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PubMed1994

Differentiation domains of the erythropoietin receptor.

Ectopic expression of the erythropoietin receptor (Epo-R) in Ba/F3, an interleukin-3 (IL-3)-dependent progenitor cell line, confers both Epo-dependent cell growth and Epo-dependent induction of beta-globin mRNA. We have used this system of limited erythroid differentiation to characterize the role of the Epo-R in differentiation. In particular, we have been interested in identifying a differentiation domain of the Epo-R. We have studied three chimeras encoding regions of the extracellular region of the Epo-R and the intracellular region of the IL-3R beta IL-3. After transfection into Ba/F3 cells, all three chimeras conferred Epo-dependent growth and induced the expression of beta-globin, suggesting that the extracellular region of the Epo-R plays a critical role in differentiation. However, a truncated Epo-R containing only the extracellular region of the Epo-R and a 15 amino acid cytoplasmic tail does not induced beta-globin expression, although it is processed to the cell surface and binds Epo. These experiments show that the extracytoplasmic region of the Epo-R is necessary but not sufficient to induce erythroid-specific differentiation in this system.

Cell Differentiation↗
PubMed2001

CD71 antibody enhances iron uptake by mouse bone marrow cells and the survival potential of erythroid progenitor cells.

Transferrin has been shown to have cytoprotective functions. The aim of this study was to evaluate the effect of antibody against CD71 (transferrin receptor) on survival potential of erythroid progenitor cells. After anti-CD71 IgG or control IgG was reacted with cells for 20 min on ice, the uptake of transferrin-bound 59Fe by the MEL cells or the mouse bone marrow cells during 2-day incubation without erythropoietin was measured. Erythropoiesis was evaluated by addition of erythropoietin after 4-5 weeks' culture without erythropoietin or beta-mercaptoethanol, and production of cells containing hemoglobin was compared by immunocytological methods. MEL cells reacted with anti-CD71 IgG incorporated more transferrin-bound 59Fe than MEL cells reacted with control IgG. Uptake of transferrin-bound 59Fe by mouse bone marrow cells reacted with anti-CD71 IgG was also greater than by cells reacted with control IgG. Erythrocytes developed from cells reacted with anti-CD71 IgG and cultured for 4-5 weeks, but few erythrocytes developed from cells reacted with control IgG. Bone marrow cells depleted of TER119+ cells, CD34+ cells, or CD45+ cells and reacted with CD71 antibody did not differentiate into erythrocytes. Survival potential of erythroid progenitor cells were enhanced by reaction with anti-CD71 antibody.

Animals↗
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↗
PubMed1999

The asymmetric distribution of interphasic silver-stained nucleolus organizer regions in human and rat proerythroblasts.

The distribution of SSPs representing AgNORs was studied in human as well as rat proerythroblasts to provide information on the distribution of these nucleolar components in highly immature and proliferating non-neoplastic cells. The distribution of SSPs was asymmetric and most of the cells contained one nucleolus which possessed a larger number of these nucleolar components than the remaining nucleoli. Such nucleolus might be functionally dominant, since the number of nucleolar SSPs is apparently related to the nucleolar biosynthetic activity. On the other hand, when a proerythroblast possessed only one nucleolus, the number of SSPs in such a cell was very similar to the sum of SSPs in a polynucleolar cell. The asymmetric distribution of SSPs characteristic for most proerythroblasts disappeared in the terminal stages of the erythroblastic development. Cells in such stages, as described previously, were characterized by the presence of a limited number of single SSPs.

Animals↗
PubMed2000

Selectively increased growth of fetal hemoglobin-expressing adult erythroid progenitors after brief treatment of early progenitors with transforming growth factor beta.

