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PubMed1996

Ex vivo manipulation of cell subsets for cell therapies.

Large-scale cell separation and ex vivo expansion technologies will form the basis for development of new cellular products for the treatment of cancer and fatal viral diseases. The cell subsets that are likely to play a significant role in cellular therapy include hematopoietic stem cells, platelet and granulocyte precursors, cytotoxic lymphocytes, and genetically modified hematopoietic or lymphoid precursors. Cell enrichment techniques are required to eliminate tumor cells from autologous stem cell grafts and to reduce the size of culture systems required for expansion or gene transfection. The consumption of expensive culture components such as cytokines and serum may be reduced by the use of perfusion bioreactor devices. Methods that have been developed for the production of cell subsets for cellular therapy are reviewed.

Blood Platelets↗
PubMed1983

The hematopoietic effects of lithium.

The observation that patients treated with Li for manic-depressive illnesses develop an associated leukocytosis has led to a series of experimental and clinical studies of the hematopoietic effects of this simple molecule. Increases in blood neutrophils, eosinophils and perhaps monocytes are observed routinely when persons with an apparently normal hematopoietic system are exposed to "therapeutic" doses of the drug. Blood platelets tend to be increased, but lymphocytes and erythrocytes are unaffected. Neutrophilia reflects a true increase in the total number of mature neutrophils in all body compartments and is due to increased production. Neutrophil function generally is unaffected by Li. In man or in other mammals, certain classes of hematopoietic stem cells are increased by Li administration. Extensive studies of the effect of Li have been carried out in cultures of cells producing colonies of neutrophils and macrophages (CFUNM) in semisolid media. The colony-forming cell itself is little affected by Li. Cells which produce the factor essential for production of normal CFUNM (CSF) are stimulated to produce more CSF by the presence of Li. Studies of changes in vivo in CSF levels yield somewhat conflicting results; serum CSF being increased in some but not in others. Thus, it is not clear if the effect of Li on cell production in vivo reflects a direct effect on granulocytic precursors, including stem cells, or is mediated by stimulation of a feed-back loop (or both). A number of trials of Li therapy designed to modify induced neutropenia or to correct existing neutropenia are reviewed. Although many of these are very difficult to interpret, there is some reason to be optimistic concerning an eventual role for Li therapy of certain diseases associated with hematologic abnormalities.

Adult↗
PubMed2000

Regulation of granulopoiesis by transcription factors and cytokine signals.

The development of mature granulocytes from hematopoietic precursor cells is controlled by a myriad of transcription factors which regulate the expression of essential genes, including those encoding growth factors and their receptors, enzymes, adhesion molecules, and transcription factors themselves. In particular, C/EBPalpha, PU.1, CBF, and c-Myb have emerged as critical players during early granulopoiesis. These transcription factors interact with one another as well as other factors to regulate the expression of a variety of genes important in granulocytic lineage commitment. An important goal remains to understand in greater detail how these various factors act in concert with signals emanating from cytokine receptors to influence the various steps of maturation, from the pluripotent hematopoietic stem cell, to a committed myeloid progenitor, to myeloid precursors, and ultimately to mature granulocytes.

Cytokines↗
PubMed1998

p40/LAIR-1 regulates the differentiation of peripheral blood precursors to dendritic cells induced by granulocyte-monocyte colony-stimulating factor.

