[Genetic sex in normal and pathological neutrophil myelocytes].
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Blood Cell Count↗
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Results for “Granulocyte Precursor Cells”
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VIRUS OF AVIAN MYELOBLASTOSIS (BAI STRAIN A). XXV. ULTRACYTOCHEMICAL STUDY OF VIRUS AND MYELOBLAST PHOSPHATASE ACTIVITY.
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Adenosine Triphosphatases↗
Specific inhibition of phorbol diester-induced granulocyte-macrophage progenitor cell (GM-CFU) differentiation by lipoxygenase inhibitors.
The induction of differentiation of SENCAR murine granulocyte-macrophage precursor cells (GM-CFU) by the tumor-promoting phorbol diester 12-O--tetradecanoyl-phorbol-13-acetate (TPA) was inhibited by agents reported to inhibit specific aspects of arachidonic acid metabolism. These agents included phospholipase A2 inhibitors, and eicosatetraynoic acid (ETYA), a competitive inhibitor of arachidonic acid oxygenases. Whereas inhibitors reported specific for lipoxygenases were also active, no comparable effect was observed for inhibitors of the corresponding cyclooxygenase. These findings are therefore consistent with the hypothesis that induced differentiation of GM-CFU cells is regulated by products of arachidonic acid metabolism formed principally via lipoxygenase activity.
5,8,11,14-Eicosatetraynoic Acid↗
Expression of ecotropic murine leukaemia virus in haemopoietic cells of AKR mice during the embryonic and neonatal period.
Cells which produce ecotropic murine leukaemia virus have been detected in the bone marrow and the spleen of weanling AKR mice, using an infectious centre technique based on the XC test. There is a noticeable increase in the number of virus-producing cells between day 3 and day 12 after birth, in both of these organs. Some of the virus-producing cells that appear after day 3 have been identified as haemopoietic precursor cells of the granulocyte-macrophage blood lineage. Such precursor cells do not produce virus during the embryonic period and they progressively become involved in virus production after day 3. By day 12, all of them are active virus producers. Thus, the ecotropic virus is expressed in precursor cells of the haemopoietic system, and the latter represent at least one-third of the virus-producing cells in the bone marrow of young AKR mice.
Animals↗
Separation of resting and proliferating granulocytic precursors.
We have obtained cells in various stages of granulocytic development by a combination of isopycnic separation and electronic cell sorting. Not only were immature cells (blast cells, promyelocytes and myelocytes) separated from mature cells (bands and polys), but the immature cells were separated into proliferating (S + G2 + M) and resting (Go/G1) compartments of the cell cycle. This permits the study of the morphological and biochemical changes associated with development apart from those changes associated with proliferation.
Animals↗
Distribution of receptors for granulocyte-macrophage colony-stimulating factor on immature CD34+ bone marrow cells, differentiating monomyeloid progenitors, and mature blood cell subsets.
Biotin-labeled granulocyte-macrophage colony-stimulating factor (GM-CSF), in combination with phycoerythrin-conjugated streptavidin, enabled flow cytometric analysis of specific cell-surface GM-CSF receptors on rhesus monkey bone marrow (BM) and peripheral blood (PB) cells. GM-CSF receptors were readily detected on PB monocytes and neutrophils, but not on lymphocytes. In BM, GM-CSF receptors were identified on monocyte and neutrophil precursors and on subsets of cells that expressed the CD34 antigen. CD34+ cells with high GM-CSF-receptor expression coexpressed high levels of the class II major histocompatibility antigen RhLA-DR, whereas CD34+/RhLA-DRlow cells, which represent developmentally earlier cells, were either GM-CSF-receptor negative or expressed GM-CSF receptors at very low levels. The fluorescence histogram of CD34bright/RhLA-DRdull cells stained with biotin-GM-CSF showed that at least a fraction of these cells expressed low levels of GM-CSF receptors. CD34+ cells with high GM-CSF-receptor expression, purified by cell sorting, did not form colonies in culture or proliferate in response to GM-CSF. Instead, GM-CSF stimulation resulted in terminal differentiation into adherent cells, showing that these cells represented monocyte precursors. A distinct subset of CD34+ cells expressed GM-CSF receptors at low-to-intermediate levels and proliferated strongly in the presence of GM-CSF during short-term culture, but produced very few erythroid or monomyeloid colonies after longer culture periods. Most colony-forming cells, also those responsive to GM-CSF alone, were recovered in the subset of CD34+ cells on which GM-CSF receptors were virtually undetectable. These cells showed weaker proliferation in short-term proliferation assays than the CD34+/GM-CSF-receptor-intermediate cells, consistent with an immature phenotype. The results show that GM-CSF-receptor expression is initiated in a subset of immature, CD34bright/RhLA-DRdull cells and is progressively increased during differentiation into mature granulocytes and monocytes. The method used provides a new way to deplete developmentally early CD34+ cell of differentiating granulocyte and monocyte precursor cells.
