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

In order to elucidate the pathologic significance of the bone marrow (BM) microenvironment in multiple myeloma (MM) and rheumatoid arthritis (RA), we established patient- or healthy donor (HD)-derived BM stromal cell lines by transfecting the plasmid for expression of SV40 large T Ag and examined their ability to support the stromal cell-dependent growth of a pre-B cell line, DW34. The means of recovered cell numbers of DW34 co-cultured with MM- and RA-derived BM stromal cell lines ranged from 6- to 10-fold more than those with HD-derived ones. Their enhanced ability to support DW34 cell growth was not caused by cytokines, including IL-6, IL-7, and c-kit ligand, although exogenous IL-7 could augment the growth-supporting ability. DW34 cell growth on the stromal cell lines was abolished by inhibiting cell-to-cell interaction with a membrane filter. FACS analysis revealed that the stromal cell lines did not express LFA-1 alpha, beta, NCAM, or ELAM-1. Both patient and HD BM stromal cell lines variably expressed ICAM-1, VCAM-1, and CD44. However, surface expression levels of these molecules did not correlate with the ability of the stromal cell lines to support DW34 cell growth. Taken together, these results suggested that BM microenvironment might play important roles in the pathogenesis of MM and RA.
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PMID:Human bone marrow stromal cell lines from myeloma and rheumatoid arthritis that can support murine pre-B cell growth. 128 Dec 1

Stem cell factor (SCF) is a hematopoietic growth factor produced by fibroblasts and endothelial cells that stimulates the growth of primitive hematopoietic cells. SCF triggers cell growth by binding to the c-kit receptor. Because endothelial cells can respond to certain hematopoietic growth factors, we tested human umbilical vein endothelial cells for display of the c-kit receptor and examined the effect of SCF on endothelial cell proliferation, adhesion molecule expression, and production of tissue factor. Quantitative binding experiments with 125I-SCF showed both high-affinity (Kd = 42 pmol/L) and low-affinity (Kd = 1.7 nmol/L) c-kit receptors. There were approximately 1,100 high-affinity c-kit receptors, and 5,400 low-affinity c-kit receptors per endothelial cell. Enzyme immunoassays showed that endothelial cells released soluble c-kit receptor and SCF. The transmembrane form of SCF was detected by indirect immunofluorescence analysis using monoclonal or polyclonal anti-SCF receptor antibodies. The addition of SCF (100 ng/mL) did not alter endothelial cell proliferation over a 7-day period. Similarly, there was no change in the release of tissue factor or expression of inducible endothelial adhesion molecules (intercellular adhesion molecule-1, endothelial-leukocyte adhesion molecule-1, and vascular cell adhesion molecule-1) measured by enzyme-linked immunosorbant assay at 4 and 24 hours after SCF addition. The neutralizing anti-c-kit receptor monoclonal antibody SR-1 blocked binding of 125I-SCF to the c-kit receptor by 98% but did not alter endothelial cell proliferation or adhesion-molecule expression. c-kit receptors were also detected on adult endothelial cells lining small blood vessels in normal human lymph nodes. These data indicate that normal human endothelial cells produce SCF and show high-affinity c-kit receptors that have the capacity to dimerize. The lack of response to exogenous SCF may be because of intracellular activation of the c-kit receptor via autocrine production of SCF. Alternatively, SCF and c-kit may play a role other than stimulation of proliferation, adhesion-molecule display, or tissue factor production by endothelial cells. The production of soluble c-kit receptors by normal human endothelial cells may serve to regulate the bioactivity of SCF within the bone marrow microenvironment.
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PMID:Human umbilical vein endothelial cells display high-affinity c-kit receptors and produce a soluble form of the c-kit receptor. 751 42

Regulation of development of hematopoietic stem cells was examined by culturing Lin- c-Kit+ Sca1+ stem cells sorted from bone marrow (BM) cells by fluorescence-activated cell sorting on a layer of TBR59, a BM stromal cell line established from simian virus 40 T-antigen gene transgenic mice. The sorted stem cells did not show self-renewal, but two waves (at 7 and 13 days) of a cobblestone formation were induced by the stromal cell layer. The cobblestones were formed by finite cell division (eight divisions on average) of sorted Lin- c-Kit+ Sca1+ stem cells, and divided cells were still immature. The c-Kithigh stem cell population was induced to form the first wave of cobblestone formation committed to myeloid lineage, whereas c-Kitlow population was induced to form the second wave of this formation committed to lymphoid lineage. Both cobblestone formations require c-Kit function, but very late activation antigen-4-vascular cell adhesion molecule-1 interaction plays different parts in the two lineages.
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PMID:Bone marrow stromal cells induce myeloid and lymphoid development of the sorted hematopoietic stem cells in vitro. 754 61

