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PubMed2002

Purification and characterization of the yeast-expressed erythropoietin mutant Epo (R103A), a specific inhibitor of human primary hematopoietic cell erythropoiesis.

A drug that specifically inhibits erythropoiesis would be clinically useful. The erythropoietin (Epo) mutant Epo (R103A) could potentially be used for this purpose. Epo (R103A) has a single amino acid substitution of alanine for arginine at position 103. Because of this mutation, Epo (R103A) is only able to bind to one of the 2 subunits of the erythropoietin receptor (EpoR) homodimer and is thus a competitive inhibitor of Epo activity. To produce large quantities of Epo (R103A) to test in animal models of thalassemia and sickle cell disease, we expressed and purified recombinant Epo (R103A) from the yeast Pichia pastoris. Using this method milligram quantities of highly purified Epo (R103A) are obtained. The yeast-expressed Epo (R103A) is properly processed and glycosylated and specifically inhibits Epo-dependent cell growth and (125)I-Epo binding. Epo (R103A) does not, however, directly induce apoptosis in 32D cells expressing EpoR. Epo (R103A) inhibits erythropoiesis of human CD34(+) hematopoietic cells and completely blocks erythroid burst-forming unit formation in normal human bone marrow colony assays. Yeast-expressed Epo (R103A) is a specific inhibitor of primary erythropoiesis suitable for testing in animal models.

Binding, Competitive↗
PubMed1996

Effect of recombinant granulocyte colony-stimulating factor on erythropoiesis in the human fetus and neonate.

Administration of large doses of recombinant granulocyte colony-stimulating factor (rG-CSF) to mice results in diminished erythropoiesis. Hyporegenerative anemia does not occur in adult humans as a consequence of treatment with rG-CSF, but it is not clear whether this will be a problem in neonates. Because rG-CSF is currently being tested as a treatment for neutropenia in neonates, we assessed the possibility that such treatment will diminish their erythropoiesis. To do this, we added rG-CSF, in vitro, to clonogenic cultures of hematopoietic progenitors obtained from the bone marrow and liver of seven human fetuses and from the umbilical cord blood of five term and five preterm infants. The range of rG-CSF concentrations tested (0.1-10.0 ng/mL) included the peak concentrations measured in the blood of neonates receiving rG-CSF treatment on experimental protocols. Inclusion of rG-CSF in the cultures did not diminish clonal maturation of fetal erythroid (erythroid colony-forming and burst-forming unit) progenitors, nor did it reduce the number of normoblasts generated per erythroid progenitor cell colony. On the basis of these studies we predict that administration of rG-CSF to neonates will not result in down-modulation of erythropoiesis.

Animals↗
PubMed1997

The importance of growth hormone in the regulation of erythropoiesis, red cell mass, and plasma volume in adults with growth hormone deficiency.

Total body water (TBW) is reduced in adult GH deficiency (GHD) largely due to a reduction of extracellular water. It is unknown whether total blood volume (TBV) contributes to the reduced extracellular water in GHD. GH and insulin-like growth factor I (IGF-I) have been demonstrated to stimulate erythropoiesis in vitro, in animal models, and in growing children. Whether GH has a regulatory effect on red cell mass (RCM) in adults is not known. We analyzed body composition by bioelectrical impedance and used standard radionuclide dilution methods to measure RCM and plasma volume (PV) along with measuring full blood count, ferritin, vitamin B12, red cell folate, IGF-I, IGF-binding protein-3, and erythropoietin in 13 adult patients with GHD as part of a 3-month, double blind, placebo-controlled trial of GH (0.036 U/kg.day). TBW and lean body mass significantly increased by 2.5 +/- 0.53 kg (mean +/- SEM; P < 0.004) and 3.4 +/- 0.73 kg (P < 0.004), respectively, and fat mass significantly decreased by 2.4 +/- 0.32 kg (P < 0.001) in the GH-treated group. The baseline RCM of all patients with GHD was lower than the predicted normal values (1635 +/- 108 vs. 1850 +/- 104 mL; P < 0.002). GH significantly increased RCM, PV, and TBV by 183 +/- 43 (P < 0.006), 350 +/- 117 (P < 0.03), and 515 +/- 109 (P < 0.004) mL, respectively. The red cell count increased by 0.36 +/- 0.116 x 10(12)/L (P < 0.03) with a decrease in ferritin levels by 39.1 +/- 4.84 micrograms/L (P < 0.001) after GH treatment. Serum IGF-I and IGF-binding protein-3 concentrations increased by 3.0 +/- 0.43 (P < 0.001) and 1.3 +/- 0.15 (P < 0.001) SD, respectively, but the erythropoietin concentration was unchanged after GH treatment. No significant changes in body composition or blood volume were recorded in the placebo group. Significant positive correlations could be established between changes in TBW and TBV, lean body mass and TBV (r = 0.78; P < 0.04 and r = 0.77; P < 0.04, respectively), and a significant negative correlation existed between changes in fat mass and changes in TBV in the GH-treated group (r = -0.95; P < 0.02). We conclude that 1) erythropoiesis is impaired in GHD; 2) GH stimulates erythropoiesis in adult GHD; and 3) GH increases PV and TBV, which may contribute to the increased exercise performance seen in these patients.

