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PubMed1990

Forskolin as an activator of adenylate cyclase complex of differentiating erythroid bone-marrow cells.

The study concerns the manner in which forskolin activates the adenylate cyclase system of differentiating rabbit bone-marrow erythroid cells. The results presented show that forskolin can stimulate the basal activity of adenylate cyclase in the absence of guanine nucleotides in an in vitro assay containing plasma membranes derived from both dividing and non-dividing cells. In the presence of guanine nucleotide the activation of adenylate cyclase by forskolin is increased, but the effect is not additive and is abolished by the beta-thio analogue of GDP. Addition of forskolin to cell cultures causes a transient increase in the activity of adenylate cyclase, which is maximal by 30 minutes and disappears within 24 hours. The conclusion is made that the effect of forskolin on adenylate cyclase complex of differentiating rabbit bone-marrow erythroblasts is similar to the effect of erythropoietin (Bonanou-Tzedaki et al., 1986) and is transdusing via stimulatory guanine nucleotide-regulatory protein.

Adenylyl Cyclases↗
PubMed1990

[Classification of erythroblastic islets of the bone marrow and the study of their cellular composition].

Cell composition of erythroblastic islands (EI), normal and at the phase of stimulation and inhibition of erythropoiesis at modelling of heat adaptation has been studied on hemopoietic tissue of 108 rats. In the hemopoietic tissue, together with EI of the 1st, 2nd and 3d classes of maturity, that have in their composition correspondingly up to 8, from 9 up to 16 and above 16 nuclei-containing erythroid cells, there are involutive and reconstructing EI. The involutive EI are presented as nuclei-containing erythroid cells, that are not able to divide and are at late stages of differentiation: polychromatophilic and oxyphilic normoblasts, as well as reticulocytes. The reconstructing EI have in their composition both erythroid cells, that are not able to divide, and erythroid cells (pro-, erythroblasts and basophilic normoblasts), that are at early stages of differentiation. Application of the EI classification suggested, takes into account the rate, with which the erythroid cell-predecessors are drawn into erythropoiesis and intensity of erythroid differentiation. Therefore, it is possible to obtain earlier and more exact data on the state of hemopoiesis in comparison with traditional hematological methods.

Animals↗
PubMed1990

Erythropoietin fails to reverse the anemia in mice continuously exposed to tumor necrosis factor-alpha in vivo.

Tumor necrosis factor-alpha (TNF) is a monokine produced by activated macrophages that has cytotoxic and cytostatic effects on erythroid progenitor cells. We have recently shown that Chinese hamster ovary cells transfected with the human TNF gene and which constitutively express TNF induced a hypoproliferative anemia, mild thrombocytopenia, and mild leukocytosis when injected into nude mice. We have used this murine model to determine if treatment with recombinant human erythropoietin can prevent or ameliorate the anemia seen with long-term continuous exposure to high concentrations of TNF. Mice bearing TNF-producing tumors became anemic with hematocrits ranging from 30% to 32%. Treatment with recombinant human erythropoietin (100-1000 U/kg body weight three times per week) increased the reticulocyte counts initially in mice bearing TNF-producing tumors but failed to reverse the anemia seen in these animals. Erythropoietin did not significantly increase the number of marrow erythroid colony-forming units (CFU-E) or erythroid burst-forming units (BFU-E) in mice bearing TNF-producing tumors. The data suggest that erythropoietin could not sufficiently overcome the decreased number of erythroid progenitors in mice bearing tumors producing high levels of TNF to correct their anemia.

Anemia↗
PubMed1989

On the induction of fetal hemoglobin by butyrates: in vivo and in vitro studies with sodium butyrate and comparison of combination treatments with 5-AzaC and AraC.

