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PubMed2001

A developmental transition in definitive erythropoiesis: erythropoietin expression is sequentially regulated by retinoic acid receptors and HNF4.

The cytokine erythropoietin (Epo) promotes erythropoietic progenitor cell proliferation and is required for erythropoietic differentiation. We have found that the Epo gene is a direct transcriptional target gene of retinoic acid signaling during early erythropoiesis (prior to embryonic day E12.5) in the fetal liver. Mouse embryos lacking the retinoic acid receptor gene RXR alpha have a morphological and histological phenotype that is comparable with embryos in which the Epo gene itself has been mutated, and flow cytometric analysis indicates that RXR alpha-deficient embryos are deficient in erythroid differentiation. Epo mRNA levels are reduced substantially in the fetal livers of RXR alpha(-/-) embryos at E10.25 and E11.25, and genetic analysis shows that the RXR alpha and Epo genes are coupled in the same pathway. We furthermore show that the Epo gene is retinoic acid inducible in embryos, and that the Epo gene enhancer contains a DR2 sequence that represents a retinoic acid receptor-binding site and a retinoic acid receptor transcriptional response element. However, unlike Epo-deficient embryos that die from anemia, the erythropoietic deficiency in RXR alpha(-/-) embryos is transient; Epo mRNA is expressed at normal levels by E12.5, and erythropoiesis and liver morphology are normal by E14.5. We show that HNF4, like RXR alpha a member of the nuclear receptor family, is abundantly expressed in fetal liver hepatocytes, and is competitive with retinoic acid receptors for occupancy of the Epo gene enhancer DR2 element. We propose that Epo expression is regulated during the E9.5--E11.5 phase of fetal liver erythropoiesis by RXR alpha and retinoic acid, and that expression then becomes dominated by HNF4 activity from E11.5 onward. This transition may be responsible for switching regulation of Epo expression from retinoic acid control to hypoxic control, as is found throughout the remainder of life.

Animals↗

PubMed1977

The assessment of red cell survival in normal subjects and in patients with haemolytic disorders and ineffective erythropoiesis using the radioiron occupancy method.

A direct method for measuring red cell lifespan in vivo using the radioiron occupancy method (Dagg et al, 1972) has been applied to eight normal subjects. The mean red cell lifespan was 116 d with a range of 104-124 d. To establish the method clinically in the presence of haemolysis and ineffective erythropoiesis, 22 patients with haemolytic disease and six patients with megaloblastic and sideroblastic anaemia were studied. All 22 patients with haemolytic anaemia had shortening of the red cell lifespan, with a range from 62 to 10 d; the results were compared with red cell lifespan derived from simultaneous radiochromium studies (Bentley et al, 1974). A close agreement between the two methods was obtained (r = 0.87; P less than 0.001). To assess the validity of the method in the presence of ineffective erythropoiesis, double isotope studies were also carried out in three patients with megaloblastic anaemia and three with sideroblastic anaemia. Close agreement was again obtained between lifespan measurements obtained from radioiron occupancy data and those derived from radiochromium studies, suggesting that the presence of significant ineffective erythropoiesis does not invalidate the method. The theoretical considerations involved in the application of the radioiron occupancy method to haemolytic states are discussed.

Anemia, Hemolytic↗

PubMed1980

Quantitative assessment of erythropoiesis in haemolytic disease.

Erythrokinetic parameters were estimated in 21 patients suffering from haemolytic disease using a mathematical model of iron kinetics. A proper definition of radioiron reflux from red cells to the plasma proved to be essential for an accurate estimate of effective and ineffective erythropoiesis in severe haemolytic conditions. Erythropoietic activity was increased in all the patients, with the marrow capable of sustaining erythropoiesis at about 6 times normal in hereditary spherocytosis and 3 times normal in autoimmune haemolytic anaemia. This proliferative effort was countered by an increase in ineffective erythropoiesis which was especially marked in hereditary spherocytosis.

Adolescent↗

PubMed1986

Relationship between erythropoiesis and the enhanced intestinal uptake of ferric iron in hypoxia in the mouse.

