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PubMed2005

Thrombospondin 1, produced by endothelial cells under the action of erythropoietin, stimulates thymidine incorporation into erythroid cells and counteracts the inhibitory action of insulin-like growth factor binding protein 3.

The nature of erythropoietin (EPO)-dependent, erythroid cell regulatory factors secreted by endothelial cells is largely unknown. The production of thrombospondin 1 (TSP-1) and insulin-like growth factor binding protein 3 (IGFBP-3) is increased in cultures of human umbilical vein endothelial cells (HUVEC) incubated with erythropoietin (EPO). Simultaneous incubation of HUVEC with EPO and interleukin 3 (IL-3) resulted in a decreased production, suggesting that both TSP-1 and IGFBP-3 belong to the EPO- and IL-3-dependent erythroid regulatory factors previously described in cultures of bone marrow endothelial cells. TSP-1 and TSP-1 derived synthetic peptides based on the CD36 and CD47 binding sites of TSPs increased thymidine incorporation into bovine erythroid cells of fetal liver. IGBBP-3 inhibited thymidine incorporation in the same cells. Preincubation of erythroid cells with TSP-1 eliminated the inhibitory activity of IGFBP-3. We suggest that EPO-dependent, endothelial-derived TSP-1 may play a positive role in red cell production by acting directly on erythroid cells, stimulating DNA synthesis and preventing the inhibitory action of IGFBP-3.

Animals↗
PubMed1979

Transcriptional regulation in avian erythroid cells.

Both the translational and transcriptional repertoires of nearly mature avian erythroid cells appear to be highly restricted: molecular hybridization experiments demonstrate the presence of about 4000 species of poly(A)+ nRNA and fewer than 100 species of poly(A)+ mRNA. This paper addresses the question of whether the nRNA of erythroid cells contains sequences which, although not expressed in the erythroid cells, are found on polysomes in another cell type. We have prepared cDNA from liver mRNA and have determined the representation of liver mRNA sequences in the erythroid cell nRNA. Liver mRNA consists of about 14 000 species of poly(A)+ RNA. Of these only about 100 species are detectable in erythroid cell nRNA. The vast majority of liver mRNA species is undetectable in erythroid cells; i.e., they are present at less than 0.03 copies per cell. The few species of liver mRNA that are detectable in erythroid cells are present in both the nuclear and polysomal RNA at concentrations less than 0.1 copies per cell. These data suggest that gene expression in avian erythroid cells is highly regulated at the transcriptional level.

Animals↗
PubMed1969

Differentiation of mammalian somatic cells: DNA and hemoglobin synthesis in fetal mouse yolk sac erythroid cells.

The relationship between the synthesis and replication of DNA and the capacity to synthesize specialized protein on a stable messenger RNA has been examined in yolk sac erythroid cells differentiating in vivo in fetal mice. Evidence is presented that by day 11 of gestation, at least 98 per cent of yolk sac erythroid cells are synthesizing hemoglobin. These cells are shown to incorporate (3)H-thymidine and to replicate, with more than twofold increase in cell number between days 10 and 11. Division of these cells continues through day 13. Hemoglobin formation in these cells is resistant to actinomycin D from day 10. During this period, ribosomal content per cell decreases by more than a factor of 2. These data indicate that in yolk sac erythroid cells, hemoglobin formation proceeds independent of continued RNA formation in cells capable of DNA synthesis and replication.

Animals↗
PubMed1994

The effect of human myelomonocytic leukemic cell line (M20) derived IL-1 inhibitor on human erythroid cell development.

The effect of an inhibitor of IL-1, purified from a human myelomonocytic cell line (M20) on the development of human erythroid cell development was studied. The inhibitor, is a protein of 52 kD molecular weight that is distinct immunologically and functionally from other reported IL-1 inhibitors. The experiments were performed in a two-phase culture system that allows separation of the erythroid cell development into an erythropoietin (EPO)-independent phase, where early erythroid-committed BFUe proliferate and differentiate into the more mature progenitors, CFUe, and EPO-dependent phase, where CFUe further proliferate and mature into hemoglobin-containing orthochromatic normoblasts. The results indicated that in both developmental stages the M20-derived inhibitor reversibly blocked cell proliferation without interfering with cell differentiation.