To obtain information on the cellular mechanism of induction of fetal hemoglobin (HbF) by sodium butyrate (NaB), we treated adult baboons with NaB and assessed its effects on HbF expression. Infusion of NaB increased F reticulocytes and F-positive CFUe and e-cluster colonies without induction of reticulocytosis or increase in progenitor cell numbers. Addition of NaB in bone marrow cultures increased the frequency of F-positive CFUe and e-clusters without increasing progenitor cell numbers. NaB induced HbF in human adult BFUe cultures and increased the gamma/gamma + beta globin chain and mRNA ratios in short-term incubations of culture-derived erythroblasts. There was a synergistic induction of HbF by NaB and 5-azacytidine (5-azaC), but not when the animal was treated with NaB and cytarabine (AraC). Our results suggest that the activation of gamma-globin expression by NaB reflects an action of this compound on globin genes or globin chromatin.

Aminobutyrates↗
PubMed1989

Metabolic development in erythropoietin-dependent maturation of erythroid cells.

1. Metabolic development was investigated in splenic erythroblasts isolated from Friend virus infected mice and maintained in culture with erythropoietin. 2. We found that immature erythroid cells not only possess a highly oxidative metabolism, but also glycolytic activity, both of which decrease drastically in the course of maturation. 3. Most purine and pyrimidine compounds which are found in immature erythroid cells are still present in mature erythrocytes. 4. While total adenine nucleotide levels fall, the 2,3-DPG pool increases during erythroid development.

Animals↗
PubMed1994

The acute-phase protein alpha 1-antitrypsin inhibits growth and proliferation of human early erythroid progenitor cells (burst-forming units-erythroid) and of human erythroleukemic cells (K562) in vitro by interfering with transferrin iron uptake.

We have previously shown that the hepatic acute-phase protein alpha 1-antitrypsin (alpha 1-AT) inhibits transferrin (tf) binding to its receptor (tfR) of human placental membranes. To evaluate the possibility that this interaction can explain the pathophysiology of the changes in iron metabolism in the course of chronic disease, subsequently leading to anemia in chronic disease (ACD), we examined the effect of alpha 1-AT on cells of the erythroid cell line. alpha 1-AT completely prevented tf binding to tfR on K562 human erythroleukemic cells and on reticulocytes. This inhibitory potency was dose-dependent and competitive, as proved in equilibrium saturation and kinetic studies. The cytokines interleukin-1 (IL-1), IL-6, and tumor necrosis factor alpha showed no such effect. Internalization of the tf-tfR complex was inhibited with alpha 1-AT in a dose-dependent manner. Furthermore, alpha 1-AT profoundly reduced the growth of K562 cells as well as their proliferation, albeit to a lesser degree. Growth of early erythroid progenitor cells (burst-forming units-erythroid) was significantly suppressed by alpha 1-AT, but no effect on the growth of late erythroid progenitor cells (colony-forming units-erythroid) was detected. These inhibitions of alpha 1-AT were seen in high physiologic concentrations attained in the course of acute-phase situations. These data show that alpha 1-AT might be a mediator of the changes in iron metabolism that are characteristic of clinical findings in the course of ACD.

Acute-Phase Proteins↗
PubMed1995

Interferon-alpha-induced apoptosis in human erythroid progenitors.

Recombinant human interferon-alpha (rIFN-alpha) inhibits erythropoiesis, in vivo and in vitro. In an attempt to clarify mechanisms related to this inhibition, effects of rIFN-alpha on highly purified human peripheral blood burst-forming units-erythroid (BFU-E) (20-60% purity) were compared with effects on erythroid progenitors in various stages of development. Day-1 and -7 cultured cells were equivalent to primitive BFU-E and colony-forming units-erythroid (CFU-E), respectively. Day-1 BFU-E supported by recombinant human erythropoietin (rEpo) and interleukin-3 (rIL-3) was inhibited by rIFN-alpha in a dose-dependent manner, and a significant inhibition occurred at 2000 U/mL rIFN-alpha. Limiting dilution analysis demonstrated that rIFN-alpha directly inhibits BFU-E rIFN-alpha inhibited the proliferative capacity or the colony expression of erythroid progenitors, with no relation to the stage of development, but inhibition of differentiation was not apparent. This evidence suggested that apoptosis of erythroid progenitors was induced by IFN-alpha. When day-7 cells were incubated with IFN-alpha in the presence of rEpo, there was an increased breakdown of total cellular DNA into DNA fragments of less than 5 kb; hence, the inhibitory effect of IFN-alpha on erythroid progenitors may mediate apoptosis.

