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PubMed1992

Uremic inhibitors of erythropoiesis: a study during treatment with recombinant human erythropoietin.

The effects of increasing amounts of uremic sera (US) on the growth of erythroid progenitor cells [burst-forming unit erythroid (BFU-E)] collected from peripheral blood of normal subjects were evaluated to assess the potential role of uremic inhibitors of erythropoiesis during a treatment with recombinant human erythropoietin (r-HuEpo). US were collected from 8 patients on regular dialysis with marked anemia (Hb 6 +/- 0.5 g%) before and after a treatment with high doses of r-HuEpo (from 300 to 525 U/kg/week). Standard cultures for BFU-E were performed in alpha-metylcellulose with fetal calf serum (FCS) and 4 U/ml of r-HuEpo (Cilag, Ortho). In successive cultures, US were added at increasing amounts to the standard culture in order to assess a possible inhibitory effect on BFU-E growth. Finally, in order to assess a possible lack of stimulatory factors, we partially substituted FCS with US. The addition of US collected either before or after therapy with r-HuEpo to the standard culture had no effect on the growth of BFU-E. Vice versa, the number of cultured BFU-E decreased when FCS was partially substituted with US collected before r-HuEpo. This effect was not evident when FCS was partially substituted with US collected after r-HuEpo. No significant differences were recorded in the tested sera collected before and after therapy considering erythropoietin levels and amino acid levels. We hypothesized that some other factors with erythropoietic stimulatory activity (burst-promoting activity?) may be deficient in uremic patients with marked anemia and can be induced during therapy with r-HuEpo.

Adult↗
PubMed2000

Erythroid progenitors differentiate and mature in response to endogenous erythropoietin.

We reported previously that stimulation of glycoprotein 130 (gp130) by a combination of human IL-6 and soluble IL-6 receptor (sIL-6R) could support proliferation, differentiation, and terminal maturation of erythroid cells in the absence of erythropoietin (EPO) from human CD34(+) cells in culture with stem cell factor (SCF). This observation suggested that differentiation of hematopoietic stem/progenitor cells to erythroid cells progressed according to an intrinsic program and that EPO receptor (EPOR) could be replaced by other cytokine receptors. In other words, EPOR appeared to be dispensable for erythropoiesis. Here we examined the role of EPOR in erythropoiesis stimulated by SCF, sIL-6R, and IL-6. Surprisingly, reduction of EPOR expression using antisense oligodeoxynucleotides suppressed erythropoiesis stimulated not only by SCF and EPO, but also by SCF, sIL-6R, and IL-6. EPO mRNA was detected in erythroid cells but not myeloid cells cultured in the presence of SCF, sIL-6R, and IL-6. Furthermore, high concentrations of anti-EPO-neutralizing antibody abrogated erythropoiesis in cultures without exogenous EPO. Based on these results, we suggest that erythroid progenitors themselves secrete EPO and that they have the potential to differentiate and mature in response to this endogenous EPO.

Antibodies↗
PubMed2002

Tumor necrosis factor-alpha expressed constitutively in erythroid cells or induced by erythropoietin has negative and stimulatory roles in normal erythropoiesis and erythroleukemia.

Binding of erythropoietin (EPO) to its receptor (EPOR) on erythroid cells induces the activation of numerous signal transduction pathways, including the mitogen-activated protein kinase Jun-N-terminal kinase (JNK). In an effort to understand the regulation of EPO-induced proliferation and JNK activation, we have examined the role of potential autocrine factors in the proliferation of the murine erythroleukemia cell line HCD57. We report here that treatment of these cells with EPO induced the expression and secretion of tumor necrosis factor alpha (TNF-alpha). EPO-dependent proliferation was reduced by the addition of neutralizing antibodies to TNF-alpha, and exogenously added TNF-alpha induced proliferation of HCD57 cells. EPO also could induce TNF-alpha expression in BAF3 and DA3 myeloid cells ectopically expressing EPOR. Addition of TNF-alpha activated JNK in HCD57 cells, and the activity of JNK was partially inhibited by addition of a TNF-alpha neutralizing antibody. Primary human and murine erythroid progenitors expressed TNF-alpha in either an EPO-dependent or constitutive manner. However, TNF-alpha had an inhibitory effect on both immature primary human and murine cells, suggestive that the proliferative effects of TNF-alpha may be limited to erythroleukemic cells. This study suggests a novel role for autocrine TNF-alpha expression in the proliferation of erythroleukemia cells that is distinct from the effect of TNF-alpha in normal erythropoiesis.

