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PubMed2006

Fibroblast growth factor 2 modulates transforming growth factor beta signaling in mouse embryonic fibroblasts and human ESCs (hESCs) to support hESC self-renewal.

Fibroblast growth factor 2 (FGF2) is known to promote self-renewal of human embryonic stem cells (hESCs). In addition, it has been shown that transforming growth factor beta (TGFbeta) signaling is crucial in that the TGFbeta/Activin/Nodal branch of the pathway needs to be activated and the bone morphogenic protein (BMP)/GDF branch repressed to prevent differentiation. This holds particularly true for Serum Replacement-based medium containing BMP-like activity. We have reinvestigated a widely used protocol for conditioning hESC medium with mouse embryonic fibroblasts (MEFs). We show that FGF2 acts on MEFs to release supportive factors and reduce differentiation-inducing activity. FGF2 stimulation experiments with supportive and nonsupportive MEFs followed by genome-wide expression profiling revealed that FGF2 regulates the expression of key members of the TGFbeta pathway, with Inhba, Tgfb1, Grem1, and Bmp4 being the most likely candidates orchestrating the above activities. In addition, restimulation experiments in hESCs combined with global expression analysis revealed downstream targets of FGF2 signaling in these cells. Among these were the same factors previously identified in MEFs, thus suggesting that FGF2, at least in part, promotes self-renewal of hESCs by modulating the expression of TGFbeta ligands, which, in turn, act on hESCs in a concerted and autocrine manner.

Animals↗
PubMed1989

Internalization and limited processing of basic fibroblast growth factor on Chinese hamster lung fibroblasts.

Using either acidic (pH 2.5) or trypsic treatments, we demonstrated that 125I-labeled basic Fibroblast Growth Factor (125I-bFGF) was submitted to an internalization process on responsive Chinese hamster lung fibroblasts (CCL39) at 37 degrees C. Various experiments based on the measurement of cell-associated radioactivity, as well as on research of degradated products of 125I-bFGF in cellular supernatants, showed that most of the internalized radioactivity remained intracellularly located after up to 5 hr of incubation. Analyses of this radioactivity by NaDodSO4-PAGE revealed the presence of labeled peptides issued from the limited processing of the native 125I-bFGF form (17 kD) and whose molecular weights were estimated to be 9 and 6 kD. Kinetic experiments indicated that proteolysis of the 125I-bFGF began early on incubation (less than 30 min) and led to a prolonged preservation of the 9- and 6-kD peptides which were still detectable after 13 hr of incubation. Preincubation of the cells with different lysosomotropic agents completely inhibited the proteolysis, indicating that this event occurred probably in an intracellular acidic compartment. Two enzyme inhibitors, leupeptin and N-alpha-tosyl-L-lysine chloromethyl ketone (TLCK), were also shown to interfere with the formation of both 9- and 6-kD peptides, thus suggesting a way to control the appearance of these fragments, and hence to determine their potential intracellular role.

Animals↗
PubMed2001

Prostaglandin E2 regulates the expression of basic fibroblast growth factor messenger RNA in normal human fibroblasts.

Prostaglandin E2 (PGE2) has been reported to control angiogenesis and play an important role in wound healing in soft tissues, although the precise mechanism is still unknown. Since basic fibroblast growth factor (bFGF) has been reported to generate neovascularization, PGE2 and bFGF might work closely, or one might control the expression of the other. In this study, we demonstrate that PGE2 enhances the expression of bFGF in normal human fibroblasts, and that calcium ionophore, A23187, and adenylate cyclase activator, forskolin, also enhances the expression bFGF mRNA. These results suggest that enhancement of bFGF mRNA stimulated by PGE2 is mainly controlled through EP1 or EP2 and EP4 receptor. In conclusion, our findings suggest that the mechanism of PGE2-induced angiogenesis and wound hearing in soft tissue could be mediated by bFGF through EP1 or EP2 and EP4 receptor.

Adenylyl Cyclases↗
PubMedDate not supplied

Influence of fluticasone propionate on the production of vascular endothelial growth factor and basic fibroblast growth factor from nasal fibroblasts in vitro.

