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At least 19 recordsLinked to original sources

PubMed1998

Up- and down-regulation by glucocorticoids of the constitutive expression of the mast cell growth factor stem cell factor by human lung fibroblasts in culture.

Stem cell factor (SCF) is a major mast cell growth factor that promotes differentiation and chemotaxis of mast cells and inhibits their apoptosis. SCF therefore may be involved in diseases associated with an increased number of tissue mast cells such as asthma, for which the major treatment is glucocorticoids. In this study, we evaluated the effect of the glucocorticoid budesonide on the constitutive expression of SCF by human lung fibroblasts in primary culture. Budesonide (0.1 microM) induced a time-dependent biphasic effect on SCF mRNA and protein production. A short treatment (2.5-10 hr) induced an inhibition of SCF protein accumulation (-58% at 2.5 hr) and mRNA expression (-69% at 2.5 hr), associated with an accelerated decay of SCF mRNA and with a decrease in SCF gene transcription observed by nuclear run-on assay. Longer treatment (24-72 hr) led to increases in SCF protein accumulation (+64% at 48 hr) and mRNA expression (+125% at 24 hr) as a consequence of transcriptional activation. Similar effects of a decrease followed by an increase in SCF production were observed using another glucocorticoid, dexamethasone. Overall, our results show that glucocorticoids potently regulate SCF expression in human lung fibroblasts, successively decreasing and increasing SCF mRNA levels according to treatment duration. Such time-dependent modulation of SCF levels may explain some current discrepant findings about the effects of glucocorticoids on SCF production and may have functional consequences during glucocorticoid treatment, such as asthma therapy.

Budesonide↗

PubMed1996

Clinical applications of stem cell factor.

Stem cell factor is an early-acting hematopoietic cytokine that probably functions constitutively to support the proliferation and survival of pluripotent progenitor cells and to increase their receptivity to lineage commitment and differentiation in response to lineage-specific cytokines. Stem cell factor also can induce proliferation and activation of mast cells. In vitro and in vivo, stem cell factor has demonstrated synergy with other hematopoietic cytokines. In clinical trials, stem cell factor has been shown to mobilize peripheral blood progenitor cells and when combined with G-CSF to increase the number of peripheral blood progenitor cells harvested. When used in lower doses and with antihistamine and beta-agonist premedication, stem cell factor therapy has been well tolerated. Phase III trials are in progress to document the efficacy of stem cell factor in peripheral blood progenitor cell harvesting protocols. Future clinical applications may include the treatment of adult and pediatric marrow failure states, the ex vivo expansion and manipulation of hematopoietic progenitor cells, and the treatment of disorders of skin pigmentation.

Adult↗

PubMed2003

[Study of recombinant stem cell factor].

Stem cell factor is an important hematopoietic growth factor. In this study, the human stem cell factor was produced by recombinant E. coli, and the structure and biological activity of the recombinant stem cell factor(rhSCF) was studied. It was indicated that the rhSCF was a uncovalent dimer in phosphate buffer,and had the correct mass spectra, mass peptides spectra, composition of amino acid, N-terminal sequernce, C-terminal sequence and intrachain disulfide linkages, rhSCF alone or synergy with rhG-CSF could mobilze hematopoietic progenitors to blood in monkey.

Animals↗

PubMed1996

In vitro expansion of murine hematopoietic progenitor cells by leukemia inhibitory factor, stem cell factor, and interleukin-1 beta.

