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)

Human mast cell growth factor (MGF, a c-kit ligand) and colony stimulating factors (Epo, GM-CSF, G-CSF, IL-3) were assessed in the absence or presence of serum for stimulation in semi-solid medium of single CD34 , CD34 HLA-DR+, or CD34 HLA-DR+CD33- cells sorted per microtiter well. The % of wells containing CFU-GM and erythroid containing (BFU-E and CFU-GEMM) colonies increased in proportion to the number of cytokines added. In the presence of serum, 1, to 4 cytokine combinations resulted in respective increases in cloning efficiencies of 10 to 21.0, 19.5 to 31.5, 35.8 to 42.9, and 46.3 to 60.0%. MGF had little effect by itself, but did act in combination with CSFs to enhance numbers and size of the colonies from isolated single cells. High cloning efficiencies were also obtained in the absence of serum when multiple cytokines were used. The results demonstrate that MGF and CSFs can act directly on the proliferation of single hematopoietic progenitor cells in the absence of accessory cells and serum.
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PMID:Influence of combinations of cytokines on proliferation of isolated single cell-sorted human bone marrow hematopoietic progenitor cells in the absence and presence of serum. 137 67

A mouse antihuman monoclonal IgG2a antibody, termed stem cell receptor-1 (SR-1), specific for a determinant of the c-kit ligand receptor (KR), was used as an immunologic probe to analyze KR expression by human bone marrow hematopoietic progenitor cells. Monoclonal antibodies to CD34 and HLA-DR were used in a multicolor staining protocol in conjunction with SR-1 to further define the phenotypes of various classes of hematopoietic progenitor cells. Expression of KR (SR-1+) on hematopoietic progenitor cells identified subpopulations of cells expressing CD34 (CD34+). While one-half of the CD34- and HLA-DR-expressing cells (CD34+ HLA-DR+) expressed the KR (SR-1+), one-third of the CD34+ cells that lacked HLA-DR expression (CD34+ HLA-DR-) were SR-1+. The CD34+ HLA-DR+ SR-1+ cell population contained the vast majority of the more differentiated progenitor cells, including the colony-forming unit (CFU) granulocyte-macrophage; burst-forming unit-erythrocyte; CFU-granulocyte, erythrocyte, macrophage, megakaryocyte; and the CFU-megakaryocyte. The overall progenitor cell cloning efficiency of this subpopulation was greater than 31%. By contrast, the CD34+ HLA-DR- SR-1+ cell population contained fewer of these more differentiated progenitor cells but exclusively contained the more primitive progenitor cells, the BFU-megakaryocyte, high proliferative potential-colony-forming cell, and long-term bone marrow culture-initiating cell. The overall progenitor cell cloning efficiency of this subpopulation was greater than 7%. Both the CD34+ HLA-DR- and CD34+ HLA-DR+ cell subpopulations lacking KR expression contained few assayable hematopoietic progenitor cells. Long-term bone marrow cultures initiated with CD34+ HLA-DR- SR-1+ but not CD34+ HLA-DR- SR-1- cells, which were repeatedly supplemented with c-kit ligand (KL) and interleukin-3, generated assayable progenitor cells of at least 2 lineages for 10 weeks. These experiments demonstrate the expression of the KR throughout the hierarchy of human hematopoietic progenitor cell development. We conclude from our data that the KL and KR play a pivotal role in cytokine regulation of both the primitive and more differentiated human hematopoietic progenitor cells.
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PMID:Further phenotypic characterization and isolation of human hematopoietic progenitor cells using a monoclonal antibody to the c-kit receptor. 137 42

