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PubMed1995

In vitro sensitivity of post-bone marrow transplantation CFU-GM and BFU-E to TNF-alpha and IFN-gamma.

Graft failure remains one of the limitations of successful marrow transplantation. T cell-depleted (TCD) bone marrow transplantation (BMT) is reported to have a higher incidence of graft failure than unmodified (UM) BMT. In most cases of secondary graft failure, no cellular immune mechanism has been identified and etiology remains unclear. In an effort to delineate a cytokine-mediated mechanism of secondary graft failure, we investigated colony-forming unit-granulocyte/macrophage (CFU-GM) and burst-forming unit-erythroid (BFU-E) growth and pattern of inhibition by tumor necrosis factor-alpha (TNF-alpha) and gamma-interferon (IFN-gamma) in the early posttransplant period (day 28). Gradient-separated bone marrow mononuclear cells (BMMNC) from 38 recipients of TCD BMT, 15 recipients of UM BMT, and 23 normal donors (NLD) were plated in cultures of semisolid, serum-containing medium with the addition of stem cell factor (SCF), erythropoietin (Epo), and granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF). Three to seven times more CFU-GM and BFU-E colonies were cultures from NLD BM-derived BMMNC than from BMMNC of recipients of TCD or UM BMT (p = 0.0001). There was no difference in colony number between recipients of UM and TCD BMT on day 28 posttransplant, however. Under G-CSF culture conditions, CFU-GM colonies from recipients of UM and TCD BMT were more susceptible (p < or = 0.05) to suppression by IFN-gamma at concentrations of 1 and 100 U/mL than NLD BMMNC-derived colonies. No other difference in IFN-gamma inhibition was detected among the three groups. Under G-CSF and GM-CSF culture conditions, maximal inhibition was obtained at TNF-alpha concentrations > 10 ng/mL. Although early posttransplant BMMNC was more sensitive to inhibition than NLD-derived BMMNC, overall, no difference in colony growth or percent of inhibition induced by TNF-alpha or IFN-gamma was observed between recipients of unmodified and T. cell-depleted transplants. In this series, two recipients of TCD BM and one recipient of UM BMT developed graft failure; no distinct pattern of colony growth or colony inhibition was evident for those patients. The optimized in vitro conditions and specific cytokines used in this study do not indicate any quantitative or qualitative differences in the hematopoietic progenitors present in recipients of unmodified and T cell-depleted bone marrow early posttransplant to explain an increased risk of graft failure following a T cell-depleted BMT compared to an unmodified BMT.

Adolescent↗
PubMed1994

Cytokine-dependent ex vivo expansion of early subsets of CD34+ cord blood myeloid progenitors is enhanced by cord blood plasma, but expansion of the more mature subsets of progenitors is favored.

Expansion of stem/progenitor cells has important implications for transplantation. We recently reported that a factor or factors in cord blood (CB), but not adult peripheral blood (PB), plasma enhanced replating of granulocyte erythroid macrophage megakaryocyte colony-forming units (CFU-GEMM) progenitors, a measure of self-renewal capacity. In this context, we evaluated effects of CB plasma, in comparison with PB plasma and fetal bovine serum (FBS), on ex vivo expansion of CD34+ column-separated (72-98% CD34+) CB cells using stroma-free cultures in the absence and presence of either PIXY321 (a granulocyte-macrophage colony-stimulating factor/interleukin-3 [GM-CSF/IL-3] fusion protein), IL-3+IL-6+IL-1, or steel factor (SLF) -/+ PIXY. CB plasma, PB plasma, or FBS alone did not sustain cell numbers. Combinations of CB plasma +SLF+PIXY induced maximal cumulative nucleated cell expansion (1044-fold), which was greater than that of PB plasma plus cytokines (633-fold) and FBS plus cytokines (142-fold). Total CD34+ cells peaked by day 7 with 7-fold expansion in the presence of CB plasma+SLF+PIXY compared with PB plasma or FBS with these same cytokines (threefold each). By day 7, total CFU-GEMM production in the presence of either PIXY, SLF+PIXY, or IL-3+IL-6+IL-1 was greater with CB plasma (maximum 11.4-fold average increases) than with PB plasma (6.8-fold increase). These increases were greater than with FBS. However, PB plasma was at least as good as CB plasma for expansion of immature and mature subsets of CFU-GM. The frequency of progenitors decreased with time, and expansion was coupled with differentiation. Although the proliferative capacity of CFU-GEMM was maintained, the capacity of CFU-GEMM to be replated decreased after time in suspension culture, suggesting age-related commitment of cells. Moreover, with plasma +SLF+PIXY for 7 days, expansion of more mature CFU-GM (responsive to GM-CSF) was greater (16-146-fold with CB plasma and 31-208-fold with PB plasma) than immature CFU-GM (responsive to GM-CSF+SFL) (4- to 14-fold with CB plasma and 6- to 17-fold with PB plasma). The results suggest that CB plasma enhances expansion of CFU-GEMM to a greater extent than PB plasma or FBS, but expansion in these cultures favors more mature subsets of cells.

