypoxemia was used as stimulus for EPO production. Plasma immuno-EPO titer after a 4-h exposure to hypobaric air was 73% higher in mice with hyperoxia-induced hypoerythropoiesis than in control mice with normal erythropoiesis. Data support the concept that the rate of erythropoiesis, perhaps through the number of the erythroid progenitor/precursor cell population, modulates O(2)-dependent EPO secretion.

Animals↗

PubMed1998

Human parathyroid hormone does not influence human erythropoiesis in vitro.

BACKGROUND: Although renal anaemia is associated with secondary hyperparathyroidism, the relationship of both conditions remains obscure. Previously it was reported that high levels of bovine parathyroid hormone (PTH) did not inhibit in vitro human erythropoiesis, but whether human PTH inhibits in vitro human erythropoiesis has not been determined. METHOD: To clarify the direct effects of human biologically active N-terminal (1-34) PTH and intact (1-84) PTH on human haematopoietic progenitor growth, we investigated colony assays of human erythropoiesis and granulomonopoiesis. RESULTS: Neither N-terminal PTH (300 ng/ml) nor intact PTH (5000 pg/ml) inhibited haematopoietic progenitor growth. CONCLUSION: Our findings confirm that human PTH does not directly inhibit human erythropoiesis.

Animals↗

PubMed1998

Integrin-associated protein (IAP, also termed CD47) is involved in stroma-supported erythropoiesis.

Erythropoiesis is regulated by the hematopoietic microenvironment of the spleen, fetal liver, and bone marrow in mice. We previously showed that established stromal cells from these organs selectively support erythropoiesis in vitro. To identify the cell surface molecule(s) on the stromal cells involved in erythropoiesis, we raised monoclonal antibodies (MAbs) to MSS62 stromal cells derived from newborn spleen and obtained MAb100.1, which partially inhibited the stroma-supported erythropoiesis in vitro. Using an expression cDNA library of MSS62 cells, we cloned a gene encoding the protein recognized by MAb100.1 and identified it as integrin-associated protein (IAP, also termed CD47), which may play a general role in integrin-mediated signal transduction. IAP/CD47 is expressed in the stromal cells of spleen, fetal liver, and bone marrow, and in a variety of hematopoietic cells including erythroblasts. Thus, IAP may be partly involved in the erythropoietic supporting ability of the stromal cells.

Amino Acid Sequence↗

PubMedDate not supplied

Plasma transferrin receptor levels and indices of erythropoiesis and iron status in healthy term infants.

PURPOSE: The goal of this study was to determine if the postnatal changes in plasma transferrin receptor (TfR) levels in healthy infants were associated with changes in erythropoiesis or iron status. SUBJECTS AND METHODS: Longitudinal blood samples were obtained monthly from healthy term infants fed iron-fortified formula for the first 7 months and analyzed for plasma TfR and indices of erythropoiesis and iron status. RESULTS: Plasma TfR level rose during the first 2 months of life (p < 0.002). When examined for its association with indices of erythropoiesis, plasma TfR was negatively associated with hemoglobin (Hb) (p < 0.01), and positively associated with plasma erythropoietin (EPO) concentration (p < 0.005) and absolute reticulocyte count (p < 0.005). Plasma TfR was not associated with erythrocyte protoporphyrin. Although indices of iron status were not suggestive of iron deficiency, plasma TfR was negatively associated with plasma ferritin, Tf saturation, and plasma iron, and positively associated with total iron binding capacity (TIBC) (p < 0.0001 for all). CONCLUSIONS: Increases in plasma TfR levels were observed during normal infancy. The increases in plasma TfR levels correlate with increases in erythropoiesis without evidence for functional iron deficiency.

Birth Weight↗

PubMed2001

Autoimmune disorders of erythropoiesis.

