scholarly journals Early CD34high cells can be separated into KIThigh cells in which transforming growth factor-beta (TGF-beta) downmodulates c-kit and KITlow cells in which anti-TGF-beta upmodulates c-kit

Blood ◽  
1995 ◽  
Vol 86 (5) ◽  
pp. 1729-1735 ◽  
Author(s):  
P Sansilvestri ◽  
AA Cardoso ◽  
P Batard ◽  
B Panterne ◽  
A Hatzfeld ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Receptor Gene ◽  
Specific Effect ◽  
Quiescent State ◽  
Tgf Beta ◽  
Hematopoietic Progenitors ◽  
Growth Factor Beta ◽  
Receptor Gene Expression

We have previously shown that early human CD34high hematopoietic progenitors are maintained quiescent in part through autocrine transforming growth factor-beta 1 (TGF-beta 1). We also demonstrated that, in the presence of interleukin-3, interleukin-6, granulocyte colony-stimulating factor, and erythropoietin, TGF-beta 1 antisense oligonucleotides or anti-TGF-beta serum have an additive effect with KIT ligand (Steel factor [SF]), which suggests that they control different pathways of regulation in these conditions. This finding also suggests that autocrine TGF-beta 1 might suppress c-kit expression in primitive human hematopoietic progenitors. We have now distinguished two subpopulations of CD34high cells. One subpopulation expresses a c- kit mRNA that can be downmodulated by exogenous TGF-beta 1 within 6 hours. Another subpopulation of early CD34high cells expresses a low or undetectable level of c-kit mRNA, but its expression can be upmodulated within 6 hours by anti-TGF-beta. These effects disappear 48 hours after induction and cannot be maintained longer than 72 hours, even if TGF- beta 1 or anti-TGF-beta serum are added every day. Similar kinetics, although delayed, are observed with KIT protein expression. On the contrary, no specific effect of TGF-beta 1 was observed on c-fms, GAPDH, and transferrin receptor gene expression in these early progenitors. These results clarify the complex interaction between TGF- beta 1 and SF in normal early hematopoietic progenitors. SF does not switch off the TGF-beta 1 inhibitory pathway. Autocrine TGF-beta 1 appears to maintain these cells in a quiescent state, suppressing cell division by downmodulating the receptor of SF, a key cytokine costimulator of early progenitors.

scholarly journals Release of early human hematopoietic progenitors from quiescence by antisense transforming growth factor beta 1 or Rb oligonucleotides.

1991 ◽  
Vol 174 (4) ◽  
pp. 925-929 ◽  
Author(s):  
J Hatzfeld ◽  
M L Li ◽  
E L Brown ◽  
H Sookdeo ◽  
J P Levesque ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Colony Formation ◽  
Transforming Growth Factor ◽  
Inhibitory Effect ◽  
Tgf Beta ◽  
Hematopoietic Progenitors ◽  
Single Cell Culture ◽  
Growth Factor Beta ◽  
Blocking Antibodies

We have used antisense oligonucleotides to study the roles of transforming growth factor beta (TGF-beta) and the two antioncogenes, retinoblastoma susceptibility (Rb) and p53, in the negative regulation of proliferation of early hematopoietic cells in culture. The antisense TGF-beta sequence significantly enhanced the frequency of colony formation by multi-lineage, early erythroid, and granulomonocytic progenitors, but did not affect colony formation by late progenitors. Single cell culture and limiting dilution analysis indicated that autocrine TGF-beta is produced by a subpopulation of early progenitors. Antisense Rb but not antisense p53 yielded similar results in releasing multipotential progenitors (colony-forming unit-granulocyte/erythroid/macrophage/megakaryocyte) from quiescence. Rb antisense could partially reverse the inhibitory effect of exogenous TGF-beta. Anti-TGF-beta blocking antibodies, antisense TGF-beta, or Rb oligonucleotides all had similar effects. No additive effects were observed when these reagents were combined, suggesting a common pathway of action. Our results are consistent with the model that autocrine production of TGF-beta negatively regulates the cycling status of early hematopoietic progenitors through interaction with the Rb gene product.

scholarly journals Transforming growth factor-beta potently inhibits the viability- promoting activity of stem cell factor and other cytokines and induces apoptosis of primitive murine hematopoietic progenitor cells

Blood ◽  
1995 ◽  
Vol 86 (8) ◽  
pp. 2957-2966 ◽  
Author(s):  
FW Jacobsen ◽  
T Stokke ◽  
SE Jacobsen
Keyword(s):  
Stem Cell ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Stem Cell Factor ◽  
Transforming Growth Factor ◽  
Present Report ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Tgf Beta ◽  
Hematopoietic Progenitors ◽  
Growth Factor Beta