Murine hematopoietic progenitor cells were markedly expanded in the presence of leukemia inhibitory factor (LIF), interleukin (IL)-1 beta and/or stem cell factor (SCF), although SCF+IL-1 beta +IL-3, LIF+SCF+IL-3, and SCF+IL-1 beta showed an appreciable effect on the in vitro expansion of hematopoietic progenitor cells as well. In the presence of LIF+SCF+IL-1 beta, highly proliferative potential colony-forming units (CFU-HPP) and colony forming units of mixed lineages (CFU-Mix) were more efficiently expanded than colony forming units granulocytes/macrophage (CFU-GM) and burst-forming units of erythroid lineage (BFU-E) compared with the colony formations of freshly obtained bone marrow cells. The cell yield on day 5 in the presence of LIF+SCF+IL-1 beta was comparable to that in SCF+IL-1 beta and SCF+IL-1 beta +IL-3. Nevertheless, colony formations were marked in LIF+SCF+IL-1 beta, thus suggesting that this combination can generate hematopoietic progenitor cells that possess greater potential for CFU-HPP, CFU-Mix, CFU-GM, and BFU-E colony formations. Hematopoietic cells expanded in the presence of LIF+SCF+IL-1 beta showed increased mRNA expressions of IL-1 beta, IL-3, IL-6, granulocyte colony-stimulating factor (G-CSF), granulocyte/macrophage (GM)-CSF, interferon gamma (IFN-gamma), and LIF compared with those of nontreated hematopoietic cells. Furthermore, LIF+SCF+IL-1 beta induced increased IL-3 and GM-CSF mRNA expression in hematopoietic cells but induced decreased macrophage inflammatory protein 1 alpha (MIP1 alpha) mRNA expression as compared with SCF+IL-1 beta +IL-3. These results suggest that the balance between stimulatory and inhibitory cytokines plays an important role in in vitro expansion of hematopoietic progenitor cells.

Animals↗

PubMed1996

Cloning and characterization of cDNAs encoding two forms of avian stem cell factor.

Stem cell factor (SCF), also known as Steel factor, is a transmembrane cytokine involved in several developmental processes and the ligand for the receptor tyrosine kinase c-kit. In several mammalian species, two isoforms of stem cell factor have been reported, a long form in which soluble SCF is released after proteolytic cleavage of the extracellular domain and a short membrane-anchored form in which a region containing a cleavage site is deleted. Currently, only the longer, soluble form has been identified in birds. Therefore, the cDNAs encoding two forms of quail stem cell factor (qSCF) were obtained using RT-PCR with nested primers. The deduced amino acid sequence of the long form of qSCF showed a high degree of homology with chicken (98%) and relatively low homology (approximately 53%) with various mammalian SCFs. Northern blot analysis with the qSCF cDNA revealed the expression of a 5.9 and a 2.7 kb transcript in several quail tissues.

Amino Acid Sequence↗

PubMed1994

[Stem cell factor].

Stem cell factor (CSF), also called c-kit ligand (KL) or mast cell growth factor (MGF) is a peptide growth factor/cytokine with broad activities, especially on hematopoiesis. Its physiological role is best understood through the naturally occurring steel and W mutations in the mouse. This cytokine has recently been made available because of molecular cloning and its expression in recombinant form SCF is produced by a variety of cells, especially fibroblast, and interacts with target cells in each of the hematopoietic lineages to stimulate proliferation and differentiation. It has been found that SCF is important for the survival, proliferation and differentiation of mast cells and that it influences all stages of their development. SCF activity is not restricted to hematopoiesis, as it plays an important role in the development of germ cells and melanocytes as well. Preclinical studies show that SCF can protect against lethal irradiation, elicit multilineage responses in peripheral blood and bone marrow cellularity and increase circulating peripheral blood progenitor cells in a dose-dependent manner. Recombinant human SCF has major clinical potential through its synergy with other factors, especially G-CSF, to enhance mobilization of stem cells in peripheral blood.

Animals↗

PubMed2004

The expression patterns of mRNA-encoding stem cell factor, internal stem cell factor and c-kit in the prepubertal and adult porcine ovary.

The receptor, c-kit, and its ligand, stem cell factor (SCF), are important regulators of ovarian follicle growth and development. The aim of this study was to identify the sites of expression of mRNA for c-kit and SCF in prepubertal and mature (pregnant and non-pregnant) animals. Ovaries were recovered from prepubertal animals, non-pregnant sows and five sows at approximately 3 months of gestation. Ovine SCF and c-kit DNA were cloned into plasmid vectors to produce RNA probes. Expression of mRNA encoding SCF and c-kit were detected via in situ hybridization. Both mRNA were detected throughout ovaries from all animals. This study provides evidence that the growth-factor complex is required throughout follicle development, and also for continued maintenance of the corpus luteum (CL) in the mature animal. SCF mRNA was localized to the granulosa cell layer and was also extensively expressed in endothelial tissue and throughout the CL. c-kit mRNA was detected in the theca layer, oocytes and also in CL. In conclusion, expression of SCF and c-kit mRNA in granulosa and theca cells, respectively, indicate an important interaction between somatic cells throughout follicle development and that in the mature animal, SCF and c-kit potentially have a role in maintaining progesterone secretion by the CL. The observations of continued expression of SCF and c-kit throughout development suggest that there may be differences in the role of this receptor-ligand complex between large mono- vs. poly ovulatory species, such as the pig.