Adult↗
PubMed1991

Effect of interleukin-9 on clonogenic maturation and cell-cycle status of fetal and adult hematopoietic progenitors.

We assessed the effect of interleukin-9 (IL-9) on clonogenic maturation and cell-cycle status of hematopoietic progenitors of fetal (umbilical cord blood) and adult (bone marrow) origin. As a single agent IL-9 supported, in a concentration-dependent fashion, maturation of burst-forming units-erythroid (BFU-E) of adult and fetal origin. However, only 1/3 the number of adult BFU-E colonies developed, as did in response to granulocyte-macrophage colony-stimulating factor (GM-CSF), and only 1/6 the number developed as did in response to IL-3. In contrast, the effect of IL-9 on fetal BFU-E colonies was equal to that of GM-CSF and IL-3. Synergistic effects of IL-9 with low concentrations (0.1 ng/mL) of GM-CSF and IL-3 were seen on adult BFU-E colony formation, but no effect was apparent at higher concentrations (1.0 ng/mL). In contrast, using fetal cells, synergistic effects of IL-9 with low and high concentrations of GM-CSF and IL-3 were apparent. Addition of IL-9 to plates containing fetal cells plus GM-CSF and IL-3 not only resulted in more BFU-E colonies, but also in more multicentered (greater than or equal to 10 individual centers) colonies, and more cells per colony. IL-9 had a wider spectrum of action on progenitors of fetal origin than on progenitors of adult origin, supporting the generation of fetal multipotent colony-forming unit (CFU)-Mix and CFU-GM colonies. Incubation with IL-9 did not accelerate cycling of adult or fetal BFU-E, CFU-Mix, or CFU-GM to the extent observed after incubation with IL-6. Thus, IL-9 primarily supported maturation of erythroid progenitors of adult origin, and its addition to plates containing GM-CSF and IL-3 (1.0 ng/mL) did not result in maturation of additional clones. In contrast, IL-9 had a wider spectrum of action on fetal progenitors and, when combined with IL-3 and GM-CSF, resulted in clonogenic maturation of progenitors that did not undergo maturation after stimulation with IL-3 and GM-CSF.

Aging↗
PubMed1990

Effect of sera from acute lymphoblastic leukemia children on proliferation and differentiation of HL-60 promyelocytic leukemia cell line.

Influence of sera of children with ALL on character (dispersed or compact) and composition (granulocyte or macrophage) of colonies, formed from the human promyelocytic leukemia cell line HL-60, was estimated. An increased activities stimulating formation of dispersed G and M colonies was found in the sera of patients before therapy. Dynamics of colonies formation and their composition in the course of treatment point to some changes in the serum the levels of these activities with a tendency to full normalization in remission.

Cell Differentiation↗
PubMed1983

Clonal karyotype abnormalities in erythroid and granulocyte-monocyte precursors in polycythaemia vera and myelofibrosis.

