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PubMed1996

Effects of spaceflight on rat erythroid parameters.

Hematologic studies were performed on 21 ground control rats and 21 rats flown during the Spacelab Life Sciences-2 14-day mission. Group A (n = 5) was used to collect blood in flight and 9 days postflight, group B (n = 5) was injected with recombinant human erythropoietin (rhEpo), group C (n = 5) received saline as a control, and group D (n = 6) was killed in flight and tissues were collected. Results indicated no significant changes in peripheral blood erythroid elements between flight and ground control rats. The nonadherent bone marrow on flight day 13 showed a lower number of recombinant rat interleukin-3 (rrIL-3)-responsive and rrIL-3 + rhEpo-responsive blast-forming unit erythroid (BFU-e) colonies in flight rats compared with ground control rats. On landing day, a slight increase in the number of rhEpo + rrIL-3-responsive BFU-e colonies of flight animals compared with ground control rats was evident. Nine days postflight, bone marrow from flight rats stimulated with rhEpo alone or with rhEpo + rrIL-3 showed an increase in the number of colony-forming unit erythroid colonies and a decrease in BFU-e colonies compared with ground control rats. This is the first time that animals were injected with rhEpo and subsequently blood and tissues were collected during the spaceflight to study the regulation of erythropoiesis in microgravity.

Animals↗

PubMed1996

Adhesion of human hematopoietic progenitor cells to bone-marrow-derived stromal cells is enhanced by antibodies to CD44.

It has been suggested that CD44 mediates adhesive interactions between hematopoietic progenitor cells and the stromal microenvironment. Ligands of CD44 include several extracellular matrix components, such as hyaluronic acid and fibronectin. Antibodies against CD44 have been shown to induce homotypic T cell aggregation, and to stimulate T and natural killer cell activity. We hypothesized that CD44 could similarly amplify interactions between blast-colony-forming cells and bone marrow stromal cells (BMSCs). Indeed, we have previously found that the anti-CD44 antibody NKI-P2 enhanced VLA-4-dependent interactions. Here, we studied an additional panel of nineteen anti-CD44 antibodies from the 5th Workshop on Leukocyte Differentiation antigens, to find out whether amplification was associated with a particular CD44 epitope. None of these antibodies showed inhibitory activity, whereas nine significantly increased the number of blast colonies more than 2-fold. Seven of these recognized epitope 1, and two epitope 2. More than 4-fold enhancement was only observed with epitope 1 antibodies: 4.C3 (4.4-fold), 212.3 (6.3-fold), L178 (9.1-fold), and NIH44-1 (9.2-fold). Our data suggest that primarily epitope 1 is associated with enhancement of colony formation. Furthermore, the findings support a role for CD44 as an amplifier in progenitor-BMSC interactions.

Antibodies, Monoclonal↗

PubMed1991

Ethanol-induced growth inhibition of erythroleukemia stem cells. Cell cycle effects.

Friend erythroleukemia stem cells are strongly growth inhibited by 60 mM ethanol. The expression of this inhibition requires several days to develop fully, and is not relieved by washing into new ethanol-containing medium even in the presence of excess folic acid. Removal of the fully inhibited cells from ethanol results in rapid growth recovery, with the onset of recovery occurring within a few hours. Cell cycle analysis reveals a G1 delay which is evident within a few hours after initial ethanol exposure. Bivariate RNA-DNA analysis indicates that this G1 delay results from restriction in late G1. It is unclear at present whether this delay can account for all the observed growth inhibition.

Cell Cycle↗

PubMed1991

Changes in Cu,Zn-superoxide dismutase gene during induced erythroid and myeloid differentiation.