Animals↗

PubMed1994

Human peripheral blood granulocytes and myeloid leukemic cell lines express both transcripts encoding for stem cell factor.

Stem cell factor (SCF), the ligand for the c-kit proto-oncogene, has been shown to play a critical role in the migration of melanocytes and germ cells during embryogenesis as well as in the proliferative control of the hematopoietic compartment. In this study we investigated the expression of both the soluble and transmembrane SCF forms in purified peripheral blood populations and in several hematopoietic cell lines. Expression of both transcripts, though in different ratios, was identified in whole bone marrow, in bone marrow stromal cells and in human peripheral blood. In peripheral blood, SCF expression could be ascribable to polymorphonuclear leukocytes (PMN), whereas no SCF expression was detected in isolated lymphocytes, monocytes and in some T lymphoid cell lines. Conversely, some hematopoietic myeloid cell lines, such as HL-60, KG1 and K562, express SCF with similar patterns.

Base Sequence↗

PubMed1995

Stem cell factor.

Stem cell factor (SCF) is the ligand for the tyrosine kinase receptor c-kit, which is expressed on both primitive and mature hematopoietic progenitor cells. In vitro, SCF synergizes with other growth factors, such as granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage-colony-stimulating factor, and interleukin-3 to stimulate the proliferation and differentiation of cells of the lymphoid, myeloid, erythroid, and megakaryocytic lineages. In vivo, SCF also synergizes with other growth factors and has been shown to enhance the mobilization of peripheral blood progenitor cells in combination with G-CSF. In phase I/II clinical studies administration of the combination of SCF and G-CSF resulted in a two- to threefold increase in cells that express the CD34 antigen compared with G-CSF alone. Other potential clinical uses include ex vivo expansion protocols and in vitro culture for gene therapy.

Animals↗

PubMed1998

Morphological alterations in rat peritoneal mast cells by stem cell factor.

Stem cell factor (SCF) stimulates mast cell adhesion and, because SCF is produced normally in tissues, it may be a major factor responsible for the adhesion of mast cells to connective tissue matrix. We found that the morphology of rat peritoneal mast cells (RPMC) altered after the addition of recombinant murine SCF (rmSCF) in vitro. The ability of rmSCF to enhance morphological alteration was dose dependent and completely abolished by anti-c-kit ACK2 monoclonal antibody. Exposure of RPMC to transforming growth factor-beta 1, wortmannin, genistein, herbimycin A, staurosporine, indomethacin and cytochalasin D before the addition of rmSCF antagonized rmSCF-induced morphological alteration. However, nordihydroguiaretic acid had no effect. Many RPMC appeared to respond also to nerve growth factor (NGF) but the total number of cells with altered morphology was much greater when the culture was stimulated by rmSCF than by NGF. We suggest that morphological alterations of mast cells by rmSCF is an important step for the participation in adhesion to tissue under resident physiological conditions.

Animals↗

PubMed1994

Analysis of steel factor (stem cell factor) isoforms in the hematopoietic microenvironment.

Hematopoietic cell proliferation and differentiation is dependent in part on the interaction of hematopoietic stem and progenitor cells with cells making up the hematopoietic microenvironment (HM). Direct cell-cell interactions appear to be important in the hematopoietic microenvironment. One mechanism to accomplish such interactions is the expression of membrane-associated growth factors. Stem cell factor (SCF), the product of the steel gene in mice (also termed mast cell growth factor, c-kit ligand, or Steel factor), is a hematopoietic growth factor demonstrating substantial synergistic activity with a number of other cytokines on primitive hematopoietic stem and progenitor cells. Cloned SCF cDNA encode both a membrane-associated and a secreted growth factor. The physiologic relevance of these isoforms is unknown at present. In order to better understand the physiologic role of these SCF isoforms in normal hematopoiesis, we have established multiple stromal cell lines expressing each isoform. We have used these cell lines to study protein sequences that are required for appropriate post-translational processing of SCF protein in HM-derived stromal cell lines. These lines have also been used to study the interaction of membrane-associated and secreted SCF with murine and human hematopoietic cells. In addition, we have generated transgenic mice expressing each isoform of murine and human SCF. These transgenic mice will be used to study the function of each isoform in hematopoiesis in vivo.

