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PubMed2002

Myeloerythroid-restricted progenitors are sufficient to confer radioprotection and provide the majority of day 8 CFU-S.

Whole-body irradiation at the minimal lethal dose causes bone marrow failure and death within 12-18 days. To identify the principal components of the hematopoietic system that are radioprotective, we transplanted lethally irradiated mice with purified progenitors: common myeloid progenitors (CMPs), megakaryocyte/erythrocyte-restricted progenitors (MEPs), or granulocyte/monocyte-restricted progenitors (GMPs). Transplanted CMPs gave rise to cells both of the granulocyte/monocyte (GM) series and the megakaryocyte/erythrocyte series, whereas GMPs or MEPs showed reconstitution of only GM or ME cells, respectively. CMPs and MEPs but not GMPs protected mice in a dose-dependent manner, suggesting that erythrocytes, platelets, or both are the critical effectors of radioprotection. Accordingly, CMPs and MEPs formed robust colonies in recipient bone marrow and spleen, whereas GMPs formed small colonies that rapidly disappeared. Direct comparisons of spleen CFU (CFU-S) potentials among each progenitor subset showed that MEPs contain the vast majority of day 8 CFU-S activity, suggesting that day 8 CFU-S are the precursors of radioprotective cell subsets. All animals radioprotected for 30 days subsequently survived for at least 6 months post-transplant, and showed only host-derived hematopoiesis after 30 days. These findings suggest that rare hematopoietic stem cells survive myeloablation that can eventually repopulate irradiated hosts if myeloerythroid-restricted progenitors transiently rescue ablated animals through the critical window of bone marrow failure.

Animals↗
PubMed2002

Autocrine-paracrine VEGF loops potentiate the maturation of megakaryocytic precursors through Flt1 receptor.

The expression/function of vascular endothelial growth factor (VEGF) receptors (VEGFR1/Flt1 and VEGFR2/KDR/Flk1) in hematopoiesis is under scrutiny. We have investigated the expression of Flt1 and kinase domain receptor (KDR) on hematopoietic precursors, as evaluated in liquid culture of CD34(+) hematopoietic progenitor cells (HPCs) induced to unilineage differentiation/maturation through the erythroid (E), megakaryocytic (Mk), granulocytic (G), or monocytic (Mo) lineage. KDR, expressed on 0.5% to 1.5% CD34(+) cells, is rapidly downmodulated on induction of differentiation. Similarly, Flt1 is present at very low levels in HPCs and is downmodulated in E and G lineages; however, Flt1 is induced in the precursors of both Mo and Mk series; ie, its level progressively increases during Mo maturation, and it peaks at the initial-intermediate culture stages in the Mk lineage. Functional experiments indicate that Mk and E, but not G and Mo, precursors release significant amounts of VEGF in the culture medium, particularly at low O(2) levels. The functional role of VEGF release on Mk maturation is indicated by 2 series of observations. (1) Molecules preventing the VEGF-Flt1 interaction on the precursor membrane (eg, soluble Flt1 receptors) significantly inhibit Mk polyploidization. (2) Addition of exogenous VEGF or placenta growth factor (PlGF) markedly potentiates Mk maturation. Conversely, VEGF does not modify Mo differentiation/maturation. Altogether, our results suggest that in the hematopoietic microenvironment an autocrine VEGF loop contributes to optimal Mk maturation through Flt1. A paracrine loop involving VEGF release by E precursors may also operate. Similarly, recent studies indicate that an autocrine loop involving VEGF and Flt1/Flk1 receptors mediates hematopoietic stem cell survival and differentiation.

Antibodies, Monoclonal↗
PubMed2002

Persistence of human parvovirus B19 in human tissues.

Human parvovirus B19 infection causes various clinical symptoms, such as rash, arthropathy, anemias and fetal death, but it can also remain asymptomatic. The arthropathies and anemias can become chronic for several years, not infrequently resembling autoimmune syndromes. B19 replicates only in red blood cell precursors of bone marrow or fetal liver, resulting in high-titred short-lived viremia, but viral DNA is detectable also in cells of several other types. Recently B19 DNA has been found, by very sensitive amplification tests, in certain tissues not only of symptomatic but also of healthy individuals for several years or decades after B19 infection. The mere presence of B19 DNA in these tissues of a symptomatic patient (e.g. joints in chronic arthritis or skin in dermatomyositis) thereby does not prove that the present disease is caused by B19. The diagnosis has to be verified by other innovative means. How and why viral DNA persists in the tissues of healthy individuals is under investigation.