An in vitro technique was used to determine the unidirectional Fe3+ uptake rates in mouse duodenal fragments. In animals in which erythropoiesis had been stimulated by hypoxia, Fe3+ uptake by the duodenal fragments was enhanced due to an increase in Vappmax, However, when erythropoiesis was increased by injections of erythropoietin, intestinal Fe3+ uptake rates were unaffected. Mice subjected to sub-total nephrectomy showed an increased Vappmax for Fe3+ after exposure to hypoxia, despite the absence of an erythropoietic response. When the bone marrow was obliterated by treatment with 89Sr, a small increase in Vappmax for Fe3+ was found: permeability studies and morphometric analyses demonstrated no apparent irradiation damage to the duodenal mucosa of these animals. Exposure of 89Sr-treated mice to hypoxia caused a further significant increase in Vappmax. These results indicate that the increase in intestinal mucosal iron uptake which follows hypoxia is not mediated by erythropoietin or other factors associated with increased erythropoiesis.

Animals↗

PubMed1993

Chronic administration of transforming growth factor-beta suppresses erythropoietin-dependent erythropoiesis and induces tumour necrosis factor in vivo.

Transforming growth factor beta is a known inhibitor of the proliferation and differentiation of early haematopoietic progenitors but has no effect on mature erythroid cells in vitro. Mice injected with rhTGF beta 1 exhibited severe and progressive suppression of erythropoiesis manifested by a decline of reticulocyte count, marrow erythroblasts and marrow and spleen CFU-E, which could be prevented by administration of erythropoietin. This suppression of erythropoiesis was associated with the appearance of tumour necrosis factor in the blood, development of pronounced cachexia and depression of serum erythropoietin levels. TGF beta induces TNF in vivo that leads to cachexia, decrease of serum erythropoietin levels and suppression of erythropoietin dependent erythropoiesis.

Animals↗

PubMed1995

Relationship between transfusion regimen and suppression of erythropoiesis in beta-thalassaemia major.

In the management of beta-thalassaemia major, different transfusion schemes are employed with baseline haemoglobin levels ranging from 8 to over 12 g/dl. We studied the relationship between transfusion regimen and suppression of erythropoiesis in 52 patients with beta-thalassaemia major whose mean pretransfusion haemoglobin levels ranged from 8.6 to 10.9 g/dl. Multiple, regression analysis showed that serum transferrin receptor was the parameter more closely related to mean pretransfusion haemoglobin (r = -0.77, P < 0.001). As measured through serum transferrin receptor, erythroid activity was 1-2 times normal for pretransfusion haemoglobin levels between 10 and 11 g/dl. 1-4 times normal for levels from 9 to 10 g/dl, and 2-6 times normal for levels from 8.6 to 9 g/dl. Mean pretransfusion haemoglobin was also inversely related to serum erythropoietin (r = -0.72, P < 0.001), whereas it showed no or a weak relationship with Hb F, reticulocyte count, or circulating nucleated red cell count. This study suggests that serum transferrin receptor is a reliable indicator of suppression of erythropoiesis in beta-thalassaemia major. On the basis of our findings, pretransfusion haemoglobin values of < or = 9 g/dl should be adopted with caution, because these levels can be associated with an insufficient inhibition of erythroid marrow expansion. However, a transfusion programme, with a baseline haemoglobin of 9-10 g/dl, may provide enough suppression of erythropoiesis and allow a reduction in blood consumption as compared with the classic hyper- or supertransfusion schemes. Since fixed haemoglobin levels may not be the best target for transfusion treatment in all thalassaemic patients, assay of serum transferrin receptor may be helpful for individualizing the transfusion regimens.

Adolescent↗

PubMed2005

Persistence of recipient plasma cells and anti-donor isohaemagglutinins in patients with delayed donor erythropoiesis after major ABO incompatible non-myeloablative haematopoietic cell transplantation.