We investigated the alteration of Cu,Zn-superoxide dismutase during erythroid and myeloid differentiation in order to elucidate its physiological significance in different types of cells. We measured enzyme activity and mRNA levels of superoxide dismutase in the process of differentiation to erythroid cells or myeloid cells. When human leukemia K562 cells are incubated in the presence of 80 microM hemin, benzidine-positive cells appear on day 1 and 80% of the cells become positive on day 5. During hemin-induced erythroid differentiation, Cu,Zn-superoxide dismutase activity increases 3.5-fold of the initial value and mRNA for Cu,Zn-superoxide dismutase increases prior to the activity to the same extent. On the other hand, when human promyelocytic leukemia HL-60 cells are incubated in the presence of 1.3% dimethyl sulfoxide, nitroblue tetrazolium-positive cells reach approximately 90% on day 5. During dimethyl sulfoxide-induced myeloid differentiation, the activity of Cu,Zn-superoxide dismutase decreases below 15% of the initial value on day 5 and mRNA for Cu,Zn-superoxide dismutase decreases as well. The results indicate that the synthesis of superoxide dismutase is linked with either the erythroid or myeloid differentiation program.

Blotting, Southern↗

PubMed1996

Erythroblastopenia associated with methylmalonic aciduria. Case report and in vitro studies.

Various cytopenias, including neutropenia, thrombocytopenia and pancytopenia, have been reported in association with inborn errors of branched amino acid metabolism. We report here on a case of anemia associated with erythroblastopenia-that is less frequent in this context-in a neonate with methylmalonic aciduria. We used a semisolid erythroid culture system to investigate the effect on in vitro erythropoiesis of organic acids found in excess in this patient: methylmalonic (MMA) and propionic (PA) acids. First, the addition of 10% serum of the patient to a normal bone marrow progenitor culture suppressed the erythrocyte colony-forming unit growth in comparison to a pool of normal serum, while the addition of a 1:1 mixture of normal and patient serum resulted in an intermediate inhibition. MMA, when added to culture medium, resulted in a moderate inhibition of erythropoiesis only at a higher concentration than observed in our patient or reported in other cases. Conversely, PA showed an inhibitory effect at a concentration commonly observed in methylmalonic aciduria. The same effect was observed when the cells were in the presence of PA only for 72 h and then secondly plated in semisolid culture. Neither MMA nor PA showed any effect on the cell number and viability after a 3-, 4- or 7-day incubation except at the highest concentration tested.

Amino Acid Metabolism, Inborn Errors↗

PubMedDate not supplied

Cytokine stimulation of human fetal hematopoietic cells.

The effects of interleukins 3 and 6, stem cell factor, and granulocyte-macrophage colony-stimulating factor on human fetal hematopoietic, bone marrow, and cord blood cells were studied on the basis of the colony-forming capacity. Fetal hematopoietic cells from 28 elective abortions, three bone marrow samples, and three cord blond samples were incubated with cytokines and investigated for the presence of BFU-E (burst-forming units--erythroid), CFU-GM (colony-forming units--granulocytes, macrophages), and CFU-GEMM (colony-forming units--granulocytes, erythrocytes, macrophages, megakaryocytes). Single and combined cytokines and preincubation versus adding cytokines in culture were investigated. Interleukin-6 alone had the most pronounced effect on BFU-E formation. All four cytokines in combination yielded the highest scores for CFU-GM (p < 0.05) and CFU-GEMM (p < 0.05), whereas BFU-E was not enhanced. The mode of cytokine exposure was not a determinant of colony formation.

Bone Marrow Cells↗

PubMed1994

Distinct roles of erythropoietin, insulin-like growth factor I, and stem cell factor in the development of erythroid progenitor cells.