Immune-mediated disorders of erythropoiesis can result in acquired severe anemia, low reticulocyte counts, and bone marrow exhibiting pure red cell aplasia or ineffective erythropoiesis. Erythropoiesis can be suppressed or impaired by humoral or cellular mechanisms. In vitro inhibition of erythroid colony growth by immunoglobulins or lymphocytes can be a strong argument for the immune origin of the disease. Classical etiologies are thymoma and hematologic malignancies such as chronic lymphocytic leukemia (CLL). Clonal proliferation of T cells has been incriminated. Recently, acquired circulating autoantibodies directed against erythropoietin have been detected in a case of pure red cell aplasia. Autoimmune mechanisms have also been detected or suggested in synartesis and in Fas-associated dyserythropoiesis, two distinct syndromes recently described where morphologic abnormalities specific to the erythroid lineage illustrate ineffective erythropoiesis.

Animals↗

PubMed2004

Beta-galactosidase of ROSA26 mice is a useful marker for detecting the definitive erythropoiesis after stem cell transplantation.

BACKGROUND: Hematopoietic reconstitution after stem cell transplantation has been analyzed by using stem cells of Ly5 congenic mice. However, the early erythropoiesis has never been analyzed because this marker is not expressed on all of the erythroid lineage cells. The transgenic mouse expressing beta-galactosidase (beta-gal) or green fluorescent protein (GFP) has been reported. Using these markers, we analyzed the early erythropoiesis after stem cell transplantation. METHODS: The beta-gal activity and GFP were examined in the hematopoietic cells of ROSA26 and GFP transgenic mice, respectively, by flow cytometry. The primitive hematopoietic stem cell fraction (Lin(-)c-kit(+)Sca-1(+)) in bone marrow (BM) cells of ROSA26 mice was transferred into lethally irradiated mice. The kinetics of hematopoietic reconstitution was analyzed in the BM and spleen after transplantation. RESULTS: The beta-gal activity, but not the GFP and Ly5, was detected in all of the erythroid (TER119+) cells. The beta-gal activity was also detected in the donor-derived myeloid (Mac-1+), B lymphoid (B220+), and T lymphoid (Thy-1+) cells in the BM and spleen after stem cell transplantation. The kinetics of the hematopoietic reconstitution demonstrated that early erythroid (TER119(low)CD71(med)) cells were developed in the BM and spleen within 2 days after transplantation before development of proerythroblasts (TER119(+)CD71(high)), and that massive erythropoiesis and myelopoiesis were observed in the spleen until 2 and 4 weeks after transplantation, respectively. Conclusions. The beta-gal of ROSA26 mice can be a useful marker to identify the donor-derived hematopoietic cells, including early erythroid cells, and the first major wave of erythropoiesis occurring in the spleen after stem cell transplantation.

Animals↗

PubMed1996

Differential effects of an erythropoietin receptor gene disruption on primitive and definitive erythropoiesis.

Although the hormone erythropoietin (Epo) and its receptor (EpoR) are known to play important roles in the regulation of erythropoiesis, several questions remain concerning the developmental role of Epo/EpoR signaling. As the functions of Epo have been defined primarily through studies of definitive erythroid cells, its importance for primitive, embryonic erythropoiesis remains uncertain, as does the significance of EpoR expression in several nonerythroid cell types. To address these questions, mouse embryonic stem cells and embryos lacking a functional EpoR gene were produced by gene targeting. The effects of the mutation were examined in embryos developing in vivo, in chimeric adult mice produced with homozygous mutant embryonic stem cells, and in hemopoietic cells cultured in vitro. No defects were apparent in nonerythroid cell lineages in which the EpoR normally is expressed, including megakaryocytes and endothelial cells. In the mutant yolk sac, primitive erythrocytes were produced in normal numbers, they underwent terminal differentiation, and expressed near normal levels of embryonic globins, although they were reduced in size and their proliferation was severely retarded after E9.5. In contrast, in the fetal liver, definitive erythropoiesis beyond the late progenitor (CFU-E) stage was drastically inhibited by the EpoR mutation, and virtually no definitive erythrocytes were produced in vivo, leading to embryonic death by E13.5. Thus, our results suggest a fundamental difference in the molecular mechanisms stimulating primitive and definitive erythropoiesis. It was also observed that a few mutant definitive erythroid cells could terminally differentiate when cultured with additional cytokines, demonstrating that although Epo/EpoR signaling is important for definitive erythroid cell survival and proliferation, it is not an obligatory step in differentiation.