Adult↗
PubMed2005

Thyroid hormone T3 acting through the thyroid hormone alpha receptor is necessary for implementation of erythropoiesis in the neonatal spleen environment in the mouse.

Thyroid hormones (THs) mediate many physiological and developmental functions in vertebrates. All these functions are mediated by binding of the active form of the TH T3 to the specific nuclear receptors TRalpha and TRbeta, which are transcription factors. Using mutant mice lacking TRs or deficient for TH production, we show that T3 influences neonatal erythropoiesis through TRalpha. The effect of T3 and TRalpha is restricted to this developmental window and is specific for the spleen but not for other erythropoietic organs. We show that T3 via TRalpha affects late steps of erythrocytic development, promoting the proliferation of late basophilic erythroblasts. In vitro, this effect is exerted directly on erythrocytic cells. In vivo, the action of T3 is also intrinsic to spleen erythrocytic progenitors, as shown by grafting experiments of splenocytes derived from wildtype and TRalpha knockout (TRalpha(0/0)) mice into wild-type and TRalpha(0/0) irradiated recipients. Our results indicate that defective spleen erythropoiesis in hypothyroid and TRalpha(0/0) mice results from impaired recognition of the spleen environment by the mutant erythrocytic progenitors. The data presented support a model in which T3 signaling through TRalpha is essential for the implementation of the transient spleen erythropoiesis at birth.

Animals↗
PubMed2006

Reflections on the European Union Eurythron Network Meeting "Molecular Control of Erythropoiesis," September 22-23, 2005, Istituto Superiore di Sanità, Rome, Italy.

Red blood cells (RBCs) mediate oxygen transport throughout the body, a function that is essential for life. RBCs are continuously produced via a process called erythropoiesis. Anemias (insufficient numbers of functional RBCs), caused by failure of erythropoiesis, are a major cause of disease worldwide. Hereditary anemias constitute the most common human genetic disorders; they have no effective cure yet. The European research training network Eurythron follows a multidisciplinary approach to clarify the important molecular mechanisms in normal and pathological erythropoiesis, with a view to develop novel therapies to cure the anemias. The aim is to generate a comprehensive molecular description of mechanisms governing specification of hematopoietic stem cells in embryogenesis, lineage commitment, differentiation, and postmitotic maturation of RBCs. We report on the Eurythron meeting in Rome, in which novel approaches in stem cell and erythroid cell biology, including in vitro expansion of primary cells, biochemistry of receptor/signal transduction complexes and transcription factors, and (epi)genetics, were discussed.

Animals↗
PubMed2004

IL-3-dependent early erythropoiesis is stimulated by autocrine transforming growth factor beta.