Autoimmune Diseases↗
PubMed2006

Primitive erythropoiesis from mesodermal precursors expressing VE-cadherin, PECAM-1, Tie2, endoglin, and CD34 in the mouse embryo.

Vascular endothelial (VE) cadherin, PECAM-1 (platelet endothelial cell adhesion molecule-1, CD31), Tie2, CD34, and endoglin are established markers for adult and embryonic endothelial cells (ECs). Here, we report that the expression of these EC markers is initiated in the extraembryonic region at the late-streak stage (nominal stage E6.75). Immunohistochemical analysis shows that EC marker-positive cells arise in a subset of Flk1 (VEGF-R2) mesodermal cells. In contrast, GATA1, a marker for primitive erythropoietic progenitors, is expressed in a more restricted subset of Flk1-positive cells. Using flow cytometry, we observed that the GATA1-positive cell population existed as a subset of the EC marker-positive cell. Consistent with this notion, we showed with the primitive hematopoietic colony assay that primitive erythropoietic progenitors are enriched in PECAM-1- and Tie2-positive cells. These results suggest that primitive hematopoietic cells arise from EC marker-positive cells. Thus, VE-cadherin, PECAM-1, CD34, endoglin, and Tie2 are expressed not only in adult and embryonic ECs but in extraembryonic Flk1-positive cells during gastrulation. The latter cell population includes progenitors that give rise to primitive hematopoietic cells, suggesting that primitive and definitive hematopoietic cells in the mouse embryo arise from EC marker-positive cells.

Animals↗
PubMed1998

Sickling of nucleated erythroid precursors from patients with sickle cell anemia.

The pathophysiology of sickle cell anemia is primarily explained in terms of the oxygen-dependent polymerization of sickle hemoglobin (HbS) followed by sickling of erythrocytes. Since the rate and extent of HbS polymerization depend on its intracellular concentration, it has been generally assumed that sickling occurs primarily in mature erythrocytes with their high intracellular hemoglobin concentration. In the present study, we investigated the propensity of nucleated erythroid precursors to undergo sickling; both cultured and fresh marrow-derived erythroid precursors from patients with homozygous sickle cell anemia were studied. The results revealed that upon deoxygenation cultured erythroblasts underwent characteristic morphological deformation in the form of fine, fragile, elongated spicules. Ultrastructural analysis demonstrated highly organized and tightly aligned hemoglobin fibers in the protruded regions. Bone marrow cells examined under partial or complete deoxygenated conditions displayed similar morphological changes. When cultured SS erythroid precursors were exposed to hydroxyurea or butyrate, drugs that may increase fetal hemoglobin (HbF) and inhibit intracellular polymerization, a significant decrease was observed in the propensity of these precursors to undergo sickling, accompanied by a three- to fivefold increase in HbF. These results suggest that, in addition to mature erythrocytes, nucleated erythroid precursors in the bone marrow have the capacity to undergo characteristic sickling as a result of HbS polymerization and may be involved in several aspects of the pathophysiology of sickle cell anemia. Treatment with HbF-stimulating drugs may benefit patients with this disease by inhibiting polymerization-induced sickling of erythroid precursors in the marrow as well as mature erythrocytes in the peripheral blood.

Anemia, Sickle Cell↗
PubMed1999

Erythrocytapheresis for chronically transfused children with sickle cell disease: an effective method for maintaining a low hemoglobin S level and reducing iron overload.

