Role of hematopoietic microenvironment in prolonged impairment of B cell regeneration in age-related stromal-cell-impaired SAMP1 mouse: effects of a single dose of 5-fluorouracil

2008 ◽  
Vol 28 (6) ◽  
pp. 797-805 ◽  
Author(s):  
Isao Tsuboi ◽  
Yoko Hirabayashi ◽  
Tomonori Harada ◽  
Morimichi Koshinaga ◽  
Tatsuro Kawamata ◽  
...  
Keyword(s):  
Single Dose ◽  
B Cell ◽  
Stromal Cell ◽  
Cell Regeneration ◽  
Hematopoietic Microenvironment ◽  
Age Related ◽  
Samp1 Mouse

Age-related decline of mast cell regeneration in senescence-accelerated mice (SAMP1) after chemical myeloablation due to senescent stromal cell impairment

2012 ◽  
Vol 237 (11) ◽  
pp. 1289-1297 ◽  
Author(s):  
Isao Tsuboi ◽  
Tomonori Harada ◽  
Yoko Hirabayashi ◽  
Jun Kanno ◽  
Tohru Inoue ◽  
...  
Keyword(s):  
Mast Cell ◽  
Stromal Cell ◽  
Cell Regeneration ◽  
Age Related ◽  
Senescence Accelerated Mice

Comprehensive Analysis of the Waldenström Macroglobulinemia “Cytokine Milieu” Reveals a Novel Role of Rantes Signaling in the Regulation of Immunoglobulin Production

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 618-618
Author(s):  
Sherine F. Elsawa ◽  
Anne J. Novak ◽  
Steven C Ziesmer ◽  
Luciana L Almada ◽  
Martin E Fernandez-Zapico ◽  
...  
Keyword(s):  
Transcription Factors ◽  
B Cells ◽  
B Cell ◽  
Stromal Cells ◽  
Binding Sites ◽  
Stromal Cell ◽  
Malignant Cells ◽  
Reporter Construct ◽  
Stimulation Of

Abstract Waldenström macroglobulinemia (WM) is a B-cell malignancy characterized by the aberrant production of a monoclonal IgM protein that may lead to hyperviscosity. Although this is a major factor causing significant morbidity in patients, little is known about the mechanisms that regulate monoclonal protein synthesis. Cytokines are protein mediators that are known to be involved in many biological processes, and can profoundly affect tumor cells and the tumor microenvironment. Many cytokines have been shown to have potent therapeutic efficacy in preclinical cancer models; however, the role of cytokine networks in WM is not fully understood and few studies have described the precise functional roles of cytokines in WM. To address this issue we performed a multiplex ELISA analysis to test cytokine levels in sera from patients with WM. We found that Rantes/CCL5 is significantly elevated in WM patients and correlates with disease activity. Elevated expression of RANTES in the serum was confirmed by ELISA and was also detected in the bone marrow of WM patients by ELISA and immunohistochemistry. RANTES expression serves as a marker for recruitment of immune cells and is associated with a wide range of immune-mediated diseases. However, the impact of RANTES in WM is not known. We analyzed the expression of receptors for Rantes by flow cytometry and found that WM B cells and stromal cells express CCR1 and CCR3, but not CCR5. Using a standard chemotaxis assay, we determined that Rantes had no effect on B cell or stromal cell recruitment. Rantes also had no effect on B cell or stromal cell survival, however it did promote stromal cell proliferation (p<0.04). The interaction between Rantes and IL-6 has been described in an autoimmune disease model. Since stromal cells secrete significantly more IL-6 than WM B cells, we treated stromal cells with Rantes for 24 hr and found that Rantes increases IL-6 secretion (p<0.03). To characterize the mechanism of Rantes-mediated IL-6 secretion, we transfected stromal cells with an IL-6 promoter construct and treated with Rantes for 12 hr and found a significant increase in IL-6 promoter activity (p<0.0162) indicating Rantes can regulate IL-6 transcription. Bioinformatics analysis of the IL-6 promoter indicates the presence of multiple candidate binding sites for transcription factors that have been previously shown to play a role in the biology of B cells, including NFkB, AP1, and GLI. Co-transfection of stromal cells with an IL-6 reporter construct and a plasmid expressing GLI1, GLI2 or GLI3 demonstrates that GLI2 and GLI3 proteins can regulate the IL-6 promoter. We then transfected stromal cells with a reporter construct containing 8X-GLI binding sites and demonstrate that Rantes can regulate GLI transcription further supporting a role for the interaction between Rantes and IL-6 through GLI transcription factors. IL-6 rich tumor microenvironment supports malignant cells. Elevated IL-6 levels have no effect on survival of BCWM.1 cells or CD19+ 138+ cells from WM patients, but leads to upregulation of IgM secretion by BCWM.1 cells and CD19+ CD138+ cells from WM patients, and increases their proliferation (p<0.0039). IL-6 activates Erk1/2 and Jak/ Stat in WM and stimulation of the IgM secreting cells BCWM.1 with IL-6 in the presence of PD98059 MAPK inhibitor had no effect on IgM secretion. However, stimulation of BCWM.1 cells with IL-6 in the presence of JakI inhibitor abolished the IL-6 mediated IgM secretion suggesting IL-6 mediated increase in IgM secretion occurs through Jak/ Stat signaling pathway. Analysis of Rantes levels in other B cell malignancies including follicular lymphoma, chronic lymphocytic leukemia, monoclonal gammopathy of undetermined significance and multiple myeloma indicates that Rantes is elevated in other B cell lymphoproliferative disorders and suggest Rantes may play a similar role in other malignancies. In summary, our data identifies a novel Rantes-GLI-IL-6 interplay in the stromal microenvironment that promotes IgM production by malignant B cells. This therefore provides multiple new potential therapeutic avenues, targeting both malignant cells and the microenvironment to control malignant cell growth, and immunoglobulin secretion in WM and Ig-mediated diseases.