p40/LAIR-1, a member of the immunoglobulin superfamily, is a surface molecule broadly distributed among leukocytes which has been shown to down-regulate T and NK cell activation. In this study, we show that p40/LAIR-1 is highly expressed in CD14+ peripheral blood mononuclear cells (PBMC). When cultured in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) for 10-14 days, CD14+ cells acquired morphologic and phenotypic features (i.e. loss of CD14 and expression of CD80bright and CD86bright) typical of dendritic cells (DC) and lost the expression of p40/LAIR-1. Engagement of p40/LAIR-1 (but not of CD58) by specific monoclonal antibodies prevented CD14+ PBMC differentiation into DC; when cultured in the presence of GM- CSF upon p40/LAIR-1 cross-linking, the resulting cells were CD14+CD80(dull)CD86(dull) and displayed a macrophage-like morphology. We have recently demonstrated that peripheral blood CD14+ cells co-expressing the CD34 progenitor marker represent the circulating precursors of CD83+ DC. Herein we show that cross-linking of p40/LAIR-1 prevented the maturation of CD14+CD34+ cells into CD83+ DC. This effect appears to be consequent to the impairment of GM-CSF receptor-mediated activation signaling. Indeed, triggering of GM-CSF receptors in both CD14+ and CD14+CD34+ cells led to increases in the intracellular free calcium concentrations which were inhibited by p40/LAIR-1 engagement. Taken together, these data suggest a possible regulating role played by p40/LAIR-1 in the process of differentiation from peripheral blood precursors into DC induced by GM-CSF.

Calcium↗
PubMedDate not supplied

Ambient air particulates stimulate alveolar macrophages of smokers to promote differentiation of myeloid precursor cells.

Studies from our laboratory have shown that exposure to air pollution particles smaller than 10 microm (PM10) induced a systemic inflammatory response that includes the release of granulocytes from the bone marrow. In the present study we tested the hypothesis that mediators released from human alveolar macrophages (AM) exposed to PM10 accelerate the maturation of granulocyte precursors. Human myeloid precursor cells (HL60 cells) were incubated with the supernatant from AM exposed to PM10. Phagocytosis of PM10 by AM resulted in the production of cytokines, particularly interleukin-6 (IL-6) and granulocyte-macrophage colony-stimulating factor (GM-CSF) (P < .05). The supernatant from AM exposed to PM10 did not influence myeloid cell proliferation but promoted cell differentiation as measured by surface GD11b and CD14 expressions compared to control supernatant (P < .05). This effect of exposed-AM supernatants on myeloid cell differentiation was blocked by anti-IL-6 monoclonal antibodies (CD11b and CD14; P < .05) and anti-GM-CSF monoclonal antibodies (CD14, P < .01). We conclude that human AM exposed to PM10 produce mediators, particularly IL-6 and GM-CSF that promote the differentiation of bone marrow myeloid cells and we speculate that these cytokines are involved in the release of granulocytes from the bone marrow associated with exposure to air pollution particulates.

Aged↗
PubMed1988

Flow cytometric analysis of I-J expression on murine bone marrow-derived macrophages.

Attempts to analyze bone marrow-derived macrophages (BMDM) by flow cytometry have been prohibited because of their high autofluorescence. Using an autofluorescence reduction method of Steinkamp and Stewart to reduce the autofluorescence of BMDM, we were able to examine several macrophage populations for their expression of I-A, I-J, and Mac-1 cell surface determinants. Bone marrow cells examined immediately after removal from the femur contain 50-60% Mac 1-positive cells (mainly granulocytes). During the next few days granulocytes and nonmacrophage precursor cells die, and the number of Mac 1-positive cells decrease. Once the bone marrow cells have been maintained in L cell conditioned medium (LCM) for 2 to 3 days, the number of cells expressing Mac 1 increases rapidly from 20% to 98% during the next 3 to 4 days. Bone marrow cells grown in LCM do not express I-J until these cells have been in culture 3 to 4 days, and the number of cells expressing I-J (up to 90% positive) parallels the increase in macrophages. Bone marrow cells maintained in LCM did not express detectable I-A during the 14 days these cells were examined. Two other macrophage populations often used in a variety of immunological studies were analyzed by flow cytometry. We found that the majority (up to 80%) of peritoneal cells expressed I-A, and only 20% of peritoneal cells had I-J cell surface determinants. On the other hand, peritoneal exudate cells collected 4 days after thioglycolate medium treatment were predominantly I-J positive (up to 70%), and only about 30% of these cells expressed I-A cell surface antigens. The binding of anti-I-J IgM antibody to BMDM was not to Fc receptors because pretreating these cells with up to 25 micrograms of an IgG2a myeloma protein did not block anti-I-J antibody binding. The addition of 25-200 micrograms of monoclonal anti-Fc receptor antibody was also ineffective in blocking the binding of a monoclonal anti-I-Jk antibody to BMDM. Pretreatment of BMDM with the IgM fraction of several control IgM antibody preparations did not block the specific binding of fluoresceinated anti-I-J IgM antibody. BMDM provide a pure population of macrophages that express a significant level of cell surface I-J antigens. Bone marrow cells grown in LCM are essentially devoid of other contaminating cells, and the increase in the number of I-J-positive cells parallels the increase in macrophages in these cultures.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Granulocytic sarcoma of the ovotestis: an association of myelodysplastic syndrome and hermaphroditism.