We have studied the effect of transforming growth factor beta (TGFbeta) on erythropoiesis in cultures from adult peripheral blood, using flow cytometric enumeration of fetal hemoglobin (HbF)-containing cells. TGFbeta caused a dramatic increase in the proportions of cells that accumulated HbF together with adult hemoglobin (HbA) (F+A+ cells). This highly significant (P <.0001) increase in F+ cell proportion was achieved by TGFbeta treatment during the first 4 days of culture and was sustained during further culture expansion in the absence of TGFbeta. The increase in F+ cell proportions did not depend on the cytokine combination (EPO+SCF+IL3, EPO+SCF, EPO+IL3, SCF+IL3) used during the phase of TGFbeta treatment. Increased F+ cell proportions were paralleled by an increased molecular ratio of HbF/ HbF+ HbA, measured by cation exchange high-performance liquid chromatography (HPLC). In addition to the effect on F+ cell proportions, TGFbeta caused a dramatic increase in overall cell division potential. By the time cultures reached terminal growth arrest (12-14 days in controls and 18-26 days after TGFbeta), the overall numbers of F+ cells produced per initially seeded clonogenic cell was approximately 10 times higher in the TGFbeta-treated cultures than in the controls. We propose to investigate whether the TGFbeta-induced increase in relative and absolute numbers of nucleated F+ cells, as demonstrated in vitro, can be translated into increased F+ erythrocytes in vivo, allowing therapeutic application for some beta-hemoglobinopathies. (Blood. 2000;95:2967-2974)

Adult↗
PubMedDate not supplied

The effects of lithium gamma-linolenic acid in reversing LPBM5 MuLV induced suppression of hematopoietic progenitor cells in vitro.

Lithium gamma linolenic acid (Li-GLA), was evaluated for its possible role as an antiviral agent. Li-GLA 15 micrograms ml-1 was administered to both normal and LP-BM5 MuLV retroviral infected murine bone marrow cultures. After 2 weeks of treatment, numbers of progenitors being produced by infected/treated cultures were reduced to some 10% that of normal cultures. In the remaining 4 weeks, numbers of CFU-GM and BFU-E hematopoietic progenitors returned within normal range. The efficacy of Li-GLA in relieving retroviral hematopoietic bone marrow suppression correlates to a reduction in interleukin-4 (IL-4) secretion, normally elevated in association with LP-BMP5 infection. These data indicate that this reduction in bone marrow suppression of LP-BMP5 infected cells may be due to a killing of infected cells by the Li-GLA, rather than stimulating hematopoiesis as with other lithium compounds. To conclude this may indicate the possible dual effect of administration of LiGLA to virally infected individuals in reducing viral titre and to lower the toxicities associated with long term drug therapy.

Animals↗
PubMedDate not supplied

The effects of lithium in reversing hydroxyurea induced suppression of hematopoietic progenitor cells in vitro using retroviral infected long-term marrow cultures.

Lithium has been known for its ability to induce the production of hematopoietic cells following administration in vivo to minimize the toxic effects on hematopoiesis as a consequence of drug treatment. The drug hydroxyurea (HU), a ribonucleotide reductase inhibitor, has been used in the treatment of a variety of neoplastic and non-neoplastic diseases, such as cancer and sickle cell anaemia. Hydroxyurea has more recently been implicated for use in the treatment of acquired immunodeficiency syndrome (AIDS). However, its major limitations have been due to its toxicity. Hydroxyurea selectively inhibits DNA synthesis and due to its brief duration, the drug is only toxic to those cells which are selectively synthesizing DNA during the period of exposure. The most important of these toxicities, and which serves as a dose limiting factor in treatment, is the induction of bone marrow suppression. In this study we investigated the possible beneficial effects of administering lithium (LiCl) to murine leukemia virus (MuLV) infected and non-infected long term bone marrow cultures (LTBMC). These cultures were then treated with either 0.2 mM hydroxyurea, 1.0 mM LiCl, or a combination of both. Samples were collected from LTBMC supernatants at 1, 2, 3, 4, 5 and 6 weeks post-treatment. Culture supernatants were then monitored to observe their repopulation of hematopoietic progenitors. The results demonstrated the effects of lithium in restoring hydroxyurea suppressed numbers of myeloid (CFU-GM) progenitors to within a normal range and also in re-establishing erythroid (BFU-E) progenitors.