Animals↗
PubMed2002

Protein kinase C mediates mutant N-Ras-induced developmental abnormalities in normal human erythroid cells.

RAS mutations are one of the most frequent molecular abnormalities associated with myeloid leukemia and preleukemia, yet there is a poor understanding of how they contribute to the pathogenesis of these conditions. Here, we describe the consequences of ectopic mutant N-Ras (N-Ras*) expression on normal human erythropoiesis. We show that during early (erythropoietin [EPO]-independent) erythropoiesis, N-Ras* promoted the amplification of a phenotypically primitive but functionally defective subpopulation of CD34(+) erythroblasts. N-Ras* also up-regulated the expression of megakaryocyte antigens on human erythroblasts. Although early erythroblasts expressing N-Ras* were able to respond to erythropoietin and generate mature progeny, this occurred with greatly reduced efficiency, probably explaining the poor colony growth characteristics of these cells. We further report that this oncogene promoted the expression and activation of protein kinase C (PKC) and that the effects of N-Ras* on erythropoiesis could be abrogated or attenuated by inhibition of PKC. Similarly, the effects of this oncogene could be partially mimicked by treatment with PKC agonist. Together, these data suggest that expression of N-Ras* is able to subvert the normal developmental cues that regulate erythropoiesis by activating PKC. This gives rise to phenotypic and functional abnormalities commonly observed in preleukemia, suggesting a direct link between RAS mutations and the pathogenesis of preleukemia.

Antigens, CD↗
PubMed2003

Functional p85alpha gene is required for normal murine fetal erythropoiesis.

In vitro studies suggest that activation of class IA phosphatidylinositol 3 (PI-3) kinase is necessary for normal erythroid cell development. However, when class IA PI-3 kinase-deficient mice were generated by a targeted deletion of the p85alpha regulatory subunit, fetal erythropoiesis was reportedly unaffected. Given the discrepancies between these studies, we performed a more detailed in vivo analysis of class IA PI-3 kinase-deficient embryos. Day-14.5 p85alpha-/- embryos are pale with a marked reduction of mature erythrocytes in their peripheral blood. Further, the absolute number and frequency of both early (erythroid burst-forming unit [BFU-E]) and late erythroid progenitors (erythroid colony-forming unit [CFU-E]) are reduced in p85alpha-/- fetal livers compared with wild-type controls, which is associated with reduced proliferation. Taken together, these data establish an important role for p85alpha and class IA PI-3 kinase in regulating the development of both early and late erythroid progenitors in fetal liver.

Animals↗
PubMed2003

Attenuated signaling by a phosphotyrosine-null Epo receptor form in primary erythroid progenitor cells.

Signals provided by the erythropoieitin receptor (EpoR) are required for erythroid development beyond the erythroid colony-forming unit (CFU-e) stage and are propagated via the EpoR-tethered Janus kinase, JAK2. JAK2 functions, in part, to phosphorylate 8 conserved EpoR phosphotyrosine (PY) sites for the binding of a diverse set of signaling factors. However, recent studies in transgenic and knock-in mice have demonstrated substantial bioactivity for PY-null EpoR forms. Presently, the activities of a PY-null EpoR-HM form in primary progenitor cells from knock-in mice were further assessed using optimized Epo dose-dependent proliferation, survival, and differentiation assays. As compared with the wild-type (wt)-EpoR, EpoR-HM activity was compromised several-fold in each context when Epo was limited to physiologic concentrations. Possible compensatory increases in serum growth factor levels also were investigated, and as assayed using embryonic stem (ES) cell-derived erythroid G1E2 cells, activities in serum from EpoR-HM mice were substantially elevated. In addition, when challenged with phenylhydrazine-induced anemia, EpoR-HM mice failed to respond with efficient splenic stress erythropoiesis. Thus, the function of this JAK2-coupled but minimal PY-null EpoR-HM form appears to be attenuated in several contexts and to be assisted in vivo by compensatory mechanisms. Roles normally played by EpoR PY sites and distal domains therefore should receive continued attention.