Granulocytic sarcomas are extramedullary tumors (EMD) of malignant myeloid precursor cells. EMD or granulocytic sarcoma of ovary is rare disease. A 15-year-old girl had complaints of abdominal pain and weight loss for 3 months. On physical examination, there were hepatosplenomegaly and a painless mass under the umbilicus. Breast development was grade II. There was no clitoris hypertrophy. Her labia majora were separate and vagina hypoplastic. Hemoglobin level was 9.3 g/dl, white blood cells count 2.8 x 10(6)/1, platelet count 31.6 x 10(9)/1. There were dysplastic features in the blood and bone marrow cells. There were 10 and 22% blasts in the peripheral blood smear and bone marrow, respectively. The levels of serum follicle stimulating and luteinizing hormones were high. An inguinal mass (diameter 9.5 x 7.6) cm was detected on computed tomography. The histopathological diagnosis of this was obtained from laporascopy was composed of ovotestis and there was marked blastic infiltration in this ovotestis which had myeloid markers on flow cytometry. In the immunohistochemical analyses of ovotestis and bone marrow, blasts were positive for LCA, CD-13, CD-33 and CD 68. The cytogenetic analysis of the bone marrow shaved 46 XY karyotype. No response was achieved with combination chemotherapy and the patient died from progressive leukemia. Here we report a rare patient with myelodysplastic syndrome, EMD and hermaphroditism. To our knowledge this is the first case of MDS, EMD and hermaphroditism.

Adolescent↗
PubMed1979

Amino acid conferred protection against melphalan: comparison of amino acids which reduce melphalan toxicity to murine bone marrow precursor cells (CFU-C) and murine L1210 leukemia cells.

The effect of the naturally occuring amino acids upon melphalan (L-phenylalanine mustard, L-PAM) toxicity to a host sensitive tissue, the granulocyte and macrophage precursor cells of murine bone marrow (CFU-C), was investigated. At physiological concentrations the L isomers of leucine and glutamine were found to be the most effective of the naturally occurring amino acids in reducing drug toxicity. Tyrosine, phenylalanine and methionine also protected murine CFU-C from melphalan toxicity although the amount of protection provided by these amino acids at physiological concentrations was less than that provided by leucine and glutamine. Little difference was observed in the pattern of amino acid protection of murine CFU-C and murine L1210 leukemia cells. Murine CFU-C however were more sensitive to melphalan both in the absence and presence of amino acids.

Amino Acids↗
PubMed2001

BCR-ABL suppresses C/EBPalpha expression through inhibitory action of hnRNP E2.

The arrest of differentiation is a feature of both chronic myelogenous leukemia cells in myeloid blast crisis and myeloid precursors that ectopically express the p210BCR-ABL oncoprotein; however, its underlying mechanisms remain poorly understood. Here we show that expression of BCR-ABL in myeloid precursor cells leads to transcriptional suppression of the granulocyte colony-stimulating factor receptor G-CSF-R (encoded by CSF3R), possibly through down-modulation of C/EBPalpha-the principal regulator of granulocytic differentiation. Expression of C/EBPalpha protein is barely detectable in primary marrow cells taken from individuals affected with chronic myeloid leukemia in blast crisis. In contrast, CEBPA RNA is clearly present. Ectopic expression of C/EBPalpha induces granulocytic differentiation of myeloid precursor cells expressing BCR-ABL. Expression of C/EBPalpha is suppressed at the translational level by interaction of the poly(rC)-binding protein hnRNP E2 with CEBPA mRNA, and ectopic expression of hnRNP E2 in myeloid precursor cells down-regulates both C/EBPalpha and G-CSF-R and leads to rapid cell death on treatment with G-CSF (encoded by CSF3). Our results indicate that BCR-ABL regulates the expression of C/EBPalpha by inducing hnRNP E2-which inhibits the translation of CEBPA mRNA.