Cerebrovascular accident (CVA) is a major complication of sickle cell disease during childhood. Long-term transfusion reduces the hemoglobin S level and generally prevents recurrent stroke, but it also results in progressive iron overload that requires regular chelation therapy. Erythrocytapheresis offers an alternative approach aimed at reducing the iron accumulation. We reviewed the results of erythrocytapheresis in eight sickle cell patients (mean age of 12.1 years) at high risk for a first or recurrent stroke. They were maintained at the standard pre-transfusion hemoglobin S (Hb S) level of 30%. Over an average of 9 months of erythrocytapheresis, none of the patients developed complications related to the procedure or to the increased blood use. Ferritin levels decreased by a mean of 26.5% in all patients. When evaluating the ferritin level in five patients, who remained on chelation therapy with deferoxamine (DFO), the level dropped by a mean of 32%. The levels remained stable in the three patients who were not on DFO. The procedure is safe and effective in reducing iron overload and can obviate the need for chelation therapy, even when the target Hb S is maintained at the standard 30% range.

Adolescent↗
PubMed2000

Mechanism for fetal hemoglobin induction by hydroxyurea in sickle cell erythroid progenitors.

Hydroxyurea (HU) is a widely used cytotoxic agent that is known to induce fetal hemoglobin (HbF) production and is presently used to ameliorate the severity of pain episodes in patients with sickle cell anemia (HbSS). Previously we have shown that HU inhibits growth of burst forming unit-erythroid (BFU-E) colonies in a dose-dependent manner, while fetal hemoglobin levels were increased. In the present report, we extended our analysis demonstrating the number of S phase cells is significantly higher for HbSS patients that respond to HU therapy. Studies were completed in vitro using erythroid progenitors derived from umbilical cord samples or peripheral blood from patients with HbS-hereditary persistence of fetal hemoglobin (HbS-HPFH) or HbSS disease. The effect of HU on (a) S phase erythroid progenitors, (b) BFU-E colony growth, (c) HbF levels in BFU-E colonies, and (d) total cellular RNA synthesis was analyzed in vitro for the three groups. The level of S phase erythroid progenitors was similar for all three groups and BFU-E colony growth was inhibited 92-94% for all samples in a dose-dependent manner. The HbF levels were increased in BFU-E colonies from HbSS patients (control, 4.0% +/- 1.15% vs. +HU, 22.67% +/- 2.03%) whereas HbF levels were decreased in BFU-E colonies derived from umbilical cord samples (control, 80% +/- 9.07% vs. +HU, 35.7% +/- 4.81%) or HbS-HPFH patients (control, 49.67% +/- 3.84% vs. +HU, 23.3% +/- 0.88%). Total RNA synthesis measured by 3H-uridine incorporation increased with increasing concentrations of HU; however, actinomycin D inhibited HU-induced RNA synthesis. These results suggest that HU can inhibit an active globin gene without preference and that newly synthesized RNA is under transcriptional control mechanisms.

Adolescent↗
PubMed1992

Relationship between cell-cycle state of erythroid progenitors and fetal hemoglobin synthesis.

DNA-synthesis state of circulating burst forming unit-erythroid (BFU-E) was evaluated in patients with sickle cell anemia and correlated with percent of fetal hemoglobin synthesized in the BFU-E-derived cells. Percentage of S-phase BFU-E inversely correlated with percent fetal hemoglobin synthesized in the BFU-E-derived cells (simple linear correlation coefficient, r = -0.8, P = 0.0302; polynomial regression, R = -0.99, P = 0.0002). This observation is of relevance to our understanding of the relationship between the developmental stage of the erythroid progenitors and expression of globin genes.

Cell Cycle↗
PubMed1992

Binding and suppressive activity of human recombinant ferritins on erythroid cells.

We studied the relation between ferritin cellular binding and suppressive activity of recombinant H- and L-ferritin on human erythroid cells at different proliferation/differentiation phases. L-ferritin failed to show any suppressive activity or detectable binding to erythroblasts at any stage of maturation. In contrast, H-ferritin demonstrated binding to erythroblasts derived from peripheral BFU-E cells which increased steadily between 7-14 days of culture up to 15,000 molecules per cell. Reticulocytes and erythrocytes failed to bind either L- or H-ferritin. H-ferritin suppressed BFU-E colony formation and reduced K562 cell proliferation at nanomolar concentrations. This suggests that the expression of H-ferritin binding sites is modulated by cellular proliferation and differentiation, that cells expressing H-ferritin binding sites are sensitive to ferritin suppressive activity and that a causal relation exists between ferritin cellular binding and suppressive activity.