Amino Acid Sequence↗

PubMed1993

Sequence of a cDNA encoding chicken stem cell factor.

Stem cell factor (SCF) is a polypeptide growth factor and the ligand for the c-kit proto-oncogene product. We cloned a chicken cDNA encoding a protein homologous to the mouse and human SCFs. The deduced amino acid (aa) sequence shows 53 and 52% identity to the mouse and human SCFs, respectively.

Amino Acid Sequence↗

PubMed1992

Blasts from patients with acute myelogenous leukemia express functional receptors for stem cell factor.

Stem cell factor (SCF) acts in concert with lineage-specific growth factors to stimulate the growth of hematopoietic colonies. To determine if neoplastic human hematopoietic cells would also respond to SCF, we cultured marrow mononuclear cells from 20 patients with newly diagnosed acute myelogenous leukemia (AML) and two normal donors with SCF, interleukin 3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), or combinations of growth factors in semisolid medium, and assessed colony growth. SCF receptors (c-kit receptors) were quantitated by equilibrium binding studies with 125I-SCF, and binding parameters were estimated using the ligand program. The cellular distribution of c-kit receptors was determined by autoradiography. Our results show that SCF alone or in combination with IL-3 or GM-CSF increased both the number and size of colonies in 10 of the patients. Receptors for SCF were identified on the blasts from all 20 AML patients. The number of receptors ranged from 600 to 29,000 per cell. In the majority of patients, both high- and low-affinity binding sites were identified. Neither the number of receptors per cell nor the finding of one or two classes of receptors correlated with growth response to SCF. Autoradiographic analysis of 125I-SCF binding to normal marrow mononuclear cells revealed grains associated with blasts and megakaryocytes. Grain counts on blasts from 10 AML patients and on normal marrow blasts suggested that high-affinity c-kit receptor expression on AML blasts is lower than or similar to that of normal blasts. These results identify c-kit receptors on human AML blasts, and indicate that SCF acts synergistically with IL-3 or GM-CSF to stimulate colony growth from the marrow cells of a portion of patients with AML.

Autoradiography↗

PubMed1998

Human mast cells express stem cell factor.

Stem cell factor (SCF) is a major cytokine regulator of mast cell growth and function. The present study demonstrates that human mast cells are able to produce SCF. Constitutive synthesis of SCF mRNA was seen in the mast cells isolated from human lung and skin by RT-PCR. This was confirmed by in situ hybridization in conjunctival mast cells of both tryptase-only (MCT) and tryptase/chymase (MCTC) subsets. SCF protein product was found in conjunctival MCT and MCTC mast cells by immunohistochemistry. Soluble SCF protein was detected in the culture supernatant of isolated lung mast cells by ELISA, and cross-linkage of IgE receptor (Fc epsilon-RI) on the lung mast cells in culture did not alter SCF mRNA expression, or the secreted soluble SCF protein. This was consistent with the finding that levels of SCF mRNA expression in conjunctival mast cells were similar between normal subjects and patients with seasonal allergic conjunctivitis (SAC). This study shows that human mast cells themselves are a cellular source of SCF, as well as being target cells for this growth factor. SCF may regulate mast cell growth and function via both paracrine and autocrine mechanisms. The production of SCF by mast cells may be regulated via mechanisms other than IgE receptor-mediated pathways.

Cell Culture Techniques↗

PubMed1996

JAK2 is associated with the c-kit proto-oncogene product and is phosphorylated in response to stem cell factor.