Autocrine/paracrine transforming growth factor beta (TGF-beta) is an important regulator of stem cell quiescence and generally suppresses stem cell proliferation. However, we show here that during the first few days of an erythroid cell culture from adult blood stem cells, the presence of neutralizing antibodies against TGF-beta had a suppressive effect on subsequent erythropoiesis, indicating a stimulatory action of autocrine TGF-beta. The suppression occured in the form of a delay in erythroblast proliferation rather than a reduction in final erythroid colony numbers. The inhibitory effect of anti-TGF-beta occured in the presence of interleukin-3 (IL-3) but not in cultures with only stem cell factor and erythropoietin. Erythroblasts expressing gamma-globin (gamma+) were more strongly suppressed than erythroblasts expressing only beta-globin (gamma-beta+), so that stem cell treatment with anti-TGF-beta caused a decrease in the proportion of gamma+ cells. Anti-TGF-beta had an inhibitory effect on erythropoiesis only when administered during the first 4 days of culture, that is, before the onset of globin expression and dependence on erythropoietin. The decreasing effect of anti-TGF-beta with delayed addition coincided with a decreasing dependence on IL-3. CD133+ stem cells were more strongly suppressed by anti-TGF-beta than the complementary CD133-CD34+ stem cells, and the latter were also much less dependent on IL-3. The treatment of very early stem cell cultures with a pulse of added TGF-beta1 in the presence of IL-3 increased the subsequent proliferation of erythroblasts. Taken together, the data suggest that IL-3-driven early erythropoiesis from immature peripheral blood stem cells is stimulated by autocrine TGF-beta.

AC133 Antigen↗
PubMed2003

The effect of breed and intrauterine crowding on fetal erythropoiesis on day 35 of gestation in swine.

In a previous report, it was suggested that intrauterine crowding impaired fetal erythropoiesis and that fetal erythropoiesis was accelerated in Meishan pigs during early pregnancy. Because these conclusions were based on limited numbers of observations, the present experiment was undertaken to provide a more extensive investigation of these phenomena. Intact white crossbred gilts, unilaterally hysterectomized-ovariectomized (UHO) white crossbred gilts, and intact Meishan gilts (n = 13 to 16 per group) were mated after at least one estrous cycle of normal duration (17 to 23 d). Gilts were laparotomized at d 35 of pregnancy, the uterine horns were exteriorized and opened near each fetus, and a blood sample was collected from each fetus. The uterine horn was then surgically removed, and each fetus and placenta was weighed. All fetal blood samples were measured for hematocrit, red blood cell number, and hemoglobin. Erythropoietin and the percentages of nucleated cells and reticulocytes were also measured in blood samples from the largest and smallest living fetus in each litter. Fetal hematocrits were not affected by treatment. Blood cell counts were greater (P < 0.01) in fetuses of Meishan gilts than in White crossbred intact or UHO gilts. Hemoglobin was less (P < 0.01) in fetuses of Meishan gilts than in fetuses of White crossbred intact or UHO gilts. The percentages of nucleated (immature) cells and reticulocytes were both less (P < 0.01) in fetuses of Meishan intact gilts. Erythropoietin was also lower (P < 0.01) in fetuses of Meishan gilts. As observed previously, fetal weight was correlated (r = 0.38; P < 0.01) with blood hemoglobin concentration. These results confirm that fetal erythropoiesis in Meishan gilts is accelerated compared with White crossbred gilts. These results are consistent with the hypothesis that faster blood cell development could be beneficial to fetal survival in swine.

Animals↗
PubMed1986

Hepatic erythropoiesis in infants of diabetic mothers: a morphometric study.

Hepatic erythropoietic tissue is inversely proportional to the gestational age both in infants of diabetic mothers and in control cases. Hepatic erythropoietic and indices range from 17.8 in fetuses and babies before 28 weeks' gestational age to about 1.0 in fetuses and babies at 40-42 weeks' gestational age. The decline with gestational age is gradual in the last 10-12 weeks of in utero development. Infants of diabetic mothers who are normally grown have normal amounts of erythropoiesis in their livers. At term, large infants of diabetic mothers have excessive hepatic erythropoiesis. Hypoxia, a frequent feature in infants of diabetic mothers, is probably responsible for the increased erythropoiesis, but an alternate mechanism may be that hyperinsulinemia directly stimulates erythroid precursors or erythropoietin production.

Birth Weight↗
PubMed1986

The anemia of thermal injury: mechanism of inhibition of erythropoiesis.