Erythropoietin (EP), insulin-like growth factor I (IGF-I) and stem cell factor (SCF) each reduce apoptosis of human erythroid progenitor cells. To determine if these growth factors have additional roles in stimulating erythropoiesis, the proliferation, maturation, and survival of highly purified human erythroid colony-forming cells (ECFCs) were studied during the application of different combinations of these growth factors in a serum-free liquid culture. EP maintained cell viability and supported heme synthesis during erythroid maturation, with little increase in viable cell number or stimulation of DNA synthesis. The addition of SCF with EP resulted in a substantial increase in DNA synthesis, which was greater than that seen with the addition of EP and was associated with a large expansion in the number of ECFCs. Thus EP, by itself, produces little increase in cell proliferation, and expansion of the number of erythroid cells depends upon the presence of SCF with EP. The addition of IGF-I with EP led to enhanced heme synthesis and moderate cellular proliferation, but also greatly enhanced nuclear condensation and enucleation in the late erythroblasts. Thus EP, by itself, is not sufficient for complete end-terminal nuclear condensation/enucleation and the presence of IGF-I is necessary for this complete process. While EP greatly reduced apoptosis during 16 h of incubation at 37 degrees C, the addition of SCF and IGF-I with EP had little additional effect, but these additions enhanced DNA synthesis > 3.4-fold. Thus SCF may have an additional role in directly stimulating proliferation through a process that is distinct from apoptosis. Our observations indicate that EP prevents apoptosis and maintains erythroid cell viability and development. IGF-I enhances erythroid maturation and proliferation, but the proliferation of erythroid progenitors is mainly controlled by the addition of SCF with EP, independent of an effect on apoptosis.

Apoptosis↗

PubMed2002

Anemia of chronic disease in rheumatoid arthritis is associated with increased apoptosis of bone marrow erythroid cells: improvement following anti-tumor necrosis factor-alpha antibody therapy.

Circumstantial evidence has implicated tumor necrosis factor alpha (TNF-alpha) in the pathogenesis of anemia of chronic disease (ACD) in rheumatoid arthritis (RA). We investigated the role of TNF-alpha in erythropoiesis of patients with active RA (n = 40) and the effect of anti-TNF-alpha antibody administration (cA2). Patients with RA had lower numbers of CD34+/CD71+ and CD36-/glycophorin A+ (glycoA+) bone marrow (BM) cells and increased proportions of apoptotic cells within the CD34+/CD71+ and CD36+/glycoA+ cell compartments, compared to healthy controls (n = 24). Erythroid burst-forming units (BFU-Es) obtained by BM mononuclear or purified CD34+ cells were significantly lower in RA patients compared to controls. These abnormalities were more pronounced among patients with ACD. Increased TNF-alpha levels in patient long-term BM culture supernatants inversely correlated with BFU-Es and hemoglobin levels and positively with the percentage of apoptotic CD34+/CD71+ and CD36+/glycoA+ cells. Following cA2 therapy, a normalization was documented in the number of CD34+/CD71+ and CD36-/glycoA+ cells, the number of BFU-Es, and the proportion of apoptotic CD34+/CD71+ and CD36+/glycoA+ cells, which was associated with a significant increase in hemoglobin levels compared to baseline. Recovery from anemia was more prominent in patients with ACD. The exogenous addition of an anti-TNF-alpha antibody in the cultures increased BFU-E number in patients prior to cA2 treatment but not after treatment, further substantiating the inhibitory role of TNF-alpha on patients' erythropoiesis. We conclude that TNF-alpha-mediated apoptotic depletion of BM erythroid cells may account for ACD in RA and that cA2 administration may ameliorate ACD in these patients by down-regulating the apoptotic mechanisms involved in erythropoiesis.

Adolescent↗

PubMed2002

Induction of C/EBPalpha activity alters gene expression and differentiation of human CD34+ cells.