Animals↗
[Hematopoietic changes in mice with transplantable Lewis lung carcinoma].
The cell composition of bone marrow, spleen, and peripheral blood as well as the content of early granulocytic and macrophagal precursor cells forming colonies in agar cultures in diffusion chambers in vivo (CFU-DC) were studied in C57B1/6 mice during the Lewis carcinoma growth after subcutaneous transplantation of tumour cells. It has been shown that in peripheral blood of such mice neutrophilic leucocytosis develops and the content of CFU-DC increases considerably. The spleen has become a source of surplus production of granulocytic and macrophagal cells from the early precursors (CFU-DC) to the mature cell forms with their delivery to the peripheral blood. No essential changes in the cell composition and CFU-DC content were found in the bone marrow of femur.
Animals↗
Prospective randomised comparison of the COBE spectra version 6 and haemonetics MCS(+) cell separators for hematopoietic progenitor cells leucapheresis in patients with multiple myeloma.
A randomised crossover trial of two separators was undertaken to compare the mononuclear cell, CD34(+) cell and CFU-GM yield, in patients (<61 years) with previously untreated symptomatic multiple myeloma. After first-line therapy, all patients received mobilising chemotherapy (cyclophosphamide 4 g/m(2)) and daily G-CSF. The first leucapheresis was performed on the first day the peripheral blood absolute CD34(+) cell count was > 20 cells/microl. All patients underwent 2 leucaphereses on consecutive days. The patients were randomised to undergo either the first or second leucapheresis using the COBE Spectra. The target duration of the procedure on the COBE Spectra was 2 total blood volumes, and for the Haemonetics MCS(+) it was 20 cycles with four recirculations. Between September 2003 and March 2005, 60 patients were entered in the study. COBE Spectra version 6 processed significantly larger volumes of blood than the Haemonetics MCS(+) (8,845 and 5,680 ml, respectively, P < 0.01). The absolute yield of mononuclear cells (2.1 vs. 1.5 x 10(8)/kg, P = 0.04), CFU-GM (11 vs. 3 x 10(4)/kg, P = 0.01) and CD34(+) cells (3 vs. 1.7 x 10(6)/kg, P = 0.02) were all significantly higher with the COBE Spectra version 6, as were the yields per unit volume of blood processed. In conclusion, our study shows that COBE Spectra Version 6 is faster and has a better yield than the Haemonetics MCS(+), in patients with multiple myeloma.
Adult↗
Phenotypic and functional characterization of porcine granulocyte developmental stages using two new markers.
Here, we describe two new surface antigens, named 6D10 and 2B2, whose expression is restricted to porcine granulocytes. 6D10 is only detected in neutrophils and its expression decreases from promyelocytes to mature cells. By contrast, 2B2 antigen is selectively expressed in mature neutrophils, eosinophils and basophils. The expression of these antigens along granulocyte maturation allows the discrimination of several developmental stages of granulocytes based on phenotypic, morphological and functional characteristics previously established. Moreover, these new markers are useful tools to easily characterize the different granulocytes lineages (neutrophils, eosinophils and basophils). By using multiparameter flow cytometric analysis, we have performed a phenotypic and functional characterization of the granulocyte subsets identified by the combination of 6D10 and 2B2 antigens.
Animals↗
N-benzyladriamycin-14-valerate (AD 198) activates protein kinase C-delta holoenzyme to trigger mitochondrial depolarization and cytochrome c release independently of permeability transition pore opening and Ca2+ influx.
Unlike nuclear-targeted anthracyclines, the extranuclear-targeted doxorubicin congener, N-benzyladriamycin-14-valerate (AD 198), does not interfere with normal topoisomerase II activity, but binds to the C1b regulatory domain of conventional and novel isoforms of protein kinase C (PKC). The resulting interaction leads to enzyme activation and rapid apoptosis in a variety of mammalian cell lines through a pathway involving mitochondrial events such as membrane depolarization (Deltapsim) and cytochrome c release. Unlike other triggers of apoptosis, AD 198-mediated apoptosis is unimpeded by the expression of Bcl-2 and Bcl-XL. We have further examined AD 198-induced apoptosis in 32D.3 mouse myeloid cells to determine how the anti-apoptotic effects of Bcl-2 are circumvented. The PKC-delta inhibitor, rottlerin, and transfection with a transdominant-negative PKC-delta expression vector both inhibit AD 198 cytotoxicity through inhibition of Deltapsim and cytochrome c release. While the pan-caspase inhibitor Z-VAD-FMK blocks AD 198-induced PKC-delta cleavage, however, it does not inhibit Deltapsim and cytochrome c release, indicating that AD 198 induces PKC-delta holoenzyme activation to achieve apoptotic mitochondrial effects. AD 198-mediated Deltapsim and cytochrome c release are also unaffected by cellular treatment with either the mitochondrial permeability transition pore complex (PTPC) inhibitor cyclosporin A or the Ca chelators EGTA and BAPTA-AM. These results suggest that AD 198 activates PKC-delta holoenzyme, resulting in Deltapsim and cytochrome c release through a mechanism that is independent of both PTPC activation and Ca flux across the mitochondria. PTPC-independent mitochondrial activation by AD 198 is consistent with the inability of Bcl-2 and Bcl-XL expression to block AD 198-induced apoptosis.