Erythroid Precursor Cells↗
PubMed2004

New insights into the regulation of erythroid cells.

The regulation of erythroid cells is complex and occurs at multiple levels. Erythroid precursors, once committed to this lineage, develop in association with specific macrophages within erythroblastic islands. While erythropoietin (Epo) is the principal regulator of erythroid progenitors, other cytokines and nuclear hormones also play an important role in the maturation of these cells. Signalling from the Epo-receptor activates several pathways, including the JAK/STAT, ras/raf/MAP kinase and PI3 kinase/Akt cascades to promote cell survival, proliferation and differentiation. Transcription factors such as GATA-1, EKLF and NF-E2 are crucial for progression along the erythroid maturation pathway; these, and a myriad of other transcription factors, must be expressed at the correct developmental stage for normal red blood cells to be formed.

Cell Differentiation↗
PubMed2000

A novel endoproteolytic processing activity in mitochondria of erythroid cells and the role in heme synthesis.

The erythroid isoform of aminolevulinate synthase (eALAS) protein is a major control point in erythroid heme synthesis and hemoglobin formation. Erythroid cells were extracted from mouse blood and bone marrow and metabolically labeled with (35)S-methionine. This was followed by immunoprecipitation of eALAS protein products. The results show that the N-terminus of the expected full-length 59-kd form of the eALAS protein is truncated in bone marrow erythroid cells by approximately 7 kd. More differentiated erythroid cells in the peripheral blood exhibit very little of this protein truncation. Erythroid cells from the bone marrow were isolated using monoclonal antibody TER-119 and were shown to contain a unique endoprotease activity that could cleave the eALAS protein to the shorter form in vitro. With or without the mitochondrial signal sequence, the eALAS protein could serve as a substrate for the cleavage. This cleavage renders a functional eALAS protein and only removes a domain of unclear function, which has previously been reported to vary in size as a result of alternative RNA splicing. The protease activity was enriched from the membranes of mitochondria from bone marrow cells and was shown to be different from mitochondrial processing peptidase, medullasin, and other known proteases. Apart from the mitochondrial processing peptidase that cleaves the import signal sequence, this is the first description of a mitochondrially located site-specific processing protease activity. (Blood. 2000;96:740-746)

5-Aminolevulinate Synthetase↗
PubMed1994

Regulation of transferrin receptor mRNA expression. Distinct regulatory features in erythroid cells.

In proliferating non-erythroid cells, the expression of transferrin receptors (TfR) is negatively regulated by the amount of intracellular iron. Fe-dependent regulation of TfR occurs post-transcriptionally and is mediated by iron-responsive elements (IRE) located in the 3' untranslated region of the TfR mRNA. IREs are recognized by a specific cytoplasmic binding protein (IRE-BP) that, in the absence of Fe, binds with high affinity to TfR mRNA, preventing its degradation. While TfR numbers are positively correlated with proliferation in non-erythroid cells, in hemoglobin-synthesizing cells, their numbers increase during differentiation and are, therefore, negatively correlated with proliferation. This suggests a distinct regulation of erythroid TfR expression and evidence, as follows, for this was found in the present study. (a) With nuclear run-on assays, our experiments show increased TfR mRNA transcription following induction of erythroid differentiation of murine erythroleukemia (MEL) with Me2SO. (b) Me2SO treatment of MEL cells does not increase IRE-BP activity which is, however, increased in uninduced MEL cells by Fe chelators. (c) Following induction of MEL cells, there is an increase in the stability of TfR mRNA, whose level is only slightly affected by iron excess. (d) Heme-synthesis inhibitors, such as succinylacetone and isonicotinic acid hydrazide, which inhibit numerous aspects of erythroid differentiation, also inhibit TfR mRNA expression in induced MEL cells. However, heme-synthesis inhibition does not lead to a decrease in TfR mRNA levels in uninduced MEL cells. Thus, these studies indicate that TfR gene expression is regulated differently in hemoglobin synthesizing as compared to uninduced MEL cells.