Animals↗
PubMed1981

The role of the nuclear protein matrix during development of rabbit granulocytes.

A proteinaceous nuclear substructure (nuclear protein matrix or nuclear pore complex-lamina) has been described in a number of cells and may be a universal feature of cell nuclei. We have investigated the nuclear protein matrix (NPM) in the rabbit blood granulocyte and its precursor cells to determine (A) whether the NPM composition is similar to other cells that have been studied and (B) to determine whether the dramatic morphological changes that the granulocyte nucleus undergoes during cell maturation are related to changes in the composition or structure of the NPM. NPM preparations from rabbit granulocytes were similar but not identical to those found in HeLa cells or rat liver nuclei. The NPM structure of more mature cells retained more DNA during the isolation procedures than did immature cell NPMs, and the DNA was less accessible to DNAse in the mature cell nuclei. Scanning and transmission electron microscopy revealed a continuous outer covering of the NPM preparation and a lattice-like internal structure. Recognizable nuclear form persisted although the preparations represented less than 20% of the original nuclear protein. NPM preparations from mature cells were similar in overall dimensions and internal structure to NPM from immature cells, suggesting reexpansion during isolation of a previously compacted NPM structure in segmented neutrophils. NPM proteins are synthesized primarily in early stages of cell development. The NPM appears to play a major, but passive, structural role in the nuclear changes observed during maturation of granulocytes.

Animals↗
PubMed1999

Synergy of growth factors during mobilization of peripheral blood precursor cells with recombinant human Flt3-ligand and granulocyte colony-stimulating factor in rabbits.

The potential of recombinant human (rh)Flt3 ligand (FL), alone or in combination with other recombinant growth factors, to mobilize peripheral blood precursor cells (PBPCs) was examined in an animal model. Adult outbred New Zealand White rabbits received subcutaneous injections daily for 14 days in a standardized protocol; whole blood cell counts and colony-forming unit-granulocyte/macrophage (CFU-GM) colonies were measured 3 times weekly during the injection period and for an additional observation period of 14 days. Two animals in each group were treated as follows: 200 or 500 microg/kg FL, 10 microg/kg granulocyte colony-stimulating factor (G-CSF), 10 or 75 microg/kg stem cell factor (SCF), 10 microg/kg G-CSF + 500 microg/kg FL, 10 microg/kg G-CSF + 75 microg/kg SCF + 500 microg/kg FL. Both G-CSF and FL induced a sustained and dose-dependent increase in the leukocyte count to a maximum of 5-fold. They were additive in combination, leading to a tenfold increase in white blood cell counts. No consistent pattern was observed for platelet counts or red blood cells. No toxic side effects were seen. Both G-CSF and FL mobilized CFU-GM in a dose-dependent fashion to a 59-fold increase for G-CSF and 116-fold for FL. Maximum mobilization occurred on day 4 with G-CSF and on day 11 with FL. G-CSF + FL in combination acted synergistically, inducing a 503-fold increase of CFU-GM over baseline. The addition of SCF to this combination did not alter leukocyte counts or CFU-GM mobilization. Our results indicate that FL is a potent and safe agent for the mobilization of PB-PCs and is synergistic with G-CSF.

Animals↗
PubMed1983

Monoclonal antibody against human macrophages/monocytes and granulocytes.