Purified natural (n) and recombinant (r) murine (mu) mast cell growth factor (MGF, a c-kit ligand) were evaluated alone and in combination with r human (hu) erythropoietin (Epo), rhu granulocyte-macrophage colony-stimulating factor (rhuGM-CSF), rhuG-CSF, and/or rhuM-CSF for effects in vitro on colony formation by multipotential (colony-forming unit-granulocyte, erythroid, monocyte, megakaryocyte [CFU-GEMM]), erythroid (burst-forming unit erythroid [BFU-E]) and granulocyte-macrophage (CFU-GM) progenitor cells from normal human bone marrow. MGF was a potent enhancing cytokine for Epo-dependent CFU-GEMM and BFU-E colony formation, stimulating more colonies and of a larger size than either rhu interleukin-3 (rhuIL-3) or rhuGM-CSF. MGF, especially at lower concentrations, also acted with rhuIL-3 or rhuGM-CSF to enhance Epo-dependent CFU-GEMM and BFU-E colony formation. MGF had little stimulating activity for CFU-GM colonies by itself, but in combination with suboptimal to optimal amounts of rhuGM-CSF enhanced the numbers and the size of CFU-GM colonies in an additive to greater than additive manner. While we did not detect an effect of MGF on CFU-G colony numbers stimulated by maximal concentrations of rhuG-CSF, MGF did enhance the size of CFU-G-derived colonies. MGF did not enhance the activity of rhuM-CSF. In a comparative assay, maximal concentrations of rmu and rhuMGF were equally effective in the enhancement of human bone marrow colony formation, but rhuMGF, in contrast to rmuMGF, did not at the concentrations tested enhance colony formation by mouse bone marrow cells. MGF effects on BFU-E, CFU-GM, and CFU-GEMM may be direct acting ones as MGF-enhanced colony formation by these cells in highly enriched progenitor cell populations of CD34 HLA-DR+ and CD34 HLA-DR+CD33- sorted cells in which greater than or equal to 1 of 2 cells was a BFU-E plus CFU-GM plus CFU-GEMM. MGF appears to be an early acting cytokine that preferentially stimulates the growth of immature hematopoietic progenitor cells.
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PMID:Effect of murine mast cell growth factor (c-kit proto-oncogene ligand) on colony formation by human marrow hematopoietic progenitor cells. 170 71

CD45 antigens are protein tyrosine phosphatases. A possible link was evaluated between expression of CD45 antigens on human myeloid progenitor cells (MPC) (colony-forming unit-granulocyte/macrophage [CFU-GM], burst-forming unit-erythroid [BFU-E], and colony-forming unit-granulocyte/erythroid/macrophage/megakaryocyte [CFU-GEMM]) and regulation of MPC by colony-stimulating factors (CSF) (interleukin 3 [IL-3], GM-CSF, G-CSF, M-CSF, and erythropoietin [Epo]), a GM-CSF/IL-3 fusion protein, and mast cell growth factor (MGF; a c-kit ligand). Treatment of cells with antisense oligodeoxynucleotides (oligos) to exons 1 and 2, but not 4, 5, or 6, of the CD45 gene, or with monoclonal anti-CD45, significantly decreased CFU-GM colony formation stimulated with GM-CSF, IL-3, fusion protein, and GM-CSF + MGF, but not with G-CSF or M-CSF. It also decreased GM-CSF, IL-3, fusion protein, and MGF-enhanced Epo-dependent BFU-E and CFU-GEMM colony formation, but had little or no effect on BFU-E or CFU-GEMM colony formation stimulated by Epo alone. Similar results were obtained with unseparated or purified (greater than or equal to one of two cells being a MPC) bone marrow cells. Sorted populations of CD343+ HLA-DR+ marrow cells composed of 90% MPC were used to demonstrate capping of CD45 after crosslinking protocols. Also, a decreased percent of CD45+ cells and CD45 antigen density was noted after treatment of column-separated CD34+ cells with antisense oligos to exon 1 of the CD45 gene. These results demonstrate that CD45 cell surface antigens are linked to stimulation of early human MPC by IL-3, GM-CSF, a GM-CSF/IL-3 fusion protein, and MGF.
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PMID:CD45 cell surface antigens are linked to stimulation of early human myeloid progenitor cells by interleukin 3 (IL-3), granulocyte/macrophage colony-stimulating factor (GM-CSF), a GM-CSF/IL-3 fusion protein, and mast cell growth factor (a c-kit ligand). 171 54