To determine whether clonal karyotype abnormalities seen in myeloproliferative disorders originate in cells of only one or of more blood cell lines, committed erythroid and granulocyte-monocyte progenitor cells were cultured in vitro by the methyl cellulose assay, and chromosome studies were carried out on the colonies. 3 patients were studied, 1 with polycythaemia vera and 2 with myelofibrosis, which was preceded by polycythaemia vera in 1 of the cases. All analysable karyotypes from both erythroid and granulocyte-monocyte colonies in every patient showed the clonal karyotype aberration which had been demonstrated in the bone marrow or blood of the patient. This finding is evidence of the involvement of a multipotent stem cell in the clonal proliferation of these diseases.

Aged↗
PubMed2003

Osteoclastic potential of human CFU-GM: biphasic effect of GM-CSF.

UNLABELLED: Human osteoclasts can be efficiently generated in vitro from cord blood mononuclear cells and derived CFU-GM colonies. However, CFU-M colonies are poorly osteoclastogenic. Short-term (2-48 h) treatment with GM-CSF stimulates osteoclast formation by proliferating precursors, whereas longer exposure favors dendritic cell formation. INTRODUCTION: Osteoclasts (OC) differentiate from cells of the myelomonocytic lineage under the influence of macrophage-colony stimulating factor (M-CSF) and RANKL. However, cells of this lineage can also differentiate to macrophages and dendritic cells (DC) depending on the cytokine environment. The aims of this study were to develop an efficient human osteoclastogenesis model and to investigate the roles of granulocyte macrophage-colony stimulating factor (GM-CSF) and M-CSF in human OC differentiation. MATERIALS AND METHODS: A human osteoclastogenesis model, using as precursors colony forming unit-granulocyte macrophage (CFU-GM) colonies generated from umbilical cord mononuclear cells cultured in methylcellulose with GM-CSF, interleukin (IL)-3 and stem cell factor (SCF), has been developed. CFU-GM, colony forming unit-macrophage (CFU-M), or mixed colonies were cultured on dentine with soluble RANKL (sRANKL) and human M-CSF with and without GM-CSF. Major endpoints were OC number, dentine resorption, and CD1a+ DC clusters. RESULTS: Osteoclast generation from CFU-GM and mixed colonies treated with M-CSF and sRANKL for 7-14 days was highly efficient, but CFU-M colonies were poorly osteoclastogenic under these conditions. Pretreatment of precursors with M-CSF for 7 or 14 days maintained the precursor pool, but OCs were smaller and resorption was reduced. The effect of GM-CSF treatment was biphasic, depending on the timing and duration of exposure. Short-term treatment (2-48 h) at the beginning of the culture stimulated cell proliferation and enhanced OC formation up to 100%, independent of sRANKL. Longer-term GM-CSF treatment in the presence of sRANKL, however, inhibited OC generation with the formation of extensive CD1a+ DC clusters, accompanied by downregulation of c-Fos mRNA. Delaying the addition of GM-CSF resulted in progressively less inhibition of osteoclastogenesis. CONCLUSIONS: Human CFU-GM, but not CFU-M, progenitors have high osteoclastogenic potential. GM-CSF plays an important role in osteoclastogenesis and has a biphasic effect: Short-term treatment potentiates OC differentiation by proliferating precursors, but persistent exposure favors DC formation.

Base Sequence↗
PubMed1977

Functional and morphologic characterization of human T cells continuously grown in vitro.

Long-term growth (now over 13 months) of thymus-derived lymphocytes from numerous normal human bone marrow and peripheral blood cell samples was accomplished by using a factor present in media obtained from mitogen-stimulated human peripheral blood lymphocytes. This long-term growth could neither be initiated nor maintained by mitogens alone. All cell cultures were greater than 90% E rosette-positive, whereas the tests for B cell markers, surface IgG and IgM, and EAC rosette were routinely negative. There was no evidence for the presence of granulocytes, monocytes, and their precursors in these cultures. The E rosette-positive cells were then tested to see if they had T cell functions. PHA, Con A, and pokeweed mitogens stimulated lymphproliferative responses in these cultures comparable to those of fresh peripheral blood cells. These proliferating cells were also able to release cell mediators, such as interferon and colony-stimulating activity. Further evidence for the T lymphocyte nature of these cultured cells was obtained from one-way mixed leukocyte cultures in which these cells responded to but were unable to stimulate allogeneic cells. The functional and morphologic characteristics of these cultured cells show that these cells are T cells that grow continuously in vitro.

