Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P10721 (c-kit)
6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nonadherent, low-density T-lymphocyte-depleted (NALT-) CD34 cells from normal human cord blood were assessed in suspension culture for the effects of recombinant cytokines on their proliferation, differentiation, and generation of myeloid progenitor cells. In this cell population, 82% of cells expressed c-kit protein as assessed by in situ hybridization, and their cloning efficiency was 85% when cells were plated at low cell numbers with combinations of growth factors. CD34 cells were sorted as 1, 5, or 10 cell(s) per well and also at 5000 cells per dish to initiate stromal-free suspension cultures in the presence of steel factor (SLF), interleukin (IL)-1 alpha, and IL-3. Forty-eight percent of the wells started with a single CD34 cell were positive for growth after 14 days, and the wells contained greater than 5 x 10(3) cells by 21-28 days. Progenitors were assayed weekly with cultures initiated with 1 or 5000 cells. While the fold expansion of nucleated cells was greater in cultures initiated with one cell per well (> 5000 compared to 791-fold expansion for 5000 cells), the fold expansion of progenitors was greater than 5000 cells were used to initiate cultures. Under optimal conditions, there was, respectively, a 160-, 164-, and 57-fold output of high proliferative potential colony-forming cells, granulocyte-macrophage colony-forming units, and erythroid burst-forming units/granulocyte erythroid macrophage megakaryocyte colony-forming units within 1-3 weeks for cultures initiated with 5000 CD34 cells compared with respective fold increases of 29, 16, and 1, for single-initiated cultures. These results demonstrate the expansion capacity of single CD34 cord blood cells and demonstrate that factors in addition to SLF, IL-1 alpha, and IL-3 are necessary for optimal expansion of progenitors from single isolated CD34 cells.
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PMID:Extensive proliferative capacity of single isolated CD34 human cord blood cells in suspension culture. 753 51

Human CD34+ bone marrow progenitors cultured in the presence of granulocyte-macrophage CSF (GM-CSF) develop along a myeloid pathway, and the addition of exogenous TNF-alpha leads to the differentiation of dendritic cells among the myeloid progeny. These bone marrow CD34+ -derived dendritic cell that develop during 2-wk culture have the same morphologic, phenotypic, and functional properties that distinguish mature dendritic cells in blood. c-kit ligand does not directly influence dendritic cell differentiation per se, but rather increases the total cell number in synergistic combination with GM-CSF and TNF-alpha. This degree of expansion translates into an effective yield of approximately 1.7 x 10(6) mature dendritic cells per single ml of normal adult human bone marrow, compared with approximately 10(6) dendritic cells usually obtained from 450 to 500 ml of peripheral blood. In addition to dendritic cells that constitute approximately 10 to 15% of the total myeloid progeny, the cultures contain monocytes/macrophages and intermediate granulocytic precursors. Monocytes/macrophages and dendritic cells together comprise all of the class II MHC-positive progeny. Sorted cells bearing the CD14+ HLA-DR+ phenotype of mature monocytes are at least 1.5 to 2 logs less active than CD14- HLA-DR+ dendritic cells as stimulators in the allogeneic MLR, even though both CD14+ and CD14- subpopulations share expression of several costimulatory ligands. The synergistic combination of c-kit ligand, GM-CSF, and TNF-alpha therefore expands substantial numbers of immunostimulatory CD14- HLA-DR+ dendritic cells from defined CD34+ progenitors in human bone marrow. This should facilitate the use of dendritic cells in the manipulation of T cell-mediated immune responses.
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PMID:Expansion of immunostimulatory dendritic cells among the myeloid progeny of human CD34+ bone marrow precursors cultured with c-kit ligand, granulocyte-macrophage colony-stimulating factor, and TNF-alpha. 753 34

CD34+ cells were enriched, using a panning method, from peripheral blood (PB) and bone marrow (BM) of healthy volunteers and of patients treated with chemotherapy plus granulocyte colony-stimulating factor (G-CSF). In healthy volunteers, PB CD34+ cells expressed CD33 and CD13 at a higher frequency than BM CD34+ cells, and PB CD34+ cells contained a greater number of burst-forming units-erythroid (BFU-E) than colony-forming units granulocyte-macrophage (CFU-GM). Administration of G-CSF to healthy volunteers induced a marked increase in the number of PB CD34+ cells, although the proportions of those expressing CD33, CD13, and c-kit among these cells as well as colony-forming ability were not changed before and after G-CSF administration. There were no significant differences in surface antigens on PB CD34+ cells between healthy volunteers and patients after chemotherapy plus G-CSF, except for low expression of c-kit in the PB of patients. However, PB CD34+ cells from patients contained almost the same number of CFU-GM as BFU-E. These results indicate that there were clear differences in the features of CD34+ cells from BM and from PB, and between healthy volunteers and patients after chemotherapy plus G-CSF. Enriched CD34+ cells are useful for analyzing the characteristics of hematopoietic progenitor cells, and such analysis may predict the usefulness of autologous or allogeneic peripheral blood stem cell transplantation.
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PMID:Characterization of enriched CD34+ cells from healthy volunteers and those from patients treated with chemotherapy plus granulocyte colony-stimulating factor (G-CSF). 754 13