A monoclonal antibody of the IgG2a isotype directed against lymphokine-activated human macrophage cell line (U937) was produced and characterized. By indirect immunofluorescence microscopy or binding assay, this antibody (MaG-1) reacted with human peripheral monocytes, peritoneal macrophages, alveolar macrophages, and peripheral granulocytes but not with lymphocytes, erythrocytes, and platelets. MaG-1 antigen was also expressed by 34% of bone-marrow cells which includes monocytic and granulocytic precursors, whereas lymphoid and erythroid precursor cells were found on MaG-1 negative population. Immunoprecipitation of 125I-labeled U937 cell extract with the Mag-1 antibody under nonreducing and reducing conditions yielded a specific band of 66 kD. Thus, this antibody defines a new human macrophage/monocyte and granulocyte-specific antigen and may be useful for studying differentiation of human macrophages/monocytes.

Antibodies, Monoclonal↗
PubMed2002

Acceleration of granulocyte colony-stimulating factor-induced neutrophilic nuclear lobulation by overexpression of Lyn tyrosine kinase.

Stimulation with granulocyte colony-stimulating factor (G-CSF) induces myeloid precursor cells to differentiate into neutrophils, and tyrosine phosphorylation of certain cellular proteins is crucial to this process. However, the signaling pathways for neutrophil differentiation are still obscure. As the Src-like tyrosine kinase, Lyn, has been reported to play a role in G-CSF-induced proliferation in avian lymphoid cells, we examined its involvement in G-CSF-induced signal transduction in mammalian cells. Expression plasmids for wild-type Lyn (Lyn) and kinase-negative Lyn (LynKN) were introduced into a murine granulocyte precursor cell line, GM-I62M, that can respond to G-CSF with neutrophil differentiation, and cell lines that overexpressed these molecules (GM-Lyn, GM-LynKN) were established. Upon G-CSF stimulation, both the GM-Lyn and GM-LynKN cells began to differentiate into neutrophils, showing early morphological changes within a few days, much more rapidly than did the parental cells, which started to exhibit nuclear lobulation about 10 days after the cells were transferred to G-CSF-containing medium. However, the time course of expression of the myeloperoxidase gene, another neutrophil differentiation marker, was not affected by the overexpression of Lyn or LynKN. Therefore, in normal cells, protein interactions with Lyn, but not its kinase activity, are important for the induction of G-CSF-induced neutrophilic nuclear lobulation in mammalian granulopoiesis.

Animals↗
PubMed1976

Experimental analysis of developing hemopoiesis in fetal bone marrow.

1. We have used fetal rats to study the following aspects of the development of hemopoiesis: (a) content of hemopoietic stem cells in fetal bone marrow, liver, and peripheral blood and (b) origin of hemopietic cells in the developing mammalian bone marrow. 2. In the studies we utilized the diffusion chamber technique to study the content of stem cells committed to granulopoiesis. The number of myelopoietic stem cells in liver peripheral blood and in "bone marrow" of 18-day-old rats is nearly identical. Since in "bone marrow" a considerable number of peripheral blood cells are present in the vessels at that time, whereas extravascular cells consist only of mesenchymal cells, one might assume that these peripheral blood cells give rise to granulocytic precursors in the cultures. Morphologically these cells are "blast" cells and lymphocytes. 3. Based on cell labeling indices of radioautograms, derived from continuous infusion of pregnant rats with [3H]thymidine, it could be shown that in the perichondral area mesenchymal cells of the fetus and newborn have a slow rate of DNA turnover whereas "bone marrow" cells are in an active state of profileration. 4. In further support of this it was also shown that injections of hydroxyurea (an agent which destroys cells in DNA synthesis) has vitrually no effect on perichondral mesenchymal cells whereas "bone marrow" cells were completely blocked in their ability to support myelopoietic differentiation in the diffusion chamber implants. 5. The conclusions would therefore be that (a) local perichondral cells, i.e., mesenchymal cells, do not contribute to marrow hemopoiesis, (b) matrix cells of the developing bone marrow cannot reconstitute hemopoiesis, and (c) hemopoietic bone marrow cells develop from migrating peripheral "stem cells", one of the sources being the liver.