Animals↗
PubMed1998

[In vivo inductive effect of hemin on the erythroid progenitor of the normal and aplastic anemia mice].

OBJECTIVE: To investigate the in vivo effect of hemin on erythroid progenitor of the normal and aplastic anemia mice. METHODS: BFU-E and CFU-E of normal and aplastic anemia(AA) mice were assayed at different time (6 h, 12 h and 24 h) after hemin injection on a dosage of 6.50 micrograms/g body weight, and at 6 h after injection of different doses of hemin (0.65 microgram/g, 6.50 micrograms/g and 13.00 micrograms/g body weight). RESULTS: The yields of BFU-E and CFU-E from AA mice were reduced compared with that from normal mice. At 6 h after hemin injection (6.50 micrograms/g b.w.), the yields of BFU-E and CFU-E from AA mice were increased from 3 +/- 2/femur and 12 +/- 3/femur to 10 +/- 2/femur (P < 0.01) and 39 +/- 12/femur (P < 0.01), respectively, and so did the case for normal mice (for BFU-E, from 1,056 +/- 160/femur to 3,410 +/- 708/femur, P < 0.01, and for CFU-E, from 12 +/- 3/five 200x fields to 38 +/- 3/five 200x fields, P < 0.01). Low dose of hemin had no inductive effect. CONCLUSION: Hemin is a in vivo inducer of erythroid progenitors both in normal and AA mice.

Anemia, Aplastic↗
PubMed2002

Fetal and adult hemoglobin production during adult erythropoiesis: coordinate expression correlates with cell proliferation.

The design and evaluation of therapies for the sickle cell and beta-thalassemia syndromes rely on our understanding of hemoglobin accumulation during human erythropoiesis. Here we report direct measurements of hemoglobin composition and messenger RNA (mRNA) levels in cultured CD34(+) cells and correlate those measurements with studies of freshly obtained bone marrow samples. Hemoglobin levels in differentiating cells were also compared with morphologic, immunophenotypic, and cell cycle assessments. A population of large preproerythroblasts was first identified within 24 hours and became the dominant population by day 5. The transition from proerythroblast to basophilic normoblast occurred later, from days 7 to 9, and correlated with a peak of 74.1% +/- 3.9% of the cells in the S phase of cell cycle. Orthochromatic normoblasts were the dominant and final cell type by day 13. High-performance liquid chromatography-based quantitation of fetal (HbF) and adult (HbA) hemoglobin and real-time polymerase chain reaction globin mRNA quantitation demonstrated a coordinate rise in the accumulation of both proteins and mRNA among these developmentally staged populations. Quantitative analyses on freshly sorted bone marrow populations demonstrated a similar rising pattern with beta-globin and HbA as the dominant species at both early and late stages of differentiation. We found no evidence for HbF dominant populations or switching during differentiation in adult cells. Instead, rapid increases in both HbF (heterocellular) and HbA (pancellular) content were observed, which coincided with the apex in cell cycling and the proerythroblast-basophilic normoblast transition. Based on these measurements, we conclude that HbF and HbA content are regulated with the rate of proliferation during adult erythropoiesis.

Adult↗
PubMed1992

Effect of activin A on globin gene expression in purified human erythroid progenitors.