To determine the potential role of autocrine growth factor production in regulating primitive human hematopoietic cell development, we examined highly purified CD34+, c-Kit+ marrow mononuclear cells for expression of c-Kit ligand (KL) and stem cell tyrosine kinase 1 (stk1) ligand (STK1-L). Normal marrow mononuclear cells coexpressing CD34 and c-Kit were isolated by a combination of immunomagnetic bead isolation and fluorescence-activated cell sorting. Purified cells were then screened for expression of KL and stk1-L mRNA using a sensitive reverse transcription-polymerase chain reaction method. Using this approach, expression of both cytokine genes at the mRNA level was found in this highly enriched cell population. We then examined the functional significance of these mRNAs by inhibiting their expression with antisense (AS) oligodeoxynucleotides (ODN). In comparison to untreated or control ODN treated cells, inhibition of KL led to a 70% and 89% inhibition in burst-forming unit-erythroid (BFU-E) and colony-forming unit-Mix (CFU-Mix) colonies but had no significant effect on CFU-granulocyte-macrophage (CFU-GM) cloning efficiency. In contrast, inhibition of STK1-L alone had no effect on colony formation. However, when STK1-L AS ODN was combined with KL AS ODN, additive inhibition of CFU-GM and CFU-MIX but not of BFU-E colonies was observed. These findings, along with those of our previous studies showing inhibition of primitive hematopoietic cell growth with antisense ODN directed towards the stk1 receptor, suggest the possibility that both receptor/ligand axes regulate primitive hematopoietic cell growth via an autocrine growth loop.
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PMID:Expression and physiologic significance of Kit ligand and stem cell tyrosine kinase-1 receptor ligand in normal human CD34+, c-Kit+ marrow cells. 754 21

Monocytes and macrophages show marked phenotypic variation dependent on their tissue of origin. Peripheral blood monocytes have been found to be sources of a variety of cytokines, but isolated marrow macrophages have not been characterized in this regard. Marrow macrophages form a predominant component of murine adherent Dexter stromal cells and can be isolated by sequential explant culture in colony-stimulating factor-1 (CSF-1). We have studied murine (Balb/c) bone marrow macrophage (BMM) cytokine production in the presence or absence of CSF-1, the lectin pokeweed mitogen (PWM) or interleukin-3 (IL-3). Biologic activity in conditioned media (cm) from control and induced BMM was assessed using the factor-dependent cell lines 32D, NFS-60, T1165, MC-6 and FDC-P1. Cell line stimulation and antibody blocking indicated the presence of c-kit ligand, interleukin-6 (IL-6) and granulocyte colony-stimulating factor (G-CSF). This stimulatory activity was increased by exposure to PWM or the combination of CSF-1 and PWM or CSF-1 and IL-3. CSF-1, as determined by radioimmunoassay (RIA), was essentially undetectable in baseline cm and induction was not seen with PWM or CSF-1. Baseline or "constitutive" expression of BMM and mRNA for CSF-1 and c-kit ligand was seen. Uninduced BMM did not express mRNA for G-CSF, granulocyte-macrophage CSF (GM-CSF), IL-6 or IL-3. CSF-1 induced increased expression of IL-6 mRNA, PWM induced increased expression of G-CSF and IL-6 mRNA and the combination of PWM and CSF-1 induced expression of CSF-1, G-CSF and IL-6 mRNA. Varying levels of CSF-1 had differential effects on cytokine production. Increasing levels of CSF-1 increased IL-6 mRNA and downmodulated CSF-1 mRNA expression. There was a biphasic response of c-kit ligand mRNA expression to CSF-1 exposure; low levels of CSF-1 (50 U/mL) induced, while higher levels (2000 U/mL) inhibited, expression. These data indicate that BMM (and by analogy the macrophage component of Dexter culture stroma), are important sources of CSF-1 and c-kit ligand but not GM-CSF or IL-3. BMM can also be induced to express IL-6 and/or G-CSF. Lastly, CSF-1, by differentially modulating BMM cytokine production in a holocrine or autocrine manner, may function as a central regulator of stromal based hematopoiesis.
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PMID:Cytokine expression from bone marrow derived macrophages. 767 17