The CCAAT/enhancer binding protein alpha (C/EBPalpha) belongs to a family of transcription factors that are involved in the differentiation process of numerous tissues, including the liver and hematopoietic cells. C/EBPalpha(-/-) mice show a block in hematopoietic differentiation, with an accumulation of myeloblasts and an absence of mature granulocytes, whereas expression of C/EBPalpha in leukemia cell lines leads to granulocytic differentiation. Recently, dominant-negative mutations in the C/EBPalpha gene and down-regulation of C/EBPalpha by AML1-ETO, an AML associated fusion protein, have been identified in acute myelogenous leukemia (AML). To better understand the role of C/EBPalpha in the lineage commitment and differentiation of hematopoietic progenitors, we transduced primary human CD34(+) cells with a retroviral construct that expresses the C/EBPalpha cDNA fused in-frame with the estrogen receptor ligand-binding domain. Induction of C/EBPalpha function in primary human CD34(+) cells, by the addition of beta-estradiol, leads to granulocytic differentiation and inhibits erythrocyte differentiation. Using Affymetrix (Santa Clara, CA) oligonucleotide arrays we have identified C/EBPalpha target genes in primary human hematopoietic cells, including granulocyte-specific genes that are involved in hematopoietic differentiation and inhibitor of differentiation 1 (Id1), a transcriptional repressor known to interfere with erythrocyte differentiation. Given the known differences in murine and human promoter regulatory sequences, this inducible system allows the identification of transcription factor target genes in a physiologic, human hematopoietic progenitor cell background.

Binding Sites↗

PubMed2003

Alpha5beta1 integrin as a cellular coreceptor for human parvovirus B19: requirement of functional activation of beta1 integrin for viral entry.

Replication of the pathogenic human parvovirus B19 is restricted to erythroid progenitor cells. Although blood group P antigen has been reported to be the cell surface receptor for parvovirus B19, a number of nonerythroid cells, which express P antigen, are not permissive for parvovirus B19 infection. We have documented that P antigen is necessary for parvovirus B19 binding but not sufficient for virus entry into cells. To test whether parvovirus B19 utilizes a cell surface coreceptor for entry, we used human erythroleukemia cells (K562), which allow parvovirus B19 binding but not entry. We report here that upon treatment with phorbol esters, K562 cells become adherent and permissive for parvovirus B19 entry, which is mediated by alpha 5 beta 1 integrins, but only in their high-affinity conformation. Mature human red blood cells (RBCs), which express high levels of P antigen, but not alpha 5 beta 1 integrins, bind parvovirus B19 but do not allow viral entry. In contrast, primary human erythroid progenitor cells express high levels of both P antigen and alpha 5 beta 1 integrins and allow beta1 integrin-mediated entry of parvovirus B19. Thus, in a natural course of infection, RBCs are likely exploited for a highly efficient systemic dissemination of parvovirus B19.

Cell Adhesion↗

PubMed2004

PU.1 determines the self-renewal capacity of erythroid progenitor cells.

PU.1 is a hematopoietic-specific transcriptional activator that is absolutely required for the differentiation of B lymphocytes and myeloid-lineage cells. Although PU.1 is also expressed by early erythroid progenitor cells, its role in erythropoiesis, if any, is unknown. To investigate the relevance of PU.1 in erythropoiesis, we produced a line of PU.1-deficient mice carrying a green fluorescent protein reporter at this locus. We report here that PU.1 is tightly regulated during differentiation-it is expressed at low levels in erythroid progenitor cells and down-regulated upon terminal differentiation. Strikingly, PU.1-deficient fetal erythroid progenitors lose their self-renewal capacity and undergo proliferation arrest, premature differentiation, and apoptosis. In adult mice lacking one PU.1 allele, similar defects are detected following stress-induced erythropoiesis. These studies identify PU.1 as a novel and critical regulator of erythropoiesis and highlight the versatility of this transcription factor in promoting or preventing differentiation depending on the hematopoietic lineage.

Animals↗

PubMed2004

Rescue of lethal c-KitW/W mice by erythropoietin.