The anemia of thermal injury is a multifactorial process and includes hemorrhage and hemolysis. Much evidence suggests that a reduced rate of erythropoiesis contributes to this anemia. Prior studies show that this anemia is temporally related to the appearance in burn patients sera of a substance(s) capable of inhibiting erythropoiesis in vitro. Four experiments were done to elucidate the mechanism of action of this inhibitor. In all experiments sera from burn patients previously shown to be inhibitory to erythropoiesis in vitro were studied. In the first, inhibitory sera were exposed to erythropoietin solutions without loss of erythropoietic activity. Second, mouse marrow cells were preincubated with serum without loss of their ability to form erythroid colonies. Third, the inhibitory effect could not be overcome with increasing amounts of erythropoietin. Finally, erythroid colony formation was effected only if the inhibitory serum was present during the first 8 to 12 hr of culture. The data suggest that the erythropoietic inhibitor in these sera acts directly on erythroid stem cells in vitro and not by inactivating or interference with erythropoietin.

Anemia↗
PubMed2002

Defective erythropoiesis in bone marrow is a mechanism of anemia in children with cancer.

Evaluation of the mechanism of anemia in cancer patients might help to select patients for the more efficient use of erythropoietin (EPO, a growth factor for erythroid precursor cells). For this, we investigated whether the production of EPO responds to anemia and the bone marrow responds to EPO appropriately, and whether chronic inflammation is inhibitory to erythropoiesis in anemic cancer children. Serum levels of EPO, soluble transferrin receptor (sTfR), tumor necrosis factor (TNF)-alpha, and erythrocyte sedimentation rate (ESR) in anemic cancer children were measured by enzyme-linked immunosorbent assay and then the correlation coefficients between those parameters and hemoglobin (Hb) were determined. Both in leukemia and in solid tumor patients, there were significant inverse correlations between Hb and EPO (leukemia: tau=-0.547, p<0.0001; solid tumor: tau=-0.591, p<0.0001), and between sTfR and EPO (leukemia: tau=-0.223, p<0.05; solid tumor: tau=-0.401, p<0.05). In contrast, sTfR showed a correlation with Hb in leukemia (tau=0.216, p<0.05) but not in solid tumor patients. sTfR was suppressed in 53% of anemic episodes of leukemia and 78% of those of solid tumor patients. Our results suggest that in cancer children, the EPO production is not defective and chronic inflammation is not inhibitory to erythropoiesis. Rather, the defective erythropoiesis itself is thought to be responsible for the anemia.

Anemia↗
PubMed1999

Thrombopoietin has a differentiative effect on late-stage human erythropoiesis.

To further explore the mechanism of the effect of thrombopoietin (TPO) on erythropoiesis, we used a two-phase culture system to investigate the effect of TPO on late-stage human erythroid lineage differentiation. In serum-free suspension and semisolid cultures of human peripheral blood derived erythroid progenitors, TPO alone did not produce benzidine-positive cells. However, in serum-containing culture, TPO alone stimulated erythroid cell proliferation and differentiation, demonstrated by erythroid colony formation, production of benzidine-positive cells and haemoglobin (Hb) synthesis. Monoclonal anti-human erythropoietin antibody and anti-human erythropoietin receptor antibody completely abrogated the erythroid differentiative ability of TPO in the serum-containing systems. This implied that binding of EPO and EPO-R was essential for erythropoiesis and the resultant signal transduction may be augmented by the signals emanating from TPO-c-Mpl interaction. Experiment of withdrawal of TPO further demonstrated the involvement of TPO in late-stage erythropoiesis. RT-PCR results showed that there was EPO-R but not c-Mpl expression on developing erythroblasts induced by TPO in serum-containing system. Our results establish that TPO affects not only the proliferation of erythroid progenitors but also the differentiation of erythroid progenitors to mature erythroid cells.