We examined the effects of interleukin-3 (IL-3) and c-kit ligand (KL) on the survival of differentiated hematopoietic progenitor cells (HPC), the burst-forming unit-erythroid (BFU-E); colony-forming unit-granulocyte, erythroid, monocyte, megakaryocyte (CFU-GEMM); and CFU-granulocyte-monocyte (CFU-GM) and more primitive hematopoietic cells that give rise to these progenitor cells (pre-colony-forming cells [pre-CFC]). CD34+ HLA-DR+ cells, which are highly enriched for committed HPC, and CD34+ HLA-DR- c-kit+ cells, which contain the most primitive assayable hematopoietic cells, including long-term bone marrow culture-initiating cells, high proliferative potential-CFC, the CFU-blast, and the BFU-megakaryocyte, were suspended in serum-free medium in the presence or absence of IL-3 or KL. CD34+ HLA-DR+ cells incubated under serum-free conditions or in the presence of KL for 96 hours lost greater than 90% of assayable unilineage or multilineage HPC, whereas those cells incubated in the presence of IL-3 retained 40% of the number of HPC present at time 0. The effect of IL-3 on HPC survival was most pronounced on the BFU-E and CFU-GEMM present within CD34+ HLA-DR+ cells. Addition of IL-3, but not of KL, to CD34+ HLA-DR+ cells delayed the appearance of morphologic changes and DNA fragmentation patterns associated with cell death occurring by apoptosis. CD34+ HLA-DR-c-kit+ cells were incubated under similar serum-free conditions in the presence or absence of IL-3 or KL, and the frequency of pre-CFC was determined by limiting dilution analysis. The frequency of pre-CFC in cells incubated for 48 hours in the absence of serum was similar to that of cells incubated in the presence of IL-3 and approximately doubled when CD34+ HLA-DR- c-kit+ cells were incubated in the presence of KL. Addition of KL to serum-free suspension cultures of CD34+ HLA-DR- c-kit+ cells delayed the appearance of DNA fragmentation patterns associated with apoptosis to a greater extent than did the addition of IL-3. These studies suggests that IL-3, but not KL, promotes HPC survival, whereas KL plays a greater role than IL-3 in sustaining more primitive HPC, such as pre-CFC. The effects of both cytokines in mediating HPC and primitive hematopoietic cell survival appear to be related, in part, to their ability to suppress apoptosis.
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PMID:Effects of interleukin-3 and c-kit ligand on the survival of various classes of human hematopoietic progenitor cells. 751 Jan 43

High proliferative-potential colony-forming cells (HPP-CFC) have been identified in the bone marrow of mice and adult humans, and have been characterized as a compartment of primitive progenitors possibly including stem cells. In this report we describe the human fetal liver (FL) as a source of HPP-CFC. These FL HPP-CFC develop in clonal cultures in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) within 3 to 4 weeks. The median frequency of HPP-CFC in FL tissues between 16 and 21 weeks of gestational age was 1 in 3,000 total FL cells. After 4 weeks of growth, FL HPP-CFC grew to a median colony size of 8.3 x 10(4) cells/colony. Using cell-sorting techniques FL HPP-CFC were shown to be predominantly contained in the CD34+ CD33+ CD38- fraction of FL cells. FL HPP-CFC were heterogeneous for HLA-DR expression, and no differences in proliferative capacities were observed between HLA-DR+ and HLA-DR- HPP-CFC. The CD34+ CD33-HLA-DR- CD38- population, previously suggested to contain stem cells, was observed to be very rare in the FL, representing approximately 1 in 1.7 x 10(5) light-density FL cells and containing almost no CFC. Therefore, it is possible that stem cells are contained in the CD33+ fraction of FL cells. Phenotypic characterization of CD34+ CD33+ CD38- lin -LDFL cells showed that these cells are also CD13+, predominantly Thy-1+, CD45RA-, CD45RO-, CD71-, and heterogenoeous for c-kit expression. These data suggest that FL HPP-CFC represent a heterogeneous compartment of primitive myeloid progenitors that may include stem cells.
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PMID:Expression of CD33, CD38, and HLA-DR on CD34+ human fetal liver progenitors with a high proliferative potential. 751 3

To understand regulation of hemopoiesis, it would be helpful to identify physiologically relevant function-associated molecules on stem cells. Here, we report the detailed examination of CD43 expression on murine and human pluripotent hemopoietic stem cells. Mouse stem cells were found within the Ly6+Lin-CD43high subpopulation of bone marrow. These cells, upon transfer into SCID mice, caused rapid repopulation of thymus, spleen, and bone marrow. Retransfer of bone marrow cells from primary SCID recipients of Ly6+Lin-CD43high cells into secondary recipients resulted in repopulation of lymphohemopoietic cells. All Ly6+Lin-CD43high cells were found to express high levels of c-kit. In contrast, Ly6+Lin-CD43-/low cells caused limited and variable thymic and splenic repopulation. These cells failed to repopulate the marrow cavity and did not contain retransplantable stem cells. These data indicate that murine pluripotent stem cells express high levels of CD43. Examination of human fetal bone marrow cells revealed a population of CD34+CD38-CD43+ cells. When single sorted cells with this phenotype were cultured in vitro, they were able to produce colonies with a dispersed growth pattern. Cells with this growth pattern have previously been shown to have myeloid and lymphoid growth potentials and extensive self-renewal capacity. Furthermore, CD34+CD38-HLA-DR+ cells, recently shown to be highly enriched in stem cell activity, expressed relatively high levels of CD43. Because CD43 has recently been shown to bind to intercellular adhesion molecule-1, these data suggest a possible role for CD43 in the regulation of hemopoiesis.
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PMID:Expression of CD43 on murine and human pluripotent hematopoietic stem cells. 752 20

