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PubMed1997

[In vitro effects of hematopoietic growth factors on CD34+ cell from patients with myelodysplastic syndromes].

OBJECTIVE: To investigate the role of recombinant human hematopoietic growth factors (HGFs) in the treatment of myelodysplastic syndromes (MDS) patients. METHODS: CD34+ cells from 16 MDS patients were purified up to 96% approximately 99% by means of a immunomagnetic beads sorting system. The effects of individual and combination of HGFs on the proliferation and differentiation of the CD34+ cells were studied in semi -solid cultures. RESULTS: CD34+ cells were impaired and none of the individual HGF (GM-CSF, IL-3, SCF) could effectively support their proliferation and differentiation. rh-SCF combined with GM-CSF, IL-3 or Epo could partly increase the colony forming capacity of MDS hematopoietic progenitor, however, an increase of undifferentiated blast cells colonies occurred in some high-risk MDS patients at the same time. CONCLUSION: Proper combination of HGFs was essential for improving hematopoiesis in MDS patients.

Animals↗
PubMed1992

In vivo regulation of hemopoiesis by transforming growth factor beta 1: stimulation of GM-CSF- and M-CSF-dependent murine bone marrow precursors.

Injection of mice with either natural bovine bone-derived or human recombinant transforming growth factor beta 1 (TGF-beta 1) resulted in a significant increase of the macrophage and macrophage-granulocyte-forming capacity of their macrophage colony-stimulating factor (M-CSF)- and granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent bone marrow precursor cells. The increased potential for generating granulocytes and/or macrophages from bone marrow cells of mice injected with TGF-beta 1 was associated with an increase of the number of M-CSF- and GM-CSF-dependent bone marrow colony-forming units (CFU). The effect was selective, in that in vivo applied TGF-beta 1 did not affect interleukin 3 (IL-3)-dependent CFU. The data suggest that TGF-beta may be useful in recovery of bone marrow granulocyte- and macrophage-forming potentials following depletion caused by chemo- or radiotherapy.

Animals↗
PubMed1992

"Stem cell" origin of the hematopoietic defect in dyskeratosis congenita.

We have used the long-term bone marrow culture (LTBMC) system to analyze hematopoiesis in three patients with dyskeratosis congenita (DC), two of whom had aplastic anemia, and the third had a normal blood count (apart from mild macrocytosis) and normal BM cellularity. Hematopoiesis was severely defective in all three patients, as measured by a low incidence of colony-forming cells and a low level of hematopoiesis in LTBMC. The function of the marrow stroma was normal in its ability to support the growth of hematopoietic progenitors from normal marrows seeded onto them in all three cases, but the generation of hematopoietic progenitors from patients marrow cells inoculated onto normal stromas was reduced, thus suggesting the defect to be of stem cell origin. The parents and unaffected brother of one of the families have also been studied in LTBMC and all showed normal hematopoietic and stromal cell function. From this study we speculate that there are some similarities between DC and the defect in the W/Wv mouse.

Adolescent↗
PubMed1990

[T-lymphocyte control over the proliferative activity of committed precursor cells of erythro- and granulomonocytopoesis in stress].

The role of T-lymphocytes in regulation of proliferation and differentiation processes of committed myelopoiesis cell precursors in F1 (CBA-C57Bl/6) mice, treated by 10-hour immobilization was studied. One of the first reactions of hemopoietic precursors at stress was estimated to be the increase of active proliferating cells-precursors, accompanied by the quantitative changes of their content. The creation of T-cell deficit by means of anti-thymic serum resulted in abolition of the above mentioned changes of erythroid and granulo-macrophage precursors marked in the processes of adaptation syndrome development.

Animals↗
PubMedDate not supplied

[Formation of mixed colonies by progenitor cells of chronic myeloid leukemia cultured in vivo].