Adult↗
PubMed1995

Regulation of ferritin H-chain expression in differentiating Friend leukemia cells.

The mechanisms that regulate the expression of ferritin, the iron storage protein, have been investigated in Friend erythroleukemia cells (FLCs) induced to differentiate by several chemical compounds. In differentiating FLCs, administration of hemin increases the steady-state level of ferritin mRNA about 15-fold and the ferritin content about 20- to 25-fold. Conversely, iron salts have only mild stimulatory effects on these parameters and iron chelators only slightly inhibited the stimulatory effect of hemin. Transient transfection experiments with a construct in which the human ferritin H-chain promoter drives the expression of the indicator chloramphenicol acetyltransferase (CAT) gene show that the increase in mRNA content is mainly due to enhanced transcription. In addition to transcriptional effects, translational regulation resulting in the further increase in ferritin synthesis is shown by CAT assays from cells transiently transfected with a construct containing the coding region for the indicator CAT mRNA under the translational control of the mRNA ferritin iron-responsive element. We conclude that, in FLCs induced to differentiate, hemin acts synergistically with the differentiation inducers, increasing ferritin expression. Both transcriptional and translational mechanisms are responsible for this synergistic effect, which appears to be characteristic of differentiated erythroid cells because it is not observed in other cell types (ie, fibroblastic cell lines).

Acetamides↗
PubMed1993

In vivo administration of stem cell factor to mice increases the absolute number of pluripotent hematopoietic stem cells.

We have examined the effects of administration of stem cell-factor (SCF) on the number and distribution of pluripotent hematopoietic stem cells (PHSC) in normal mice. Using the competitive repopulation assay we found that in vivo administration of SCF increases the absolute number of PHSC per mouse threefold. The increased numbers of PHSC are found in the peripheral blood and spleen of the SCF-treated animals. The spleen and peripheral blood stem cells completely repopulated the erythroid, myeloid, and lymphoid lineages of irradiated or W/Wv hosts, similar to bone marrow PHSC. PHSC from the peripheral blood of SCF-treated mice have a lineage marker-negative, c-kit-positive phenotype that is indistinguishable from that of bone marrow PHSC. The increase in the absolute number of spleen PHSC is associated with efficient gene transfer to these cells without prior treatment with 5-fluorouracil. This is a US government work. There are no restrictions on its use.

Animals↗
PubMed1993

Regulated expression of K+ channel genes in electrically silent mammalian cells by linkage to beta-globin gene-activation elements.

Fundamental studies of the mechanism of human beta-like globin gene-expression have identified DNA sequences (locus control regions or LCRs) which directly influence the specific activation of beta-globin genes in erythroid cells. Here we report the first applications of LCR-mediated gene-activation to stable electrophysiological expression of several homomultimeric ion channel proteins. We describe expression driven from a native K+ channel gene promoter region, contiguous to an intronless coding sequence, within a single excised human genomic DNA fragment. In addition, cDNAs encoding both inactivating and non-inactivating mammalian K+ currents have been expressed by insertion between the promoter and second intron of the human beta-globin gene. Expression levels are characteristically independent of integration position and are proportional to LCR-gene copy number, a parameter specific for each clonal cell line. K+ channel expression is inducible by erythroid differentiation and has been demonstrated by electrophysiological recordings of cells taken directly from culture.

Amino Acid Sequence↗
PubMed1993

[Acute basophilic leukemia with an intense erythroblastic reaction].