Animals↗
PubMed1997

High thrombopoietin production by hematopoietic cells induces a fatal myeloproliferative syndrome in mice.

To evaluate the effects of long-term, high-dose exposure to thrombopoietin (TPO), lethally irradiated mice were grafted with bone marrow cells infected with a retrovirus carrying the murine TPO cDNA. Mice were studied for 10 months after transplantation. In plasma, TPO levels were highly elevated (10(4) U/mL) throughout the course of the study. All mice developed a lethal myeloproliferative disorder evolving in two successive phases. During the first phase (7-9 weeks posttransplant), platelet and white blood cell (WBC) counts rose four- and ten-fold, respectively, whereas hematocrits decreased slightly to 29% +/- 3%. The WBC were mainly mature granulocytes, but myeloid precursor cells were invariably observed as well as giant platelets with an irregular granule distribution. The striking features were a massive hyperplasia of megakaryocytes and granulocytes in the spleen and bone marrow and a hypoplasia of erythroblasts in bone marrow. Total numbers of megakaryocyte colony-forming cell, burst-forming unit-erythroid, and granulocyte macrophage colony-forming cells were increased but colony-forming unit-erythroid numbers decreased. From 10 weeks posttransplant and thereafter, WBC, platelets, and red blood cell numbers declined dramatically. The absolute numbers of progenitor cells were very low in the spleen and bone marrow, but sharply increased in the blood and peritoneal cavity. Extramedullary hematopoiesis was observed in several organs. Histologic sections of the spleen and bones revealed severe fibrosis and osteosclerosis. The mean survival time was 7 months posttransplant and mice died with severe pancytopenia. Notably, two mice died between 3 and 4 months posttransplant with a leukemic transformation. This disorder was transplantable into secondary recipients who developed an attenuated form of the disease similar to the one previously described (Yan et al, Blood 86:4025, 1995). Taken together, our data show that high and persistent TPO production by transduced hematopoietic cells in mice results in a fatal myeloproliferative disorder that has a number of features in common with human idiopathic myelofibrosis.

Animals↗
PubMed1977

Bone marrow colony-forming cells in mice with virus-induced lymphoid leukemia: relation to serum colony-stimulating activity and blood granulocytes.

Mice with advanced lymphoid leukemia have elevated peripheral blood granulocytes and elevated serum colony-stimulating activity, which promotes the in vitro growth of granulocyte and/or macrophage colonies. The number of bone marrow precursor cells of the in vitro granulocyte and/or macrophage colonies varied from normal to 10% of normal. The elevation of colony-stimulating activity correlated best with a combination of increased blood granulocytes and a deficiency of bone marrow precursor cells, which suggested that colony-stimulating activity is a leukopoietin that increases the efficiency and rate of production of granulocytes.

Animals↗
PubMed1981

The thymus as haematopoietic tissue of non-lymphoid cells.

Non-lymphoid haematopoiesis in the thymus was studied in 33 cases ranging from 14 weeks gestation up to 15 months postnatally. All thymuses displayed focally granulopoiesis in the connective tissue septa and in the lymphoid tissue, where it was localized in the peripheral cortex and at the cortico-medullary junction. Within the lymphoid tissue the granulocytic series showed many precursor cells with large rounded nuclei. Their origin could only be identified by the naphtol AS D chloroacetate esterase stain. In cases with thymic atrophy these precursor cells were present in relatively large numbers. Within the connective tissue septa many granulocytes with nuclear segmentation were intermingled with precursor cells. The erythroid series were detected with an immunohistochemical method for demonstration of haemoglobin. The positively stained nucleated cells occurred mainly in nests mostly localized in the peripheral cortex. These precursor cells were usually found in different places from the granulopoietic cells. No megakaryocytes were found. With appropriate techniques non-lymphoid haematopoiesis can be demonstrated in the developing thymus and must be considered as an expression of normal growth.

Connective Tissue Cells↗