The influence of fluticasone propionate (FP) on vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) production from nasal polyp fibroblasts (NPFs) was examined in vitro. NPFs, at a density of 2.5 x 10(5) cells/ml, were stimulated with 25 ng/ml TNF-alpha in the presence or absence of FP for 24 h. FP at more than 10(-6) M could suppress VEGF production from NPFs. bFGF production induced by TNF-alpha stimulation was also suppressed by FP, when the agent was added to cell cultures at more than 10(-7) M. The present results also showed the suppressive activity of FP on mRNA expression for VEGF and bFGF, which were increased by TNF-alpha stimulation.

Androstadienes↗
PubMed1990

Guanosine 5'-O-(3-thiotriphosphate) and guanosine 5'-O-(2-thiodiphosphate) activate G proteins and potentiate fibroblast growth factor-induced DNA synthesis in hamster fibroblasts.

Addition of guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) to intact Chinese hamster lung fibroblasts (CCL39) depolarized by high K+ concentrations results in activation of phosphoinositide-specific phospholipase C (PLC) (at GTP gamma S concentrations greater than 0.1 mM), inhibition of adenylate cyclase (between 10 microM and 0.5 mM), and activation of adenylate cyclase (above 0.5 mM). Since GTP gamma S-induced activation of PLC is dramatically enhanced upon receptor-mediated stimulation of PLC by alpha-thrombin, we conclude that in depolarized CCL39 cells GTP gamma S directly activates various guanine nucleotide-binding regulatory proteins (G proteins) coupled to PLC (Gp(s)) and to adenylate cyclase (Gi and Gs). Pretreatment of cells with pertussis toxin strongly inhibits GTP gamma S-induced activation of PLC and inhibition of adenylate cyclase. GTP gamma S cannot be replaced by other nucleotides, except by guanosine 5'-O-(2-thiodiphosphate) (GDP beta S), which mimics after a lag period of 15-20 min all the effects of GTP gamma S, with the same concentration dependence and the same sensitivity to pertussis toxin. We suggest that GDP beta S is converted in cells into GTP beta S, which acts as GTP gamma S. Since cell viability is not affected by a transient depolarization, these observations provide a simple method to examine long-term effects of G protein activation on DNA synthesis. We show that a transient exposure of G0-arrested CCL39 cells to GTP gamma S or GDP beta S under depolarizing conditions is not sufficient by itself to induce a significant mitogenic response, but markedly potentiates the mitogenic action of fibroblast growth factor, a mitogen known to activate a receptor-tyrosine kinase. The potentiating effect is maximal after 60 min of pretreatment with 2 mM GTP gamma S. GDP beta S is equally efficient but only after a lag period of 15-20 min. Mitogenic effects of both guanine nucleotide analogs are suppressed by pertussis toxin. Since the activation of G proteins by GTP gamma S under these conditions vanishes after a few hours, we conclude that a transient activation of G proteins facilitates the transition G0----G1 in CCL39 cells, whereas tyrosine kinase-induced signals are sufficient to mediate the progression into S phase.

Adenylate Cyclase Toxin↗
PubMed1989

Stimulation of human synovial fibroblast DNA synthesis by platelet-derived growth factor and fibroblast growth factor. Differences to the activation by IL-1.

The pronounced synovial hyperplasia often found in the joints of patients with rheumatoid arthritis could be explained partially by the action of monocyte-macrophage polypeptides (monokines). This report demonstrates that two cytokines which may be derived from monocyte-macrophage populations, namely platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF), stimulate the DNA synthesis and proliferation of human synovial fibroblast-like cells cultured in low (i.e., 1%) fetal bovine serum. Epidermal growth factor, insulin-like growth factor-I, insulin-like growth factor-II (multiplication stimulating activity) and substance P were inactive. Unlike IL-1, PDGF and FGF do not also stimulate PGE2, plasminogen activator, and hyaluronic acid levels. Thus PDGF and FGF, arising from stimulated monocyte-macrophages, may play a role in the stimulation of mesenchymal cell proliferation that often accompanies chronic inflammatory arthritic disease. The synovial cells respond to a variety of cytokines in different ways suggesting multiple-signaling pathways.