Anemia↗
PubMed2003

Targeted disruption of oncostatin M receptor results in altered hematopoiesis.

Oncostatin M (OSM) is a multifunctional cytokine that belongs to the interleukin 6 (IL-6) family. As OSM is expressed in adult as well as embryonic hematopoietic tissues, OSM has been considered to play a role in hematopoiesis. To uncover roles of OSM, we have generated mutant mice deficient in the OSM-specific receptor beta subunit (OSMR). While OSMR-/- mice were healthy and fertile, hematologic analysis of OSMR-/- mice demonstrated that the numbers of peripheral erythrocytes and platelets were reduced compared with wild-type mice. Consistent with this, progenitors of erythroid and megakaryocyte lineages were reduced in OSMR-/- bone marrow (BM), suggesting that OSM is required for the maintenance of erythroid and megakaryocyte progenitor pools in BM. To investigate whether OSM acts on the hematopoietic progenitors directly or indirectly, we performed BM transplantation experiments. The OSMR-/- mice, engrafted with wild-type BM cells, failed to produce erythrocytic and megakaryocytic progenitors to the levels in wild-type mice, indicating that OSM affects hematopoietic microenvironments. On the other hand, erythrocytic and megakaryocytic progenitors were reduced in the wild-type mice reconstituted with OSMR-/- BM cells. Thus, OSM regulates hematopoiesis in vivo by stimulating stromal cells as well as hematopoietic progenitors, in particular megakaryocytic and erythrocytic progenitors.

Animals↗
PubMed2003

Pivotal role of granulocyte colony-stimulating factor in the development of progenitors in the common myeloid pathway.

Granulocyte colony-stimulating factor (G-CSF) is the principal cytokine regulating granulopoiesis. G-CSF receptor-deficient mice (G-CSFR-/-) are neutropenic but have only a modest reduction of committed myeloid progenitors. Since it is likely that compensatory mechanisms are induced by the severe neutropenia present in G-CSFR-/- mice, a competitive repopulation assay was performed. These data show that under basal conditions, G-CSF drives nearly all of granulopoiesis through multiple mechanisms. Most importantly, G-CSFR signals regulate the production and/or maintenance of committed-myeloid progenitors. Surprisingly, G-CSFR signals also play a significant role in the regulation of primitive multipotential progenitors in vivo. The contribution of G-CSFR-/- cells to the hematopoietic stem cell compartment is modestly reduced. Moreover, a marked decrease in the contribution of G-CSFR-/- cells to other progenitors in the myeloid pathway, including erythroid and megakaryocytic progenitors, is observed. In contrast, relative to the hematopoietic stem cell compartment, the contribution of G-CSFR-/- cells to the lymphoid lineages is increased. These data suggest that G-CSFR signals may play a role in directing the commitment of primitive hematopoietic progenitors to the common myeloid lineage. Thus, regulation of G-CSF levels may provide a mechanism for directing primitive hematopoietic progenitors into the common myeloid lineage in response to environmental stresses.

Animals↗
PubMed2003

Imatinib mesylate inhibits autonomous erythropoiesis in patients with polycythemia vera in vitro.