Homozygous natural white-spotted (W) mutations in the gene encoding the receptor tyrosine kinase c-Kit are associated with hypoplastic bone marrow, severe macrocytic anemia, and lethality during early postnatal life. c-Kit(W/W) mice can be rescued by wild-type hematopoietic stem cells (HSCs), but it is not known whether the lethality of c-Kit(W/W) mice is the result of HSC failure or defects specific for erythropoiesis. Here we show that transgenic expression of erythropoietin (EPO) can overcome the lethality caused by the c-Kit(W/W) mutation. In W mutant mice rescued by EPO, termed WEPO, erythrocyte colony-forming units (CFU-Es) are rescued to normal frequencies. Hence, Epo receptor signals can partially bypass the strict requirement for c-Kit signaling in erythropoiesis in the absence of c-Kit in vivo. Using a series of W and rescue mouse strains, we define here the erythropoietic threshold permitting survival in vivo. The lethality of c-Kit(W/W) mice has precluded analysis of this crucial receptor-ligand pair in adult stem/progenitor cells. Our strategy to generate viable c-Kit(W/W) mice will be useful to analyze the role of this important receptor tyrosine kinase in adult life in vivo.

Aging↗

PubMed2005

Erythropoietin stimulates phosphorylation and activation of GATA-1 via the PI3-kinase/AKT signaling pathway.

Erythropoietin (Epo) stimulation of its receptor's downstream signaling pathways and optimum function of GATA-1 transcription factor are both essential for normal erythroid cell development. Epo-receptor (EpoR) signaling and GATA-1 regulate proliferation, survival, differentiation, and maturation of erythroid cells. Whether any signal that is generated by EpoR targets GATA-1 or affects GATA-1 transcriptional activity is not known. Here, we demonstrate that stimulation of EpoR results in phosphorylation of GATA-1 at serine 310 (S310) in primary fetal liver erythroid progenitors and in cultured erythroid cells. We show that phosphorylation of GATA-1 is important for Epo-induced maturation of fetal liver erythroid progenitor cells. The PI3-kinase/AKT signaling pathway is identified as a mediator of Epo-induced phosphorylation of GATA-1. AKT serine threonine kinase phosphorylates GATA-1S310 in vitro and in erythroid cells and enhances GATA-1 transcriptional activity. These data demonstrate that EpoR signaling phosphorylates GATA-1 and modulates its activity via the PI3-kinase/AKT signaling pathway.

Animals↗

PubMed2005

Ectodermally derived steel/stem cell factor functions non-cell autonomously during primitive erythropoiesis in Xenopus.

Signals derived from nonhematopoietic tissues are essential for normal primitive erythropoiesis in vertebrates, but little is known about the nature of these signals. In Xenopus, unidentified factors secreted by ectodermal cells during gastrulation are required to enable the underlying ventral mesoderm to form blood. Steel is expressed in the ectoderm of early Xenopus embryos and is known to regulate definitive erythroid progenitor survival and differentiation in other organisms, making it an excellent candidate regulator of primitive erythropoiesis. In this study, we tested whether steel signaling is required for primitive red blood cell differentiation in mice and frogs. We show that Xsl is expressed in the ectoderm in Xenopus gastrulae and that c-kit homologs are expressed in the underlying mesoderm at the same stages of development. We present loss of function data in whole Xenopus embryos and explants that demonstrate a requirement for ectodermally derived steel to signal through c-kit in the mesoderm to support early steps in the differentiation of primitive erythroid but not myeloid cells. Finally, we show that primitive erythropoiesis is not disrupted in mouse embryos that lack c-kit function. Our data suggest a previously unrecognized and unique function of steel/c-kit during primitive erythropoiesis in Xenopus.

Animals↗

PubMed2001

Erythropoiesis in the absence of janus-kinase 2: BCR-ABL induces red cell formation in JAK2(-/-) hematopoietic progenitors.