Amino Acid Chloromethyl Ketones↗
Highly glycosylated alpha1-acid glycoprotein is synthesized in myelocytes, stored in secondary granules, and released by activated neutrophils.
Alpha-1-acid glycoprotein (AGP) is an acute-phase protein produced by hepatocytes and secreted into plasma in response to infection/injury. We recently assessed the transcriptional program of terminal granulocytic differentiation by microarray analysis of bone marrow (BM) populations highly enriched in promyelocytes, myelocytes/metamyelocytes (MYs), and BM neutrophils. These analyses demonstrated a transient, high mRNA expression of genuine secondary/tertiary granule proteins and AGP in MYs. In agreement with this, immunocytochemistry revealed the presence of AGP protein and the secondary granule protein lactoferrin in cells from the MY stage and throughout granulocytic differentiation. Immunoelectron microscopy demonstrated the colocalization of AGP and lactoferrin in secondary granules of neutrophils. This finding was substantiated by the failure to detect AGP and lactoferrin in blood cells from a patient with secondary/tertiary (specific) granule deficiency. In addition, Western blot analysis of subcellular fractions isolated from neutrophils revealed that neutrophil-derived AGP, localized in secondary granules, was abundant and highly glycosylated compared with endocytosed, plasma-derived AGP localized in secretory vesicles. Exocytosis studies further demonstrated a marked release of AGP and lactoferrin by activated neutrophils. Finally, induction of CCAAT/enhancer-binding protein (C/EBP)-epsilon in a myeloid cell line was shown to increase AGP transcript levels, indicating that AGP expression in myeloid cells, like in hepatocytes, is partially regulated by members of the C/EBP family. Overall, these findings define AGP as a genuine secondary granule protein of neutrophils. Hence, neutrophils, which constitute the first line of defense, are likely to serve as the primary local source of AGP at sites of infection or injury.
CCAAT-Enhancer-Binding Proteins↗
[Genetic sex in normal and pathological neutrophil myelocytes. Note II].
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Blood Cell Count↗
Serine protease inhibitor 2A is a protective factor for memory T cell development.
An essential event in the development of memory CD8(+) T lymphocytes is the escape of progenitors from programmed cell death, but how this is mediated is unclear. Here we report that the gene encoding serine protease inhibitor 2A (Spi2A), an inhibitor of lysosomal executioner proteases dependent on transcription factor NF-kappaB, is upregulated in memory cell precursors. Spi2A upregulation protected lymphocytic choriomeningitis virus-specific memory progenitors from programmed cell death. Thus, Spi2A promotes the survival of cytotoxic T lymphocytes, allowing them to differentiate into memory CD8 T cells. These findings suggest a model in which commitment to the memory lineage is facilitated by the upregulation of protective genes.
Animals↗
Retinoid acid supports granulocytic but not erythroid differentiation of myeloid progenitors in normal bone marrow cells.
In the new context of the use of retinoic acid (RA) therapy as an inducer of leukemic differentiation and a selective inhibitor of human myeloid leukemia cell growth, we undertook to explore the potential physiological role of retinoids on the proliferation and differentiation of normal bone marrow myeloid progenitors. The effects of continuous exposure of all-trans-RA, its naturally occurring isomer, 13-cis-RA, and its metabolite 4-oxo-all-trans-RA were studied on the growth of normal human bone marrow cells in soft agar, directly and after liquid culture. Retinoids enhanced the total number of granulocytic colony and macrocluster formation in the presence of exogenous colony-stimulating factor (n = 9). Dose-response curve were bell-shaped, with a maximal increment between concentration of 0.5 and 0.05 nM. In all cases, a concomitant decrease of macrophagic colonies was noted. The positive effect on granulocytic colony formation was observed with each of the retinoids tested (all-trans, 13-cis and 4-oxo-all-trans) (n = 5). On erythroid colony formation, all-trans-RA had the opposite effect. Constant suppression of CFU-E and BFU-E colony formation and coloring was observed in a dose-related fashion from 0.1 to 10 microM (n = 5). Thus, in granulocytic, as in erythroid colony formation, retinoids affected both proliferation and differentiation parameters. However, after short-term suspension culture in the presence of all-trans-RA, an increase of both CFU-GM and BFU-E colonies, was observed. These results suggest a specific effect of retinoids on late myeloid precursors and places retinoids as possible candidates for enhancement of normal granulocytic differentiation.