The clonal growth of multipotential progenitor cells of chronic myeloid leukemia (CML) in diffusion chamber implanted into peritoneal cavity of neutropenic and anemic rats was assessed. CML precursors formed in methylcellulose culture enriched with medium conditioned by phytohemagglutinin activated lymphocytes mixed neutrophilic-erythroid colonies, in number significantly higher then normal cells. Mixed colonies produced by CML cells, in contrast to the normal precursors, contained also macrophages, eosinophils and megakaryocytes. We conclude that modified diffusion chamber culture technique may be a suitable tool for multipotential progenitor study in CML.

Adult↗
PubMed1983

Cyclic neutropenia: amplification of granulocyte oscillations by lithium and long-term suppression of cycling by plasmapheresis.

A patient with well documented cyclic neutropenia (CN) was given chronic lithium therapy as well as a short course of plasmapheresis with therapeutic intention. While on lithium therapy, an increase in the amplitude of the granulocyte oscillations was observed, but recurrent agranulocytotic periods persisted. A 2-wk course of plasmapheresis (total exchange 17 liters) resulted in a gradual decrease of granulocyte oscillations, with the granulocyte count remaining above 500/cu mm at all times, and the patient became asymptomatic. The improvements in the clinical state of the patient have now persisted for more than 9 mo. Quantitative analysis of the oscillation period and the phase lags between peak counts of the hematologic cell lines revealed a 20-day cycle for granulocytes, monocytes, reticulocytes, and platelets, but not for lymphocytes. The observed phase lags, together with the literature values for the intramarrow maturation times of the hematologic cell lines, suggest that the feedback regulation abnormality, believed to be at the basis of CN, primarily affects the stem cell that is still capable of differentiating into granulocytes and monocytes, but that the oscillations of reticulocytes and platelets are the result of a stem cell competition for uncommitted precursor cells by the primarily oscillating granulocyte and monocyte production.

Aged↗
PubMed1994

Stem cell factor improvement of proliferation and maintenance of hemopoietic progenitors in myelodysplastic syndromes.

Human recombinant stem cell factor (rSCF) was tested for its capability of improving the defective growth of hemopoietic progenitors in 28 cases of myelodysplastic syndromes (MDS). In vitro growth and response to rSCF were quite variable. However, in most cases, rSCF stimulated CFU-GM growth induced by rG-CSF, rGM-CSF, rIL-3, 5637 conditioned medium (50-1400% enhancement). rSCF effect was slightly more evident on day 14 CFU-GM and in the presence of rIL-3. BFU-E growth induced by rEPO or rIL-3 + rEPO was enhanced by rSCF in about 50% of cases, in linear correlation with the levels of patients' hemoglobin. rSCF did not increase CFU-E growth, whereas it slightly stimulated CFU-Mk in 33% of the cases. EPO, SCF and, particularly, their combination, enhanced the recovery of normal CFU-E and BFU-E after 7 days of liquid culture. This was less evident in cultures of MDS patients. Conversely, CFU-GM generation in long term liquid cultures, although highly variable, was stimulated by rSCF and, above all, by rSCF + rG-CSF, similarly to what was observed with normal bone marrow samples. SCF seems to enhance in vitro erythropoiesis only in MDS cases presenting without severe anemia. It has little effect on megakaryocytopoiesis, while it seems to be more active on CFU-GM growth and maintenance.

Cell Division↗
PubMed1994

Adhesion of committed human hematopoietic progenitors to synthetic peptides from the C-terminal heparin-binding domain of fibronectin: cooperation between the integrin alpha 4 beta 1 and the CD44 adhesion receptor.