The overproduction of red blood cells in patients with polycythemia vera (PV) is reflected in vitro by the formation of erythroid burst-forming units (BFU-Es) in the absence of exogenous erythropoietin. In contrast to other myeloproliferative disorders, the molecular mechanism of PV is unknown and no specific chromosomal abnormality has been described. We speculated that imatinib mesylate may reverse the pathological overproduction of red cells by inhibition of autonomous erythropoiesis. In the present study, imatinib mesylate was found to either block or strongly inhibit autonomous BFU-E formation in vitro in all patients tested. Moreover, autonomous BFU-E growth was also markedly reduced by exposure of PV cells to imatinib mesylate prior to cultivation in semisolid medium. The profound effect of imatinib mesylate on autonomous erythropoiesis suggests the involvement of an as yet unidentified kinase in the pathogenesis of PV and should provide the rationale for a forthcoming clinical trial.

Antineoplastic Agents↗
PubMed2004

PECAM-1 is expressed on hematopoietic stem cells throughout ontogeny and identifies a population of erythroid progenitors.

Platelet endothelial cell adhesion molecule-1 (PECAM-1) (CD31) is an adhesion molecule expressed on endothelial cells and subsets of leukocytes. Analysis of phenotypically defined hematopoietic stem cells (HSCs) from the yolk sac, fetal liver, and adult bone marrow demonstrates CD31 expression on these cells throughout development. CD31+ c-kit+ cells, but not CD31- c-kit+ cells, isolated from day-9.5 yolk sac give rise to multilineage hematopoiesis in vivo. Further evaluation of the CD31+ lineage marker-negative fraction of adult bone marrow reveals functionally distinct cell subsets. Transplantation of CD31+ Lin- c-kit- cells fails to protect lethally irradiated recipients, while CD31+ Lin- c-kit+ Sca-1- cells (CD31+ Sca-1-) provide radioprotection in the absence of long-term donor-derived hematopoiesis. Although donor-derived leukocytes were not detected in CD31+ Sca-1- recipients, donor-derived erythroid cells were transiently produced during the initial phases of bone marrow recovery. These results demonstrate CD31 expression on hematopoietic stem cells throughout ontogeny and identify a population of CD31+ short-term erythroid progenitors cells that confer protection from lethal doses of radiation.

Age Factors↗
PubMed2004

Successful correction of the human beta-thalassemia major phenotype using a lentiviral vector.

beta-thalassemias are the most common single gene disorders and are potentially amenable to gene therapy. However, retroviral vectors carrying the human beta-globin cassette have been notoriously unstable. Recently, considerable progress has been made using lentiviral vectors, which stably transmit the beta-globin expression cassette. Thus far, mouse studies have shown correction of the beta-thalassemia intermedia phenotype and a partial, variable correction of beta-thalassemia major phenotype. We tested a lentiviral vector carrying the human beta-globin expression cassette flanked by a chromatin insulator in transfusion-dependent human thalassemia major, where it would be ultimately relevant. We demonstrated that the vector expressed normal amounts of human beta-globin in erythroid cells produced in in vitro cultures for unilineage erythroid differentiation. There was restoration of effective erythropoiesis and reversal of the abnormally elevated apoptosis that characterizes beta-thalassemia. The gene-corrected human beta-thalassemia progenitor cells were transplanted into immune-deficient mice, where they underwent normal erythroid differentiation, expressed normal levels of human beta-globin, and displayed normal effective erythropoiesis 3 to 4 months after xenotransplantation. Variability of beta-globin expression in erythroid colonies derived in vitro or from xenograft bone marrow was similar to that seen in normal controls. Our results show genetic modification of primitive progenitor cells with correction of the human thalassemia major phenotype.

Animals↗
PubMed2006

Enhanced natural-killer cell and erythropoietic activities in VEGF-A-overexpressing mice delay F-MuLV-induced erythroleukemia.