The receptor-associated protein tyrosine kinase janus-kinase 2 (JAK2) is essential for normal red cell development and for erythropoietin receptor (EpoR) signaling. JAK2(-/-) embryos are severely deficient in erythropoiesis and die at an early stage of development from fetal anemia. The binding of erythropoietin (Epo) to the EpoR triggers the activation of JAK2, the phosphorylation of the EpoR, and the initiation of the EpoR signaling cascade. In addition to Epo binding to its receptor, signaling pathways downstream of the EpoR can also be stimulated by the BCR-ABL oncoprotein. This study explored whether JAK2 is required for BCR-ABL-mediated stimulation of erythropoiesis. Here, it is shown that JAK2 is constitutively tyrosine phosphorylated in cultured and primary erythroid cells expressing BCR-ABL. However, BCR-ABL effectively supports normal erythroid proliferation, differentiation, and maturation in JAK2-deficient fetal liver cells. Using mutants of BCR-ABL, this study shows that certain signaling pathways activated by BCR-ABL segments distinct from its tyrosine kinase domain are essential for rescue of erythropoiesis in JAK2(-/-) progenitors. The consequences of these multiple signaling pathways for normal erythroid development are discussed.

Amino Acid Substitution↗

PubMed2001

Diagnostic utility of flow cytometric immunophenotyping in myelodysplastic syndrome.

The myelodysplastic syndromes (MDSs) are characterized by bilineage or trilineage dysplasia. Although diagnostic criteria are well established for MDS, a significant number of patients have blood and bone marrow findings that make diagnosis and classification difficult. Flow cytometric immunophenotyping is an accurate and highly sensitive method for detection of quantitative and qualitative abnormalities in hematopoietic cells. Flow cytometry was used to study hematopoietic cell populations in the bone marrow of 45 patients with straightforward MDS. The results were compared with those obtained in a series of patients with aplastic anemia, healthy donors, and patients with a history of nonmyeloid neoplasia in complete remission. The immunophenotypic abnormalities associated with MDS were defined, and the diagnostic utility of flow cytometry was compared, with morphologic and cytogenetic evaluations in 20 difficult cases. Although morphology and cytogenetics were adequate for diagnosis in most cases, flow cytometry could detect immunophenotypic abnormalities in cases when combined morphology and cytogenetics were nondiagnostic. It is concluded that flow cytometric immunophenotyping may help establish the diagnosis of MDS, especially when morphology and cytogenetics are indeterminate. (Blood. 2001;98:979-987)

Adult↗

PubMed2004

Pathophysiology of intensive care unit-acquired anemia.

The formation of red blood cells (RBCs) in the bone marrow is regulated by erythropoietin in response to a cascade of events. Anemia in the intensive care unit can be caused by a host of factors. Patients in the intensive care unit may have decreased RBC production and a blunted response to erythropoietin. Administration of recombinant human erythropoietin may stimulate erythropoiesis, increase hematocrit levels and hemoglobin concentration, and reduce the need for RBC transfusions.

Anemia↗

PubMed1992

Enhanced response of human circulating erythroid progenitor cells to hGH and to IGF-I in children with insufficient growth hormone secretion.

The response of hematopoietic progenitors to the growth promoting effects of hGH and IGF-I has been documented. In this study, the effects of recombinant hGH and IGF-I on the growth of circulating erythroid burst forming cells (BFU-E) from growth-IGF-I retarded children with insufficient growth hormone secretion (IGHS) were evaluated and compared with values obtained from either children with short stature and normal growth hormone levels (SNGH) or normal donors. Both recombinant hGH and IGF-I had significantly greater stimulatory effects on the growth of BFU-E from the IGHS compared with the SNGH and with the normally growing children. At its optimal concentration of 200 micrograms/L, recombinant hGH had a stimulatory effect on the growth of BFU-E from 11 IGHS children yielding a mean +/- SD value of 2.0 +/- 0.3-fold above the unstimulated controls compared with 1.45 +/- 0.16-fold and 1.36 +/- 0.04-fold stimulation of BFU-E from six SNGH and five normal donors, respectively. Similarly, IGF-I, at its optimal concentration of 0.065 nmol/L (0.5 ng/mL), stimulated IGHS-derived BFU-E growth 1.67 +/- 0.25-fold above unstimulated controls, compared with 1.28 +/- 0.17-fold and 1.3 +/- 0.1-fold stimulation of BFU-E from SNGH and from normal donors, respectively. The hGH- and IGF-I-induced stimulatory effects could be neutralized by their respective specific MAb.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