THE ROLE OF THE OESTROGEN SECRETED BEFORE OESTRUS IN THE PREPARATION OF THE UTERUS FOR IMPLANTATION IN THE MOUSE

1970 ◽  
Vol 47 (4) ◽  
pp. 431-438 ◽  
Author(s):  
C. A. FINN ◽  
L. MARTIN
Keyword(s):  
Single Dose ◽  
Cell Division ◽  
Epithelial Cells ◽  
Stromal Cells ◽  
Cellular Response ◽  
Stromal Cell ◽  
Abrupt Change ◽  
Maximal Effect ◽  
Ovariectomized Mice

SUMMARY Priming of ovariectomized mice with 0·1 μg. oestradiol-17β for 3 days modified the subsequent cellular response of the uterus to oestrogen and progesterone. A single dose of oestradiol-17β (0·02 μg.), or progesterone (1 mg.), or of both hormones given simultaneously, stimulated mitosis in the epithelial cells of the endometrium (although not in the stromal cells). However, the same hormones administered to primed mice stimulated considerable stromal cell division and reduced epithelial mitosis. The maximal effect was found when both hormones were given on the 4th day after the end of priming. It is suggested that the priming of the uterus by oestrogen secreted by the ovary before mating is concerned in the abrupt change from epithelial to stromal cell division that occurs between days 3 and 4 of pregnancy, and is of importance in the sensitization of the uterus for implantation.

scholarly journals Differential roles of stromal cells, interleukin-7, and kit-ligand in the regulation of B lymphopoiesis

Blood ◽  
1992 ◽  
Vol 79 (5) ◽  
pp. 1185-1192 ◽  
Author(s):  
LG Billips ◽  
D Petitte ◽  
K Dorshkind ◽  
R Narayanan ◽  
CP Chiu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cell ◽  
Cell Line ◽  
Stromal Cells ◽  
Stromal Cell ◽  
Kit Ligand ◽  
Interleukin 7 ◽  
Stromal Cell Line ◽  
Differentiation And Proliferation

