scholarly journals Cytokine Receptor Expression on Hematopoietic Stem and Progenitor Cells

Blood ◽  
1997 ◽  
Vol 89 (1) ◽  
pp. 65-71 ◽  
Author(s):  
William J. McKinstry ◽  
Chung-Leung Li ◽  
John E.J. Rasko ◽  
Nicos A. Nicola ◽  
Gregory R. Johnson ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Population ◽  
Progenitor Cell ◽  
Cell Populations ◽  
Colony Stimulating Factor ◽  
Hematopoietic Stem ◽  
Gm Csf ◽  
Macrophage Colony ◽  
Stimulating Factor

Hematopoietic stem and progenitor cell populations were obtained by fluorescence activated cell sorting of murine bone marrow (BM) cells into Rhodamine-123lo lineage−Ly6A/E+ c-kit+ (primitive stem cells highly enriched for long-term BM repopulating activity), Rhodamine-123med/hi lineage− Ly6A/E+ c-kit+ (mature stem cells highly enriched for short-term BM repopulating activity and day 13 spleen colony-forming activity) and lineage− Ly6A/E− c-kit+ (enriched for in vitro colony forming cells) populations. Neither stem cell population responds to single cytokines in vitro and each requires the synergistic action of two or more cytokines for proliferation, whereas the progenitor cell population proliferates in response to single cytokines. Since each of these cell populations was sorted as c-kit+, they express receptors for stem cell factor. Cell populations were also analyzed by autoradiography for their ability to specifically bind iodinated cytokines and this revealed that both stem cell populations expressed receptors for interleukin-1α (IL-1α), IL-3, IL-6, and granulocyte colony-stimulating factor (G-CSF ), but lacked receptors for macrophage colony-stimulating factor (M-CSF ), granulocyte-macrophage colony stimulating factor (GM-CSF ), and leukemia inhibitory factor (LIF ). Cells within the progenitor cell population specifically bound IL-3, GM-CSF, G-CSF, IL-6, and IL-1α, whereas no receptors were detected for M-CSF and LIF. Within each cell population examined, heterogeneity was observed in the percentage of cells labeled and the number of receptors per cell. These results suggest that stem cell populations can be further subdivided according to their cytokine receptor profile and it will be of interest to determine if such subpopulations have distinctive functional properties.

scholarly journals Cytokine Receptor Expression on Hematopoietic Stem and Progenitor Cells

Blood ◽  
1997 ◽  
Vol 89 (1) ◽  
pp. 65-71 ◽  
Author(s):  
William J. McKinstry ◽  
Chung-Leung Li ◽  
John E.J. Rasko ◽  
Nicos A. Nicola ◽  
Gregory R. Johnson ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Population ◽  
Progenitor Cell ◽  
Cell Populations ◽  
Colony Stimulating Factor ◽  
Hematopoietic Stem ◽  
Gm Csf ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract Hematopoietic stem and progenitor cell populations were obtained by fluorescence activated cell sorting of murine bone marrow (BM) cells into Rhodamine-123lo lineage−Ly6A/E+ c-kit+ (primitive stem cells highly enriched for long-term BM repopulating activity), Rhodamine-123med/hi lineage− Ly6A/E+ c-kit+ (mature stem cells highly enriched for short-term BM repopulating activity and day 13 spleen colony-forming activity) and lineage− Ly6A/E− c-kit+ (enriched for in vitro colony forming cells) populations. Neither stem cell population responds to single cytokines in vitro and each requires the synergistic action of two or more cytokines for proliferation, whereas the progenitor cell population proliferates in response to single cytokines. Since each of these cell populations was sorted as c-kit+, they express receptors for stem cell factor. Cell populations were also analyzed by autoradiography for their ability to specifically bind iodinated cytokines and this revealed that both stem cell populations expressed receptors for interleukin-1α (IL-1α), IL-3, IL-6, and granulocyte colony-stimulating factor (G-CSF ), but lacked receptors for macrophage colony-stimulating factor (M-CSF ), granulocyte-macrophage colony stimulating factor (GM-CSF ), and leukemia inhibitory factor (LIF ). Cells within the progenitor cell population specifically bound IL-3, GM-CSF, G-CSF, IL-6, and IL-1α, whereas no receptors were detected for M-CSF and LIF. Within each cell population examined, heterogeneity was observed in the percentage of cells labeled and the number of receptors per cell. These results suggest that stem cell populations can be further subdivided according to their cytokine receptor profile and it will be of interest to determine if such subpopulations have distinctive functional properties.