The regulatory control of human erythropoiesis through a purified protein, activin A, was examined. Previous studies using mixed populations of bone marrow cells suggested that activin A has an indirect effect on cellular proliferation and DNA synthesis of erythroid progenitors through the mediation of accessory cells. In present studies, the cultures of purified erythroid progenitors were used to examine the effect of activin A on globin gene expression. Human erythroid burst-forming units (BFU-E) were partially purified from peripheral blood, and after 8 days of culture the cells generated consisted mainly of erythroid colony-forming units (CFU-E). It was found that the subsequent 7-day cultures of these purified progenitors yielded similar numbers and size distributions of erythroid colonies, regardless of the presence of activin A in the cultures. In addition, these erythroid progenitor cells were responsive, in terms of stimulation of DNA synthesis, to the addition of erythropoietin, but not to treatment by activin A. Therefore, once the erythroid progenitors are depleted of accessory cells, activin A has little effect on both the proliferation and the DNA synthesis of these progenitors. However, when these purified erythroid progenitors were cultured in the presence of activin A, the levels of all alpha, beta, and epsilon globin transcripts and hemoglobins were significantly increased. In addition, disuccinimidyl suberate was found to chemically cross-link 125I-activin A to cell surface binding proteins (45 to 54 Kd) in both purified erythroid progenitors and K562 cells. The labeling of these binding proteins was specifically inhibited by the presence of unlabeled activin A, but not transforming growth factor-beta. These results suggest that, in addition to its indirect effect on DNA synthesis and cellular proliferation of erythroid progenitors, activin A directly affects the levels of globin mRNAs and hemoglobins in developing human erythroid cells through its specific surface binding receptor(s).

Activins↗
PubMed1992

[Function, molecular structure and gene expression regulation of erythroid differentiation factor (EDF/activin A)].

Erythroid differentiation factor (EDF), initially found as a differentiation inducer of murine erythroleukemia cells, also acts on normal erythroid progenitors in vitro and in vivo. Furthermore, it is produced endogenously and supporting in vivo erythropoiesis. EDF is structurally identical to activin A, a gonadal protein with follicle stimulating hormone releasing activity, and belongs to TGF beta superfamily. Its activity could be regulated by follistatin, a binding protein with neutralizing activity against EDF/activin A. Molecular cloning of EDF/activin A receptor cDNA has revealed its domain structure characteristic to serine/threonine kinase.

Activin Receptors↗
PubMed1992

Modulation of normal erythroid differentiation by the endogenous thyroid hormone and retinoic acid receptors: a possible target for v-erbA oncogene action.

The v-erbA oncogene, a mutated version of the thyroid hormone receptor alpha (c-erbA/TR-alpha), inhibits erythroid differentiation and constitutively represses transcription of certain erythrocyte genes, suggesting a normal function of the proto-oncogene c-erbA in erythropoiesis. Here we demonstrate that the endogenous thyroid hormone receptor alpha (c-erbA/TR-alpha) and the closely related retinoic acid receptor alpha (RAR-alpha) play a role in the regulation of normal erythroid differentiation. Retinoic acid (RA) distinctly modulated the erythroid differentiation program of normal erythroid progenitors and erythroblasts reversibly transformed by a conditional tyrosine kinase oncogene. When added pulsewise to immature cells, differentiation was accelerated while more mature cells underwent premature cell death. Thyroid hormone (T3) alone caused similar but weaker effects. Interestingly, T3 strongly enhanced the action of RA, suggesting cooperative action of the two receptors in modulating erythroid differentiation. Expression of the human RAR-alpha in receptor-negative erythroblasts conferred RA-induced regulation of differentiation to the otherwise unresponsive cells, thus showing that the RAR-alpha is essential for the RA effect. Likewise, enhanced expression of exogenous c-erbA/TR-alpha in erythroblasts rendered them susceptible to modulation of differentiation by T3, suggesting a similar function of both receptors.

Bone Marrow Cells↗
PubMed1992

Integrin expression profiles during erythroid differentiation.