We have established nurse cell-like clones from long-term cultures of the human skin. These human skin nurse cell (HSNC)-like clones were type I collagen+, type IV collagen-, vimentin+, cytokeratin-, CD44+, CD54+, and weakly positive for VCAM-1, and easily identified by the pseudoemperipolesis that allowed T lymphocytes to migrate beneath the HSNCs. HSNCs and various T cell lines formed a typical complex in the hanging drop culture system. The majority of human and murine T cells, and some of the tumor cell lines other than T cells, including B lymphoma and myeloblastoma cells, migrated beneath the HSNC clones. HSNC clones produced various cytokines, including IL-6, IL-7, IL-8, IL-9, granulocyte CSF (G-CSF), granulocyte-macrophage CSF (GM-CSF), macrophage CSF (CSF-1), TGF-beta 1, and c-kit ligand, but could not produce IL-1 alpha, IL-1 beta, IL-2, IL-3, IL-4, TNF-alpha, or TNF-beta. These characteristics were similar to those of nurse cells established from the murine thymus. Furthermore, IFN-gamma-pretreated HSNC clones that expressed MHC class II Ags induced autologous mixed lymphocyte reaction (AMLR) in autologous PBMCs to proliferate and exhibit the cytotoxicity against altered autologous cells and various tumor cells. These results suggest that HSNCs play an important role in the immunoregulation at skin tissues.
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PMID:Establishment and characterization of nurse cell-like clones from human skin. Nurse cell-like clones can stimulate autologous mixed lymphocyte reaction. 808 78

A mouse spleen stromal cell line, MSS62, can create an in vitro erythropoietic microenvironment in which development of erythropoietin-responsive progentor cells is stimulated by cell-cell contact via stem cell factor (SCF)/c-Kit and vascular cell adhesion molecule-1 (VCAM-1)/very late activation antigen-4 (VLA-4) interactions between stromal and erythroid cells. To find out the effect of src on the erythropoietic microenvironment, MSS62 cells were transfected with v-src oncogene, and its effect on erythropoietic stimulatory activity was measured. Transfectants with high v-Src activity showed reduction in erythropoietic stimulatory activity. A decrease in cell-surface VCAM-1 and SCF mRNA was accompanied by high v-Src activity. These results suggest that v-Src interferes with the erythropoietic stimulatory activity of the stromal cells through repression of VCAM-1 and SCF.
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PMID:v-src interferes with the in vitro erythropoietic stimulatory ability of spleen stromal cells through repression of vascular cell adhesion molecule-1 and stem cell factor. 869 46

Bone marrow microvascular endothelial cells (BMEC) are a functional component of the bone marrow stroma and have been shown to release hematopoietic regulatory factors as well as to selectively adhere and support the proliferation and differentiation of CD34+ hematopoietic progenitors. An early passage of these cells was immortalized by transfection with a vector (pSVT) encoding the large T antigen of SV40. The transformed cell line (CDC/CU.BMEC-1) expresses the SV40 transcript, retains the primary cell expression of Ulex europeaus and vWF/ FVIII, and incorporates acetylated low-density lipoprotein. In addition, BMEC-1 mirrors the phenotype of the primary cells with only a few exceptions. Both cell populations express the cellular adhesion molecules ICAM-1 and PECAM and also VCAM-1 and ELAM-1 after upregulation by tumor necrosis factor-alpha. The fibronectin receptor, hyaluronate receptor, collagen receptor, integrins VLA-alpha 3, VLA-alpha 4, and beta 4, endoglin, collagen IV, CD58, and CD61 are also expressed. The only differences are that BMEC-1 expresses higher levels of ICAM-1, CD58, CD34, CD36, and c-kit than the primary cells. The supernatants of primary cell and BMEC-1 contain stem cell factor, interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-1 alpha, IL-11, and G-CSF. The functional significance of these hematopoietic cytokines was demonstrated in transwell cultures. Both cell populations supported the expansion of progeny from CD34+ cell-enriched cord blood mononuclear cells suspended in the upper chamber. These characteristics, plus the fact that BMEC-1 can be maintained independently of exogenous growth factors and exhibit contact inhibition, indicate that this cell line can be used to further define the role of BMEC in hematopoiesis.
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PMID:BMEC-1: a human bone marrow microvascular endothelial cell line with primary cell characteristics. 895 64