Cell Differentiation↗
PubMed2000

Improvement of erythropoiesis in beta-thalassemic mice by continuous erythropoietin delivery from muscle.

beta-Thalassemias are highly prevalent genetic disorders that can cause severe hemolytic anemia. The main pathophysiologic feature of beta-thalassemia is the accumulation of unpaired alpha-globin chains in erythrocyte precursors and red blood cells (RBCs). This accumulation alters cell membrane function and results in early cell destruction and ineffective erythropoiesis. Correction of globin chain imbalance through the induction of fetal hemoglobin (HbF) synthesis is a tentative therapeutic approach for this class of diseases. In short-term in vitro or in vivo assays, recombinant human erythropoietin increases the frequency of erythroid precursors programmed to HbF in humans and to beta-minor globin in mice. In contrast, long-term treatment of beta-thalassemic patients did not induce HbF significantly. We took advantage of highly efficient adeno-associated virus-mediated (AAV-mediated) gene transfer into mouse muscle to induce a robust and sustained secretion of mouse erythropoietin in beta-thalassemic mice, which represent a suitable model for human beta-thalassemia intermedia. A 1-year follow-up of 12 treated animals showed a stable correction of anemia associated with improved RBC morphology, increased beta-minor globin synthesis, and decreased amounts of alpha-globin chains bound to erythrocyte membranes. More effective erythropoiesis probably accounted for a reduction of erythroid cell proliferation, as shown by decreased proportions of circulating reticulocytes and by reduced iron 59 ((59)Fe) incorporation into erythroid tissues. This study indicates that the continuous delivery of high amounts of autologous erythropoietin induced a sustained stimulation of beta-minor globin synthesis and a stable improvement of erythropoiesis in the beta-thalassemic mouse model. (Blood. 2000;95:2793-2798)

Animals↗
PubMed2000

Effectiveness of erythropoiesis on supervised intradialytic oral iron and vitamin C therapy is correlated with Kt/V and patient weight.

BACKGROUND: Poor compliance to oral medication and diet is common in hemodialysis (HD) patients and limits the ability of oral iron therapy to support erythropoiesis. Intravenous (i.v.) iron may be associated with undesirable and sometimes life-threatening complications. PATIENTS AND METHODS: We hypothesized that intradialytic oral iron therapy can overcome compliance problems and support effective maintenance erythropoiesis, which will keep Hct in the range of 33% to 36% and EPO requirements up to 50 units/week/kg. In a prospective observational study, SC EPO-treated hospital-based HD patients without conditions known to cause EPO resistance, were managed on intradialytic oral administration of iron and vitamin C. The primary endpoints were EPO requirements and resistance to EPO which standardized EPO requirements by the Hct level. Secondary endpoints included parameters that might affect the primary endpoints. Exclusion criteria were refusal to take oral medication, prestudy Hct < 27%, recent i.v. iron therapy or transfusions, bleeding, clinical conditions obligating Hct > 30% and known causes of EPO resistance. Twelve patients completed minimal follow-up period of 9 months. RESULTS: Mean Hct was 34.4% (range: 31.8% - 40.2%). EPO requirements were 61.7 +/- 28.2 units/kg and below 52.5 units/kg in 50% of patients. Patients were classified into equal groups according to resistance to EPO, which was positively correlated (r = 0.71 p < 0.01) with body weight and Kt/V (r = -0.38, p < 0.05). CONCLUSION: In conclusion, intradialytic oral iron therapy can support effective maintenance erythropoiesis in 50% of patients without known causes for EPO resistance. High response to EPO and low EPO requirement are correlated with lower body weight and possibly improved dialysis.

Administration, Oral↗
PubMed2000

Erythropoietin, iron, and erythropoiesis.

Recent knowledge gained regarding the relationship between erythropoietin, iron, and erythropoiesis in patients with blood loss anemia, with or without recombinant human erythropoietin therapy, has implications for patient management. Under conditions of significant blood loss, erythropoietin therapy, or both, iron-restricted erythropoiesis is evident, even in the presence of storage iron and iron oral supplementation. Intravenous iron therapy in renal dialysis patients undergoing erythropoietin therapy can produce hematologic responses with serum ferritin levels up to 400 microg/L, indicating that traditional biochemical markers of storage iron in patients with anemia caused by chronic disease are unhelpful in the assessment of iron status. Newer measurements of erythrocyte and reticulocyte indices using automated counters show promise in the evaluation of iron-restricted erythropoiesis. Assays for serum erythropoietin and the transferrin receptor are valuable tools for clinical research, but their roles in routine clinical practice remain undefined. The availability of safer intravenous iron preparations allows for carefully controlled studies of their value in patients undergoing erythropoietin therapy or experiencing blood loss, or both.