Close interaction of human hematopoietic progenitors with the bone marrow microenvironment is important for the ordered progression of human hematopoiesis. Progenitor cell adhesion to stroma has a complex molecular basis, involving various cell-extracellular matrix and cell-cell interactions. We have previously shown that adhesion of colony-forming cells (CFC) to fibronectin, present in stromal extracellular matrix, involves multiple sites, including two heparin-binding synthetic peptides (FN-C/H I and FN-C/H II) and the alpha 4 beta 1 integrin-binding peptide CS1. These synthetic peptides are located in close proximity in the type III repeat 14 and the immediately adjacent type IIIcs region of fibronectin. In the current study, we evaluate receptors expressed by CFC responsible for their adhesion to fibronectin. We show that the alpha 4 beta 1 integrin mediates adhesion to CFC to the peptides FN-C/H I and CS1. Adhesion of CFC to fibronectin is also mediated by proteoglycans, because removal of cell surface chondroitin-sulfate proteoglycans resulted in decreased adhesion of CFC to FN-C/ I and FN-C/H II. The core protein of this proteoglycan was identified by immunoprecipitation as a 90-kD member of the CD44 group of adhesion molecules. Interestingly, although the proteoglycan core protein failed to adhere to FN-C/H II affinity columns, anti-CD44 monoclonal antibodies blocked CFC adhesion to FN-C/H II, indicating that these monoclonal antibodies may interfere with core protein-mediated intracellular signalling. Finally, we show that CD44 and alpha 4 beta 1 may cooperate in establishing progenitor adhesion, because anti-CD44 antibodies potentiated the adhesion-inhibitory effects of suboptimal concentrations of anti-alpha 4 or anti-beta 1 monoclonal antibodies. These results provide a working model for progenitor cell recognition of fibronectin (and possibly the marrow micro-environment) in which the coordinated action of integrins and cell surface proteoglycans is necessary for cell adhesion. This model can now be used to study the complex relationship between progenitor cell adhesion and the regulation of their proliferation and differentiation.

Amino Acid Sequence↗
PubMed1993

In vivo administration of stem cell factor to mice increases the absolute number of pluripotent hematopoietic stem cells.

We have examined the effects of administration of stem cell-factor (SCF) on the number and distribution of pluripotent hematopoietic stem cells (PHSC) in normal mice. Using the competitive repopulation assay we found that in vivo administration of SCF increases the absolute number of PHSC per mouse threefold. The increased numbers of PHSC are found in the peripheral blood and spleen of the SCF-treated animals. The spleen and peripheral blood stem cells completely repopulated the erythroid, myeloid, and lymphoid lineages of irradiated or W/Wv hosts, similar to bone marrow PHSC. PHSC from the peripheral blood of SCF-treated mice have a lineage marker-negative, c-kit-positive phenotype that is indistinguishable from that of bone marrow PHSC. The increase in the absolute number of spleen PHSC is associated with efficient gene transfer to these cells without prior treatment with 5-fluorouracil. This is a US government work. There are no restrictions on its use.

Animals↗
PubMed1993

Interleukin-3/erythropoietin fusion proteins: in vitro effects on hematopoietic cells.

Erythropoietin (Epo) acts synergistically with interleukin-3 (IL-3) to induce proliferation and differentiation of erythroid progenitors. This synergy occurs at IL-3 concentrations that have little or no effect alone. To determine whether optimal expansion of erythroid cells results when they are targeted by a molecule with both IL-3 and Epo activities, fusion proteins were generated and analyzed. Expression vectors were constructed in which the coding regions of human IL-3 and Epo cDNAs were joined by either a short (2 to 3 amino acids) or long (23 amino acids) linker sequence and expressed in Chinese hamster ovary (CHO) cells. Analysis of equilibrium binding properties of the IL-3 and Epo moieties revealed that in all fusion proteins each retained the ability to bind receptor. When IL-3 was connected to Epo by a short linker, the binding affinity of the IL-3 moiety was lower. In vitro proliferative activity of each moiety was observed on cell lines responsive to IL-3, Epo or a combination of the two cytokines. Fusion of IL-3 to Epo through its amino terminus was found to result in partial loss of its function. All the fusion proteins were biologically active on human bone marrow. When IL-3 was located at the amino domain of the protein, induction of erythroid colonies was similar to that of a mixture of IL-3 and Epo. These results indicate that biological integrity of both IL-3 and Epo can be maintained when these cytokines are fused, but that enhancement of erythropoiesis over that observed with a mixture of the two cytokines cannot be achieved by their fusion alone. Other requirements such as the coexpression of the IL-3 and Epo receptors and the sharing of a receptor subunit are likely to be needed for an optimal cell response to the fusion growth factors.