Stem cell factor (SCF) is a hematopoietic growth factor that interacts with the receptor tyrosine kinase, c-kit. We have found that SCF-stimulates rapid and transient tyrosine phosphorylation of JAK2 in human and murine cell lines, as well as in normal human progenitor cells. JAK2 and c-kit were associated in unstimulated cells with further recruitment of JAK2 to the c-kit receptor complex after SCF stimulation. Treatment of cells with JAK2 antisense oligonucleotides resulted in a 46% decrease in SCF-induced proliferation. These data demonstrate that SCF induces tyrosine phosphorylation of JAK2 and suggest that JAK2 is a component of the SCF signal transduction pathway.

Animals↗

PubMed1996

JAK2 is constitutively associated with c-Kit and is phosphorylated in response to stem cell factor.

Stem cell factor (SCF) interacts with the receptor tyrosine kinase c-Kit and has potent effects on hematopoiesis. We have examined the role of JAK2 in the SCF signal transduction pathway. JAK2 and c-Kit were constitutively associated, and treatment with SCF resulted in rapid and transient tyrosine phosphorylation of JAK2. Incubation of cells with JAK2 antisense oligonucleotides resulted in significant decreases in SCF-induced proliferation. These data suggest that JAK2 plays a role in SCF-induced proliferation.

Animals↗

PubMed2001

Human peripheral blood eosinophils express stem cell factor.

Stem cell factor (SCF) or c-Kit ligand is a cytokine associated with the differentiation, survival, and activation of mast cells. Eosinophils have pleiotropic functions in several diseases and, together with mast cells, are key cells in allergy. Mast cell-eosinophil interactions can take place during the late and chronic phases of allergy. It was, therefore, investigated whether eosinophils can produce SCF and consequently influence mast cells. Human peripheral blood eosinophils variably expressed mRNA for the soluble and uncleaved forms of SCF (reverse transcription-polymerase chain reaction) and produced the 18.5-kd protein backbone of SCF (Western blot analysis). After overnight incubation in medium, eosinophils also produced SCF of higher molecular weight (42-45 kd) that might represent its glycosylated forms. Eosinophils expressed cytoplasmic SCF that colocalized with major basic protein (confocal laser microscopy). Freshly isolated eosinophils contained 8.9 +/- 1.7 pg SCF/10(6) (mean +/- SEM; enzyme-linked immunosorbent assay). Although overnight incubation of the eosinophils in either culture medium or in phorbol 12-myristate 13-acetate-calcium ionophore did not cause the secretion of SCF, the addition of chymase induced SCF release. In summary, it was demonstrated that human peripheral blood eosinophils are a source of SCF. These results may contribute to a better understanding of the interactions between eosinophils and mast cells in allergic inflammation.

Blood Proteins↗

PubMed1999

Human mast cells produce and differentially express both soluble and membrane-bound stem cell factor.

Stem cell factor (SCF), characterized as mast cell growth factor, is known to be produced by fibroblasts, keratinocytes and endothelial cells. Two different splice variants encode for either a soluble (SCF-1) or a membrane-bound (SCF-2) form. In order to explore whether mast cells themselves can produce SCF, we examined cultured cord blood (CBMC) and peripheral-blood-derived mast cells (PBMC), mast/basophil cell lines (HMC-1 and KU-812), and skin mast cells for SCF expression. On immunocytochemistry, cytoplasmatic SCF-reactivity was observed in HMC-1 cells, with additional cell membrane staining in KU-812, skin and cultured mast cells. Low amounts of SCF could be detected by ELISA in lysates of isolated and unstimulated mast cells and in supernatants of skin cells stimulated with anti-IgE or Ca-ionophore A23187. SCF mRNA was detected in all cells, although marked quantitative differences were observed among the various cell types. SCF-2 mRNA expression was low in HMC-1 cells while it was marked in skin mast cells, KU-812 cells, CBMC and PBMC. A time-dependent, increasing induction of both SCF forms was seen in CBMC and PBMC during culture. After stimulation with A23187 and phorbol myristate acetate, an up-regulation of SCF mRNA was noted in HMC-1 and KU-812 cells, without changes in the relationship of the two splice variants. The differential expression of SCF-specific mRNA splice variants in immature and mature human mast cells and the secretion of this molecule by these cells may play a role in autocrine stimulation, maintenance of survival and the differentiation of tissue mast cells.

Cell Line↗