Delayed donor erythropoiesis and pure red-cell aplasia (PRCA) complicate major-ABO mismatched non-myeloablative allogeneic stem-cell transplantation. To characterize these events, we analysed red-cell serology and chimaerism in lymphohaematopoietic lineages, including plasma cells and B cells, in 12 consecutive major-ABO incompatible transplants following cyclophosphamide/fludarabine-based conditioning. Donor erythropoiesis was delayed to more than 100 days in nine (75%) patients including six (50%) who developed PRCA. During PRCA, all patients had persistent anti-donor isohaemagglutinins and recipient plasma cells (5-42%), while myeloid and T cells were completely donor in origin. In contrast, B-cell chimaerism was frequently full-donor when significant anti-donor isohaemagglutinins persisted. Four patients with early mixed haematopoietic chimaerism and the prolonged presence of anti-donor isohaemagglutinins and recipient plasma cells developed delayed-onset (>100 days post-transplant) red cell transfusion dependence and PRCA after myeloid chimaerism converted from mixed to full donor. These findings confirm that donor-erythropoiesis is impacted by temporal disparities in donor immune-mediated eradication of recipient lymphohaematopoietic cells during major-ABO incompatibility and suggest that plasma cells are relatively resistant to graft-versus-host haematopoietic effects.

Adult↗

PubMed1986

A case of macrocytosis and megaloblastic erythropoiesis of unknown aetiology.

The clinical and laboratory features in a non-anaemic 23-year-old female with marked macrocytosis and florid megaloblastic erythropoiesis of unknown aetiology are described. The bone marrow cells gave a normal deoxyuridine-suppressed value indicating that the megaloblastic erythropoiesis was not caused by vitamin B12 or folate deficiency or an impairment of the methylation of deoxyuridylate due to any other cause. The megaloblastic changes were associated with a marked degree of dyserythropoiesis, the most frequent ultrastructural abnormality being the presence of single or multiple intranuclear clefts. The characteristic light and electron microscope features of type I and type III congenital dyserythropoietic anaemia, in which mild megaloblastic changes may be seen, were absent. The distribution of the erythroblasts in the cell cycle was grossly abnormal and similar to that in severe pernicious anaemia; a high proportion of the cells were in the G2 phase and a substantial proportion seemed to have become arrested after progressing through part of the S phase. The bone marrow macrophages contained phagocytosed erythroblasts indicating that erythropoiesis was ineffective. It seems likely that the primary biochemical defect in the erythroblasts was some congenital disorder of DNA or nucleoprotein synthesis.

Adult↗

PubMed1984

Uncoupled synthesis of H1o-like histone H1s during late erythropoiesis in Xenopus laevis.

This study investigated the synthesis of Xenopus histones during erythropoiesis. Although cessation of DNA replication in the mid-stages of erythroid maturation is accompanied by arrested synthesis of histone H1 and core histones, synthesis of H1o (an H1o-like histone) was found to continue into late stages of erythropoiesis, as has been reported for avian erythrocyte histone H5. This was accompanied by a threefold increase in the relative amount of Xenopus H1s, similar to the accumulation reported for H5 during avian erythropoiesis and for H1o in some differentiated mammalian cells. The structural and metabolic homologies of avian H5, mammalian H1o, and Xenopus H1s imply that these lysine-rich histones have closely related functions distinct from those of H1, and thus represent a subclass of lysine-rich histones.

Anemia↗

PubMed1977

Erythropoiesis in the anaemia of chronic disease.

The amount and effectiveness of erythropoiesis was measured using 59Fe in 10 patients with the anaemia of chronic disease and in 10 iron deficient patients with a comparable degree of anaemia. In both conditions the anaemia was the result of the failure of the marrow to compensate for a modest degree of peripheral haemolysis but ineffective erythropoiesis was significantly greater in iron deficiency than in chronic disease. The results suggest that although the peripheral blood picture is similar in both conditions the anaemia of chronic disease cannot be attributed simply to iron deficient erythropoiesis.

Anemia↗

PubMed1980

Quantification of ineffective erythropoiesis in megaloblastic anaemia by determination of endogenous production of 14CO after administration of glycine-2-14C.