We have characterized the adhesion molecule HEMCAM, which is expressed by hemopoietic progenitors of embryonic bone marrow. HEMCAM belongs to the immunoglobulin superfamily and consists of the V-V-C2-C2-C2 Ig domains. There are three mRNA splice variants. One has a short cytoplasmic tail; another has a long tail; while the third seems to lack transmembrane and cytoplasmic regions. Except for the NH2-terminal sequence, HEMCAM is identical to gicerin, a molecular involved in neurite outgrowth and Wilm's kidney tumor progression in the chicken and it is significantly homologous with MUC18 a molecule involved in melanoma progression and metastasis in human beings. In the bone marrow the HEMCAM+ cell population contains c-kit+ subsets. HEMCAM+ cells coexpressing the receptor tyrosine kinase c-kit give rise to T cells at a frequency of 0.17 when injected intrathymically in congenic animals. As HEMCAM+, c-kit+ cells differentiate into myeloid and erythroid CFU's the double-positive cell population seems to contain precursors for multiple lineages. HEMCAM promotes cell-cell adhesion of transfected cells. Cross-linking of murine HEMCAM leads to cell spreading of T-lymphocyte progenitors adhering to the vascular adhesion molecules, PECAM-1 and VCAM-1. Thus, HEMCAM is likely to be involved in cellular adhesion and homing processes.
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PMID:HEMCAM, an adhesion molecule expressed by c-kit+ hemopoietic progenitors. 897 30

The alpha 4 beta 1 integrin very late activation antigen-4 (VLA-4) has been implicated to play a role in the adhesive interactions between hematopoietic progenitor cells (HPC) and bone marrow stromal cells which express the vascular cell adhesion molecule-1 (VCAM-1) or produce fibronectin (FN). Here, we summarize some of the recent advances made in the elucidation of the role of these particular adhesive interactions for the regulation of normal hematopoiesis. HPC bind to stroma mainly through VLA-4/VCAM-1 interactions. There is evidence which suggests that more primitive HPC constitutively express VLA-4 in a high-affinity state. In vitro studies in the mouse have shown that monoclonal antibodies (mAb) against VLA-4 partly block the development of lymphocytes, myelopoietic cells, and erythropoiesis, whereas in the human system outgrowth of TdT+ B cells is severely retarded by such mAb. In vivo studies revealed that VLA-4 is involved in erythropoietic development, and is particularly important for homing and lodgement of HPC in the bone marrow. Hematopoiesis in mice with deficient expression of alpha 4 integrin or VLA-4's ligand VCAM-1 appears to develop normally. However, chimeras developed from wild-type blastocysts and beta 1 -/- embryonic stem cells do not contain beta 1 -/- hematopoietic cells, although these are present as blood islands in the yolk sac. These beta 1 -/- hematopoietic cells are capable of forming colonies, indicating that beta 1-integrin is not involved in hematopoietic differentiation, but is primarily important for migration of hematopoietic cells into the fetal hematopoietic organs. In addition to the role of VLA-4 in migration, it may also have other regulatory functions. It has been demonstrated that ligation of VLA-4 induces phosphorylation of the protein tyrosine kinase (PTK) pp125FAK as well as other proteins which may be involved in the regulation of ligand affinity. Indeed, it has been shown that tyrosine kinase-dependent stimulation of CD34+ hematopoietic cell lines with c-kit ligand (KL), IL-3 or GM-CSF transiently activates the ability of VLA-4 to bind to VCAM-1 or FN. These events are most probably involved in the induction of quiescence in HPC which adhere to stromal cells. This claim was recently substantiated: when HPC were treated with Fab fragments of an anti-VLA-4 mAb, entry into S-phase of the cell cycle was prevented. Taken together, the present data point to a role for VLA-4 in HPC migration, cell cycle regulation, erythropoiesis and B-lymphopoiesis. Moreover, these insights may explain how defects in adhesive behavior of leukemic HPC through VLA-4 contribute to their dysregulated growth and provide a rationale for therapeutically correcting those defects.
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PMID:VLA-4-mediated interactions between normal human hematopoietic progenitors and stromal cells. 908 34