A patient is presented who had acute basophilic leukaemia with intense erythroblastic reaction. The patient, a 66 year-old man, complained of general malaise, increased abdominal perimeter and melena. Leucocytosis, as well as severe anaemia and thrombocytopenia, were found in his peripheral blood. Basophils were present in all maturation stages, along with 7% blast-cells showing basophilic stippling, and there were 210 erythroblasts per 100 white cells. Erythropoietic hyperplasia (75%) was found in the bone-marrow aspirate, without dyserythropoietic signs; the PAS-stain reaction was negative. Of the non-erythroid cells, 63% were basophils and 34% blast-cells, some of them showing basophilic stippling plus metachromasia for tholuidin-blue, positivity for omegaexonuclease and negativity for peroxidase stains. The diagnosis of acute basophilic leukaemia was confirmed upon demonstration of basophilic stippling in the ultrastructural study of the blast-cells. The patient developed acute liver failure and renal insufficiency which led him to death. The basis of the diagnosis of acute basophilic leukaemia is discussed, as well as the differential diagnosis with other conditions presenting with basophilia and the probably reactive erythroblastic increase appearing in this case.

Aged↗
PubMed1994

Myelosuppressive effects in vivo with very low dosages of monomeric recombinant murine macrophage inflammatory protein-1 alpha.

Macrophage inflammatory protein (MIP)-1 alpha has myelosuppressive/myeloprotective effects in vivo in mice. We recently reported that > 99.7% of recombinant murine (rm) MIP-1 alpha polymerizes rapidly at relatively high concentrations in physiological salt solution, and it is the monomeric form of MIP-1 alpha that is active in vitro as a myelosuppressive factor. Polymerized MIP-1 alpha is inactive in this effect and does not block the myelosuppressive action of monomeric MIP-1 alpha. MIP-1 alpha could be maintained in monomeric form in physiological saline if diluted to low concentrations. This led us to reevaluate the actual amounts of MIP-1 alpha necessary for myelosuppression in vivo. C3H/HeJ mice were injected intravenously (i.v.) with monomeric rmMIP-1 alpha or control diluent and effects were evaluated on progenitor cells--multipotent colony-forming units (CFU-GEMM), burst-forming units-erythroid (BFU-E), and colony-forming units-granulocyte/macrophage (CFU-GM)--as described in previous studies in which MIP-1 alpha concentrations were used that we now know to have been mainly in polymerized form. Monomeric MIP-1 alpha rapidly decreased cycling rates and absolute numbers of myeloid progenitor cells in marrow and spleen. These effects, which occurred with about 1000-fold less MIP-1 alpha than we previously reported, were dose-dependent, time-related, and reversible. Suppressive effects were noted within 3 hours for cell cycling and within 24 hours for absolute numbers of progenitor cells in marrow and spleen and were lost by 48 hours. Decreased circulating neutrophils were noted at 48 hours. Column-separated polymerized rmMIP-1 alpha was inactive in vivo. These results demonstrate the potency of low doses of monomeric MIP-1 alpha in vivo. Since clinical administration of large amounts of an agent that is mainly in an inactive form may result in severe pharmacological side effects, the information presented here is of relevance for potential clinical trials using MIP-1 alpha as a myelosuppressive/myeloprotective agent.

Animals↗
PubMed1993

Effect of Cordyceps sinensis on erythropoiesis in mouse bone marrow.

The effect of Cordyceps sinensis crystal (CS-Cr) on stimulating proliferation of erythroid progenitor cells (CFU-E and BFU-E) in LACA mouse marrow in vivo and in vitro by methyl cellulose gel culture system is reported. The numbers of CFU-E and BFU-E were increased after 5 consecutive daily treatment with 100, 150 and 200 mg/kg of CS-Cr with a peak at 150 mg/kg. Higher doses (> 150 mg/kg) of CS-Cr resulted in a reduction of the peak of CFU-E and BFU-E and then, the numbers returned to the control level with increased doses. The cytosine arabinoside (Ara-C) suicide test showed significant increases in the percentage of CFU-E and BFU-E in S-phase after CS-Cr treatment. Pretreatment of mice with CS-Cr could protect CFU-E and BFU-E against the cytotoxic agent--harringtonine. Addition of CS-Cr to culture system also promoted the generation of CFU-E and BFU-E at concentrations of 150-200 micrograms/ml in vitro. With a liquid culture technique, a stimulatory action of CS-Cr on fibroblast colony-forming units (CFU-F) proliferation was seen in vivo and in vitro.