Binding Sites↗
PubMed1995

Flow cytometric assessment of peripheral blood contamination and proliferative activity of human bone marrow cell populations.

Bone marrow aspiration is superior to bone marrow biopsies due to less discomfort to the volunteer or patient, but it is inferior concerning the reproducibility of cytokinetic information. Therefore, a method that could select aspirates of quality and reproducibility equal to those of biopsies was sought. Low-density (mononucleated) bone marrow cells were labelled with T200 common leukocyte antigen, CD45, which differentiate cells into erythroid, myeloid, and lymphocyte + monocyte subpopulations based on their immunofluorescence intensity. A hypotonic propidium iodide solution was added, and DNA cell cycle characteristics of the total cells and the subpopulations were obtained. Twenty-two aspirations were performed on three healthy men. There was a strong negative correlation between the amount of CD45-gated lymphocytes + monocytes, indicative of peripheral blood cell contamination in the aspirate, and the percentage of total cells and subpopulations in DNA S phase. A marked reduction in the percentage of cells in S phase was observed when the lymphocyte + monocyte counts were higher than 30%; this level was used to exclude aspirates with an unacceptable degree of peripheral blood cell admixture. Twelve of the aspirates were found to be of acceptable quality due to their low lymphocyte + monocyte count. These aspirates were compared with 11 bone marrow biopsy expellates from hematologically normal patients undergoing open cardiac surgery. The 12 aspirates were found to have almost identical mean percent S-phase cells as the biopsy expellates, both for the total cell population (14% +/- 3.45% vs. 15% +/- 1.5%) and for the erythroid (24% +/- 6% vs. 24.4% +/- 3.3%) and myeloid (10% +/- 2.4% vs. 10.7% +/- 2.5%) subpopulations.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Regulation of programmed death in erythroid progenitor cells by erythropoietin: effects of calcium and of protein and RNA syntheses.

Erythropoietin (EPO) retards DNA breakdown characteristic of programmed cell death (apoptosis) and promotes survival in erythroid progenitor cells. The mechanism by which EPO inhibits programmed death is unknown. In the well-characterized model of glucocorticoid-treated thymocytes, activation of a Ca2+/Mg(2+)-sensitive endonuclease and new protein and RNA syntheses have been found necessary for apoptosis. We examined the effects of EPO on the free intracellular calcium ion concentration ([Ca2+]i), and the roles of Ca2+ and RNA and protein syntheses on DNA cleavage in erythroid progenitor cells. The murine model of erythroid differentiation using Friend leukemia virus-infected proerythroblasts (FVA cells) was used. EPO did not affect the [Ca2+]i in FVA cells. Decreasing [Ca2+]i by extracellular Ca2+ chelation with EGTA facilitated DNA breakdown. Increasing [Ca2+]i with the calcium ionophore 4-bromo-A23187 increased DNA cleavage; however, DNA fragments generated by high [Ca2+]i were much larger than those seen in the absence of EPO or presence of EGTA. Increased [Ca2+]i also inhibited DNA breakdown to small oligonucleosomal fragments characteristic of cells cultured without EPO. However, no concentration of ionophore protected the high molecular weight DNA as did EPO. Cycloheximide inhibited DNA breakdown in a dose dependent manner in cultures lacking EPO, but two other protein synthesis inhibitors, pactamycin and puromycin, did not prevent DNA breakdown. Inhibition of RNA synthesis with actinomycin D did not prevent DNA breakdown. Cells with morphological characteristics similar to those reported in other cells undergoing programmed death accumulated in EPO-derived cultures. These studies demonstrate that although DNA cleavage and morphological changes are common to apoptotic cells, the roles for Ca2+ and protein and RNA syntheses are not universal and suggest that apoptosis can be regulated by different biochemical mechanisms in different cell types.

Animals↗
PubMedDate not supplied

Parvovirus B19 and the pathogenesis of anaemia.