Animals↗
PubMed2001

Assessment of erythropoiesis activity during hemodialysis therapy by soluble transferrin receptor levels and ferrokinetic measurements.

The erythropoietic activity (EA) and degree of erythropoiesis attained by patients undergoing hemodialysis (HD) administered recombinant human erythropoietin (rHuEPO) were studied using ferrokinetic measurements and tests of soluble transferrin receptor (sTfR) levels, assessing which parameter is most useful for measurements in clinical practice. Plasma iron 59 ((59)Fe) clearance (half-life [T(1/2)] (59)Fe), plasma iron turnover (PIT), erythron transferrin uptake (ETU), and erythrocyte (59)Fe incorporation were determined in 23 patients before and at 4 months after administration of rHuEPO. sTfR levels, hematopoietic parameters, and iron metabolism parameters were measured periodically. T(1/2) (59)Fe was shortened (P: = 0.004), PIT and ETU were increased (P: = 0.032 and P: = 0.013, respectively), and the time taken by erythrocytes to incorporate 80% of the (59)Fe administered was reduced from 9.6 to 6.1 days. sTfR levels were increased by 15 days; this increase was significant (P: < 0.05) at 30 days, reaching a maximum of 3.22 mg/dL at day 45. A positive correlation was seen between sTfR levels and hemoglobin (Hb) (P: = 0.001), hematocrit (P: = 0.001), and reticulocytes (P: = 0.038) that was not found between ferrokinetic parameters and those evaluating efficient erythropoiesis (P: = 0.345 between ETU and Hb). In conclusion, EA is increased, shown by ETU and sTfR level. sTfR levels correlate with the parameters that evaluate efficient erythropoiesis, and their measurement does not involve the technical and/or ethical limitations of studies of ferrokinetics, making them the tool of choice in clinical practice for the evaluation of EA in patients undergoing HD administered rHuEPO.

Adult↗
PubMed2000

[Regulatory mechanisms of erythropoiesis by leukocytes in inflammation].

On the model of carrageenan-induced acute aseptic peritonitis in rats with use of the inhibitors of some leukocytic products it is shown that lysosomal proteinases inhibit erythropoiesis activation in inflammation. Lipoxygenase metabolites stimulate erythropoiesis. Eicosanoids as a whole stimulate erytropoiesis still more. Reactive oxygen species promote the development of erythron hyperplasia. Dexamethasone administration increases the erythropoiesis intensification.

Acute Disease↗
PubMed2001

[Erythropoiesis disorders and other central autoimmune anemias].

Immune-mediated acquired disorders of erythropoiesis can result in 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 humoral factors or lymphocytes is a strong argument for the immune origin of the disease. Classical aetiologies are thymoma and hematological malignancies such as chronic lymphocytic leukaemia. Clonal proliferation of T cells has also 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 suggested in two dyserythropoietic syndromes recently described.

Anemia↗
PubMed1976

The anemia of chronic renal failure and chronic diseases: in vitro studies of erythropoiesis.

The presence of a serum factor in chronic renal failure (CRF) which inhibits erythropoietin-stimulated erythropoiesis was studied, using a technique in which dog marrow cells were stimulated to produce heme in the presence of human serum. In the total series comparing 27 normal sera with 52 CRF sera, less heme was synthesized when the system contained CRF sera (total series, p = 0.0001). There was no evidence of inhibition of heme synthesis by serum from 12 patients with the anemia of chronic diseases (CD). Mixing experiments with normal and CRF sera suggested that this defect in CRF serum was not due to lack of a factor necessary for heme synthesis. Addition of urea, creatinine, and guanidinosuccinic acid to normal serum did not impair its ability to support erythropoiesis in this system. These data demonstrated that serum from patients with CRF contains a material inhibiting erythropoiesis in vitro, We propose that the material is responsible, in part, for the clinically severe anemia seen in these patients.

Adolescent↗