We have previously reported that VEGF-A, in combination with MCP-5, contributes to leukemia progression within the splenic microenvironment of mice infected with F-MuLV. To study the influence of constitutively elevated VEGF-A levels on the progression of erythroleukemia, mice heterozygous for a VEGF-A "hypermorphic" allele (Vegfhi/+) were inoculated with F-MuLV. Unexpectedly, a significant delay in erythroleukemia was observed in Vegfhi/+ mice when compared with wild-type controls. These results suggested an altered physiologic response arising from elevated VEGF-A levels that decelerated erythroleukemic progression. Characterization of hematopoiesis in Vegfhi/+ spleens showed a higher natural killer cell activity, elevated B cells, and a decrease in T-cell number. Furthermore, higher erythroid progenitors (ie, CD34+, CD36+, and Ter119+ cells) were evident in the bone marrow, spleen, and peripheral blood of Vegfhi/+ mice. The CFU-E levels were significantly elevated in Vegfhi/+ bone marrow cultures, and this elevation was blocked by a neutralizing antibody to VEGF-A receptor (VEGFR-2). Moreover, erythroleukemic mice were treated with recombinant erythropoietin and, similar to diseased Vegfhi/+ mice, showed a delay in disease progression. We propose that a compensatory erythropoietic response combined with increased natural killer (NK) cell activity account for the extended survival of erythroleukemic, Vegfhi/+ mice.

Animals↗
PubMed2006

Growth factor receptors as regulators of hematopoiesis.

Nearly 15 years have elapsed since the US Food and Drug Administration last approved a major new hematopoietic cytokine. Promiscuous binding to multiple receptors, or to receptors expressed by multiple tissues, reduces growth factor specificity and promotes side effects. Here we show that hematopoiesis can be differentially regulated using receptors rather than ligands. Conditional derivatives of both fibroblast growth factor receptor-1 (F36VFGFR1) and the thrombopoietin receptor (F36VMpl) induced a sustained expansion of mouse marrow cells ex vivo, and erythroid cells in vivo. Only F36VFGFR1 could support the ex vivo expansion of short-term repopulating hematopoietic stem cells (HSCs), the ex vivo survival of long-term repopulating HSCs, and the prolonged in vivo expansion of granulocytes, monocytes, and platelets. Only F36VMpl induced a response sufficiently rapid to accelerate recovery from radiation-induced anemia. These results establish receptors as a new class of hematopoietic regulators possessing activities unobtainable with growth factors.

Amino Acid Substitution↗
PubMed2006

The hypomorphic Gata1low mutation alters the proliferation/differentiation potential of the common megakaryocytic-erythroid progenitor.

Recent evidence suggests that mutations in the Gata1 gene may alter the proliferation/differentiation potential of hemopoietic progenitors. By single-cell cloning and sequential replating experiments of prospectively isolated progenitor cells, we demonstrate here that the hypomorphic Gata1low mutation increases the proliferation potential of a unique class of progenitor cells, similar in phenotype to adult common erythroid/megakaryocytic progenitors (MEPs), but with the "unique" capacity to generate erythroblasts, megakaryocytes, and mast cells in vitro. Conversely, progenitor cells phenotypically similar to mast cell progenitors (MCPs) are not detectable in the marrow from these mutants. At the single-cell level, about 11% of Gata1low progenitor cells, including MEPs, generate cells that will continue to proliferate in cultures for up to 4 months. In agreement with these results, trilineage (erythroid, megakaryocytic, and mastocytic) cell lines are consistently isolated from bone marrow and spleen cells of Gata1low mice. These results confirm the crucial role played by Gata1 in hematopoietic commitment and identify, as a new target for the Gata1 action, the restriction point at which common myeloid progenitors become either MEPs or MCPs.

Animals↗
PubMed2001

Fetal liver myelopoiesis occurs through distinct, prospectively isolatable progenitor subsets.