Human parvovirus B19 (B19) infection causes human bone marrow failure, by affecting erythroid-lineage cells which are well-known target cells for B19. The anaemia induced by B19 infection is of minor clinical significance in healthy children and adults, however, it becomes critical in those afflicted with haemolytic diseases. This condition is called transient aplastic crisis, and the pathogenesis is explained by the short life-span of red blood cells. Similarly, fetuses are thought to be severely affected by B19-intrauterine infection in the first and second trimester, as the half-life of red blood cells is apparently shorter than RBC at the bone marrow haematopoietic stage. On the other hand, B19 is also the causative agent of persistent anaemia in immunocompromised patients, transplant recipients and infants. The deficiencies of appropriate immune responses to B19 impair viral elimination in vivo, which results in enlargement of B19-infected erythroid-lineage cells. The B19-associated damage of erythroid lineage cells is due to cytotoxicity mediated by viral proteins. B19-infected erythroid-lineage cells show apoptotic features, which are thought to be induced by the non-structural protein, NS1, of B19. In addition, B19 infection induces cell cycle arrests at the G(1) and G(2) phases. The G(1) arrest is induced by NS1 expression prior to apoptosis induction in B19-infected cells, while the G(2) arrest is induced not only by infectious B19 but also by UV-inactivated B19, which lacks the ability to express NS1. In this review, we address the clinical manifestations and molecular mechanisms for B19-induced anaemia in humans and a mouse model, and of B19-induced cell cycle arrests in erythroid cells.

Adult↗
PubMed1997

In vitro proliferation and differentiation of erythroid progenitors of cord blood.

Stem cell factor (SCF) is known to synergize with erythropoietin (EPO) for erythropoiesis in vitro. Clonogenic assay and suspension culture were used to assess the effect of EPO alone or its combination with SCF on the proliferation and differentiation of erythroid progenitors of cord blood. Colony formation, increase in cell count, and cell cycling status for the proliferation as well as expression of Glycophorin A (Gly A) and hemoglobinization as the marker of differentiation were determined with each stimulation. The cell cycle status of the cells in suspension cultures was determined using FACScan after labeling of cells with propidium iodide. Expression of Gly A and degree of hemoglobinization were determined by FACScan and spectrophotometer on the cells plucked from colonies in semisolid culture. Larger increases in cell counts in suspension culture were observed with EPO + SCF after 12 days of inoculation than with EPO alone. Mean doubling time was 14.2 h with EPO + SCF and 22.7 h with EPO alone. The proportion of cells in S and G2 + M phase in day 14 suspension culture was 48% with EPO + SCF and 43% with EPO alone (no significant difference). Mean colony counts per 10(5) nonadherent mononuclear cells were 76 +/- 14 with EPO + SCF and 51 +/- 15 with EPO at day 14 (p < 0.05). The number of macroscopic colonies with > 0.5 mm diameter was 10.7 +/- 1.2 with EPO + SCF and 0.3 +/- 0.5 with EPO (p < 0.05). Percent of Gly A+ cells was 75% for both EPO + SCF and EPO colonies at day 14. Hemoglobin concentration/10(5) cells at day 14 was 0.70 +/- 0.17 microgram with EPO + SCF, and 1.16 +/- 0.32 micrograms with EPO alone (p < 0.05). In conclusion, SCF in the combination with EPO showed a synergistic effect for erythroid proliferation in colony number as well as colony size derived from cord blood, while SCF with EPO decreased hemoglobin synthesis but not Gly A expression at day 14.

Blood Cell Count↗
PubMed1993

Granulocyte colony-stimulating factor treatment of mice modulates differently the sensitivity of blood and bone marrow hematopoietic progenitors to retroviral vector infection.

The effect of recombinant human granulocyte colony-stimulating factor (G-CSF) administration to mice on the retroviral-mediated transfer of the selectable marker gene neo to hematopoietic cells was studied. After G-CSF treatment, blood mononuclear cells and bone marrow cells were infected with the retrovirus, and the efficiency of gene transfer into myeloid progenitors was increased in peripheral blood and decreased in bone marrow cells. Bone marrow four to six months after transplantation from G-CSF treated mice revealed the presence of the transferred neo gene in 4 out of 104 mice, which is an eightfold lower proportion than in the control group. These data suggest that G-CSF in vivo treatment decreases bone marrow sensitivity and increases the sensitivity of peripheral blood cells to retroviral infection.