Aminolevulinic Acid↗
PubMed2002

Production of IL-10, TNF-alpha, IFN-gamma, TGF-beta1 by different populations of erythroid cells derived from human embryonal liver.

It has previously been determined that erythroid cells of mice are capable of expressing such cytokines as interleukin (IL) 1 alpha and beta, IL-4, IL-6, interferon gamma (IFN-gamma), granulocyte-macrophage colony-stimulating factor (GM-CSF) and transforming growth factor beta (TGF-beta). It has been shown that glycophorin A(+) (GlA(+)) and antigen erythroblasts (AG-EB(+)) (both human erythroid cells of embryonic origin) are also capable of producing a series of cytokines such as IL-1 beta, IL-2, IL-4 and IL-6. The aim of this work was to study the capacity of erythroid cells from human embryonic liver to produce such cytokines as IFN-gamma, TGF-beta1, tumour necrosis factor alpha (TNF-alpha) and IL-10. The erythroid cells were isolated by means of antibodies specific to erythroblasts (GlA and AG-EB), as well as those from single erythroid colonies. The production level of some cytokines varies insignificantly under the action of erythropoietin (Epo) and quantitatively differs in GlA(+) and AG-EB(+) erythroid cells. Hence, the erythroid cells express IFN-gamma, TGF-beta1, TNF-alpha and IL-10. The erythroid cells could be involved through the production of these cytokines in the regulation of such processes as self-renewal, proliferation and differentiation of cells of other blood-forming sites.

Cells, Cultured↗
PubMed1985

Human spleen cell generation of factors stimulating human pluripotent stem cell, erythroid, and myeloid progenitor cell growth.

Mitogen-stimulated murine spleen cells produce humoral substances capable of supporting murine hematopoiesis and pluripotent stem cell proliferation in vitro. Thus, we evaluated conditioned media generated by human spleen cells (SCM) in the presence or absence of mitogens for factors stimulatory for human pluripotent (CFU-GEMM), erythroid (BFU-E), and myeloid (CFU-GM) precursors. Two and one half percent to 10% SCM stimulated proliferation of all three types of precursor cells from nonadherent buoyant human marrow target cells. Mitogen-stimulated SCM augmented CFU-GM (175% to 225%), whereas CFU-GEMM and BFU-E growth was essentially unchanged. Cell separation procedures used to determine which cells provided these microenvironmental stimuli indicated that nonadherent mononuclear spleen cells provided the bulk of the CSF-GM, whereas adherent cells (95% nonspecific esterase + monocyte-macrophages) and nonadherent cells provided similar proportions of CSF-mix and erythroid burst-promoting activity (BPA). The nonadherent cells generating high levels of CSF-mix, BPA, and CSF-GM were predominantly Leu-1-negative, ie, non-T, cells. In the presence or absence of mitogens, SCM was a more potent source (1.3- to 3.8-fold) than peripheral leukocyte CM of the growth factors for the three progenitor cell types. Specific in situ cytochemical stains for analyzing morphology of myeloid colonies demonstrated that SCM stimulated the proliferation of the same types and proportions of colonies as human placental CM, suggesting that these CMs may contain similar CSF-GMs. These data show the contribution of spleen cell subsets to the generation of hematopoietic growth factors and the responsiveness of these cells to various mitogenic stimuli.

Bone Marrow Cells↗
PubMed1990

Microenvironment created by stromal cells is essential for a rapid expansion of erythroid cells in mouse fetal liver.

Mouse stromal cell lines (FLS lines), established from the livers of 13-day gestation mouse fetus, supported the proliferation and differentiation of the erythroid progenitor cells from mouse fetal livers and bone marrow in a semisolid medium in the presence of erythropoietin. A large erythroid colony of over 1000 benzidine-positive erythroid cells was developed from a single erythroid progenitor cell on the FLS cell layer after 4 days of culture. When in close contact with the layer, the erythroid progenitor cells divided rapidly with an average generation time of 9.6 h and mature erythroid cells, including enucleated erythrocytes, were produced. The present studies demonstrate that the microenvironment created by the stromal cells can support the rapid expansion of erythropoietic cell population in the fetal liver of mice.