Animals↗
PubMed1993

Expression of membrane-bound burst-promoting activity is mediated by allogeneic effector cells.

To investigate whether "self" and "non-self" recognition processes are involved in murine erythropoiesis, the expression of membrane-bound burst-promoting activity (mBPA) was determined for B lymphocytes purified from spleens of CF-1, C57 BL/6J, B6021-7115, and CAF-1J mice using syngeneic and allogeneic bone marrow cultures. Addition of B lymphocyte conditioned medium (LCM), shed membrane-derived vesicles, or intact plasma membranes prepared from syngeneic murine cells stimulated erythroid burst-forming unit (BFU-E) proliferation by two- to three-fold above control levels. BFU-E proliferation was increased by six- to eight-fold, however, when LCM, shed membrane vesicles, or plasma membranes purified from allogenic B lymphocytes were used as sources of growth-stimulatory activity. Bioactivity was immunoprecipitated from detergent extracts of membranes purified from both allogeneic and syngeneic lymphocytes with a monoclonal antibody that specifically recognizes mBPA, suggesting that the factors expressed by these cells share antigenic determinants. The results indicate that allogeneic effector cells are a more potent source of mBPA-like molecules than are syngeneic cells, suggesting that immune mechanisms may be involved in inducing erythroid growth factor expression at the B cell surface.

Animals↗
PubMed1993

In vivo and in vitro effects of 3-hydroxypyridin-4-one chelators on murine hemopoiesis.

The effects of 3-hydroxypyridin-4-one (HPO) iron chelators and desferrioxamine (DFO) on murine hemopoiesis in vivo and in vitro have been compared in order to investigate the mechanism by which leucopenia in mice and granulocytopenia in man occurs with 1,2-,dimethyl-HPO (CP20). Administration of 60 doses of 200 mg/kg CP20 to Balb/c mice resulted in significant anemia, lymphopenia and granulocytopenia accompanied by bone marrow hypocellularity. DFO and CP94 (1,2,diethyl-HPO) at the same dose also caused lymphopenia but marrow cellularity was unaffected. When marrow from untreated mice was incubated with HPOs and DFO, erythroid burst-forming cells (BFU-E) and granulocyte/macrophage colony forming units (CFU-G+Mac), colony growth was inhibited in a dose-dependent manner at micromolar concentrations. The addition of iron to saturate the chelators abrogated the effects of DFO, but not those of the HPOs. With the HPO-iron complexes, addition of sufficient iron to saturate the transferrin in the medium reversed the inhibitory effects of the relatively hydrophilic CP20-iron complex but not those of the more lipophilic CP94-iron complex. Addition of further iron-saturated transferrin also corrected inhibition by the CP94-iron complex. These results show that HPO-iron complexes potentially have antiproliferative effects unlike DFO-iron complex (FO). The difference in the relative effects of CP20 to CP94 on hemopoiesis in vivo and in vitro suggests that additional factors to those inhibiting hemopoiesis in marrow cultures may operate with the long-term administration of iron chelators in vivo.

Animals↗
PubMed1993

Dynamics of erythropoietic recovery following bone marrow transplantation: role of marrow proliferative capacity and erythropoietin production in autologous versus allogeneic transplants.