Animals↗
PubMed1989

Feline parvovirus propagates in cat bone marrow cultures and inhibits hematopoietic colony formation in vitro.

Feline parvovirus (FPV) causes leukopenia in naturally infected cats. We investigated the mechanism of hematopoietic depression by this virus in feline bone marrow cultured in vitro. In suspension cultures we demonstrated FPV propagation and replication using DNA molecular hybridization. Viral RNA and DNA were observed by in situ hybridization in about 10% of marrow cells at day 3. Granulocytes and their precursors were virtually absent from infected cultures after six days. Infected cells showed viral capsid protein predominantly in nuclei by immunofluorescence. In clonal assays, FPV most efficiently inhibited hematopoietic colony formation by myeloid progenitor cells (CFU-GM), but erythroid colony formation (BFU-E and CFU-E-derived) was also depressed in the presence of virus. Inhibition of colony formation could be abrogated by physical inactivation of the virus or preincubation with specific neutralizing antibodies. Recombinant human colony stimulating factors GM-CSF and G-CSF supported feline myelopoiesis in progenitor assays, and FPV completely inhibited factor dependent colony formation.

Animals↗
PubMed1996

Opposing effects of the basic helix-loop-helix transcription factor SCL on erythroid and monocytic differentiation.

The SCL gene (also called Tal-1 or TCL5) was identified because of its association with chromosomal translocations in childhood T-cell lymphoid leukemias. SCL codes for a basic helix-loop-helix (bHLH) factor that can function as a transcriptional activator or repressor. In the adult, SCL expression is restricted to hematopoietic cells and tissues, but its function in the process of lineage commitment is unknown. The present study was designed to address the role of SCL in hematopoietic cell differentiation. SCL expression was determined in primary hematopoietic cells through the screening of cDNA samples obtained by reverse transcription-polymerase chain reaction (RT-PCR) from single cells at different stages of differentiation. SCL RNA expression was highest in bipotential and committed erythroid precursors and diminished with subsequent maturation to proerythroblasts and normoblasts. In contrast, SCL mRNA was low to undetectable in precursors of granulocytes and monocytes and their maturing progeny. The same pattern of expression was observed after erythroid or monocytic differentiation of a bipotent cell line, TF-1, in that SCL mRNA levels remained elevated during erythroid differentiation and were downregulated with monocytic differentiation. Accordingly, TF-1 was chosen as a model to investigate the functional significance of this divergent pattern of SCL expression in the two lineages. Four independent clones stably transfected with an SCL expression vector exhibited enhanced spontaneous and delta-aminolevulinic acid-induced erythroid differentiation as measured by glycophorin expression and hemoglobinization, consistent with the view that SCL is a positive regulator of erythroid differentiation. Furthermore, constitutive SCL expression interfered with monocytic differentiation, as assessed by the generation of adherent cells and the expression of Fc gamma RII in response to TPA. These results suggest that the downregulation of SCL may be required for monocytic differentiation.

Adult↗
PubMed2002

Local regulation of proliferation and differentiation of hemopoietic precursors during experimental neuroses.

Intensive formation of hemopoietic islets and secretion of humoral hemopoiesis stimulators by cells of the hemopoietic microenvironment underlie activation of proliferation and differentiation of erythroid and granulocyte-macrophage precursors in conflict situation. Stimulation of division and maturation of committed granulomonocytic precursors during paradoxical sleep deprivation is primarily related to intensive secretion of humoral factors by hemopoietic elements. The inhibition of proliferative activity and differentiation of erythroid precursors is associated with the impaired formation of erythroid hemopoietic islets and suppressed secretion of humoral erythropoiesis stimulators by nonadherent fractions of the hemopoietic microenvironment.