Cells, Cultured↗
PubMed1998

Bcl-3 expression and nuclear translocation are induced by granulocyte-macrophage colony-stimulating factor and erythropoietin in proliferating human erythroid precursors.

Bcl-3 is a proto-oncogene involved in the chromosomal translocation t(14;19) found in some patients with chronic lymphocytic leukemia. It shares structural similarities with and is a member of the IkappaB family of proteins. In this report, involvement of Bcl-3 in hematopoietic growth factor-stimulated erythroid proliferation and differentiation was examined. In TF-1 cells, an erythroleukemia cell line, granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (Epo) greatly enhanced Bcl-3 expression at both the protein and mRNA levels in association with stimulation of proliferation. Bcl-3 protein was also highly expressed in early burst-forming unit-erythroid (BFU-E)-derived erythroid precursors (day 7) and decreased during maturation (days 10 and 14), suggesting that Bcl-3 is involved in normal erythroid proliferation. In these hematopoietic cells, Bcl-3 was hyperphosphorylated. GM-CSF and Epo modulated the subcellular localization of Bcl-3. Upon stimulation of TF-1 cells with GM-CSF or Epo, the nuclear translocation of Bcl-3 was dramatically enhanced. Overexpression of Bcl-3 in TF-1 cells by transient transfection along with the NF-kappaB factors p50 or p52 resulted in significant induction of an human immunodeficiency virus-type 1 (HIV-1) kappaB-TATA-luceriferase reporter plasmid, demonstrating that Bcl-3 has a positive role in transactivation of kappaB-containing genes in erythroid cells. Stimulation with GM-CSF enhanced c-myb mRNA expression in these cells. Bcl-3 in nuclear extracts of TF-1 cells bound to a kappaB enhancer in the c-myb promoter together with NF-kappaB2/p52 and this binding activity was enhanced by GM-CSF stimulation. Furthermore, cotransfection of Bcl-3 with p52 or p50 in TF-1 cells resulted in significant activation of a c-myb kappaB-TATA-luceriferase reporter plasmid. These findings suggest that Bcl-3 may participate in the transcriptional regulation of certain kappaB-containing genes involved in hematopoiesis, including c-myb.

B-Cell Lymphoma 3 Protein↗
PubMed2001

CD41+ and CD42+ hematopoietic progenitor cells may predict platelet engraftment after allogeneic peripheral blood stem cell transplantation.

The objective of this study was to quantify subpopulations of CD34+ cells such as CD41+ and CD42+ cells that might represent megakaryocyte (MK) precursors in peripheral blood stem cell (PBSC) collections of normal, recombinant human granulocyte-colony stimulating factor (rhG-CSF) primed donors and to determine whether there is a statistical association between the dose infused megakaryocytic precursors and the time course of the platelet recovery following an allogeneic PBSC transplantation. Twenty-six patients with various hematologic malignancies transplanted from their HLA identical siblings between July 1997 and December 1999 were used. All patients except one with severe aplastic anemia who had cyclophosphamide (CY) alone received busulfan-CY as preparative regimen and cyclosporine-methotrexate for GVHD prophylaxis. Normal healthy donors were given rhG-CSF 10 microg/kg/day subcutaneously twice daily and PBSCs were collected on days 5 and 6. The median number of infused CD34+, CD41+ and CD42+ cells were 6.61 x 10(6)/kg (range 1.47-21.41), 54.85 x 10(4)/kg (5.38-204.19), and 49.86 x 10(4)/kg (6.82-430.10), respectively. Median days of ANC 0.5 x 10(9)/L and platelet 20 x 10(9)/L were 11.5 (range 9-15) and 13 (8-33), respectively. In this study, the number of CD41+ and CD42+ cells infused much better correlated than the number of CD34+ cells infused with the time to platelet recovery of 20 x 10(9)/L in 26 patients receiving an allogeneic match sibling PBSC transplantation (r = -0.727 and P < 0.001 for CD41+ cells, r = -0.806 and P < 0.001 for CD42+ cells, r = -0.336 and P > 0.05 for CD34+ cells). There was an inverse correlation between the number of infused CD41+ and CD42+ cells and duration of platelet engraftment. Therefore, as the number of CD41+ and CD42+ cells increased, duration of platelet engraftment (time to reach platelet count of > or = 20 x 10(9)/L) shortened significantly. Based on this data we may conclude that flow cytometric measurement of CD41+ and CD42+ progenitor cells may provide an accurate indication of platelet reconstitutive capacity of the allogeneic PBSC transplant.