The mechanisms of erythrocyte recovery after BMT are not known. We investigated the respective role of marrow function and erythropoietin production in 31 ABMT and 47 allogeneic BMT by analysing peripheral counts, serum erythropoietin levels, and serum transferrin receptor (TfR) levels which have been shown to be a quantitative measurement of erythropoiesis. Median times to complete neutrophil (25 vs 48 days, p < 0.0001) and platelet (45 vs 263 days, p < 0.001) recovery were faster after allogeneic BMT than ABMT, but complete erythrocyte recovery was slower (218 vs 101 days, p < 0.001). After ABMT, erythrocyte recovery paralleled that of neutrophils and platelets, and erythropoietin levels remained appropriate for the degree of anemia. After allogeneic BMT, erythrocytes developed independently of the other cell lines and defective erythropoietin production delayed recovery of adequate erythropoietic activity. This correlated with an alteration of renal function only in those patients remaining erythropoietin deficient beyond day 180. However, supranormal erythropoietin levels in interstitial pneumonia suggests that erythropoietin response to hypoxia is not abrogated. CMV infection could also affect erythropoiesis through erythropoietin production after ABMT as well as allogeneic BMT. It is concluded that after ABMT the development of erythropoiesis is determined by the overall marrow proliferative activity and erythropoietin plays only a facilitating role. After allogeneic BMT, erythropoiesis depends on erythropoietin levels which remain inadequate for prolonged periods of time. The results suggest that the administration of recombinant human erythropoietin could reduce transfusion requirements after BMT.

Adolescent↗
PubMed1996

Insights into the cellular mechanisms of erythropoietin-thrombopoietin synergy.

Using suspension cultures of purified bone marrow CD34+ cells, we have analyzed the effects of the combination of erythropoietin (Epo) and thrombopoietin (Tpo) on the in vitro differentiation toward erythropoiesis and thrombopoiesis. The number of CD41+ cells that accumulated over 2 weeks of culture, as well as the number of globin+ cells in the same cultures, was found to be significantly higher with the Epo+Tpo combination compared to either cytokine alone. No evidence was found that Tpo affected the differentiative action of Epo. Instead, there was a significant expansion of erythroid progenitors, both erythroid colony-forming and burst-forming units (CRU-E and BFU-E), by 7 days in culture, suggesting a proliferative effect of Tpo on erythroid cells in vitro. To determine the phenotypic features of erythroid progenitor cells which were targets of Tpo's action, and specifically to inquire whether the effect was directed mainly toward bipotent erythroid/megakaryocytic (E+Mk) progenitors, we isolated subsets enriched for both erythroid and megakaryocytic progenitors from CD34+ cells. We found that 1) BFU-E and CFU-Mk co-segregate in the subset of CF34+ cells that is negative for the phosphatase isoform CD45RA; 2) the presence of CD41 on this subset appears to segregate late erythroid and late CFU-Mk from early erythroid and early CFU-Mk, which are CD41-negative; 3) bipotent erythroid/Mk progenitors, studied by single-cell culture assays, were found mainly in the CD41+ and rarely in the CD41- subsets which included more multipotent progenitors; 4) by comparing the frequencies of pure erythroid or pure megakaryocytic progenitors to that of bipotent E+Mk progenitors, we conclude that the erythroid-enhancing effect of Tpo is directed mainly toward pure erythroid progenitors expressing CD41 and Mpl, as suggested by independent experiments employing anti-Mpl antibody, rather than only on bipotent E+Mk progenitors.

Antigens, CD34↗
PubMedDate not supplied

[A new class of small RNP (alpha-RNP) containing antisense RNA in K-562 cells. I. Their characteristics and changes during erythroid differentiation].

A new class of small RNP (alpha-RNP) has been detected and identified in nuclei and cytoplasm of A-562 erythroid leukemia cell line; these RNPs have a characteristic spectrum of proteins containing conservative and specific components and a special RNA component, which contains a small antisense component (alpha-RNA), a homolog of short dispersed Alu repeats. alpha-RNP is highly stable, tightly associated with chromatin in the nucleus, and is found in the free state in cytoplasm. The composition of nuclear and cytoplasmic alpha-RNP differ and have a specific pattern of changes in response to dimethylsulfoxide, an agent causing differentiation.

Cell Differentiation↗