scholarly journals Tec kinase associates with c-kit and is tyrosine phosphorylated and activated following stem cell factor binding

1994 ◽  
Vol 14 (12) ◽  
pp. 8432-8437
Author(s):  
B Tang ◽  
H Mano ◽  
T Yi ◽  
J N Ihle
Keyword(s):  
Stem Cell ◽  
Stem Cell Factor ◽  
Colony Stimulating Factor ◽  
Hematopoietic Stem ◽  
Gm Csf ◽  
Amino Terminal ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Stem cell factor (SCF) plays a crucial role in hematopoiesis through its interaction with the receptor tyrosine kinase c-kit. However, the signaling events that are activated by this interaction and involved in the control of growth or differentiation are not completely understood. We demonstrate here that Tec, a cytoplasmic, src-related kinase, physically associates with c-kit through a region that contains a proline-rich motif, amino terminal of the SH3 domain. Following SCF binding, Tec is tyrosine phosphorylated and its in vitro kinase activity is increased. Tyrosine phosphorylation of Tec is not detected in the response to other cytokines controlling hematopoiesis, including colony-stimulating factor-1 (CSF-1), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-3 (IL-3). Conversely, the cytoplasmic kinase JAK2 is activated by IL-3 but not by SCF stimulation. The activation of distinct cytoplasmic kinases may account for the synergy seen in the actions of SCF and IL-3 on hematopoietic stem cells.

scholarly journals Tec kinase associates with c-kit and is tyrosine phosphorylated and activated following stem cell factor binding.

1994 ◽  
Vol 14 (12) ◽  
pp. 8432-8437 ◽  
Author(s):  
B Tang ◽  
H Mano ◽  
T Yi ◽  
J N Ihle
Keyword(s):  
Stem Cell ◽  
Stem Cell Factor ◽  
Colony Stimulating Factor ◽  
Hematopoietic Stem ◽  
Gm Csf ◽  
Amino Terminal ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Stem cell factor (SCF) plays a crucial role in hematopoiesis through its interaction with the receptor tyrosine kinase c-kit. However, the signaling events that are activated by this interaction and involved in the control of growth or differentiation are not completely understood. We demonstrate here that Tec, a cytoplasmic, src-related kinase, physically associates with c-kit through a region that contains a proline-rich motif, amino terminal of the SH3 domain. Following SCF binding, Tec is tyrosine phosphorylated and its in vitro kinase activity is increased. Tyrosine phosphorylation of Tec is not detected in the response to other cytokines controlling hematopoiesis, including colony-stimulating factor-1 (CSF-1), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-3 (IL-3). Conversely, the cytoplasmic kinase JAK2 is activated by IL-3 but not by SCF stimulation. The activation of distinct cytoplasmic kinases may account for the synergy seen in the actions of SCF and IL-3 on hematopoietic stem cells.

Phase I Study of Chimeric Human/Murine Anti–Ganglioside GD2Monoclonal Antibody (ch14.18) With Granulocyte-Macrophage Colony-Stimulating Factor in Children With Neuroblastoma Immediately After Hematopoietic Stem-Cell Transplantation: A Children’s Cancer Group Study

2000 ◽  
Vol 18 (24) ◽  
pp. 4077-4085 ◽  
Author(s):  
M. Fevzi Ozkaynak ◽  
Paul M. Sondel ◽  
Mark D. Krailo ◽  
Jacek Gan ◽  
Brad Javorsky ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Neuroblastoma Cells ◽  
Colony Stimulating Factor ◽  
Hematopoietic Stem ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