Animals↗
PubMed1997

Translational control of erythroid delta-aminolevulinate synthase in immature human erythroid cells by heme.

Heme formation in immature erythroid cells is subject to end-product negative feedback control. Although studies with immature erythroid cells obtained from animals have shown that increased intracellular hemin inhibits the acquisition of iron from transferrin, our experiments with human reticulocytes indicate that feedback inhibition of heme biosynthesis is primarily regulated at one or more steps that lead to formation of the first committed precursor, delta-aminolevulinate (ALA). To identify the site of control of heme biosynthesis in the human erythron further, region-specific antibodies to human erythroid delta-ALA synthase (e-ALA synthase) were used to immunoprecipitate newly-synthesised enzyme from human reticulocytes after biosynthetic labelling. Low concentrations of exogenous hemin (30-35 microM) inhibited the biosynthetic labelling of mature erythroid ALA synthase that was detected by exon 4 peptide-specific antibodies and antibodies raised against the entire recombinant human erythroid ALA synthase molecule. Pulse-chase experiments after biosynthetic labelling indicated no differences in the effect of hemin on the turnover of the radiolabelled enzyme and hemin did not influence the distribution of precursor froms of the ALA synthase molecule. Parallel experiments using antibodies directed against human H-chain ferritin confirmed the specificity of the effects of hemin on translation of the e-ALA synthase mRNA. At the concentrations of hemin used to inhibit heme formation from 14C-glycine, no significant effects on the rate of overall protein synthesis were observed. We conclude that heme regulates synthesis of the first committed precursor of the porphyrin biosynthetic pathway in immature human erythroid cells by effects on the synthesis of the e-ALA synthase molecule. Although the mechanism of hemin action is unknown, it is apparently independent of 5'-iron-response elements and influences the translational activity of erythroid ALA synthase mRNA.

5-Aminolevulinate Synthetase↗
PubMed2004

The C-terminal peptide of thrombospondin-4 stimulates erythroid cell proliferation.

Erythropoietin (EPO) stimulates the production of small erythroid cell stimulating factors (molecular weight <5 kDa) in cultures of bone marrow endothelial cells. We identified a fragment of thrombospondin-4 (TSP-4) as an EPO-stimulated protein in endothelial cell lysates. Pre-incubation of the low molecular weight fractions from supernatants of EPO-treated umbilical cord endothelial cells (HUVEC) with antibodies against the C-terminal residues of TSP-1,2 and TSP-4 decreased the erythroid cell stimulating activity. The C-terminal TSP-1 section corresponding to a molecular weight lower than 6 kDa has the integrin-associated protein binding motif VVM. The corresponding TSP-4 fragment, lacking the three residue sequence VVM, has a distinctive acidic peptide comprising the last 21 amino acids (C21) with the characteristics of an amphipathic helix. C21 stimulated thymidine incorporation into bovine erythroid cells, increased cell numbers in cultures of cord blood CD36+ erythroid precursors and skin fibroblasts, and decreased HUVEC proliferation. SC21, a homologous peptide of identical amino acid composition but with interchanged residues, was non-amphipathic and had no erythroid cell stimulating activity.

Amino Acid Sequence↗
PubMed1994

Transferrin-binding capacity by rat bone marrow populations containing different proportions of erythroid cells.

The transferrin-binding capacity of rat bone marrow cells and different erythroid-enriched populations from rat bone marrow has been studied and compared with that previously reported for pure reticulocyte populations. Two components with different transferrin-binding capacities were found. The one with higher affinity was present mainly in erythroid cells and showed an association constant similar to that observed in reticulocyte populations. The component with a lower transferrin affinity was observed mainly in bone marrow fractions containing low proportions of erythroid cells.