Hematopoietic fate maps in the developing mouse embryo remain imprecise. Definitive, adult-type hematopoiesis first appears in the fetal liver, then progresses to the spleen and bone marrow. Clonogenic common lymphoid progenitors and clonogenic common myeloid progenitors (CMPs) in adult mouse bone marrow that give rise to all lymphoid and myeloid lineages, respectively, have recently been identified. Here it is shown that myelopoiesis in the fetal liver similarly proceeds through a CMP equivalent. Fetal liver CMPs give rise to megakaryocyte-erythrocyte-restricted progenitors (MEPs) and granulocyte-monocyte-restricted progenitors (GMPs) that can also be prospectively isolated by cell surface phenotype. MEPs and GMPs generate mutually exclusive cell types in clonogenic colony assays and in transplantation experiments, suggesting that the lineage restriction observed within each progenitor subset is absolute under normal conditions. Purified progenitor populations were used to analyze expression profiles of various hematopoiesis-related genes. Expression patterns closely matched those of the adult counterpart populations. These results suggest that adult hematopoietic hierarchies are determined early in the development of the definitive immune system and suggest that the molecular mechanisms underlying cell fate decisions within the myeloerythroid lineages are conserved from embryo to adult. (Blood. 2001;98:627-635)

Age Factors↗
PubMed2002

In vitro proliferation and differentiation of erythroid progenitors from patients with myelodysplastic syndromes: evidence for Fas-dependent apoptosis.

Erythropoiesis results from the proliferation and differentiation of pluripotent stem cells into immature erythroid progenitors (ie, erythroid burst-forming units (BFU-Es), whose growth, survival, and terminal differentiation depends on erythropoietin (Epo). Ineffective erythropoiesis is a common feature of myelodysplastic syndromes (MDS). We used a 2-step liquid-culture procedure to study erythropoiesis in MDS. CD34(+) cells from the marrow of patients with MDS were cultured for 10 days in serum-containing medium with Epo, stem cell factor, insulin-like growth factor 1, and steroid hormones until they reached the proerythroblast stage. The cells were then placed in medium containing Epo and insulin for terminal erythroid differentiation. Numbers of both MDS and normal control cells increased 10(3) fold by day 15. However, in semisolid culture, cells from patients with refractory anemia (RA) with ringed sideroblasts and RA or RA with excess of blasts produced significantly fewer BFU-Es than cells from controls. Fluorescence in situ hybridization analysis of interphase nuclei from patients with chromosomal defects indicated that abnormal clones were expanded in vitro. Epo-signaling pathways (STAT5, Akt, and ERK 1/2) were normally activated in MDS erythroid progenitors. In contrast, apoptosis was significantly increased in MDS cells once they differentiated, whereas it remained low in normal cells. Fas was overexpressed on freshly isolated MDS CD34(+) cells and on MDS erythroid cells throughout the culture. Apoptosis coincided with overproduction of Fas ligand during the differentiation stage and was inhibited by Fas-Fc chimeric protein. Thus, MDS CD34(+)-derived erythroid progenitors proliferated normally in our 2-step liquid culture with Epo but underwent abnormal Fas-dependent apoptosis during differentiation that could be responsible for the impaired erythropoiesis.

Adult↗
PubMed2001

Trichothecene toxicity on human megakaryocyte progenitors (CFU-MK).

Trichothecenes are mycotoxins produced by various species of fungi, which can occur on various agricultural products. Among these compounds, T-2 toxin, HT-2 toxin, diacetoxyscirpenol (DAS) and deoxynivalenol (DON) are the most naturally encountered and the most potent trichothecenes. Consumption of trichothecene contaminated foods by farm animals and humans leads to mycotoxicosis. Trichothecenes are known to induce haematological disorders such as neutropenia, aplastic anemia and thrombocytopenia in humans and animals. Four trichothecenes, T-2 toxin, HT-2 toxin, DAS and DON have been tested on human platelet progenitors (CFU-MK) using a culture model of CFU-MK optimized for toxicological studies. Trichothecenes cause, at low concentrations, cytotoxic effects in megakaryocyte progenitors, which could induce thrombocytopenia. Sensitivity of human CFU-MK is compared to respective sensitivities of human red blood cell progenitors (BFU-E) and white blood cell progenitors (CF-U-GM) that were described in previous works.

Cells, Cultured↗