Bone Marrow Cells↗
In vitro regulation of granulopoiesis in human leukemia: application of an assay for colony-inhibiting cells.
We describe two assays to detect the action of colony-inhibiting cells. In the first assay, we used a simple density separation technique to remove dense neutrophils (PMN) from suspensions of blood and of bone marrow cells prior to culture in semisolid agar. Conditions were arranged to ensure that control suspensions of unseparated cells and test suspensions of buoyant mononuclear cells differed only in their content of neutrophils. The control and test suspensions contained equal numbers of mononuclear cells (and granulocyte precursors). Colony (and cluster) formation was invariably enhanced in neutrophil-depleted cultures of normal cells. In the second assay, dense PMN, treated by an adherence separation procedure, were recovered, and the non-adherent dense PMN were added back to PMN-depleted cultures. A reproducible dose-related decrease in colony (and cluster) formation to basal levels resulted. The inhibitory effect was identical when the PMN were added directly to the culture (overlayer) or to the underlayer. In PMN-depleted cultures obtained from patients with leukemia and other hemopoietic disorders, neither colony nor cluster formation was enhanced, and sometimes it was reduced. When we compared the effect of adding patient and normal non-adherent PMN to target cultures of normal and patient PMN-depleted cells, some leukemic PMN were noninhibitory. Our results suggest that abnormalities of cellular interactions in vitro detected in the first assay may have more than one explanation, as shown when they are subjected to the closer scrutiny possible with the second assay.
Bone Marrow↗
Effects of filgrastim on granulopoietic cells of mice pretreated with methotrexate.
We have evaluated the effect of filgrastim on proliferation and differentiation activity of granulopoietic cells in mice pretreated with methotrexate. Filgrastim was injected daily, from day 8 to 28 after cytotoxic agent administration. The granulopoiesis changes were measured by assessment of GM-CFU cells content, marrow and spleen granuloid cells pool as well as circulating neutrophils. In MTX pretreated mice, bone marrow GM-CFU oscillating values were higher than normal values, but these changes were not followed by high proliferative activity in granuloid precursor cell compartment. After MTX treatment, filgrastim administration was unable to stimulate marrow granulopoiesis as observed in normal mice. In the spleen, MTX led to dramatic changes in the proliferative activity of GM-CFU cells, but did not result in spleen granuloid cell changes. However, filgrastim treatment induced a spleen granuloid amplification, similar to the changes observed in circulating neutrophils values. We suggest that these findings can be explained by inhibition of differentiation of marrow GM-CFU cells into the more mature granulopoietic cells and/or by an inhibited proliferative activity of marrow granuloid cells. They can be also explained in terms of an unfavorable marrow microenvironment for granulopoiesis, contrary to a supportive spleen microenvironment.
Animals↗
Haematopoietic effects induced in mice by the snake venom toxin jararhagin.
Venom toxins have been tested as anti-thrombotic, and anti-metastatic drugs in experimental models. The jararhagin toxin, from Bothrops jararaca snake venom, acts upon several biological processes, as inflammation, pain, platelet aggregation, etc. In this article, the systemic effects of intra-peritoneal injections of different jararhagin doses were determined in mice. About 50% significant decrease was observed in total blood leukocytes in the first (48 ng), and second (24 ng) weeks. The reduction of lymphocytes, monocytes and neutrophils accounted for this leucopoenia up to the sixth week. Significant increase in red blood cells was observed, especially on the third and fourth weeks (6 and 12 ng). A significant reduction in leukocyte infiltration was found in peritoneum (6, 12, 48 ng), whereas the infiltration was significantly increased in bronchial alveolar exudates (6 and 12 ng). The differential analysis of bone marrow cells showed significant increase, particularly of myelocytes (12 and 24 ng). These results show, at low doses, the toxin jararhagin induces red blood cells production, which is compensating the reduction of different leukocyte types. This severe leucopoenia suggests the occurrence of anti-proliferate activity or direct citotoxicity of jararhagin in the differentiation level of myeloid, and lymphoid stem precursor cells.
Animals↗
The significance of Howell-Jolly bodies and giant metamyelocytes in marrow smears.
Howell-Jolly bodies in erythroid precursors can be found in the marrow in a variety of diseases. More than 1% in the later erythroblasts is rarely found except in vitamin B(12) or folic acid deficiency states.Giant metamyelocytes are probably always the result of vitamin B(12) or folic acid deficiency. A distinction is drawn between the deficiency of, and therapeutic need for, vitamin B(12) and folic acid.
Bone Marrow↗