Anemia↗
PubMed1984

The effect of progesterone on hemoglobin synthesis in suspension cultures of fetal erythroid cells from calf liver.

When fetal calf liver erythroid cells were incubated in the presence of small amounts of progesterone (10(-7)-10(-8) M), the hemoglobin synthesis in these cells was significantly increased. The increase in the amount of radioactivity in de novo synthesized hemoglobins could be demonstrated when techniques such as isoelectric focusing, chromatography on DEAE-cellulose and gel chromatography on Sephadex G-100 were used to isolate the hemoglobin fraction. Using the latter technique, it was shown that the synthesis of cytoplasmic non-hemoglobin proteins in erythroid-cell lysates was also stimulated by progesterone. The presence of hepatocytes in culture nullified the hormone action. It was necessary that progesterone was present during the first hours of culture. Delayed addition of the steroid to the cells had no effect on hemoglobin synthesis. Erythropoietin was necessary to obtain stimulation by progesterone. These results suggest that the target cell of the hormone is an erythropoietin-sensitive cell. High concentrations of progesterone (10(-4) M) strongly inhibited hemoglobin synthesis in fetal calf erythroid cells. Culture of cells under this condition, however, gives rise to a cell population that preferentially synthesizes adult hemoglobin. Our results suggest that in the erythropoietic calf liver, high concentrations of progesterone may preferentially stimulate adult hemoglobin synthesis, or that those cells which have a high capacity to synthesize adult hemoglobins are less sensitive to toxic concentrations of the hormone. The effects of stimulation of hemoglobin synthesis in fetal calf erythroid cells occur at hormone concentrations that suggest a possible physiological role of progesterone in fetal, and eventually also in maternal, erythropoiesis.

Animals↗
PubMed2000

Autophagy in embryonic erythroid cells: its role in maturation.

Yolk sac-derived embryonic erythroid cells differentiate synchronously in the peripheral blood of Syrian hamster. The stage of differentiation on day 10 of gestation is equivalent to polychromatophilic erythroblast stage and that on day 13 is equivalent to the reticulocyte stage in adult animals. The cytoplasm of embryonic erythroid cells became scant and devoid of most organelles on day 12 of gestation. In addition, there were very few non-erythroid cells in circulation before day 13. Thus the embryonic erythroid cells serve a pure and synchronous system to study the mechanisms of terminal differentiation. The number of mitochondria in the embryonic erythroid cells decreased to about 10% of the initial number during the period between day 10 and day 12 of gestation. In contrast, the frequency of autophagy of mitochondria increased 4.6-fold in the same period. The cytochrome c content of the cell decreased as the mitochondria became extinct. However, release of cytochrome c into the cytoplasm was not detectable through day 10-13 of gestation, suggesting that the mitochondria were digested within a closed compartment. Decomposed mitochondria and ferritin particles were detected in lysosomes by electron microscopy on and after day 12 of gestation, which also suggested digestion in a closed compartment. Mitochondrial ATP synthase subunit c, which is known to be a protease-refractory protein, was retained in the cells even after the disappearance of mitochondria, indicating that most of the mitochondria were not extruded from the cells. The digestion of mitochondria in autolysosomes may allow the cells to escape from rapid apoptotic cell death through concomitant removal of mitochondrial death-promoting factors such as cytochrome c.

ATP Synthetase Complexes↗
PubMed1971

Erythroid cell RNase: activation by urea and localization to the cell membrane.

Assays of ribonuclease activity in components of mature and immature mammalian erythroid cells indicate that RNase activity is present both in the membrane-free hemolysate and the washed membranes. Erythroid cell RNase exists in an active and latent form. The majority of total cell RNase activity is in the latent state, and is localized to the erythroid cell membrane. Both total and latent RNase activity decline as the cell matures. The latent RNase is released from its relatively firm attachment to the cell membrane and activated by centrifugation or, optimally, by exposure to 4 M urea. The active sites of membrane-associated RNase are apparently oriented toward the inner side of the cell membrane. The properties of the latent membrane-bound RNase which is activated by urea, including K(m), pH optimum, inhibition of enzyme activity by cations, and response to metabolic inhibitors, do not differ significantly from those of the soluble RNase in the membrane-free hemolysate, suggesting that there is only one type of RNase in the erythroid cell. Binding of Rnase to the erythroid cell membrane stabilized the enzyme against inactivation during incubation at 37 degrees C, and the findings suggest that membrane-bound RNase may play a particular part in degrading ribosomes. The findings indicate that the cell membrane has a major role in RNA metabolism in the maturing mammalian erythroid cell.