To study the expression of integrins at the erythroid progenitor level we isolated selected populations of cells from human fetal liver after immunoadherence to anti-beta 2 integrin (CD18) coated plates. These CD18 adherent cells (CD18-Ad), in contrast to CD18 nonadherent cells (CD18-NAd), have a blastlike cell morphology and are highly enriched in all progenitor types (14% to 37% progenitors). By several criteria progenitor cells present in CD18-Ad cells appear to have a higher proliferative potential and diversity than the ones found in CD18-NAd, which were mostly later erythroid progenitors. Positivity of CD18-Ad cells with the common beta 2 integrin (CD18) is largely attributable to expression of alpha L (CD11a) chain, rather than alpha M (CD11b). CD11a is present in all types of progenitors, but it is selectively lost at later stages of erythroid differentiation/maturation. By contrast, CD11b appears to be virtually absent from all progenitors but it has an enhanced expression during granulomonocytic differentiation/maturation. In addition to beta 2 integrins, CD18-Ad cells express several other cytoadhesion molecules (VLA-4, VLA-5, I-CAM, H-CAM) as well as other progenitor cell antigens (CD34, HLA-DR, CD38). Cells expressing all these antigens were selectively enriched in CD18-Ad cells. Our data add new information on the regulation of CD11a and CD11b molecules in hematopoiesis and on the composite profile of integrin expression at several stages of erythroid differentiation.

Antigens, CD↗
PubMed1992

Influence of steel factor on hemoglobin synthesis in sickle cell disease.

A new hematopoietic growth factor (Steel factor) has been identified which stimulates erythroid proliferation both in vitro and in vivo. We evaluated the influence of recombinant Steel factor on hemoglobin synthesis in peripheral blood (PB) BFU-E-derived cells from normal donors by radioimmunoassay (RIA) and compared it with stimulation with GM-CSF and interleukin-3 (IL-3). Only Steel factor stimulated a significant increase in BFU-E-derived colony size and a significant increase in fetal hemoglobin (HbF) in BFU-E-derived erythroblasts from 0.49% +/- 0.27% to 6.33% +/- 1.11% in serum-deprived media and from 1.88% +/- 0.24% to 11.17% +/- 0.91% in serum. To determine whether this influence on hemoglobinization also occurred in sickle cell disease, we studied 13 patients with sickle cell disease. In serum-deprived conditions, there was a significant increase in the number and size of BFU-E-derived colonies with Steel factor that was dose-dependent. In addition, the proportion of HbF in progenitor-derived cells increased by 66% from 4.1% +/- 0.6% to 6.8% +/- 1.2% with Steel factor. In serum-containing conditions studied in 12 patients, the increase in percentage of HbF was even greater, from 10.7% +/- 0.9% in control cultures to 22.5% +/- 2.6% with Steel factor. These increases in percentage of HbF were significant and dose-dependent. An increase in percentage of HbF was observed in erythroblasts harvested on day 11, 14, and 18 of culture. A decrease in mean picograms of total Hb per cell after coculture with Steel factor was noted, suggesting that growth kinetics influenced complete hemoglobinization. In serum-deprived conditions, picograms of HbF per cell was not affected by Steel factor, and in serum-containing conditions that augment in vitro HbF production it was enhanced. Thus, Steel factor stimulated a significant increase in percentage of HbF in erythroid cells from normal donors and patients with SCA in vitro.

Anemia, Sickle Cell↗
PubMed1992

[Stem cell factor/c-kit interaction in primordial germ cell, melanoblast and hematopoietic progenitors].

Mutation at S1 or W loci are characterized by lacks of pigmentation, gametogenesis and hematopoiesis. Stem cell factor and its receptor, which is encoded by c-kit proto-oncogene, play an important role in the survival and proliferation of these primitive cells. Primordial germ cell is maintained and expanded on cells transfected with membrane-bound SCF gene. Pigmentation of mouse embryo is influenced by administration of monoclonal antibody for c-kit product, ACK 2, because of inhibition of melanoblast migration to epidermal tissue. Moreover, hematopoietic progenitors are considered to be maintained and expanded in liquid culture in the presence of SCF and other growth factors. All of these primitive cells express c-kit product and the direct action of SCF is expected. However, two types of SCF, soluble form and membrane-bound form, exist and the physiological significance of these forms in vivo remain unsolved.

Animals↗