The determination of the early peak of 14CO production that results from haem turnover after administration of glycine-2-14C was studied in patients with pernicious anaemia. The accuracy of this technique in measuring ineffective erythropoiesis was assessed by comparison with other measurements of the severity of the disease. 6 patients were studied before specific treatment and 2 of these also after treatment. The endogenous production of 14 CO was calculated from determinations of the production of CO by a rebreathing technique and of the specific activity of CO washed out from the body CO store by oxygen breathing. The early labelled peak was increased 7-39 times compared to that in healthy control subjects and represented 35-86% of the total production of 14CO as compared to 13% in controls. The early labelled peak was significantly correlated to the Hb concentration, mean red cell volume and endogenous production of CO. 2 patients, twice examined, showed a moderately increased early labelled peak also after specific treatment. This was attributed to persistence of some ineffective erythropoiesis in 1 patient and possibly increased hepatic haem turnover in the other. The magnitude of the early labelled peak and the maximal activity of 14CO found in the samples of CO collected from the body CO store were significantly correlated. In conclusion, with the present method the early peak of 14CO reflected the ineffective erythropoiesis in patients with pernicious anaemia. The early labelled peak could be predicted from the maximal activity of 14CO found in the samples of CO washed out from the body CO store.

Aged↗

PubMed1982

Assessment of bone marrow and splenic erythropoiesis in myelofibrosis.

The iron uptake in bone marrow and spleen was measured in 29 patients with myelofibrosis using 52Fe and quantitative scanning. In 10 patients, no iron uptake in the marrow could be observed and active erythropoiesis was extramedullary only. In the bone marrow of patients with myelofibrosis, the iron uptake per nucleated red cell was less than that observed in conditions without myelofibrosis or extramedullary erythropoiesis. Increasing splenic iron uptake was likely to be associated with a decreasing bone marrow iron uptake and was related to the size of the spleen. The data suggest that in myelofibrosis, the spleen dominates iron uptake through intense erythropoiesis and a high splenic blood flow, thus restraining iron supply to the bone marrow.

Adult↗

PubMed1984

Polycythaemia following splenectomy in myelofibrosis with myeloid metaplasia. A reorganization of erythropoiesis.

3 patients with myelofibrosis with myeloid metaplasia were splenectomized because of anaemia and disturbing splenomegaly. In the course of the 6 months following splenectomy, a polycythaemia developed. Erythrokinetic studies demonstrated that in all cases a reduction in plasma volume and an increase in red cell volume was obtained. Total erythropoiesis decreased along with normalization of ineffective erythropoiesis and peripheral haemolysis. The reappearance of an erythropoietic activity measured over the sacrum was a constant finding, while in 1 patient, a depression of activity over the liver was observed. The new distribution and organization of erythropoiesis in the splenectomized patients is hypothesized as being due to the removal of the influence of an enlarged spleen on erythropoietic organs.

Aged↗

PubMed1990

Serum erythropoietin and erythropoiesis in patients with myelodysplastic syndromes.

Ineffective erythropoiesis is an early feature of the myelodysplastic syndromes (MDS), usually accompanying an hypercellular marrow. In a previous study, concentrations of serum erythropoietin (EPO) in MDS have been shown to correlate inversely both with haemoglobin concentration and with % bone marrow erythroblasts. We have measured erythroid production using a radioisotopic technique in 20 patients with MDS. Although haemoglobin concentration shows a weak inverse relationship with serum EPO concentration there is considerable variation in EPO concentration at a given haemoglobin level. There is no correlation between serum EPO and total erythroid production, though there is a weak correlation with effective erythropoiesis. The data suggests that control mechanisms of erythropoiesis in patients with MDS are complex.

Bone Marrow↗

PubMed1994

Erythropoiesis of very low-birth-weight infants dependent on prenatal growth rate and protein status.

This study investigated erythropoiesis in very low-birth-weight infants with special reference to the role of protein status in the regulation of erythropoiesis in 22 appropriate- and 11 small-for-gestational-age infants. Blood samples were drawn at three and six weeks of age. The serum concentrations of erythropoietin, estimated by a solid-phase enzyme immunoassay, were similar in the two groups at both study ages. The total circulating erythrocyte volume and the serum concentration of prealbumin were higher in the appropriate- than in the small-for-gestational-age infants at three and six weeks of age. The former group had a better protein status, although their protein intake was similar or lower. We conclude that erythropoiesis in very low-birth-weight infants is influenced more by protein status and prenatal growth than by serum concentration of erythropoietin.