Adolescent↗
PubMed2000

Cloning, sequencing, and analysis of cDNA encoding bovine granulocyte-colony stimulating factor.

Neutrophils play a critical role in defending against bacterial infections. Hematopoietic growth factors are a class of regulatory cytokines that are required for stimulation, proliferation, and differentiation of blood cells. Granulocyte colony stimulating factor (G-CSF) is a cytokine that induces proliferation and maturation of precursor myeloid cells in the bone marrow into fully differentiated neutrophils. G-CSF also modulates the functional activity of mature neutrophils. Treatment with G-CSF significantly enhances neutrophil phagocytic activity and killing of bacteria and fungi. We have isolated and sequenced a cDNA clone encoding bovine G-CSF (bG-CSF) from an endothelial cell cDNA library using primers designed from ovine G-CSF. The full length cDNA is 1460 nucleotides with 585 nucleotides comprising the open reading frame. Sequence analysis shows 95% identity with ovine, 89% with porcine, 85% with human, and 76% with murine G-CSF. The deduced G-CSF protein consists of 174 amino acids with 95% identity to ovine, 86% to porcine, 81% to human, and 71% to murine. The signal peptide of G-CSF is 21 amino acids long which is nine amino acids shorter than that of human and murine G-CSF. RT-PCR analysis shows that neither freshly isolated nor ConA stimulated neutrophils express G-CSF mRNA. Mononuclear cells, however, expressed G-CSF mRNA after 48 h incubation with or without ConA stimulation.

Amino Acid Sequence↗
PubMed2006

Multifunctional reversible knockout/reporter system enabling fully functional reconstitution of the AML1/Runx1 locus and rescue of hematopoiesis.

Mice deficient in the runt homology domain transcription factor Runx1 die of severe anemia in utero by embryonic day (E)12.5. A reactivatable Runx1 knockout embryonic stem cell (ESC) and mouse systems were generated by the targeted insertion of a loxP-flanked multipartite gene stop/trap cassette designed to simultaneously ablate the expression of Runx1 and report on the activity of its promoters. The cassette's in-frame LacZ reporter enabled activities of the proximal and the distal promoters to be differentially monitored. Although Runx1-null ESCs were capable of primitive erythroid differentiation in vitro, their capacity to generate granulocyte/macrophage or mixed myelo-erythroid embryoid bodies was lost. Cre-mediated reactivation restored Runx1 structural integrity and rescued the hematopoietic differentiation potential of ESCs. Mice with the reactivated allele survived, showed no hematopoietic deficit, and expressed all major splice isoforms of Runx1 appropriately. This multipurpose mouse model will be useful for the analysis of the critical Runx1-dependent check-point(s) in hematopoietic development.

Alternative Splicing↗
PubMed1987

Osteoclast-like cell formation in fetal and newborn long-term baboon marrow cultures is more sensitive to 1,25-dihydroxyvitamin D3 than adult long-term marrow cultures.