Animals↗

PubMed1976

Quantitation of ineffective erythropoiesis from the incorporation of [15N] delta-aminolaevulinic acid and [15N] glycin into early labelled bilirubin. II. Anaemic patients.

The incorporation of [15N]delta-aminolaevulinic acid and [15N glycine into haemoglobin haem and early labelled bilirubin was measured in subjects with various haematological disorders. The clearance of [14C bilirubin was used to measure bilirubin production rate, and the magnitude of the various sources of bilirubin production and the percentage ineffective erythropoiesis were calculated. Ineffective erythropoiesis was found to be a major factor in the production of the anaemia in patients with the following disorders: megaloblastic anaemia associated with the Lesch-Nyhan syndrome, thalassaemia intermedia, sideroblastic anaemia, and the anaemia of chronic disorders. In three patients with iron-deficiency anaemia ineffective erythropoiesis was increased, but was of minor importance in the production of the anaemia, while in two patients with aplastic anaemia and one with macrocytosis of alcoholism there was no increase in ineffective erythropoiesis.

Adolescent↗

PubMed1976

Quantitative studies of splenic erythropoiesis in polycythaemia vera and myelofibrosis.

A quantitative scanning method employing cyclotron-produced 52Fe has been developed to assess splenic erythropoiesis in patients with myeloproliferative disorders. In 12 patients with myelofibrosis splenic uptake of 52Fe was from 5.0% to 48% of the injected dose. Although a single patient with classical polycythaemia vera had a minor uptake of 2.8% of six other patients with this diagnosis showed no concentration of isotope in the splenic area. The fraction of 52Fe in the spleen of four patients with 'transitional' myeloproliferative disorders characterized by a high red cell mass, hypercellular bone marrow and a leucoerythroblastic blood film varied from 5% to 41%. No clear relationship was noted between the degree of splenic erythropoiesis as defined by this technique and the level of haemoglobin, the degree of splenomegaly, the effectiveness of erythropoiesis of traditional 59Fe surface counting. If splenectomy is considered in patients with myelofibrosis splenic 52Fe quantitation will provide more precise data on the contribution of splenic erythropoiesis than 59Fe surface counting alone.

Erythropoiesis↗

PubMed1978

Erythropoiesis and mean red-cell lifespan in normal subjects and in patients with the anaemia of active rheumatoid arthritis.

Recently developed ferrokinetic methods offer a tool to measure effective and ineffective erythropoiesis and mean red-cell lifespan (Ricketts et al, 1975). We have used this tool to investigate erythropoiesis in normal subjects and in patients with the anaemia of active rheumatoid arthritis. In normal subjects the results are comparable with the results published by Cavill et al (1977). In patients with the anemia of active rheumatoid arthritis there appears to be a total and an effective red-cell production as in the normal subjects. The ineffective erythropoiesis in the patients is increased and the produced red cells have a shortened mean lifespan in the circulation. The increased ineffective erythropoiesis is probably due to inadequate supply of iron to the marrow and the shortened mean red-cell lifespan to an extra-corpuscular haemolytic factor. The impaired marrow response to the anaemia of active rheumatoid arthritis has been confirmed.

Adult↗

PubMed1990

A mathematical model of erythropoiesis in mice and rats. Part 4: Differences between bone marrow and spleen.