Although sustained production of committed human hematopoietic progenitor cells in long-term bone marrow cultures (LTBMC) is well documented, evidence for the generation and expansion of human primitive hematopoietic progenitor cells (PHPC) in such cultures is lacking. For that purpose, we attempted to determine if the human high proliferative potential colony-forming cell (HPP-CFC), a primitive hematopoietic marrow progenitor cell, is capable of generation and expansion in vitro. To that effect, stromal cell-free LTBMC were initiated with CD34+ HLA-DR-CD15- rhodamine 123dull bone marrow cells and were maintained with repeated addition of c-kit ligand and a synthetic interleukin-3/granulocyte-macrophage colony-stimulating factor fusion protein. By day 21 of LTBMC, a greater than twofold increase in the number of assayable HPP-CFC was detected. Furthermore, the production of HPP-CFC in LTBMC continued for up to 4 weeks, resulting in a 5.5-fold increase in HPP-CFC numbers. Weekly phenotypic analyses of cells harvested from LTBMC showed that the number of CD34+ HLA-DR- cells increased from 10(4) on day 0 to 56 CD34+ HLA-DR- cells increased from 10(4) on day 0 to 56 x 10(4) by day 21. To examine further the nature of the in vitro HPP-CFC expansion, individual HPP-CFC colonies were serially cloned. Secondary cloning of individual, day 28 primary HPP-CFC indicated that 46% of these colonies formed an average of nine secondary colony-forming unit--granulocyte-macrophage (CFU-GM)--derived colonies, whereas 43% of primary HPP-CFC gave rise to between one and six secondary HPP-CFC colonies and 6 to 26 CFU-GM. These data show that CD34+ HLA-DR- CD15- rhodamine 123dull cells represent a fraction of human bone marrow highly enriched for HPP-CFC and that based on their regeneration and proliferative capacities, a hierarchy of HPP-CFC exists. Furthermore, these studies indicate that in the presence of appropriate cytokine stimulation, it is possible to expand the number of PHPC in vitro.
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PMID:Long-term generation and expansion of human primitive hematopoietic progenitor cells in vitro. 767 96

Steel factor (SLF, c-kit ligand), a potent costimulating cytokine in vitro for myeloid progenitor cells from normal donors, is currently being evaluated in clinical trials for effects on hematopoiesis. Based on a preliminary observation that colony-stimulating factor (CSF)-responsive myeloid progenitor cells (CFU-GM) from a few patients with acute myeloid leukemia (AML) did not respond to the costimulating effects of SLF, we evaluated responsiveness of bone marrow or blood CFU-GM from 26 patients with either AML, chronic myeloid leukemia (CML) or myelodysplastic syndrome (MDS) to the effects in vitro of SLF and/or granulocyte-macrophage CSF (GM-CSF). Cells from all 26 patients responded to the stimulating effects of GM-CSF, but marked heterogeneity was detected in each disease category to the costimulating effects of SLF. Nine of 13 patients with AML, 2 of 6 patients with CML and 4 of 7 patients with MDS had clonogenic cells that did not respond significantly to the costimulating effects of SLF. In a more limited study of cells from patients with MDS, it was noted that if the CFU-GM of that patient did not respond to SLF enhancement of CSF-induced colony formation, neither did the erythropoietin (Epo)-dependent erythroid (BFU-E) or multipotential (CFU-GEMM) cells of that patient (3 cases of refractory anemia [RA] evaluating bone marrow and in 1 case blood progenitors as well). If CFU-GM responded, BFU-E and CFU-GEMM responded (bone marrow from 1 patient with chronic myelomonocytic leukemia [CMMol]). Clinical criteria did not readily distinguish between patients who had SLF-responsive vs. -nonresponsive clonogenic cells. While the mechanistic reason for this heterogeneity in responsiveness is not clear, these differences should be carefully considered for possible clinical trials with SLF in patients with acute and chronic myeloid leukemia and MDS.
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PMID:Differential responses of myeloid progenitor cells from patients with myeloid leukemia and myelodysplasia to the costimulating effects of steel factor in vitro. 768 84