It is unknown if osteoclasts derived from animals at different developmental stages differ. To study this question, we used a long-term baboon marrow culture system in which osteoclast-like multinucleated cells (MNC) are formed. Fetal, newborn, or adult baboon marrow cultures were tested to determine if they differ in their responsiveness to osteotropic hormones. In fetal and newborn marrow cultures 1,25-dihydroxyvitamin D3 (1,25D3) at 10(-10) M significantly increased MNC formation with a maximal effect seen at 10(-9) M. Higher concentrations of 1,25D3 progressively decreased MNC formation. In contrast, in adult baboon marrow cultures, 10(-9) M 1,25D3 was required to significantly increase MNC formation, with a maximal affect at 10(-8) M 1,25D3. Calcitonin (25-200 ng/ml) inhibited MNC formation in fetal, newborn, or adult baboon marrow cultures treated with 1,25D3 in an identical manner. The effects of 1,25D3 on granulocyte-macrophage progenitor cells (CFU-GM), the probable precursors of MNC, were identical in fetal and adult baboon marrow cultures, with a significant inhibition of CFU-GM colony formation at 10(-8) M 1,25D3. These results suggest that 1) osteoclast precursors are more sensitive to some osteotropic hormones during the fetal and newborn periods, and 2) differences in the 1,25D3 sensitivity of osteoclast-like MNC formation in fetal, newborn, and adult baboon marrow cultures are not due to effects on early proliferating precursors but may result from effects of 1,25D3 on fusion of later precursors for MNC.

Age Factors↗
PubMed1993

Differentiation of dendritic cell populations in macrophage colony-stimulating factor-deficient mice homozygous for the osteopetrosis (op) mutation.

In op/op mice, immunohistochemical and electron microscopic techniques were used to examine the effects of the OP mutation on dendritic cell populations in lymphoid tissues and skin. In the thymic medulla, T cell zone of lymph nodes, and splenic white pulp of op/op mice, numbers of NLDC-145-positive dendritic cells were not decreased. Compared to the normal littermates, numbers of BM8-positive macrophages were reduced in various tissues of the mutant mice, including the lymphoid tissues. These dendritic cells of op/op mice expressed Ia antigens but not F4/80 and BM8 antigens. Ultrastructurally, the dendritic cells developed a tubulovesicular system typical of interdigitating cells, but they were abnormal in that interdigitation of their cytoplasmic processes was not prominent. In the epidermis of the op/op mice, dendritic cells expressed NLDC-145, F4/80, Ia antigens, and adenosine diphosphatase or adenosine triphosphatase activity, and numbers of NLDC-145-, Ia-, or ADPase-positive dendritic cells were reduced slightly, but these reductions were not significant statistically. Birbeck granules were detected in most of them electron microscopically. These results indicate that nonlymphoid dendritic cells develop in the lymphoid tissues and skin of op/op mouse, suggesting that they are differentiated from granulocyte-macrophage colony-forming cells or earlier hematopoietic cell precursors.

Adenosine Triphosphatases↗
PubMedDate not supplied

Concomitant development of granulocytosis and enhancement of metastases formation in tumor-bearing mice.

The experiments reported here show concomitant development of granulocytosis and enhancement of metastasis formation in C3Hf/Kam mice bearing NFSA fibrosarcoma. Both phenomena developed at approximately 2 weeks after s.c. transplantation of tumor cells, at a time when the tumor was approximately 10 mm in diameter. The number of granulocytes in the blood doubled approximately every 3.5 days, reaching about 30 times control levels shortly before the death of the mice. The magnitude of the metastasis enhancement formation by i.v. injection of tumor cells was three to four times the control value. Mice bearing NFSA had a significant increase in the number of endogenous CFUs. Plasma from NFSA-bearing mice and medium from cultured NFSA cells stimulated in vitro growth of granulocyte and macrophage colonies from normal bone marrow cell precursors, and induced granulocytosis upon i.v. injection into normal mice. This shows that NFSA tumor secretes factor(s) with potent granulopoietic activity. Injection of plasma from tumor-bearing animals followed by i.v. injection of NFSA cells did not lead to the enhancement of metastasis, implying that granulocytosis might be rather concomitant manifestation than a causative factor of the enhancement of metastasis formation. Importance of granulocytosis as a paraneoplastic manifestation during tumor growth is discussed.

Agranulocytosis↗
PubMed1983

Investigation of granulocytopoietic kinetics by microdensitometric evaluation of primary granule naphthol-AS-D-chloroacetate esterase activity.