It was the objective of the study to characterize CD34+ hematopoietic progenitor cells from peripheral blood (PB) and bone marrow (BM) in a group of 24 cancer patients. After cytotoxic chemotherapy, R-metHu granulocyte colony-stimulating factor (R-metHuG-CSF; filgrastim, 300 micrograms daily, subcutaneously) was given to shorten the time of neutropenia as well as to increase the rebound of peripheral blood progenitor cells (PBPC) for harvesting. The proportion of CD34+ cells in the leukapheresis products (LPs) was 1.4-fold greater than in BM samples that were obtained at the same day (LP: median, 1.4% v BM: median, 1.0%, P < .01). Two- and three-color immunofluorescence showed that blood-derived CD34+ cells comprised a greater proportion of a particular early progenitor cell than CD34+ cells of bone marrow. Blood-derived progenitor cells tended to have a higher mean fluorescence intensity of CD34 and expressed significantly lower levels of HLA-DR (mean fluorescence intensity of HLA-DR: 442.6 +/- 44.9 [LP] v 661.5 +/- 64.6 [BM], mean +/- SEM, P < .01). Furthermore, the blood-derived CD34+ cells comprised a 1.7-fold greater proportion of Thy-1+ cells (LP: median, 24.4% v BM: median, 14.4%, P < .001) and expressed significantly less c-kit (LP: median, 20.5% v BM: median, 31.0%, P < .01). Three-color analysis showed that high levels of Thy-1 expression were restricted to CD34+/HLA-DRdim or CD34+/HLA-DR- cells confirming the early developmental stage of this progenitor cell subset. The proportion of CD34+/CD45RA(bright) cells representing late colony-forming unit granulocyte-macrophage (CFU-GM) was smaller in LPs compared with BM (P < .05). For an examination of BM CD34+ cells before the mobilization chemotherapy, samples of 16 patients were available. The mean proportion of c-kit expressing CD34+ cells in the bone marrow during G-CSF-stimulated reconstitution decreased 1.8-fold compared with baseline values. There was no difference in the proportion of BM-derived CD34+/Thy-1+ cells and CD34+/CD45RA+ cells between steady-state hematopoiesis and G-CSF-supported recovery. Our data suggest that during G-CSF-enhanced recovery, CD34+ cells in the PB are enriched with more primitive progenitor cells to evenly replenish the BM after the chemotherapy-related cytotoxic damage.
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PMID:Blood-derived autografts collected during granulocyte colony-stimulating factor-enhanced recovery are enriched with early Thy-1+ hematopoietic progenitor cells. 753 95

Steel factor (SF) acts synergistically with other hematopoietic growth factors to support the proliferation of progenitor cells in a variety of culture systems. To determine whether SF alone could directly stimulate proliferation of early hematopoietic progenitor cells, isolated CD34+ cells from adult bone marrow and umbilical cord blood were studied in a short-term suspension culture in serum-free medium. Numbers of CD34+ and proliferating cells were quantified by flow cytometry; proliferation was assessed by simultaneous measurement of expression of the nuclear antigen Ki67 and DNA content (propidium iodide [PI]). In the absence of growth factors, the numbers of CD34+ and cycling cells declined over 2 days. Cells cultured in the presence of SF alone maintained the number of CD34+ and cycling cells at levels equal to the starting population. Withdrawal of growth factors led to a dramatic decrease in the number of cells in G1. Compared to cells grown in the absence of growth factors, cells grown in the presence of SF had significantly higher numbers of CD34+ and cycling cells (mean fold increase = 1.3 and 2; p < 0.05 and 0.01, respectively). SF increased the numbers of cells in both G1 and later phases of the cell cycle. Addition of interleukin-3 (IL-3) to SF led to further significant increases in CD34+ and cycling cells. The effects of SF could not be attributed to inhibition of apoptosis. CD34+ cells isolated from peripheral blood (PB) from patients with chronic myelogenous leukemia (CML) displayed similar characteristics. As assessed by binding of phycoerythrin (PE)-labeled ligand and flow cytometry, c-kit was expressed on 65 +/- 6% of isolated CD34+ cells and was detected on HLA-DRlow, CD38low, and Thy1+ subsets, as well as on more mature progenitor cells. Thus, while the effects of SF are most marked in combination with other growth factors, SF appears to bind to and directly maintain the active cell-cycle characteristics of isolated CD34+ cells.
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PMID:Steel factor supports the cycling of isolated human CD34+ cells in the absence of other growth factors. 753 83

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


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