PURPOSE: Ganglioside GD2is strongly expressed on the surface of human neuroblastoma cells. It has been shown that the chimeric human/murine anti-GD2monoclonal antibody (ch14.18) can induce lysis of neuroblastoma cells by antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. The purposes of the study were (1) to determine the maximum-tolerated dose (MTD) of ch14.18 in combination with standard dose granulocyte-macrophage colony-stimulating factor (GM-CSF) for patients with neuroblastoma who recently completed hematopoietic stem-cell transplantation (HSCT), and (2) to determine the toxicities of ch14.18 with GM-CSF in this setting.PATIENTS AND METHODS: Patients became eligible when the total absolute phagocyte count (APC) was greater than 1,000/μL after HSCT. ch14.18 was infused intravenously over 5 hours daily for 4 consecutive days. Patients received GM-CSF 250 μg/m2/d starting at least 3 days before ch14.18 and continued for 3 days after the completion of ch14.18. The ch14.18 dose levels were 20, 30, 40, and 50 mg/m2/d. In the absence of progressive disease, patients were allowed to receive up to six 4-day courses of ch14.18 therapy with GM-CSF. Nineteen patients with neuroblastoma were treated.RESULTS: A total of 79 courses were administered. No toxic deaths occurred. The main toxicities were severe neuropathic pain, fever, nausea/vomiting, urticaria, hypotension, mild to moderate capillary leak syndrome, and neurotoxicity. Three dose-limiting toxicities were observed among six patients at 50 mg/m2/d: intractable neuropathic pain, grade 3 recurrent urticaria, and grade 4 vomiting. Human antichimeric antibody developed in 28% of patients.CONCLUSION: ch14.18 can be administered with GM-CSF after HSCT in patients with neuroblastoma with manageable toxicities. The MTD is 40 mg/m2/d for 4 days when given in this schedule with GM-CSF.

Effect of granulocyte-macrophage colony-stimulating factor on oral mucositis after hematopoietic stem-cell transplantation.

1994 ◽  
Vol 12 (9) ◽  
pp. 1917-1922 ◽  
Author(s):  
B Gordon ◽  
A Spadinger ◽  
E Hodges ◽  
E Ruby ◽  
R Stanley ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Oral Mucositis ◽  
Airway Compromise ◽  
Colony Stimulating Factor ◽  
Hematopoietic Stem ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

PURPOSE Oral mucositis following high-dose chemotherapy may result in systemic infection and airway compromise, and the severity of oral mucositis may be dose-limiting. Here we investigate the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF), which significantly shortens duration of neutropenia after hematopoietic stem-cell transplantation (HSCT) on oral mucositis. PATIENTS AND METHODS Thirteen children undergoing HSCT were prepared with etoposide (VP-16), thiotepa (TT), and total-body irradiation (TBI), and 13 with VP-16, TT, and cyclophosphamide (CPM). Following transplantation, 14 patients received GM-CSF at a dose of 125 micrograms/m2/d by continuous intravenous infusion (six prepared with VP-16, TT, and TBI, and eight prepared with VP-16, TT, and CPM), and 12 patients received no growth factor. RESULTS Mucositis was more severe and persisted longer in patients prepared with the TBI-containing regimen. For this regimen, the duration of severe oral mucositis was shortened by the administration of GM-CSF, although the severity of mucositis was unaffected. No statistically significant effect of GM-CSF could be shown in patients who received VP-16, TT, and CPM. The incidence of positive fungal oral or blood cultures did not appear different whether patients received GM-CSF or not. CONCLUSION For patients undergoing stomatotoxic HSCT regimens, GM-CSF may reduce the duration of oral mucositis, but is unlikely to effect the severity of oral mucositis or risk of airway compromise, and the severity of mucositis is likely to remain dose-limiting.

scholarly journals Enhanced expression of the granulocyte-macrophage colony stimulating factor gene in acute myelocytic leukemia cells following in vitro blast cell enrichment

Blood ◽  
1988 ◽  
Vol 72 (4) ◽  
pp. 1329-1332 ◽  
Author(s):  
DC Kaufman ◽  
MR Baer ◽  
XZ Gao ◽  
ZQ Wang ◽  
HD Preisler
Keyword(s):  
T Cell ◽  
Leukemic Cells ◽  
Acute Myelocytic Leukemia ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Myelocytic Leukemia ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Expression of the granulocyte-macrophage colony-stimulating factor (GM- CSF) gene in acute myelocytic leukemia (AML) was assayed by Northern blot analysis. GM-CSF messenger RNA (mRNA) was detected in the freshly obtained mononuclear cells of only one of 48 cases of AML, in contrast with recent reports that GM-CSF mRNA might be detected in half of the cases of AML when RNA is prepared from T-cell- and monocyte-depleted leukemic cells. We did find, however, that expression of the GM-CSF gene was detectable in five of ten cases after in vitro T-cell and monocyte depletion steps. Additional studies suggest that expression of GM-CSF in the bone marrow of the one positive case, rather than being autonomous, was under exogenous control, possibly by a paracrine factor secreted by marrow stromal cells. These studies emphasize the potential for altering in vivo patterns of gene expression by in vitro cell manipulation.