Abstract Newly formed B lymphocytes are a population of rapidly renewed cells in the bone marrow of mammals and their steady state production presumably depends on a cascade of regulatory cells and cytokines. Although considerable information has been forthcoming about the role of interleukin-7 (IL-7) in potentiating pre-B-cell proliferation, few studies have addressed the possibility that multiple cytokines are involved in the progression of early events in cellular differentiation and proliferation in this hematopoietic lineage. Our laboratory previously described pre-B-cell differentiation mediated by the bone marrow stromal cell line S17. In this study, we further delineate the role of stromal cells in differentiation and proliferation of pre-B cells. These experiments show that the stromal cell line S17 potentiates the proliferative effect of IL-7 on B-lineage cells and that this S17-derived potentiator can be replaced with recombinant kit- ligand (KL). Our results further show that pre-B-cell formation from B220-, Ig- progenitor cells and expression of mu heavy chain of immunoglobulin is uniquely dependent on the presence of S17 stromal cells and cannot be reproduced with IL-7, KL, or costimulation with both IL-7 and KL. These data contribute to a rapidly evolving model of stromal cell regulation of B-cell production in the marrow and suggest unique roles for IL-7, KL, and as yet uncharacterized stromal cell- derived lymphokines in this process.

Re-Examining the Role of IL-7 in Human B Lymphopoiesis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 338-338
Author(s):  
Sonja E. Johnson ◽  
Nisha Shah ◽  
Timothy Singleton ◽  
Angela Panoskaltsis-Mortari ◽  
Tucker W. LeBien
Keyword(s):  
B Cell ◽  
Stromal Cells ◽  
Stromal Cell ◽  
B Cell Development ◽  
B Lymphopoiesis ◽  
Alpha Chain ◽  
B Lineage ◽  
Human B Cell ◽  
B Lineage Cells

Abstract The role of IL-7 in human B-cell development is still not well understood in contrast to its role in murine B-cell development. Adult mice with targeted disruptions in the IL-7 receptor (R) alpha chain or IL-7 genes completely lack B-lineage cells, while human severe combined immunodeficiency (SCID) patients with mutations in the IL-7R alpha chain have normal numbers of circulating B-lymphocytes. The goal of this study was to re-examine the functional consequences of IL-7R signaling in human B-cell precursors. This was accomplished using a xenogeneic culture system consisting of human CD34+ cord blood hematopoietic stem cells (HSC) plated on the MS-5 murine stromal cell line supplemented with G-CSF and SCF. Following the robust development of monocyte-like precursors and cells encompassing the later stages of granulocyte differentiation by 2 weeks, cells that emerged at 2.5–4 weeks were phenotypically pro-B cells (CD19+/CD10+/CD20lo/CD22+/CD24+/CD34-/pre-BCR-). The pro-B cells harbored functional heavy chain rearrangements, since re-plating them on MS-5 stromal cells supplemented with anti-CD40 and IL-4 led to the development of pre-BCR+ cells. CD19+ cells purified from HSC/MS-5 cultures underwent rapid cell death within 24 hours, and IL-7 had minimal effect on survival. Purified CD19+ cells re-plated in direct contact with MS-5 stromal cells survived for 7–10 days, but did not proliferate. However, addition of human (h) IL-7 from 0.01 to 10 ng/mL promoted dose-dependent proliferation of CD19+ cells re-plated on MS-5. Approximately one-third of the CD19+ cells that emerged at 2.5–4 weeks expressed the IL-7R. FACS-purified IL-7R+/CD19+ cells were larger and proliferated on MS-5 in response to hIL-7, while IL-7R-/CD19+ cells were smaller and did not expand on MS-5 after stimulation with hIL-7. These results suggested that the IL-7R+/CD19+ cells that emerged in the HSC/MS-5 culture might be responding to murine (m) IL-7 produced by MS-5. In order to determine if endogenous IL-7 could be contributing to B-lymphopoiesis, murine and human-specific ELISAs were used to screen HSC/MS-5 culture supernatants. Supernatants from 3 and 4 week HSC/MS-5 cultures contained 20–30 pg/mL mIL-7 and 0.1–2.0 pg/mL hIL-7. Analysis of the kinetics of mIL-7 accumulation in steady-state cultures of confluent MS-5 (no HSC present) showed an increase from 8.0 pg/mL at 2 days, to nearly 150 pg/mL after 2.5 weeks. Flow cytometric analysis of STAT5 phosphorylation in IL-7R+/CD19+ cells demonstrated that hIL-7 and mIL-7 were capable of transducing a signal through the human IL-7R resulting in STAT5 phosphorylation. Furthermore, a monoclonal antibody to the human IL-7R alpha chain blocked STAT5 phosphorylation by both hIL-7 and mIL-7. Inclusion of goat anti-mouse IL-7 neutralizing antibody in HSC/MS-5 cultures effectively reduced the concentration of bioactively available mIL-7 to less than 6 pg/mL. This resulted in a 33% and 67% reduction in the number of CD19+ cells by 3 and 4 weeks, respectively. These collective results are the first to reveal a crucial role for stromal cell-derived IL-7 in promoting the proliferative expansion of human CD19+ B-lineage cells, and support a model wherein IL-7 can transduce a proliferative/replicative signal that cooperates with a stromal cell-derived co-stimulus to regulate development of human B-lineage cells.