We evaluated mature peripheral blood eosinophils for their expression of the surface tyrosine kinase, c-kit, the receptor for the stromal cell-derived cytokine, stem cell factor (SCF). Cytofluorographic analysis revealed that c-kit was expressed on the purified peripheral blood eosinophils from 8 of 8 donors (4 nonatopic and 4 atopic) (mean channel fluorescence intensity 2.0- 3. 6-fold, average 2.8 +/- 0.6-fold, greater than the negative control). The uniform and selective expression of c-kit by eosinophils was confirmed by immunohistochemical analysis of peripheral blood buffy coats. The functional integrity of c-kit was demonstrated by the capacity of 100 ng/ml (5 nM) of recombinant human (rh) SCF to increase eosinophil adhesion to 3, 10, and 30 microg/ml of immobilized FN40, a 40-kD chymotryptic fragment of plasma fibronectin, in 15 min by 7.7 +/- 1.4-, 5.3 +/- 3.3-, and 5.4 +/- 0. 2-fold, respectively, and their adhesion to 0.1, 0.5, and 1.0 microg/ml vascular cell adhesion molecule-1 (VCAM-1), by 12.7 +/- 9. 2-, 3.8 +/- 2.5-, and 1.7 +/- 0.6-fold, respectively. The SCF-stimulated adhesion occurred without concomitant changes in surface integrin expression, thereby indicating an avidity-based mechanism. rhSCF (100 ng/ml, 5 nM) was comparable to rh eotaxin (200 ng/ml, 24 nM) in stimulating adhesion. Cell adhesion to FN40 was completely inhibited with antibodies against the alpha4 and beta1 integrin subunits, revealing that the SCF/c-kit adhesion effect was mediated by a single integrin heterodimer, very late antigen 4 (VLA-4). Thus, SCF represents a newly recognized stromal ligand for the activation of eosinophils for VLA-4-mediated adhesion, which could contribute to the exit of these cells from the blood, their tissue localization, and their prominence in inflammatory lesions.
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PMID:Human peripheral blood eosinophils express a functional c-kit receptor for stem cell factor that stimulates very late antigen 4 (VLA-4)-mediated cell adhesion to fibronectin and vascular cell adhesion molecule 1 (VCAM-1). 922 61

Effective hematopoiesis is usually induced by interactions between hematopoietic progenitor cells (HPC) and stromal cells. In cord blood (CB), umbilical vein endothelial cells (HUVEC) can support HPC as a stromal microenvironment. EC activated mainly by IL-1 and TNFalpha produce a variety of cytokines and growth factors such as IL-1, IL-4, IL-6, GM-CSF and G-CSF. Since HPC express c-kit on their surface, the SCF produced by HUVEC plays an important role in the hematopoiesis of CB. We examined the expression of cytokines and growth factors on HUVEC by PCR. Resting HUVEC expressed high level of SCF, and low levels of IL-6, IL-7, and IL-8. Thus, a variety of cytokines and growth factors are produced by EC, and this cytokine network is thought to play an important role in regulating hematopoiesis. Activated EC can also express various adhesion molecules including E-selectin, VCAM-1 and ICAM-1, and facilitate the adhesion of hematopoietic cells to the endothelium. Furthermore, the interaction of CB cells with HUVEC has recently been shown in vitro. We previously showed that the culture media of HUVEC induced high numbers of colony formation. Suitable cytokine productions are thus provided to HPC by the interaction of HUVEC and cord MNC. On the basis of these findings, several mechanisms to support hematopoiesis in CB can be considered. Specific growth factors produced by EC bind to HPC to induce proliferation. While cell-cell interactions involve adhesion of HPC to HUVEC via adhesion molecules, and the adhesion of HPC to EC will facilitate interaction with cytokines and growth factors. Thus HPC in CB proliferate and are maintained by growth factors, and adhesion molecules produced by HUVEC, and HPC themselves.
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PMID:Role of umbilical vein endothelial cells in hematopoiesis. 972 Jul 15


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