Using a scanning microscope photometer we determined quantitatively the enzymecytochemical reaction product for naphthol-AS-D-chloroacetate esterase in neutrophilic granulocytes and their precursors in man. Evaluation of neutrophilic cells from three healthy donors resulted in a logarithm-normal distribution. After subdivision of these cells in their morphologically defined maturational stages no statistically bimodal distribution was shown within the single cell groups. Myelocytes showed twice the amount of the polymorphonuclear neutrophil absorption values. The highest promyelocyte obsorptions were double the values of the myelocyte absorptions. The standard deviation of the absorbance obtained with promyelocytes (which encompass cells already producing granules up to cells reaching their maximal granule content) was significantly higher than the standard deviation of the myelocytes. As already known, primary granules are only synthesized at the promyelocyte stage and - according to the present knowledge - their chloracylesterase and peroxidase activities are not lost during further maturation. Consequently, our results indicate that only enzyme-rich, late promyelocytes undergo mitosis transforming into myelocytes. Correspondingly, their absorption value was halved. Since the absorbance from myelocytes to polymorphonuclears is again halved, myelocytes divide only once. Metamyelocyte absorptions in part correspond to that of myelocytes. This indicates that no distinction can be made between myelocytes with mitotic capacity and "true" if only the size and the nuclear shape are considered metamyelocytes which are not longer capable of undergoing mitosis.

Adult↗
PubMed1993

Early circulating erythroid progenitors (BFU-E) in sickle cell anemia.

Sickle cell anemia (SS) patients can be divided into two sub-populations according to peripheral HbF levels. Patients with low (< 9%) HbF levels (LFSS) are characterized by an increased number of circulating BFU-E in active DNA synthesis, and release of burst promoting activity (BPA) by unstimulated low density (LD) adherent cells. In contrast, circulating BFU-E from SS patients with high (> 9%) HbF levels (HFSS) are normal in number, largely in resting phase, and their LD cells do not release BPA-like activity. More recently further heterogeneity has been found among these two groups. In LFSS patients GM-CSF is constitutively produced by unstimulated monocytes. In contrast, HFSS patients' adherent cell depletion increases cycling of BFU-E in culture. CM from HFSS patients inhibits BFU-E expression in culture. Hence, LD adherent cells from HFSS patients may release an inhibitory factor(s). The nature of this factor has to be determined. In addition, there are distinct subpopulations of BFU-E responsiveness to growth factor (GM-CSF, IL-3): a) LFSS patients have a homogeneous BFU-E population, equally responsive to GM-CSF and IL-3; b) HFSS patients, in addition to this subpopulation, have a subset of BFU-E dependent exclusively on IL-3 which is 20 to 40% of the total number of circulating BFU-E. This is similar to BFU-E from normal individuals. Hence, LFSS BFU-E represent an actively proliferating population, equally responsive to GM-CSF and IL-3, controlled by at least constitutively produced GM-CSF and possibly other factors. These observations suggest a significant modification in BFU-E behavior in the subset of SS patients with low HbF levels and high hemopoietic stress. The heterogenous regulation of BFU-E in SS disease seems to be an epiphenomenon of HbF levels, and not vice-versa.

Anemia, Sickle Cell↗
PubMed1994

Selection and characterization of an erythroeosinophilic subclone (LAMA-87) and an eosinophilic subclone (LAMA-88) from the multipotential cell line LAMA-84.

The human leukemic cell line LAMA-84 was established and characterized as an erythromegakaryocytic cell line. In the present study we show that these cells can differentiate in estrone-treated athymic mice and give rise to an erythroeosinophilic cell line (LAMA-87). This new cell line expressed glycoporin A, alpha beta and gamma globin chain mRNA but also eosinophilic peroxidase. Hemin slightly increased the total hemoglobin production of the cells and phorbol diester (TPA), dimethyl sulfoxide (DMSO) and sodium butyrate (SB) increased the expression of megakaryocytic markers (gpIIb/IIIa complex). When inoculated into non-treated athymic mice, LAMA-87 cells can differentiate to give rise to eosinomonocytic cells (LAMA-88). This new cell line expresses eosinophilic peroxidase, Luxol fast blue stain and synthesizes lysozyme. Depending on the inducer used, LAMA-88 can differentiate along a monocytic lineage (TPA, DMSO, SB and vitamin D3). These three LAMA cell lines should be useful in further studies of the molecular regulation of the pluripotent cell commitment and may provide a model for the understanding of human hematopoiesis.

Animals↗