In contrast with the extensively characterized effects of transforming growth factor-beta (TGF-beta) on proliferation and differentiation of hematopoietic progenitors, little is known about the effects of TGF-beta on viability of normal hematopoietic progenitors. In the present report, we demonstrate that TGF-beta potently counteracts hematopoietic growth factor (HGF)-induced survival of individually cultured primitive Lin-Sca-1+ bone marrow progenitors. Specifically, 74% of single Lin-Sca- 1+ cells cultured for 40 hours in the presence of stem cell factor (SCF) survived, whereas only 16% survived in the presence of SCF plus TGF-beta. Similarly, the enhanced survival of primitive hematopoietic progenitors in response to granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-1, IL-6, or IL-11 was also potently opposed by TGF-beta. Furthermore, it is demonstrated that neutralization of endogenous TGF-beta present in the cultures enhances survival of Lin- Sca-1+ progenitors in the absence, as well as in the presence, of HGFs such as SCF and IL-6. The reduced HGF-induced survival of primitive hematopoietic progenitors in the presence of TGF-beta was associated with increased apoptosis, as detected by an in situ terminal deoxynucleotidyl transferase (TdT) assay. After 16 hours of incubation in the absence of HGFs, 61% +/- 6% of the hematopoietic progenitors had DNA strand breaks characteristic of apoptosis. The presence of SCF reduced the frequency of apoptic cells to 27% +/- 5%, whereas 55% +/- 3% of the cells had signs of apoptosis in the presence of SCF plus TGF- beta.

scholarly journals Transforming growth factor-beta potently inhibits the viability- promoting activity of stem cell factor and other cytokines and induces apoptosis of primitive murine hematopoietic progenitor cells

Blood ◽  
1995 ◽  
Vol 86 (8) ◽  
pp. 2957-2966 ◽  
Author(s):  
FW Jacobsen ◽  
T Stokke ◽  
SE Jacobsen
Keyword(s):  
Stem Cell ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Stem Cell Factor ◽  
Transforming Growth Factor ◽  
Present Report ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Tgf Beta ◽  
Hematopoietic Progenitors ◽  
Growth Factor Beta

Abstract In contrast with the extensively characterized effects of transforming growth factor-beta (TGF-beta) on proliferation and differentiation of hematopoietic progenitors, little is known about the effects of TGF-beta on viability of normal hematopoietic progenitors. In the present report, we demonstrate that TGF-beta potently counteracts hematopoietic growth factor (HGF)-induced survival of individually cultured primitive Lin-Sca-1+ bone marrow progenitors. Specifically, 74% of single Lin-Sca- 1+ cells cultured for 40 hours in the presence of stem cell factor (SCF) survived, whereas only 16% survived in the presence of SCF plus TGF-beta. Similarly, the enhanced survival of primitive hematopoietic progenitors in response to granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-1, IL-6, or IL-11 was also potently opposed by TGF-beta. Furthermore, it is demonstrated that neutralization of endogenous TGF-beta present in the cultures enhances survival of Lin- Sca-1+ progenitors in the absence, as well as in the presence, of HGFs such as SCF and IL-6. The reduced HGF-induced survival of primitive hematopoietic progenitors in the presence of TGF-beta was associated with increased apoptosis, as detected by an in situ terminal deoxynucleotidyl transferase (TdT) assay. After 16 hours of incubation in the absence of HGFs, 61% +/- 6% of the hematopoietic progenitors had DNA strand breaks characteristic of apoptosis. The presence of SCF reduced the frequency of apoptic cells to 27% +/- 5%, whereas 55% +/- 3% of the cells had signs of apoptosis in the presence of SCF plus TGF- beta.

scholarly journals Identification of a novel transforming growth factor-beta (TGF-beta 5) mRNA in Xenopus laevis.

1990 ◽  
Vol 265 (2) ◽  
pp. 1089-1093 ◽  
Author(s):  
P Kondaiah ◽  
M J Sands ◽  
J M Smith ◽  
A Fields ◽  
A B Roberts ◽  
...  
Keyword(s):  
Growth Factor ◽  
Xenopus Laevis ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Tgf Beta ◽  
Growth Factor Beta

scholarly journals Recombinant type 1 transforming growth factor beta precursor produced in Chinese hamster ovary cells is glycosylated and phosphorylated.

1988 ◽  
Vol 8 (5) ◽  
pp. 2229-2232 ◽  
Author(s):  
A M Brunner ◽  
L E Gentry ◽  
J A Cooper ◽  
A F Purchio
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Chinese Hamster Ovary ◽  
Transforming Growth Factor ◽  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Tgf Beta ◽  
Ovary Cells ◽  
Growth Factor Beta

Analyses of cDNA clones coding for simian type 1 transforming growth factor beta (TGF-beta 1) suggest that there are three potential sites for N-linked glycosylation located in the amino terminus of the precursor region. Analysis of [3H]glucosamine-labeled serum-free supernatants from a line of Chinese hamster ovary cells which secrete high levels of recombinant TGF-beta 1 indicate that the TGF-beta 1 precursor, but not the mature form, is glycosylated. Digestion with neuraminidase resulted in a shift in migration of the two TGF-beta 1 precursor bands, which suggests that they contain sialic acid residues. Endoglycosidase H had no noticeable effect. Treatment with N-glycanase produced two faster-migrating sharp bands, the largest of which had a molecular weight of 39 kilodaltons. TGF-beta 1-specific transcripts produced by SP6 polymerase programmed the synthesis of a 42-kilodalton polypeptide which, we suggest, is the unmodified protein backbone of the precursor. Labeling with 32Pi showed that the TGF-beta 1 precursor was phosphorylated in the amino portion of the molecule.

scholarly journals Transforming growth factor beta suppresses human immunodeficiency virus expression and replication in infected cells of the monocyte/macrophage lineage.