Embryonic and Fetal Development↗

PubMed2006

Polyamines as an inhibitor on erythropoiesis of hemodialysis patients by in vitro bioassay using the fetal mouse liver assay.

The pathogenesis of anemia in patients with chronic renal failure has been greatly attributed to erythropoietin (EPO) deficiency. Recently, however, there has been some thought that uremic inhibitors might suppress the activity of EPO and reduce the maturation of erythropoiesis. Polyamines are well known to be involved in the regulation of cellular proliferation and differentiation. Furthermore, the polyamine levels in the serum or erythrocytes are elevated in chronic hemodialysis patients, and can be lowered immediately by hemodialysis. In the present study, we first measured the polyamines levels (putrescine, spermidine, spermine) by high performance liquid chromatography (HPLC) in 20 chronic hemodialysis patients, and investigated the effects of polyamines on erythropoiesis by in vitro bioassay using fetal mouse liver cells. The direct effects of polyamines in erythroid colony formation in the medium with and without EPO were evaluated. Each polyamine level in chronic hemodialysis patients was higher than in the healthy subjects, and a significant negative correlation was found between polyamines and erythropoiesis. Polyamines inhibited the activity of EPO, but they did not have any direct effect on colony formation of the fetal mouse liver cells. These results suggest that polyamines have inhibitory effects on the proliferation or maturation of erythroid precursor cells and are intimately involved in the pathogenesis of renal anemia in chronic hemodialysis patients.

Adolescent↗

PubMed1990

Regulated expression of globin chains and the erythroid transcription factor GATA-1 during erythropoiesis in the developing mouse.

Erythropoiesis in vertebrates is characterized by sequential changes in erythropoietic site, erythroblast morphology, and hemoglobin synthesis. We have examined the expression of globin chains and the major erythroid transcription factor GATA-1 (previously known as GF-1/NF-E1/Eryf 1) from days 7.5 to 17.5 of mouse development. mRNAs for embryonic (epsilon y2, beta H1, and zeta) and adult (alpha and beta) globin chains were quantitated by RNase protection assays. Switching of globins within the alpha-globin cluster (alpha and zeta) was not strictly coordinated with that within the beta-globin cluster (epsilon y2, beta H1, and beta). Regulation of globin switches during development was primarily transcriptional. Of particular note, we found two developmental switches (beta H1 to epsilon y2 and epsilon y2 to beta) in the mouse, more analogous than previously thought to shifts found in human development. The erythroid transcription factor GATA-1, believed to be a principal regulator of genes expressed in erythroid cells, first appeared in the embryo in yolk sac at the time of blood island formation and remained at a low level during embryonic erythropoiesis (8 to 11 days) relative to that found later in fetal liver (12 to 15 days). The rise in GATA-1 mRNA in fetal liver paralleled and preceded the rapid accumulation of adult beta-globin RNA. RNase protection assays and a GATA-1-specific peptide antiserum were used to establish that a single GATA-1 polypeptide is expressed throughout mouse development. Overall, these findings suggest that the levels of this erythroid transcription factor during development may contribute to the differential gene activation characteristic of definitive versus primitive erythropoiesis.

Animals↗

PubMed1997

Genetics of erythropoiesis: induced mutations in mice and zebrafish.

Production of red blood cells (erythropoiesis) in the vertebrate embryo is critical to its survival and subsequent development. As red cells are the first blood cells to appear in embryogenesis, their origin reflects commitment of mesoderm to an hematopoietic fate and provides an avenue by which to examine the development of the hematopoietic system, including the hematopoietic stem cell (HSC). We discuss the genetics of erythropoiesis as studied in two systems: the mouse and zebrafish (Danio rerio). In the mouse, targeted disruption has established several genes as essential at different stages of hematopoiesis or erythroid precursor cell maturation. In the zebrafish, numerous mutants displaying a wide range of phenotypes have been isolated, although the affected genes are unknown. In comparing mouse knockout and zebrafish mutant phenotypes, we propose a pathway for erythropoiesis that emphasizes the apparent similarity of the mutants and the complementary nature of investigation in the two species. We speculate that further genetic studies in mouse and zebrafish will identify the majority of essential genes and define a regulatory network for hematopoiesis in vertebrates.

Animals↗