Chronic exposure of mice to 1,3-butadiene produces a macrocytic-megaloblastic anemia, thymic hypoplasia, and an increased incidence of T-cell lymphoma/leukemia. This is reminiscent of pathologies observed in mice bearing mutations at the W and Sl loci, which are deficient in c-kit and c-kit ligand (CKL), respectively. The influence of 3,4-epoxybutene (EB), the primary metabolite of 1,3-butadiene, on the colony-forming response of hematopoietic progenitor cells (HPCs) from C57BL/6, Sl, and W mice was investigated in order to elucidate the role of altered HPC regulation in the pathogenesis of 1,3-butadiene toxicity. EB pretreatment suppressed interleukin 3 colony formation and abrogated CKL synergism of the granulocyte-macrophage/colony-stimulating factor (GM-CSF) response in C57BL/6 cells, had no effect on colony formation induced by GM-CSF or granulocyte/colony-stimulating factor (G-CSF) alone, and failed to suppress CKL-induced synergism of the G-CSF response. Experiments conducted with cells from Sl and W mice revealed that they lack the same primitive HPC targeted by EB. EB pretreatment in vitro and butadiene exposure in vivo mimic hematopoietic defects seen in W and Sl mice, suggesting that the pleotypic pathologies encountered in these murine models may be largely due to a common defect in primitive HPCs. Susceptibility to EB appears to define a functional subpopulation of primitive HPCs and illustrates that differences observed in the susceptibility of specific cytokine responses to chemical/drug exposure may provide a valuable tool for characterizing functional subpopulations of HPCs.
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PMID:Chemical suppression of a subpopulation of primitive hematopoietic progenitor cells: 1,3-butadiene produces a hematopoietic defect similar to steel or white spotted mutations in mice. 768 89

Steel factor (SF), the ligand for the c-kit, also called kit ligand, stem cell factor, or mast cell growth factor, was evaluated on colony formation alone or in combination with other cytokines, from purified human hematopoietic CD34+ cells in low density cell culture. SF alone had a slight effect on granulocyte (G) and macrophage (M) colony formation. It synergized with other cytokines on colony formation from colony-forming unit-granulocyte, erythroid, macrophage, megakaryocyte (CFU-GEMM), erythroid and granulocyte-macrophage (CFU-GM) progenitors. However, combination of SF with lineage-specific factors, such as erythropoietin (Epo) or/and granulocyte colony-stimulating factor (G-CSF) was not sufficient for the proliferation of multipotential progenitors (CFU-GEMM). These multipotential progenitors required the presence of multi-lineage factors, such as interleukin 3 (IL3) or granulocytic-macrophage CSF(GM-CSF) for their development.
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PMID:Co-stimulatory effects of steel factor, the c-kit ligand, on purified human hematopoietic progenitors in low cell density culture. 768 20

The growth and differentiation of selected bone marrow CD34+ cells stimulated with hematopoietic growth factors in lipid cultures were evaluated to determine whether cell types that may be useful for reducing the neutropenia associated with high-dose chemotherapy (HDC) can be produced and quantitated in vitro. CD34+ cells enriched from bone marrow were cultured for up to 5 weeks in interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) with or without stem cell factor (SCF) (also termed c-kit ligand). The mixture of IL-3, GM-CSF and G-CSF resulted in an 18-fold increase in cells after 10 to 12 days of culture and a 94-fold increase after 21 days. A 3-fold increase in colony-forming unit granulocyte-macrophage (CFU-GM) was observed after 10 days of culture. The addition of SCF during the first 10 days of culture further augmented the proliferation of cell numbers to 24-fold and colony-forming cells (CFC) to 8-fold after 10 days while cell numbers increased 130-fold after 21 days. Two-color flow cytometry defined phenotypes expressing CD11b and CD15 that represented maturation stages of neutrophils. Maturation of neutrophils in these cultures could be followed by the initial appearance after 3 to 7 days of a CD15+CD11b- phenotype representing promyelocytes, which gave rise after 2 to 3 weeks to a CD15+CD11b+ phenotype representing more mature neutrophil forms (metamyelocytes to segmented neutrophils). In contrast to normal neutrophil development, only a small fraction (10 to 15%) of the culture-derived neutrophils expressed CD16. These data define the kinetics and differentiation of neutrophils and neutrophil precursors from selected CD34+ cells in liquid cultures.
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PMID:Expansion of neutrophil precursors and progenitors in suspension cultures of CD34+ cells enriched from human bone marrow. 768 2


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