Cell Division↗
PubMed1993

Fibroblast growth factor receptor 4 is a high affinity receptor for both acidic and basic fibroblast growth factor but not for keratinocyte growth factor.

A cDNA predicted to encode a transmembrane tyrosine kinase receptor with sequence features characteristic of known fibroblast growth factor (FGF) receptors was isolated from an expression library constructed from the human mammary epithelial cell line B5/589. This cDNA, designated cl44, encodes a product of 803 amino acid residues and was readily distinguishable from known FGF receptors. During the course of our studies, Partanen et al. (Partanen, J., Makela, T. P., Eerola, E., Korhonen, J., Hirvonen, H., Claesson, W. L., and Alitalo, K. (1991) EMBO J. 10, 1347-1354) isolated a new FGF receptor, designated FGFR4, from the human leukemia cell line, K562. Its amino acid sequence is identical to that of cl44 with the exception of 1 residue. The 5'-untranslated sequences of the two cDNAs diverged far upstream of the initiation codon. A myoblast line, L6E9, which lacks FGF receptors, was utilized to express high levels of FGFR4. We found, in contrast to Partenen et al., who reported only binding of acidic FGF, that FGFR4 bound both acidic and basic FGF with dissociation constants of 10-15 and 120 pM, respectively. No detectable binding of keratinocyte growth factor was observed. In studies aimed to determine whether FGF receptors contribute to the development of human tumors, we screened RNAs prepared from cell lines derived from a variety of solid tumors. High levels of the cl44 transcript were detected in 8 of 14 and 6 of 9 human mammary and kidney carcinomas, respectively, but only infrequently in other types of tumors. In contrast, FGFR1 was found to be frequently expressed in kidney, but not in breast tumor cells, suggesting a possible role for FGFR4 in human mammary cancer.

Amino Acid Sequence↗
PubMed2000

Fibroblast growth factor-9 modulates the expression of myelin related proteins and multiple fibroblast growth factor receptors in developing oligodendrocytes.

The effect of fibroblast growth factor (FGF)-9 on the expression of FGF receptors (FGFR) and the major myelin proteins was examined in cultures of developing rat brain oligodendrocytes (OLs), using immunological techniques. FGFR-1, -3, and -4 were expressed at all developmental stages but were not present in isolated myelin fractions. By contrast, FGFR-2 protein was predominantly localized to differentiating cells and myelin. FGF-9 altered FGFR and myelin protein levels during OL differentiation; there was increased expression of FGFR-1 and decreased levels of both FGFR-2 and myelin proteins. Further, FGF-9 stimulated mitogen-associated protein kinase (MAPK) phosphorylation. The effect of FGF-9 on MAPK, however, was transient and less robust in progenitor cells than in differentiated oligodendrocytes. The effects of FGF-9 and FGF-2 on FGFR and myelin protein levels were comparable; both up-regulated FGFR-1, and down-regulated FGFR-2, CNP, PLP and MBP. These findings suggest that FGF-9 may be important for glial cell development.

2',3'-Cyclic Nucleotide 3'-Phosphodiesterase↗
PubMed2005

Expression of fibroblast growth factor-8 and its cognate receptors, fibroblast growth factor receptor (FGFR)-3c and-4, in fetal bovine preantral follicles.

Paracrine cell signaling is thought to be important for ovarian follicle development, and a role for some members of the fibroblast growth factor (FGF) family have been suggested. In the present study, we tested the hypothesis that FGF-8 and its cognate receptors (FGFR-3c and FGFR-4) are expressed in bovine preantral follicles. Reverse transcription-polymerase chain reaction was used to amplify bovine FGF-8, FGFR-3c, and FGFR-4 from preantral follicle samples and a variety of fetal and adult tissues. All three genes were widely expressed in fetal tissues, with a restricted expression pattern in adult tissues. FGF-8 and FGFR-3c were expressed in secondary follicles in 70% of fetuses examined, whereas FGFR-4 expression was significantly less frequent (20%). FGFR-3c expression frequency was significantly lower in primordial compared to secondary follicles, and FGF-8 expression showed a similar trend. FGFR-4 was only observed when all follicle classes of an individual were expressing both FGF-8 and FGFR-3c. We conclude that FGF-8 and its receptors are expressed in preantral follicles in a developmentally regulated manner.