Animals↗
PubMed1995

[The follow-up of the mobilization of circulating hematopoietic progenitor cells by granulocyte growth factor (G-CSF) using flow cytometry].

BACKGROUND: The aim of the present study was to investigate the characteristics of the mobilization of hematopoietic precursor cells CD34+ in peripheral blood following stimulation with recombinant granulocytic colony stimulating factor (G-CSF). METHODS: Fourteen patients (10 males, 4 females: mean age 33 years; range 14-58 years) diagnosed with oncohematologic neoplasms, in complete remission were studied. The patients had not received antineoplastic for at least four weeks prior to inclusion in the study. Recombinant G-CSF (8 micrograms/kg) was administered subcutaneously over a minimum of 4 days. Peripheral blood control were performed prior to administration of G-CSF (day 0), the third (day +3) day, and the sixth day (day +6). Daily leukapheresis was initiated at day +3 in 5 patients and at day +4 in 9 patients. The CD34+ cell content was determined in both peripheral blood and leukapheretic material by flow cytometry with an anti CD-34 monoclonal antibody conjugated with fluorescein. RESULTS: No significant differences were observed between the mononuclear cells and CD34+ counts obtained at the first apheresis and those performed at days +3 or +4 (32 +/- 14 x 10(9) vs 29 +/- 19 x 10(9) and 240 +/- 125 x 10(6) vs 162 +/- 160 x 10(6), respectively). The content of the apheresis products in CD34+ cells correlated positively with the number of these cells circulating in peripheral blood (r = 0.53, p = 0.001). In the second apheresis, the presence of mononuclear cells decreased approximately 20% with respect to the first, remained constant in later collections. To the contrary, a constant maintained decrease was observed in the collection of CD34+ on each leukaphesis in that the fourth apheresis only contributed in approximately 10% of the total quantity of CD34+ cells collected. CONCLUSIONS: Maximum mobilization of precursor cells was achieved on the third day at a dosage of 8 micrograms/kg/day, with the data found suggesting that three leukapheretic procedures are enough to collect most of the CD34+ cells mobilized.

Adolescent↗
PubMed1996

Isolation and characterization of c-fos-expressing murine bone marrow stromal cell lines supporting myeloid differentiation.

We have previously reported that constitutive expression of c-fos oncogene allows long-term proliferation of primary mouse bone marrow stromal cells favoring the granulocytic differentiation of myeloid precursors in an in vitro assay. Retrovirus-mediated gene transfer of the human c-fos gene was used here for immortalizing nine mouse bone marrow cell lines which were studied in detail. However, due to low expression of the ectopic c-fos gene, none of them showed characteristics of transformation as assayed by dependence upon serum for growth, the inability to form colonies in agar and contact inhibition. All of them displayed a fibroblastoid phenotype, as deduced from morphological observation and analysis of several differentiation markers. They mostly supported the granulocytic differentiation of bone marrow myeloid precursors in a GM-assay, as did c-fos-expressing primary stromal cells. Their potential for supporting myeloid progenitor proliferation was however significantly lower than that of the whole adherent layer of the Dexter-type long-term bone marrow culture they derived from (STNT cells). They showed significant variations with respect to their cytokine gene expression analyzed at the RNA level in keeping with the notion of stromal cell heterogeneity in the bone marrow. Interestingly, none of them secreted GM-CSF, SCF or IL-3, which are cytokines reputed for their ability to stimulate hematopoietic progenitors, and strikingly, only two of them were able to produce detectable levels of G-CSF in culture supernatants despite the propensity of all of them to favor granulocyte differentiation. Finally, in coculture assay, bone marrow cells were able to diminish the expression of several cytokine genes albeit at a much lower degree than in the original STNT cells.