scholarly journals Dexamethasone and 1,25-dihydroxyvitamin D3, but not cyclosporine A, inhibit production of granulocyte-macrophage colony-stimulating factor in human fibroblasts

Blood ◽  
1991 ◽  
Vol 77 (9) ◽  
pp. 1912-1918 ◽  
Author(s):  
A Tobler ◽  
HP Marti ◽  
C Gimmi ◽  
AB Cachelin ◽  
S Saurer ◽  
...  
Keyword(s):  
Human Fibroblasts ◽  
Tnf Alpha ◽  
Colony Stimulating Factor ◽  
Dihydroxyvitamin D3 ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Csf Production

Abstract Tumor necrosis factor alpha (TNF alpha) stimulates granulocyte- macrophage colony-stimulating factor (GM-CSF) production in human fibroblasts and other mesenchymal cells. However, relatively little is known about agents that downregulate cytokine production in these cells. In the present report we show that dexamethasone (Dexa), a synthetic glucocorticoid, markedly reduced GM-CSF production in TNF alpha-stimulated fibroblasts at both the protein and the RNA levels. CSF activity, GM-CSF protein, and RNA levels, determined by an in vitro colony-forming assay in normal human bone marrow cells, by an enzyme immunoassay, and by Northern blotting assay, were reduced to greater than 90% of control values by Dexa (1 mumol/L). Similarly, 1,25- dihydroxyvitamin D3 [1,25(OH)2D3], a hormone with possible physiologic immunoregulatory significance, reduced GM-CSF expression in a concentration- and time-dependent manner. However, this repression was less pronounced than that of Dexa, and in part due to a decreased proliferative activity. In contrast, cyclosporine A (CsA), another immunosuppressive agent, did not alter GM-CSF expression in TNF alpha- stimulated fibroblasts. Our in vitro studies suggest that by inhibiting GM-CSF production in fibroblasts, glucocorticoids and possibly 1,25(OH)2D3, but not CsA, may attenuate TNF alpha-mediated inflammatory processes and influence the regulation of hematopoiesis.

scholarly journals Premature expression of the macrophage colony-stimulating factor receptor on a multipotential stem cell line does not alter differentiation lineages controlled by stromal cells used for coculture.

1991 ◽  
Vol 173 (5) ◽  
pp. 1267-1279 ◽  
Author(s):  
T Kinashi ◽  
K H Lee ◽  
M Ogawa ◽  
K Tohyama ◽  
K Tashiro ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stromal Cells ◽  
Signal Transduction Pathway ◽  
Transduction Pathway ◽  
Colony Stimulating Factor ◽  
Stem Cell Line ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

We are interested to know whether expression of a lineage-specific growth factor receptor is deterministic to lineage commitment during hematopoiesis. For this purpose, we introduced the human c-fms gene into the multipotential stem cell clone LyD9 and two myeloid progenitor clones, L-GM3 and L-G3, cells that differentiate in response to granulocyte/macrophage colony-stimulating factor (GM-CSF) and granulocyte (G)-CSF, respectively. Although LyD9 cells have differentiation potential to become macrophages, c-fms transfectants of LyD9 and L-GM3 cells did not differentiate in response to human macrophage (M)-CSF. However, c-fms transfectants of L-G3 cells differentiated to neutrophils in response to human M-CSF. These results indicate that the M-CSF receptor requires a specific signal transduction pathway to exert its differentiational and proliferative effects. Furthermore, the M-CSF receptor can convey a granulocyte-type differentiation signal possibly by cooperating with the G-CSF receptor signal transduction pathway. The c-fms-transfected LyD9 cells as well as the original LyD9 cells differentiated predominantly into GM-CSF- and G-CSF-responsive cells by coculturing with PA6 and ST2 stromal cells, respectively. The results indicate that differentiation lineage is not affected by premature expression of the M-CSF receptor. Instead, the stromal cell used for coculture apparently controls lineage-selective differentiation of the multi-potential stem cell line.

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