Animals↗
PubMed2002

Chronic hypoxia up-regulates fibroblast growth factor ligands in the perinatal brain and induces fibroblast growth factor-responsive radial glial cells in the sub-ependymal zone.

A number of signaling molecules have been implicated in the acute response to hypoxia/ischemia in the adult brain. In contrast, the reaction to chronic hypoxemia is largely unexplored. We used a protocol of chronic hypoxia in rat pups during the first three postnatal weeks, encompassing the period of cellular plasticity in the cerebral cortex. We find that the levels of fibroblast growth factor 1 (FGF1) and FGF2, two members of the FGF family, increase after 2 weeks of chronic hypoxia. In contrast, members of the neurotrophin family are unaffected. FGF2 is normally expressed in the nucleus of mature, glial fibrillary acidic protein (GFAP)-containing astrocytes. Under hypoxia, most FGF2-containing cells do not express detectable levels of GFAP, suggesting that chronic low O(2) induces their transformation into more immature glial phenotypes. Remarkably, hypoxia promotes the appearance of radial glia throughout the sub-ventricular and ependymal zones. Most of these cells express vimentin and brain lipid binding protein. A subset of these radial glial cells expresses FGF receptor 1, and are in close contact with FGF2-positive cells in the sub-ventricular zone. Thus, FGF receptor signaling in radial glia may foster cell genesis after chronic hypoxic damage. From the results of this study we suggest that after the chronic exposure to low levels of oxygen during development, the expression of radial glia increases in the forebrain periventricular region. We envision that astroglia, which are the direct descendants of radial glia, are reverting back to immature glial cells. Alternatively, hypoxia hinders the normal maturation of radial glia into GFAP-expressing astrocytes. Interestingly, hypoxia increases the levels of expression of FGF2, a factor that is essential for neuronal development. Furthermore, chronic hypoxia up-regulated FGF2's major receptor in the periventricular region. Because radial glia have been suggested to play a key role in neurogenesis and cell migration, our data suggests that hypoxia-induced FGF signaling in radial glia may represent part of a conserved program capable of regenerating neurons in the brain after injury.

Animals↗
PubMed1999

Parathyroid hormone regulates the expression of fibroblast growth factor-2 mRNA and fibroblast growth factor receptor mRNA in osteoblastic cells.

We examined the effect of parathyroid hormone (PTH) on basic fibroblast growth factor-2 (FGF-2) and FGF receptor (FGFR) expression in osteoblastic MC3T3-E1 cells and in neonatal mouse calvariae. Treatment of MC3T3-E1 cells with PTH(1-34) (10-8M) or forskolin (FSK; 10-5M) transiently increased a 7 kb FGF-2 transcript with a peak at 2 h. The PTH increase in FGF-2 mRNA was maintained in the presence of cycloheximide. PTH also increased FGFR-1 mRNA at 2 h and transiently increased FGFR-2 mRNA at 1 h. FGFR-3 and FGFR-4 mRNA transcripts were not detected in MC3T3-E1 cells. In cells transiently transfected with an 1800-bp FGF-2 promoter-luciferase reporter, PTH and FSK increased luciferase activity at 2 h and 4 h. Immunohistochemistry showed that PTH and FSK increased FGF-2 protein labeling in the nuclei of MC3T3-E1 cells. PTH also increased FGF-2 mRNA, and FGFR-1 and FGFR-2 mRNA levels within 30 minutes in neonatal mouse calvarial organ cultures. We conclude that PTH and cAMP stimulate FGF-2 mRNA abundance in part through a transcriptional mechanism. PTH also regulated FGFR gene expression. We hypothesize that some effects of PTH on bone remodeling may be mediated by regulation of FGF-2 and FGFR expression in osteoblastic cells.