In a preceding analysis we hypothesized that the most important parameter controlled by erythropoietic regulation in vivo is the degree of amplification (number of cell divisions) in the CFU-E and erythroblast cell stages. It was concluded that erythropoietic amplification in vivo is controlled according to a sigmoidal dose-response relationship with respect to the control parameter which is the haematocrit (or haemoglobin concentration). Here, this hypothesis is extended to include the differences in murine bone marrow and splenic erythropoiesis that are described and quantified by different dose-response relationships. Comparing several sets of experimental data with mathematical model simulations, this approach leads to the following conclusions: (i) in the unperturbed normal steady state at least one extra erythropoietic cell division takes place in the spleen compared with the bone marrow; (ii) a strong erythropoietic stimulus, such as severe bleeding or hypoxia, can induce five to six additional cell divisions in the spleen but only two to three additional divisions in the bone marrow; this results in a considerable increase in the spleen's contribution to erythropoiesis from about 10% in normal animals to over 40% during strong stimulation; (iii) under erythropoietic suppression, such as red cell transfusion, a similar number of cell divisions is skipped in both organs and the splenic contribution to erythropoiesis remains unchanged. In conclusion, the concept that bone marrow and spleen microenvironments differ in the dose-response relationship for erythropoietic regulation provides an explanation for the changing contribution of splenic murine erythropoiesis following a variety of experimental treatments.

Animals↗

PubMed2004

Ineffective erythropoiesis underlies the clinical heterogeneity of congenital dyserythropoietic anemia type II (CDA II).

BACKGROUND: Congenital dyserythropoietic anemia type II (CDA II) is an autosomal recessive disease, and is the most common CDA. The qualitative and quantitative defects of erythropoiesis in CDA II, as estimated by the hematological and biochemical parameters at the time of diagnosis, may not reflect the heterogeneity of the disease course of each patient. METHODS: Three pediatric patients with CDA II are herein presented, having an heterogeneous clinical course. In addition to bone marrow morphology, Ham test and SDS-PAGE of erythrocyte membrane protein, the present study also examined erythroid marrow activity, by measuring serum Erythropoietin (Epo), soluble Transferrin Receptors (sTfR) concentrations and Reticulocyte Production Index (RPI). RESULTS: All patients demonstrated the same pattern of ineffective erythropoiesis, having increased Epo (350-389 IU/L), sTfR concentrations (6.2-7.8 mg/L) and low RPI values (0.8-1.3). Erythron expansion was expressed by RPI values nearly twofold higher than normal values in parallel to raised sTfR and high Epo production. Despite the same degree of ineffective erythropoiesis seen in all patients, the severity of the clinical course was diverse in terms of frequency and clinical relevance of transfusion needs. CONCLUSION: An analysis of the parameters expressing ineffective erythropoiesis in CDA II can provide a better understanding of the degree of dyserythropoiesis, however it is not useful for predicting the clinical course of disease in patients, because the underlying genetic heterogeneity of this disorder remains obscure.

Anemia, Dyserythropoietic, Congenital↗

PubMed1982

The pattern of reactivated fetal erythropoiesis in bone marrow disorders of childhood.

The expression of fetal characteristics of erythropoiesis (haemoglobin F concentration, haemoglobin A2 concentration, haemoglobin F cells, globin chain synthesis, carboanhydrase isoenzyme B, hexokinase isoenzymes, erythrocyte membrane antigens of the iI- and the ABH-system) was examined in red cells of twelve patients with different bone marrow disorders (juvenile chronic myeloid leukaemia (JCML), erythroleukaemia (EL), acute myelogenous leukaemia (AML), aplastic anaemia (AA) and Diamond-Blackfan anaemia (DB)). In JCML and EL all red cell parameters studied appeared to be fetal including the distribution of hexokinase isoenzymes. No fetal signs could be found in red cells of patients with AML. In two patients with DB who were treated by transfusion no fetal erythropoiesis could be detected. In one patient with DB under cortisone treatment i-antigen, ABH-antigens, haemoglobin F concentration, globin chain synthesis and hexokinase isoenzyme distribution were of the fetal or mixed type. In patients with AA only slight elevations of haemoglobin F were detectable. The nearly total reversion to fetal erythropoiesis in JCML and EL seems to be a part of the disorder itself, whereas in the other disorders the reactivation of fetal erythropoiesis could be the result of an erythropoietic stress.

Adolescent↗

PubMed1994

Recombinant human insulin-like growth factor 1 (rh-IGF-1) stimulates erythropoiesis in adult, but not in newborn mice.