1991 ◽  
Vol 173 (3) ◽  
pp. 589-597 ◽  
Author(s):  
G Poli ◽  
A L Kinter ◽  
J S Justement ◽  
P Bressler ◽  
J H Kehrl ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Growth Factor ◽  
Cell Line ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Tgf Beta ◽  
Immunodeficiency Virus ◽  
Growth Factor Beta

The pleiotropic immunoregulatory cytokine transforming growth factor beta (TGF-beta) potently suppresses production of the human immunodeficiency virus (HIV), the causative agent of the acquired immunodeficiency syndrome, in the chronically infected promonocytic cell line U1. TGF-beta significantly (50-90%) inhibited HIV reverse transcriptase production and synthesis of viral proteins in U1 cells stimulated with phorbol myristate acetate (PMA) or interleukin 6 (IL-6). Furthermore, TGF-beta suppressed PMA induction of HIV transcription in U1 cells. In contrast, TGF-beta did not significantly affect the expression of HIV induced by tumor necrosis factor alpha (TNF-alpha). These suppressive effects were not mediated via the induction of interferon alpha (IFN-alpha). TGF-beta also suppressed HIV replication in primary monocyte-derived macrophages infected in vitro, both in the absence of exogenous cytokines and in IL-6-stimulated cultures. In contrast, no significant effects of TGF-beta were observed in either a chronically infected T cell line (ACH-2) or in primary T cell blasts infected in vitro. Therefore, TGF-beta may play a potentially important role as a negative regulator of HIV expression in infected monocytes or tissue macrophages in infected individuals.

Early gene responses to transforming growth factor-beta in cells lacking growth-suppressive RB function

1991 ◽  
Vol 11 (10) ◽  
pp. 4952-4958
Author(s):  
A Zentella ◽  
F M Weis ◽  
D A Ralph ◽  
M Laiho ◽  
J Massagué
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Lung Epithelial Cells ◽  
Early Gene ◽  
Tgf Beta ◽  
Suppressive Function ◽  
Growth Factor Beta ◽  
Pai 1

The growth-suppressive function of the retinoblastoma susceptibility gene product, RB, has been implicated in the mediation of growth inhibition and negative regulation of certain proliferation related genes by transforming growth factor-beta 1 (TGF-beta 1). Early gene responses to TGF-beta 1 were examined in order to determine their dependence on the cell cycle and on the growth-suppressive function of RB. TGF-beta 1, which rapidly elevates the steady-state level of junB and PAI-1 mRNAs and decreases that of c-myc mRNA, induces these responses in S-phase populations of Mv1Lu lung epithelial cells containing RB in a phosphorylated state. Since in this state RB is presumed to lack growth-suppressive activity, the response to TGF-beta 1 was also examined in DU145 human prostate carcinoma cells whose mutant RB product lacks growth-suppressive function. In these cells, TGF-beta 1 also decreases c-myc expression at the transcription initiation level. These results suggests that the c-myc, junB, and PAI-1 responses to TGF-beta 1 are not restricted to the G1 phase of the cell cycle and that down-regulation of c-myc expression by TGF-beta 1 can occur through a mechanism independent from the growth-suppressive function of RB.

In vitro modulation of endothelial fenestrae: opposing effects of retinoic acid and transforming growth factor beta

1988 ◽  
Vol 91 (2) ◽  
pp. 313-318
Author(s):  
T. Lombardi ◽  
R. Montesano ◽  
M.B. Furie ◽  
S.C. Silverstein ◽  
L. Orci
Keyword(s):  
Endothelial Cells ◽  
Retinoic Acid ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Surface Density ◽  
Transforming Growth Factor ◽  
Control Cell ◽  
Tgf Beta ◽  
Growth Factor Beta

Cultured endothelial cells isolated from fenestrated capillaries express many properties characteristic of their in vivo differentiated phenotype, including the formation of a limited number of fenestrae. In this study, we have investigated whether physiological factors that control cell differentiation might regulate the surface density of fenestrae in capillary endothelial cells. We have found that treatment of the cultures with retinoic acid (10 microM) induces a more than threefold increase in the surface density of endothelial fenestrae, whereas transforming growth factor beta (TGF beta) (2 ng ml-1) causes a sevenfold decrease in the surface density of these structures. These results show that the expression of endothelial fenestrae is susceptible to bidirectional modulation by physiological signals, and suggest that retinoids and TGF beta may participate in the regulation of fenestral density of capillary endothelium in vivo.

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