scholarly journals Differential roles of stromal cells, interleukin-7, and kit-ligand in the regulation of B lymphopoiesis

Blood ◽  
1992 ◽  
Vol 79 (5) ◽  
pp. 1185-1192 ◽  
Author(s):  
LG Billips ◽  
D Petitte ◽  
K Dorshkind ◽  
R Narayanan ◽  
CP Chiu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cell ◽  
Cell Line ◽  
Stromal Cells ◽  
Stromal Cell ◽  
Kit Ligand ◽  
Interleukin 7 ◽  
Stromal Cell Line ◽  
Differentiation And Proliferation

Newly formed B lymphocytes are a population of rapidly renewed cells in the bone marrow of mammals and their steady state production presumably depends on a cascade of regulatory cells and cytokines. Although considerable information has been forthcoming about the role of interleukin-7 (IL-7) in potentiating pre-B-cell proliferation, few studies have addressed the possibility that multiple cytokines are involved in the progression of early events in cellular differentiation and proliferation in this hematopoietic lineage. Our laboratory previously described pre-B-cell differentiation mediated by the bone marrow stromal cell line S17. In this study, we further delineate the role of stromal cells in differentiation and proliferation of pre-B cells. These experiments show that the stromal cell line S17 potentiates the proliferative effect of IL-7 on B-lineage cells and that this S17-derived potentiator can be replaced with recombinant kit- ligand (KL). Our results further show that pre-B-cell formation from B220-, Ig- progenitor cells and expression of mu heavy chain of immunoglobulin is uniquely dependent on the presence of S17 stromal cells and cannot be reproduced with IL-7, KL, or costimulation with both IL-7 and KL. These data contribute to a rapidly evolving model of stromal cell regulation of B-cell production in the marrow and suggest unique roles for IL-7, KL, and as yet uncharacterized stromal cell- derived lymphokines in this process.

The Response of Testes Cells to Low Level, Single dose Helium Particle Irradiation

1982 ◽  
Vol 40 ◽  
pp. 252-253
Author(s):  
D.E. Philpott ◽  
W. Sapp ◽  
C. Williams ◽  
J. Stevenson ◽  
S. Black ◽  
...  
Keyword(s):  
Stem Cell ◽  
Single Dose ◽  
B Cell ◽  
Cell Survival ◽  
Spermatogonial Stem Cell ◽  
Low Doses ◽  
Particle Irradiation ◽  
Stem Cell Survival ◽  
Irradiation Injury ◽  
Radio Sensitivity

Spermatogonial stem-cell survival after irradiation injury has been studied in rodents by histological counts of surviving cells. Many studies, including previous work from our laboratory, show that the spermatogonial population demonstrates a heterogeneous response to irradiation. The spermatogonia increase in radio-sensitivity as differentiation proceeds through the sequence As - Apr - A1 - A2 - A3 - A4 - In - B. The stem (As) cell is the most resistant and the B cell is the most sensitive. The purpose of this work is to investigate the response of spermatogonial cell to low doses (less than 10 0 rads) of helium particle irradiation.

Age-related memory deficit: Role of study time and encoding strategies

2010 ◽  
Author(s):  
Charlotte Froger ◽  
Badiaa Bouazzaoui ◽  
Laurence Taconnat
Keyword(s):  
Memory Deficit ◽  
Study Time ◽  
Age Related ◽  
Encoding Strategies
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