Animals↗
PubMed1996

The effect of in vitro human immunodeficiency virus infection on dendritic-cell differentiation and function.

CD1a+ dendritic cells (DC) differentiate from a major population of nonadherent CD13(hi)lin- cells that appear when human cord blood CD34+ hematopoietic progenitor cells are cultured with stem-cell factor, granulocyte/macrophage (MA) colony-stimulating factor, and tumor necrosis factor-alpha (TNF-alpha) for 5 days. CD13hilin- cells, which also comprise MA and granulocyte precursors, are CD4+ and can thus be targets of human immunodeficiency virus (HIV). Low replication was noted when these day 5 cells were infected with lymphotropic HIV-1LA1 (p24: < or = 4 ng/mL on day 8 postinfection [PI]), while high virus production occurred with MA-tropic HIV-1Ba-L, HIV-1Ada, or HIV-1-m-n. (p24: 50 to > or = 1,000 ng/mL). Strong cytopathicity (CPE) was then observed in nonadherent cells as in adherent MA. However, FACS analysis on day 7 PI showed that HIV did not affect differentiation of DC that survived CPE: apart from CD4 downmodulation related to HIV production, overall expression of CD40, CD80, and CD86 costimulatory molecules, and of HLA-DR, was unchanged relative to controls. At that time, the capacity of DC from HIV-infected cultures to stimulate the mixed leukocyte reaction was only altered less than 10-fold. Immunocytochemistry on day 7 PI showed that most HIV-infected cells were included in syncytia that were stained by anti-CD1a, anti-S100, and anti-CD14 antibodies, indicating that syncytia consisted of DC and cells of the MA lineage. Polymerase chain reaction analysis of FACS-sorted CD1a+ cells confirmed that they harbored then HIV DNA. Viral DNA was also detected in CD1a+ DC from noninfected cultures that had been exposed to HIV only after sorting. Therefore, we examined whether in infected cultures DC precursors were infected at the onset or if virus spread later from other infected cells to differentiated DC. This was answered by showing that, 24 hours postexposure to HIV, viral DNA was preferentially detected in day 5 sorted CD13hilin- versus CD13hilin- cells, and that it was found in the CD1a+ progeny of CD13(hi)lin- cells 48 hours later. In addition, HIV replication did not affect myeloid clonogenic progenitors in day 0 to day 7 PI cultures, although viral DNA was detected in colony-forming unit-granulocyte/macrophage (CFU-GM)/CFU-M colonies derived from day 3 and 7 PI cultures. Thus, precursors of DC and their progeny are susceptible to HIV in vitro, but, apart from CPE, the effect of virus production on DC differentiation or function is limited.

Antigens, CD↗
PubMed1985

Effect of anti-CSF on in vivo hemopoiesis.

Studies were undertaken to determine whether colony-stimulating factor in the serum is important in the control of granulopoiesis and monocytopoiesis. Groups of mice were injected with either antiserum to colony-stimulating factor (CSF) or normal rabbit serum every 12 h for intervals of 6-7 days. Antibody treatment did not lead to a reduction in circulating granulocytes or monocytes nor a decrease in marrow cellularity. In further studies, two dose levels of purified anti-CSF were employed; rabbit IgG served as a control. Virtually no effect was observed on blood monocytes, blood granulocytes, or marrow granulocytes; however, antibody treatment did cause a decline in marrow colony-forming cells and a reciprocal increase in erythroid progenitor cells. Immunoassays showed a virtual absence of serum anti-CSF after five days, despite continued administration of the antibody. Modified immunoassays indicated that this was due to development of murine antibodies directed against anti-CSF. In further experiments, mice received the purified antibody or whole antiserum in conjunction with cortisone to reduce murine antibody formation. Despite persistent anti-CSF levels in the serum, blood granulocytes, blood monocytes, and marrow precursor cells were unaffected. These findings suggest that serum levels of CSF do not appear to be responsible for in vivo granulopoiesis or monocytopoiesis.

Animals↗