The in vivo effect of recombinant human insulin-like growth factor (rh-IGF-1) upon erythropoiesis was studied in inbred BALB/C mice. Unweaned, rapidly growing 20 days old mice and adult female mice received subcutaneous rh-IGF-1 or control injections every 6 h for 48 h. The mice were killed either 12 or 48 h after the last injection, i.e. a study time of 60 and 96 h, respectively. Bone marrow erythroid colony forming units (CFU-E), reticulocytes, haematocrit, serum immunoreactive erythropoietin (siEPO) and body and organ weight were measured. An additional group of young mice were given iron prior to the rh-IGF-1 injections to ensure sufficient available iron. No differences in overall body or organ weights were observed. In the young mice erythropoiesis as measured by bone marrow CFU-E, reticulocytes and haematocrit did not differ between rh-IGF-1 group and controls. When iron alone was given, reticulocytes (P < 0.05) and haematocrit (P < 0.0001) increased significantly, but no further stimulation was seen when rh-IGF-1 injections were given in addition to iron. The adult female mice responded with significantly increased erythropoiesis as judged by increased reticulocyte counts following rh-IGF-1 injections (P < 0.001). No significant effect upon CFU-E and haematocrit was detected. The reticulocyte response was more pronounced at 96 than at 60 h after the first rh-IGF-1 injection. SiEPO was significantly (P < 0.01) lower in the adult 96 h rh-IGF-1 group than in the appropriate control group. In conclusion parenteral iron significantly increased haematocrit in unweaned mice. Short time rh-IGF-1 treatment did not stimulate erythropoiesis in these rapidly growing mice, whether or not iron supplementation had been given.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

PubMed1972

Protein synthesis: its control in erythropoiesis.

Erythropoiesis in the fetal mouse provides a model to study several important aspects of the regulation of cell differentiation and differentiated protein synthesis. Changes in the patterns of hemoglobins formed during fetal and postfetal development are shown to be associated with the substitution of the liver erythroid cell line. In the course of differentiation of yolk sac erythroid cells there are at least two classes of proteins distinguishable with respect to dependence on continued RNA formatoin. The bulk of nuclear proteins, "nondifferentiated" proteins, appear to be dependent on relatively short-lived messenger RNA while synthesis of differentiated proteins, the hemoglobins, proceeds on relatively stable molecules of messenger RNA. Hemoglobin formation occurs in those cells which are actively synthesizing DNA and dividing. On the average, two to three cell divisions may occur after the formation and stabilization of the messenger RNA for globin. Yolk sac erythropoiesis, at least from day 10 of gestation, is unresponsive to erythropoietin. By comparison, in fetal liver erythropoiesis, the hormone, erythropoietin, acts selectively on the most immature erythroid cell precursor to induce differentiation, cell replication, and hemoglobin formation. The erythropoietin responsive cell in the liver is apparently differentiated from the progenitor, pluripotential stem cell and committed to erythroblast formation and hemoglobin synthesis on exposure to the hormone. The initial effects of erythropoietin on macromolecular synthesis are to stimulate RNA synthesis, which temporally is followed by cell replication and the increase in hemoglobin formation. During liver erythropoiesis, there appears to be a transition from hemoglobin synthesis dependent on RNA formation to hemoglobin synthesis directed by relatively stable messenger RNA.

Animals↗

PubMed1977

Role of ineffective erythropoiesis in the anaemia of rheumatoid arthritis.

The importance of inadequate haemoglobin synthesis and ineffective erythropoiesis in the anaemia of rheumatoid arthritis was studied by measuring the incorporation of 15N glycine into haemoglobin haem and early labelled bilirubin in a patient with severe anaemia before and after response to gold therapy. Initially, total erythroid haem turnover was decreased but haem turnover due to ineffective erythropoiesis was markedly increased, accounting for 29% of total erythroid haem turnover. Gold therapy resulted in marked clinical improvement, accompanied by a rise in haemoglobin to normal. Total erythroid haem turnover increased and the percentage ineffective erythropoiesis fell to normal. Ineffective erythropoiesis may thus be an important reversible factor in the production of the anaemia of rheumatoid arthritis.

Anemia↗