Animals↗
PubMed1989

Regulated expression of the overlapping ubiquitous and erythroid transcription units of the human porphobilinogen deaminase (PBG-D) gene introduced into non-erythroid and erythroid cells.

The human gene coding for porphobilinogen deaminase (PBG-D) is transcribed into two distinct transcription units giving two mRNAs. These units originate from two adjacent promoters distant of 3 kilobase pairs. The upstream promoter is active in all cell types, whereas the downstream promoter is active only in erythroid cells. We have studied the expression of this gene either after introduction of the corresponding human chromosome into murine erythroid cells using somatic hybrids or after transfection into both erythroid and non-erythroid cells. Using somatic hybrids, we showed that activation of the erythroid-specific promoter of the PBG-D gene did not reduce the rate of initiation of the ubiquitous promoter. Transfection experiments in erythroid cells showed that the PBG-D erythroid transcription unit, controlled by the PBG-D erythroid promoter, was correctly transcribed and regulated. Furthermore, we found that the PBG-D erythroid promoter alone was sufficient for correct expression and regulation of a reporter gene during erythroid differentiation. When the human PBG-D gene was transfected into non-erythroid cells, only the ubiquitous promoter was active. Deletion of the ubiquitous promoter did not lead to any activation of the erythroid promoter, suggesting that its inactivity in non-erythroid cells was not due to promoter occlusion but to a strict erythroid specificity.

Ammonia-Lyases↗
PubMed1977

External surface membrane proteins in normal and neoplastic murine erythroid cells.

The development pattern of one class of plasma membrane proteins, the external surface proteins, was examined in neoplastic and nonneoplastic differentiating murine erythroid cells. Neoplastic erythroid precusor cells were obtained from spleens of CD-1 mice after infection with Friend erythroleukemia virus while the nonneoplastic ellls were obtained from spleens of mice with phenylhydrazine-stimulated erythroid hyperplasia. Erythroid precursors at different stages of development were isolated from these erythroid cell populations by sedimentation at unit gravity. The surface proteins were labeled by lactoperoxidase-catalyzed iodination, solubilized in sodium dodecyl sulfate, and separated by sodium dodecyl sulfate gradient gel electrophoresis. Multiple labeled bands were found at all stages of neoplastic and nonneoplastic erythroid differentiation examined. The pattern of external membrane proteins labeled in nonneoplastic erythrocytes and in reticulocytes from peripheral blood were qualitatively similar and not altered by infection with Friend virus. The nucleated precursor cells from noninfected mice exhibited distinct differences from erythrocytes, and with increaseing differentiation an evolutionary pattern of several minor proteins was seen. Clear-cut differences in lactoperoxidast-reactive proteins were also observed between neoplastic and nonneoplastic precursors. The most marked differences were observed between the most immature cells. The youngest neoplastic cells from CD-1 mice possessed a protein with a molecular weight of 8000 not seen in normal erythroid cells. Additionally, there was an absence of a normally occurring protein with a molecular weight of 13,000 and increased amounts of a protein with a molecular weight of 140,000. With increasing maturation of the neoplastic cells, labeling of the protein with a molecular weight of 8,000 decreased while the protein with a molecular weight of 13,000 became apparent, so that a labeling pattern similar to that of nonneoplastic cells was obtained. These studies deomnstrate both distinct alterations of lactoperoxidase-reactive surface membrane proteins in nonneoplastic erythroid cells druring cell maturation in neoplastic erythroid cells as compared with nonneoplastic erythroid cells at similar stages of development.

Animals↗