Animals↗
PubMed1976

Specific anti-fibroblast cytotoxicity of antibodies to fibroblast surface antigen.

An antiserum to SF antigen was shown to be selectively cytotoxic to two human fibroblast lines, while two tumor cell lines (one melanoma and one Hela cell line) were resistant. The selective cytotoxicity was also demonstrable in mixtures of fibroblasts and tumor cells. The cytotoxic effect was abrogated by admixture of human serum containing SFA.

Antigen-Antibody Reactions↗
PubMed1984

Differential growth response of normal human diploid fibroblasts and in vitro transformed human fibroblasts in serum-free defined culture medium.

Two neoplastic human cell lines, WI-38 CT-1 and SUSM-1, which were transformed in vitro with gamma rays and 4-nitroquinoline 1-oxide, respectively, grew continuously in a serum-free defined medium. The defined medium used was a 1:1 mixture by volume of Dulbecco's modified Eagle's medium and Ham's F12 (DF) supplemented with 0.1% bovine serum albumin fraction V, 10 micrograms/ml of transferrin, 1 microgram/ml of insulin, and 5 micrograms/ml of oleic acid. In the case of SUSM-1, 100 micrograms/ml of fetuin were added to cultures when the cells were subcultured. Under these conditions the growth rates of the two transformed human cell lines were almost the same as those in a DF medium containing 10% fetal bovine serum (FBS). In addition, the defined medium permitted the cells to grow indefinitely without a lag period when they were transferred from serum-containing medium into this defined medium, indicating that no selection or adaptation of the cells had occurred. Interestingly, these cell lines did not require for their growth any polypeptide growth factors such as epidermal, platelet-derived or fibroblast growth factors. On the other hand, the control WI-38 cells stopped growing in the defined medium after about 2 divisions. Another control normal cell strain of fibroblasts derived from a human embryo showed a decreased growth rate in the defined medium as compared with that in the DF medium with 10% FBS. These results suggest that the defined medium described here is useful for the selective growth of human cells transformed in vitro after treatment with carcinogens from an untransformed cell population. In addition, the defined medium for transformed human cells should contribute to studies on their growth mechanisms.

Cell Division↗
PubMed1985

Natural killing (NK) of cytomegalovirus (CMV)-infected fibroblasts: a comparison between two strains of CMV, uninfected fibroblasts, and K562 cells.

Spontaneous cytolysis of uninfected human fibroblasts (HF), K562 cells, and HF cells infected with cytomegalovirus (CMV) was associated with nonadherent peripheral blood leukocytes (PBL) that passed through a nylon wool column, and rosetted with sheep erythrocytes at low affinity; cytolysis was further associated with enriched preparations of large granular lymphocytes (LGL). The Leu-7 marker did not correlate as a cell phenotype with functional activity in normal donors. The HF cells infected with the AD169 strain of CMV were as sensitive to cytolysis as K562 cells, although the kinetics of cytolysis differed; HF cells infected with the Davis strain of CMV were generally less sensitive to cytolysis than uninfected fibroblasts. Equivalent amounts of interferon were detected in NK assays containing Davis targets, AD169 targets, or K562 cells; interferon was not detected in NK assays of HF cells. Neither uninfected nor infected HF cells competed effectively against 51Cr-labeled K562 cells in cold competition experiments; K562 cells, however, competed effectively against 51Cr-labeled AD169-CMV targets. Uninfected HF cells were efficient competitors of AD169-CMV targets. Davis-CMV-infected cells were less effective, however, than uninfected HF cells in competition experiments, suggesting that fewer receptors for NK cells were present on these targets.

Adult↗
PubMed1995

Differential cytotoxicity of cadmium to rat embryonic fibroblasts and human skin fibroblasts.