Animals↗
PubMed1999

Tyrosine residues of the erythropoietin receptor are dispensable for erythroid differentiation of human CD34+ progenitors.

To study the role of the cytoplasmic domain and particularly the tyrosine residues of the erythropoietin receptor (EpoR) in erythroid differentiation of human primary stem cells, we infected cord blood-derived CD34+ cells with retroviruses encoding chimeric receptors containing the extracellular domain of the prolactin receptor (PRLR) and the cytoplasmic domain of either the normal EpoR or a truncated EpoR devoid of tyrosine residues. Erythroid differentiation of the infected progenitors could thus be studied after stimulation by PRL. The complete PRLR was used to assess its ability to substitute for EpoR in erythroid differentiation. Typical erythroid day-14 colonies were observed from CD34+ cells grown in PRL when infected with any of the three viral constructs. These results demonstrate that: (i) the activation of the virally transduced PRLR leads to erythroid colony formation showing that erythroid terminal differentiation can be induced by a non-erythroid receptor in human progenitors; (ii) a chimeric receptor PRLR/EpoR is able to transduce a signal leading to terminal erythroid differentiation of human CD34+ cells; (iii) in contrast to results previously reported in murine models, tyrosine residues of the EpoR are not required for growth and terminal differentiation of human erythroid progenitors.

Antigens, CD34↗
PubMedDate not supplied

In vitro mass production of human erythroid cells from the blood of normal donors and of thalassemic patients.

We describe a new two-step culture method for mass production in vitro of erythroid cells from either CD34+ (10(5) cells/mL) or light-density (10(6) cells/mL) cells purified from the blood of normal donors and thalassemic patients. The method includes (i) culture of the cells in the presence of dexamethasone and estradiol (10(-6) M each) and (ii) the growth factors SCF (50 ng/mL), IL-3 (1 ng/mL), and EPO (1 U/mL). In their proliferative phase, these cultures generated approximately 1.2 x 10(7) erythroblasts for each milliliter of blood collected from normal donors or thalassemic patients. They were composed mostly (90%) of CD45(low)/glycophorin (GPA)(neg)/CD71(1ow) cells at day 7, 50-60\% of which became CD45(neg)/GPA+/CD71high by days 15-20. However, when cells from days 7 to 12 of the proliferative phase were transferred in differentiation medium containing EPO and insulin, they progressed to mature erythroblasts (g90% benzidine(pos) and CD45(neg)/GPA+/CD71medium) in 4 days. Because of the high number of erythroid cells that are generated from modest volumes of blood, this method will prove useful in donor-specific studies of erythroid differentiation.

Antigens, CD34↗
PubMed1989

Long-term expression of the human beta-globin gene after retroviral transfer into pluripotent hematopoietic stem cells of the mouse.

We have studied the regulation of the human beta-globin gene after retroviral transfer into a variety of transformed and normal hematopoietic cells. After transfer into murine erythroleukemia cells (MEL) expression from the human beta-globin gene responds to inducers of erythroid maturation in parallel to the endogenous murine globin genes. After infection of human BFU-E, RNA expression from the virally-transferred beta-globin gene was measured at 2.5%-5% of the endogenous beta-globin level. The most improved globin vectors can transfer the human beta-globin gene into pluripotent hematopoietic stem cells in mouse bone marrow. Mice reconstituted with infected marrow show human beta-globin RNA and protein expression in peripheral blood cells for over 4 months. In these animals, both myeloid and lymphoid cells carry the integrated provirus at a level of about 1 copy per cell. In serial transplantation experiments, bone marrow from these animals is capable of repopulating secondary and tertiary recipient animals which go on to show long-term human beta-globin expression. Retroviral vectors thus provide a practical way to refine models of globin gene regulation through in vivo tests and to evaluate the feasibility of protocols for gene addition therapy.

Animals↗