In order to identify why cadmium is differentially toxic to humans and rats, we compared cadmium-induced cytotoxic responses in rat embryonic fibroblasts (REF) and human skin fibroblasts (HFW). According to the values of the lethal concentration 50% for cadmium, REF were about 13-fold more sensitive than HFW to cadmium acetate (1.5 vs 25 microM). Furthermore, progression of S phase cells was more severely delayed by cadmium in REF than in HFW. At doses that killed 90% of REF or HFW (5 or 50 microM, respectively), 50% of DNA synthesis was inhibited in REF, whereas DNA synthesis was not apparently inhibited in HFW. The differential sensitivity to cadmium could not be simply due to different basal levels of metallothionein, since the cellular metallothionein content in HFW was only 1.6 times that in REF, and metallothionein was apparently induced by cadmium in both cells with similar synthesis rates. Furthermore, elevation of cellular metallothionein levels by zinc sulfate pretreatment decreased cadmium toxicity in both cell types, but did not alter their relative sensitivity to cadmium. The differential sensitivity was also not due to differences in cadmium accumulation, since HFW accumulated more cadmium than REF after a 24-hr exposure to 1 or 5 microM cadmium acetate. Although most of the cadmium remained in the cytoplasm, the nuclei of REF contained 12-fold more cadmium than nuclei of HFW (1.31 vs 0.11 micrograms Cd/mg nuclear protein). Therefore, our results indicate that a high level of cadmium accumulation in nuclei of REF may be responsible for cell killing through breakdown of nuclear functions.

Animals↗
PubMed1975

Globin synthesis in fibroblasts fused with erythroblasts. I. Avian fibroblasts.

Heterokaryons of chick embryo erythroblasts fused with other avian fibroblasts were studied with regard to globin production. After the incorporation of radioactive amino acids, soluble proteins were separated on SDS-urea polyacrylamide gels. There was a striking increase in radioactivity above background in the globin region from lysates of fusion cultures when compared with fibroblast cultures. This was maximal at 24 hours after fusion, and then declined. Electrophoresis on acid-or alkaline-urea gels further identified the material as globin chains. Tryptic digestion and fingerprinting revealed methionine-labeled peptides characteristic of chick embryo erythroblast globin. An apparent stimulation of globin chain synthesis by heterokaryons compared to erythroblasts was found to be due to a difference in the specific activity of the precursor amino acid pools in the different cell types.

Amino Acids↗
PubMed1986

Fibroblast growth factor induces a transient net K+ influx carried by the bumetanide-sensitive transporter in quiescent BALB/c 3T3 fibroblasts.

The bumetanide-sensitive transport system performed a net efflux of K+ in serum deprived quiescent cells. The addition of partially purified fibroblast growth factor (FGF) to G0/G1 phase 3T3 fibroblasts induced a transient net influx of K+, carried out by the bumetanide-sensitive transport system for 2-6 minutes. The stimulation of the bumetanide-sensitive K+ influx by FGF was followed by stimulation of the ouabain-sensitive K+ influx. In addition, both the bumetanide-sensitive and the ouabain-sensitive K+ influxes were found to be similarly stimulated when the G0/G1 3T3 cells were treated with insulin. These results suggest that growth factors such as FGF and insulin induce a change in the action of the bumetanide-sensitive transporter from performing net K+ efflux along its concentration gradient to an uphill transport pumping of K+ into the cell. We propose, therefore, that the bumetanide-sensitive transporter contributes to the increase in the intracellular K+ (and probable Na+) stimulated by growth factors such as FGF and insulin in early G1 phase of the cell cycle.

Animals↗
PubMed1987

c-fos expression in human skin fibroblasts by reperfusion after oxygen deficiency: a recovery change of human skin fibroblasts after oxygen deficiency stress.

A dramatic and specific induction of c-fos mRNA was observed in human skin fibroblasts in vitro culture by oxygen reperfusion after oxygen deficiency treatment. C-fos mRNA reached a maximum about 30-60 min after oxygen reperfusion and declined to basal level after 120 min. And this phenomenon was duration of oxygen deficiency-dependent, and remarkably observed for 0.5-2 hr of oxygen deficiency. More long duration of oxygen deficiency induced a decreasing tendency of c-fos mRNA overexpression due to essential and irreversible cellular damage. Thus increased c-fos gene expression might be an early event in cellular recovery process in particularly human skin fibroblasts with oxygen deficiency.

Cells, Cultured↗